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Fight Aging! Newsletter


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#31 reason

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Posted 07 October 2012 - 05:54 PM

FIGHT AGING! NEWSLETTER
October 8th 2012

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

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CONTENT

- A Way to Target Senescent Cells
- A Speculative Order of Arrival for Rejuvenation Biotechnologies
- Video: Basil Gelpke Talks With Aubrey de Grey
- On Zinc Transport Dysregulation With Aging
- Discussion
- Latest Headlines from Fight Aging!
    - Noting Progress in Artificial Cornea Development
    - A Cryonics Photo Essay at Wired
    - Shared Mechanisms for Longevity via Calorie Restriction and AC5 Knockout
    - Reporting on a Recent Presentation by Aubrey de Grey
    - Telomere Length Alone is Not a Good Biomarker of Aging
    - Manipulating Immune Response to Boost Nerve Regeneration
    - Notes on Alcor's 2012 Strategy Meeting
    - Several Vital Cell Populations Could Grow in Lymph Nodes
    - What Failure Will Look Like: A Pill for Healthy Aging
    - Inroads into Making Old Immune Cells More Responsive

A WAY TO TARGET SENESCENT CELLS

Exciting signs of progress are emerging from research groups aiming to selectively destroy senescent cells, thus removing their contribution to degenerative aging:

http://www.fightaging.org/archives/2012/10/a-way-to-target-senescent-cells.php

"Last year, researchers demonstrated that the onset of age-related degeneration in mice can be delayed by culling senescent cells. The method used was convoluted, however, and involved gene therapy - which makes it a poor candidate for anything other than demonstrating that removal of senescent cells is a good thing. There's no building a near-term therapy from that work.

"The path to building a useful and straightforward therapy that kills senescent cells is pretty clear, however. There are any number of ways to kill a cell; the trick lies in picking out the cells you want to kill from the forest of their peers. Fortunately, the cancer research community has been very focused on this problem for many years now: how to deliver any of the proven cell-killing drugs to a specific set of cells that look slightly different from their neighbors without harming any of those neighbors. The past decade has seen great strides in the development of nanoparticles that can carry a payload, attached to some form of biological machinery capable of discriminating between cells based on one or more aspects of their surface chemistry. Flood the body with suitable nanoparticle delivery systems and they will find and kill only the cells you want to kill.

"Cell surface chemistry is complex and far from black and white, of course. Nonetheless, work on targeting and delivery mechanisms is progressing rapidly in the laboratory. The results are very relevant to our desire to selectively and safely destroy senescent cells, and the real challenge here lies in the reliable identification of senescent cells. As noted last year, we need a robust way of identifying senescent cells; that is the one vital ingredient not yet in place that will allow all that cell-killing expertise present in the cancer research community to be turned to senescent cells.

"It was only a matter of time, however, and here we have a first attempt at a targeting mechanism for senescent cells - which is exciting news if it pans out and the chemical signature of senescence that the researchers focused on here is a good distinguishing mark throughout the different tissue types in the body:

"The nanodevice that we have developed consists of mesoporous nanoparticles with a galactooligosaccharide outer surface that prevents the release of the load and that only selectively opens in degenerative phase cells or senescent cells. The proof of concept demonstrates for the first time that selected chemicals can be released in these cells and not in others ... The researchers have evaluated the utility of the new nanodevices in primary cell cultures derived of patients with accelerated aging syndrome dyskeratosis congenita (DC). Such cultures show a high percentage of senescence characterized by elevated levels of beta-galactosidase activity, an enzyme characteristic of senescent state. 'The aging cells overexpress this enzyme so we have designed nanoparticles that open when detected and release their contents in order to eliminate senescent cells, prevent deterioration or even reactivate for their rejuvenation'."

A SPECULATIVE ORDER OF ARRIVAL FOR REJUVENATION BIOTECHNOLOGIES

Rejuvenation of the old will require a toolkit of various therapies and approaches, each of which repairs one of the forms of low-level biochemical damage that cause aging. These therapies must all be developed, as any one part of aging can still kill people, but what can we say about the likely order of their arrival?

http://www.fightaging.org/archives/2012/10/a-speculative-order-of-arrival-for-important-rejuvenation-therapies.php

"Research is underway for all of these classes of therapy, but very slowly and with very little funding in some cases. The funding situation spans the gamut from that of the stem cell research community, where researchers are afloat in money and interest, to the search for ways to break down advanced glycation endproducts (AGEs), which is a funding desert by comparison, little known or appreciated outside the small scientific community that works in that field.

"While bearing in mind that progress in projects with little funding is unpredictable in comparison to that of well-funded projects, I think that we can still take a stab at a likely order of arrival for various important therapies needed to reverse aging. Thus an incomplete list follows, running from the earliest to the latest arrival, with the caveat that it is based on the present funding and publicity situation. If any one of the weakly funded and unappreciated lines of research suddenly became popular and awash with resources, it would probably move up in the ordering."

VIDEO: BASIL GELPKE TALKS WITH AUBREY DE GREY

You'll find an interview with Aubrey de Grey and a trailer for Basil Gelpke's Human 2.0 in the Fight Aging! post linked below:

http://www.fightaging.org/archives/2012/10/aubrey-de-grey-on-longevity-science.php

"The human being will be the first species able to understand its own blueprint. The rapidly increasing knowledge of genetics, nanotechnology, robotics, and AI will dwarf everything philosophers, scientists, science fiction writers and other visionaries have ever conceived. Human life without disease and possibly even without death doesn't seem impossible anymore."

ON ZINC TRANSPORT DYSREGULATION WITH AGING

While the following post does discuss zinc metabolism in aging, it should be taken more in the way of an explanation as to why Fight Aging! steers clear of any discussion of the intersection between supplements and aging. It requires a page of preamble and afterword to be able to do so sensibly while ensuring that the right point is being made:

http://www.fightaging.org/archives/2012/10/on-zinc-transport-dysregulation-with-aging.php

"I don't often talk about anything related to the overlap between supplements and aging. For one, that entire industry is irrelevant given the scope of regenerative medicine and rejuvenation biotechnology: the future is deliberately designed and targeted medical technologies, not the lingering remnants of past medical practices influenced by oral fixation and magical thinking. You can't fix anything of significance in human aging by digging around for found compounds to stick into your mouth - that is characteristic of the just-about-up-to-dealing-with-infections medicine of the last millennium, and the sooner this model ceases to dominate the public imagination the better.

"Secondly, there are any number of vocal resources out there that talk about nothing but naturally occurring things that you can stick into your mouth. Many of them want to sell you those naturally occurring things, and of those folk a sizable contingent spend their time making loud and unsupported claims with regard to their products and human aging. Unfortunately there is so much money in that business that sense and ethics largely fled a long time ago.

"Lastly, nothing you can presently buy, consume, or wear is anywhere near as effective as either exercise or calorie restriction when it comes to health over the long term. Science tells us that much, with a great weight of evidence, and anyone claiming otherwise has a tall hill indeed to climb to make any sort of a case. They try nonetheless, day in and day out, and merchant voices often outweigh those of the scientific community in our popular culture when it comes to the relationship between people, medicine, and aging.

"So I don't often talk about anything related to supplements. It isn't productive. Still, occasionally research does show up to suggest that there might be meaningful benefits to some form of therapy using a common supplement or food item. It's pretty rare, however - next to nonexistent. The only one springing to mind right this instant is the evidence suggesting that the body processes the essential amino acid luceine increasingly poorly with aging. This contributes to the muscle wasting of sarcopenia, but, unlike nearly all such issues, can be staved off by adding more luceine to the diet.

"Again, let me emphasize that this sort of situation is rare. It is almost never the case that a specific progressive failure in the body's biochemistry can be ameliorated by sticking more of something related to the failure into your mouth. Biology is far more complex than that - imagining that you can affect a specific portion of your biochemistry in some desired way by consuming one of the compounds involved in a reaction somewhere in the process is basically a form of magical thinking.

So that all said as a sort of preamble, let me point you to a study on zinc-related mechanisms that's presently doing the rounds ... If a progressively disarrayed zinc metabolism does impact inflammation and immune function in a fairly general way, one would expect to see some beneficial effect on life span from suitably zinc-fortified diets. You might look at another recent paper for an example of researchers pumping extra zinc into laboratory animals to see what happens - I'm sure that there's much more out there from past decades if you care to go digging.

"In any case, I note this research for its rarity rather than its potential utility. At the end of the day, how much zinc you put into your diet will not swing your life span by anywhere near as much as even a mediocre level of progress towards biotechnologies that can repair the root causes of aging. As a culture, we need to tear ourselves away from the propaganda of the supplement industry and the fascination with dietary tinkering: none of that will save lives or meaningfully deal with the fact that we're all aging to death.

"Biotechnology is where we must look to the future of medicine: gene therapies, ways to precisely alter specific cellular components, targeted nanoparticles to remove senescent cells, stem cell engineering, tailored bacterial enzymes to break down unwanted intracellular waste products - these and many similar lines of research are the future and the path to living in good health for many more years than were available to our ancestors."

DISCUSSION

The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!

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LATEST HEADLINES FROM FIGHT AGING!

NOTING PROGRESS IN ARTIFICIAL CORNEA DEVELOPMENT
Friday, October 5, 2012
http://www.fightaging.org/archives/2012/10/noting-progress-in-artificial-cornea-development.php
The development of artificial replacements proceeds in parallel with tissue engineering as a way to build replacement parts for damaged corneas. Here, publicity materials tout recent progress in artificial corneas: "ArtCornea is based on a polymer with high water-absorbent properties. [Researchers] have added a new surface coating to ensure anchorage in host tissue and functionality of the optic. The haptic edge was chemically altered to encourage local cell growth. These cells graft to the surrounding human tissue, which is essential for anchorage of the device in the host tissue. The researchers aimed to enlarge the optical surface area of the implant in order to improve light penetration beyond what had previously been possible ... Once ArtCornea is in place, it is hardly visible, except perhaps for a few stitches. It's also easy to implant and doesn't provoke any immune response The specialists have also managed to make a chemically and biologically inert base material biologically compatible for the second artificial cornea, ACTO-TexKpro. [They] achieved this by selectively altering the base material, polyvinylidene difluoride, by coating the fluoride synthetic tissue with a reactive molecule. This allows the patient's cornea to bond together naturally with the edge of the implant, while the implant's inner optics, made of silicon, remain free of cells and clear. The ACTO-TexKpro is particularly suitable as a preliminary treatment, for instance if the cornea has been destroyed as a consequence of chronic inflammation, a serious accident, corrosion or burns. TexKpro and ArtCornea [were] first tested by the doctors in the [laboratory] in vivo in several rabbits. After a six month healing process, the implanted prostheses were accepted by the rabbits without irritation, clearly and securely anchored within the eye. Tests carried out following the operation showed that the animals tolerated the artificial cornea well. [Clinical trials will] soon commence at the Eye Clinic Cologne-Merheim."

A CRYONICS PHOTO ESSAY AT WIRED
Friday, October 5, 2012
http://www.fightaging.org/archives/2012/10/a-cryonics-photo-essay-at-wired.php
Wired is running a photo essay on cryonics, the low-temperature preservation technique that intends to preserve the structure of the mind sufficiently well for patients to be restored to life by future technology: "The Prospect of Immortality is a six-year study by UK photographer Murray Ballard, who has traveled the world pulling back the curtain on the amateurs, optimists, businesses and apparatuses of cryonics. "It's not a large industry," says Ballard, who visited the Alcor Life Extension Foundation in Phoenix, Arizona; the Cryonics Institute in Detroit, Michigan; KrioRus in Moscow, Russia; and Suspended Animation Inc in Boytan Beach, Florida; among others. Cryonics is the preservation of deceased humans in liquid nitrogen at temperatures just shy of its boiling point of -196°C/77 Kelvin. Cryopreservation of humans is not reversible with current science, but cryonicists hypothesize that people who are considered dead by current medical definitions may someday be recovered by using advanced future technologies. Stats are hard to come by, but it is estimated there are about 2,000 people signed up for cryonics and approximately 250 people currently cryopreserved. Over 100 pets have also been placed in vats of liquid nitrogen with the hopes of a future recovery."

SHARED MECHANISMS FOR LONGEVITY VIA CALORIE RESTRICTION AND AC5 KNOCKOUT
Thursday, October 4, 2012
http://www.fightaging.org/archives/2012/10/shared-mechanisms-for-longevity-via-calorie-restriction-and-ac5-knockout.php
One of the handful of genetic alterations shown to extend life in mice is removal of adenylyl cyclase 5 (AC5). Researchers have noted in the past that this seems to share mechanisms with the longevity induced by calorie restriction - indeed, it is suspected that many of the varied known ways of altering laboratory animals to extend healthy life are in fact different methods to activate the same few base changes in metabolism. Here is another paper on this topic: "Adenylyl cyclase type 5 knockout mice (AC5 KO) live longer and are stress resistant, similar to calorie restriction (CR). AC5 KO mice eat more, but actually weigh less and accumulate less fat compared to [wild type] mice. CR applied to AC5 KO result in rapid decrease in body weight, metabolic deterioration and death. These data suggest that despite restricted food intake in CR, but augmented food intake in AC5 KO, the two models affect longevity and metabolism similarly. To determine shared molecular mechanisms, mRNA expression was examined genome-wide for brain, heart, skeletal muscle and liver. Significantly more genes were regulated commonly rather than oppositely in all the tissues in both models, indicating commonality between AC5 KO and CR. Gene Ontology analysis identified many significantly regulated, tissue-specific pathways shared by the two models, including sensory perception in heart and brain, muscle function in skeletal muscle, and lipid metabolism in liver. Moreover, when comparing gene expression changes in the heart under stress, the glutathione regulatory pathway was consistently upregulated in the longevity models but downregulated with stress. In addition, AC5 and CR shared changes in genes and proteins involved in the regulation of longevity and stress resistance, including Sirt1, ApoD and olfactory receptors in both young and intermediate age mice. Thus, the similarly regulated genes and pathways in AC5 KO and CR [suggest] a unified theory for longevity and stress resistance."

REPORTING ON A RECENT PRESENTATION BY AUBREY DE GREY
Thursday, October 4, 2012
http://www.fightaging.org/archives/2012/10/reporting-on-a-recent-presentation-by-aubrey-de-grey.php
SENS Foundation cofounder Aubrey de Grey is a tireless advocate for engineering the end of aging, and steers the work taking place on the foundations of rejuvenation biotechnology at the Foundation's research center and in a halo of allied laboratory groups. He gives a great many presentations on the work and goals of the Foundation in the course of any given year, and here is an article noting one such recent event at Princeton University: "The seminar, called "The Science and Ethics of Eliminating Aging," was sponsored by the University's Center for Human Values and chaired by bioethics professor Peter Singer. De Grey presented his research on anti-aging therapy, promoted his vision for a world in which humans do not experience the negative effects of aging and evaluated the benefits of and objections to this future society. De Grey began his presentation by defining aging. He said his foundation does research on ways to limit damages done to the human body by natural metabolic processes and that he hopes the research will allow them to identify a physical state in which one could perpetually "look and feel and function like a young adult." There are seven specific types of damage aging does to the body, de Grey noted. Although solutions to these have not been reached, he described a scientific breakthrough his group achieved several months ago; a study they had performed showed increased viability of cells in a culture, which he said could have implications for stopping the damage that causes cardiovascular disease. De Grey then described the feasibility and societal benefits of successful development of anti-aging technology. He said his research suggests a "50-50 chance of developing these therapies within the next 25 years to a level of sophistication that will confer ... robust human rejuvenation." On a slide comparing two pictures, de Grey simply summarized his views on the positives and negatives of anti-aging: one of young people at play labeled "Fun" and another of a sickly senior citizen labeled "Not Fun." Therefore, he argued that everyone - from biologists to journalists to ordinary citizens practicing advocacy - should work to achieve successful anti-aging solutions. Finally, de Grey suggested that a society in which people live indefinite life spans would have a higher quality of life. He noted that critics argue that indefinite life spans would lead to overpopulation and that living forever might not be desirable. However, those are not reasons to halt research into anti-aging solutions and those are ethical questions best decided by future generations, he said. "Even if we did have a problem [arising from anti-aging development] and humanity had a choice to make ... that's a choice humanity of the future is entitled to make for itself rather than having that choice imposed on it by our not choosing to develop these therapies," de Grey said."

TELOMERE LENGTH ALONE IS NOT A GOOD BIOMARKER OF AGING
Wednesday, October 3, 2012
http://www.fightaging.org/archives/2012/10/telomere-length-alone-is-not-a-good-biomarker-of-aging.php
Different people age at different rates. Efforts have long been underway to find a reliable, effective way to measure physiological age in order to relate that to remaining life expectancy and mortality rate. Without a biomarker of aging that can be easily measured, it will remain very challenging to evaluate future therapies that intervene in the aging process: how do you know whether a particular medical technology worked, or whether it worked better or worse than a competing therapy? The wait and see approach for determining effects on life span requires years and millions of dollars in mouse studies, while finding a definitive answer in humans is out of the question on the time scales involved here. The whole field of medicine will be transformed over the next two decades, but it would take much longer than that to even begin to answer simple questions as to effects of prospective rejuvenation therapies in humans. Telomeres are protective caps at the end of chromosomes. Their length is determined by a number of dynamic lengthening and shortening processes, but on average tends to erode with age or ill health. Thus telomere length has been proposed as a biomarker of aging, but as this paper shows simple measures of average telomere length are not all that useful in and of themselves: "The search for biomarkers of aging (BoAs) has been largely unsuccessful to-date and there is widespread skepticism about the prospects of finding any that satisfy the criteria developed by the American Federation of Aging Research. This may be because the criteria are too strict or because a composite measure might be more appropriate. Telomere length has attracted a great deal of attention as a candidate BoA. We investigate whether it meets the criteria to be considered as a single biomarker of aging, and whether it makes a useful contribution to a composite measure. Using data from a large population based study, we show that telomere length is associated with age, with several measures of physical and cognitive functioning that are related to normal aging, and with three measures of overall health. In the majority of cases, telomere length adds predictive power to that of age, although it was not nearly as good a predictor overall. We used principal components analysis to form two composites from the measures of functioning, one including telomere length and the other not including it. These composite BoAs were better predictors of the health outcomes than chronological age. There was little difference between the two composites. Telomere length does not satisfy the strict criteria for a BoA, but does add predictive power to that of chronological age. Equivocal results from previous studies might be due to lack of power or the choice of measures examined together with a focus on single biomarkers. Composite biomarkers of aging have the potential to outperform age and should be considered for future research in this area." In this context, you may want to look at another recent paper where the authors suggest that more sophisticated measures of telomere dynamics, such as counting changes in the proportion of very short telomeres, are in fact good biomarkers of aging.

MANIPULATING IMMUNE RESPONSE TO BOOST NERVE REGENERATION
Wednesday, October 3, 2012
http://www.fightaging.org/archives/2012/10/manipulating-immune-response-to-boost-nerve-regeneration.php
One of the reasons that nerves regenerate poorly has to do with the way in which the immune system responds to traumatic injury. In essence its behavior tends towards the formation of scar tissue that blocks nerve regrowth rather than allowing for regeneration. With greater understanding of the underlying mechanisms, researchers can try to change this state of affairs: "By altering activity of the macrophage cells that respond to injuries, researchers dramatically increased the rate at which nerve processes regrew. Influencing the macrophages immediately after injury may affect the whole cascade of biochemical events that occurs after nerve damage, potentially eliminating the need to directly stimulate the growth of axons using nerve growth factors. Macrophages can exist in several different phenotypes depending on the signals they receive. Among the macrophage phenotypes are two classes - M2a and M2c - that encourage healing. [The] research team used an interleukin 4 (IL-4) cytokine to convert macrophages within the animal model to the "pro-healing" phenotypes. They placed a gel that released IL-4 into hollow polymeric nerve guides that connected the ends of severed animal sciatic nerves that had to grow across a 15 millimeter gap to regenerate. The IL-4 remained in the nerve guides for 24 hours or less, and had no direct influence on the growth of nerve tissue in this short period of time. Three weeks after the injury, the nerve guides that released IL-4 were almost completely filled with re-grown axons. The treated nerve guides had approximately 20 times more nerve regeneration than the control channels, which had no IL-4-treated macrophages. Research is now underway to develop the technique for determining how soon after injury the macrophages should be treated, and what concentration of IL-4 would be most effective."

NOTES ON ALCOR'S 2012 STRATEGY MEETING
Tuesday, October 2, 2012
http://www.fightaging.org/archives/2012/10/notes-on-alcors-2012-strategy-meeting.php
Cryonics provider Alcor is becoming more transparent and communicative under CEO Max More, which I see as a good thing. One of the long-term challenges faced by Alcor (and all cryonics providers, for that matter) relates to the common model for customer membership and setting prices, insofar as that is impacted by increasing costs brought on by inflation that takes place over the decades that elapse between a customer initially signing up and later being cryopreserved. It's hard to solve that problem gracefully without a great deal of dialog with the customer community, as it basically boils down to either losing a bunch of money, thus endangering the business, or asking customers to pay more than they originally agreed to: "The 2012 Strategic Meeting took place from Friday September 7 until Sunday September 9. All Alcor directors attended in person, as did Alcor president Max More. The Strategic Meeting is the annual, intensive review of the organizations priorities and performance. You will find a more extensive discussion of several of the outcomes in a forthcoming issue of Cryonics magazine, but here are the main resolutions and priorities on which agreement was reached: ... As minimum requirements for funding of cryopreservation inevitably go up over time, members who did not take out insurance well over the minimum of the day - or who do not regularly add to their savings in the form of a trust or other fund reserved for cryopreservation - may find it difficult to meet new, higher minimums. For older members, adding to life insurance may be too expensive or not an option. Other assets may be illiquid yet substantial, real estate being a common example. At the meeting, the board and president discussed alternative funding methods and resolved further to pursue possible options. If cryonics is to become more widely accepted in the general scientific community, we need to add to existing evidence for the effectiveness of our procedures. One way to do this is to gather more data during all stages of stabilization, transport, and cryoprotection. We can also gather evidence of the quality and effectiveness of brain perfusion and structural preservation by routine CT scanning of neuro patients and by conducting biopsies of spinal cord and possibly other samples for all patients. The board expressed general support for carefully moving forward with this, ensuring that members understand what we propose to do."

SEVERAL VITAL CELL POPULATIONS COULD GROW IN LYMPH NODES
Tuesday, October 2, 2012
http://www.fightaging.org/archives/2012/10/several-vital-cell-populations-could-grow-in-lymph-nodes.php
A replacement liver (or thymus or other organ) doesn't necessarily have to look like or be structured in the same way as the original - it just has to do the same job as the original. This is perhaps more obvious in the development of wholly artificial electromechanical organs than for tissue engineering, but it's still the case there as well. Here is some interesting research that illustrates this point. In some cases specialized cell populations within an organ's structure are the important component of that organ, and thus to replace the organ's functions it is sufficient for those cells to exist in some useful location: "Lymph nodes can provide a suitable home for a variety of cells and tissues from other organs, suggesting that a cell-based alternative to whole organ transplantation might one day be feasible. [Researchers] showed for the first time that liver cells, thymus tissue and insulin-producing pancreatic islet cells, in an animal model, can thrive in lymph nodes despite being displaced from their natural sites. In the study, [researchers] tested the possibility of using lymph nodes, which are abundant throughout the body and have a rich blood supply, as a new home for cells from other organs in what is called an "ectopic" transplant. They injected healthy liver cells from a genetically-identical donor animal into lymph nodes of mice at various locations. The result was an enlarged, liver-like node that functioned akin to the liver; in fact, a single hepatized lymph node rescued mice that were in danger of dying from a lethal metabolic liver disease. Likewise, thymus tissue transplanted into the lymph node of mice that lacked the organ generated functional immune systems, and pancreatic islet cell transplants restored normal blood sugar control in diabetic animals. "Our goal is not necessarily to replace the entire liver, for example, but to provide sufficient cell mass to stabilize liver function and sustain the patient's life. That could buy time until a donor organ can be transplanted. Perhaps, in some cases, ectopic cell transplantation in the lymph node might allow the diseased organ to recover.""

WHAT FAILURE WILL LOOK LIKE: A PILL FOR HEALTHY AGING
Monday, October 1, 2012
http://www.fightaging.org/archives/2012/10/what-failure-will-look-like-a-pill-for-healthy-aging.php
There is a forking of the way in aging research, and it matters greatly which path comes to dominate: whether the mainstream (a) continues as in the past, ignoring all mention of engineered longevity and doing nothing more than investigating aging, (b) focuses on limited ways to slow aging, largely in the name of compression of morbidity while trying to minimize talk of extended life spans, or © works on ways to reverse and repair the root causes of aging, with the explicit goal of extending healthy and maximum human life spans. Of these options only © will greatly help those of us who will need ways to repair the damage caused by aging a few decades from now. Ways to slow aging do little for people who are already old. Unfortunately very little of the research community is presently interested in or working on repair of the root causes of aging - though that faction is larger today than in the past, thanks to persistent advocacy and organizations like the Methuselah Foundation and SENS Foundation. This article shows us what failure will look like: what the end goal will be some decades from now if the "only work to slow aging" and "don't talk about extending life" factions continue to dominate the research community: "Dame Linda Partridge, a geneticist at University College London, claimed drugs will soon be available which can lower the risk of diseases like cancer and dementia by tackling the root cause - age itself. Rather than promising immortality, taking the drugs from middle age or earlier could dramatically shorten the period of illness and frailty that we typically experience before we die. Speaking at the EMBO life sciences meeting in Nice, France this week Dame Linda said several existing drugs have already been shown to have unexpected and welcome side effects, such as aspirin which reduces the risk of cancer. Other therapies will be produced that mimic the effects of a severely restricted diet, which animal studies suggest can protect against a host of age-related conditions including heart disease and diabetes, she said. Speaking after her keynote lecture, she said: "One obvious approach in trying to deal with the very rapidly increasing incidence of age related diseases is to tackle the underlying aging process itself, because it is the major risk factor. What we want is, rather than a lingering period of ill health, to have a fairly sudden death when it comes. We are not talking about immortality, we are trying to get rid of that period of ill health that people get towards the end of their lives, to hold off age related disease for longer.""

INROADS INTO MAKING OLD IMMUNE CELLS MORE RESPONSIVE
Monday, October 1, 2012
http://www.fightaging.org/archives/2012/10/inroads-into-making-old-immune-cells-more-responsive.php
One of the reasons that the adaptive immune system declines with age is that too much of its limited resources become devoted to uselessly chasing persistent herpesviruses like CMV. But there are other mechanisms at work too - not just a depletion of cells ready to act, but a decline in these cells' ability to act. So we have research such as this, in which scientists chase down age-related molecular mechanisms that hold back the effectiveness of immune cells, and try to reverse them: "Circulating T-helper cells fall into two broad categories. "Naïve" T-helper cells have never encountered an antigen before (as in the case of, say, a rare or emerging pathogen or a new vaccine), but are capable of wheeling into action once they do. It takes a week or two to reach full tilt. "Memory" T-helper cells have previously been exposed to an antigen. These cells are long-lived and narrowly fixed on that particular antigen. They can rapidly transition to an activated state should the same antigen ever cross their path again. That's why prior exposure - through infection or a vaccine - renders us more resistant. [Researchers] showed that faulty regulation in memory T-helper cells, due to aging-related increased levels of a protein called DUSP4, inhibits the activation of those cells, with their consequent failure to ignite a good B-cell (antibody-producing) response. This time around, the investigators uncovered a similar effect with a related protein, DUSP6, on naïve T-helper cells. In test tubes, they compared blood cells drawn from people ages 20-35 versus 70-85 in response to stimulation. In naïve T-helper cells (but not in memory cells), there were age-associated differences in a specific chain of biochemical events involved in the cells' activation, proliferation and differentiation. Laboratory tests showed that the culprit behind the cells' fecklessness in older people was DUSP6, [with levels that were] much higher in older people's naïve T-helper cells. Further experimentation revealed that DUSP6's increase in aging naïve T-helper cells was caused by an age-associated easing up on a brake pedal called miR-181a, one among hundreds of small molecules made of RNA (called microRNA) that regulate proteins' production. ... Artificially boosting miRNA-181a levels in naïve human T cells caused DUSP6 levels to plummet, commensurately increasing those cells' readiness to activate on exposure to a given dose of influenza vaccine. In contrast, artificially increasing the levels of DUSP6 blocked the beneficial effects of heightened miR-181a levels."

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#32 reason

  • Guardian Reason
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Posted 14 October 2012 - 04:09 PM

FIGHT AGING! NEWSLETTER
October 15th 2012

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

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CONTENT

- Thoughts on Optimizing Health
- Longevity Science and Moral Imperatives
- Where to Find Data on Aging Research?
- Discussion
- Latest Headlines from Fight Aging!
    - Comparing Longevity and Damage Resistance in Bivalves
    - Considering Longevity in Terms of Damage Versus Damage Repair
    - Treating Neurodegeneration by Increasing Neural Plasticity
    - Working Thyroid Cells Created From Stem Cells
    - Complications in Developing Drugs to Slow Aging
    - Commentary on FGF Signaling and Stem Cell Aging
    - Converting Supporting Brain Cells into New Neurons
    - Lung Health and Brain Function
    - An Example of Present Stem Cell Therapy Trials
    - The Glenn Foundation Funds Another New Aging Research Lab

THOUGHTS ON OPTIMIZING HEALTH

With regard to personal health, a great deal of time and energy is spent in pursuit of what is probably an unobtainable goal, while ignoring paths that are likely to produce real benefits:

http://www.fightaging.org/archives/2012/10/achieving-the-8020-point-in-general-health-is-easy-but-anything-more-is-near-impossible.php

"So the future of medicine is golden, biotechnology is in the throes of a vast expansion of capabilities and free-fall in costs, and we have a good idea as to how to go about reversing aging - if the research community would just stop tinkering with efforts to merely slow down aging and get on with achieving the all-round better goal of rejuvenation. We should all donate money and time to help out, because it's not as though we can take it with us and irreplaceable time is ticking away. A shot at lifespans of centuries and longer is coming, with not so much time left in which to reach for that goal.

Putting all of that to one side for the moment, there is the arguably less important question of how to optimize heath and life span given the present poor tools to hand. Many people spend a great deal of time talking and debating on this topic, immersing themselves in the world of what presently exists, and giving little thought to what might lie ahead. A vast industry caters to people who think they've found the better mousetrap when it comes to personal health and aging. They're all wrong, of course, but that doesn't stop the flow of commerce.

"The sad truth of the matter is that it's simple and easy to achieve the 80/20 result in health and longevity within the bounds of the tools we have available to us today, provided you're starting out as a basically ordinary, healthy individual. Exercise regularly, the 30 minutes daily of aerobic exercise that has been recommended by physicians since way back when, and practice calorie restriction with optimal nutrition - i.e. eat a sane diet, not very much of it, and obtain the necessary levels of micronutrients while doing so. There's also the matter of not harming yourself greatly, but just as I shouldn't have to mention avoidance of knives and falling rocks, I shouldn't have to mention things like giving up smoking.

"These things are not rocket science. They are widely known and most have been advocated for centuries. The supporting statistical data is far better now than at any point in the past, and so you have no excuses: if you're not adopting these practices then it is because you have decided to accept a shorter life expectancy and greater odds of ill health in exchange for the dissipations that you presently enjoy. No-one's perfect, right?

"But here is an interesting thing about trying to reliably forge ahead beyond the 80/20 point in personal health, in search of the optimum level of improvement: it's next to impossible to go further or reliably measure that you have gone further. The research community has expended billions without being able to determine how you can do that - so what makes you think that you can do any better given your far more limited resources? Metabolism and its interactions are so very, very complex. We can list with some confidence what is good for you, but talking about what is optimal is far beyond present capabilities.

"Instead of trying to go further in a presently impossible attempt at optimization, a better use of that time and energy lies in supporting research and development of rejuvenation biotechnology. Even a magically optimized personal health program would not allow most people to live to 100 with today's technology - the only way that the vast majority of us will get to see a three digit birthday cake is through progress in longevity science and its clinical applications. So if you're going to spend any effort on this whole living longer in good health thing, spend it wisely. Don't chase rainbows."

LONGEVITY SCIENCE AND MORAL IMPERATIVES

A range of different arguments and philosophies can be turned to support the idea that we are morally obliged to develop the means to defeat aging through biotechnology. Here you'll find links to the start of a discussion based on social justice and egalitarianism, noteworthy because adherents of those philosophies are usually opposed to the development of life-extending medicine:

http://www.fightaging.org/archives/2012/10/the-moral-imperative-for-longevity-science-as-seen-from-the-social-justice-point-of-view.php

"The concepts and ideology relating to egalitarianism and social justice are associated with advocates and a community largely hostile to engineered human longevity. To the lay egalitarian extending healthy life looks like more inequality in the making, so they oppose longevity science for the same reasons they oppose every new idea that they believe might benefit the wealthy first of all: death for everyone before inequality for anyone is, depressingly, pretty much exactly where they stand. You can see manifestations of this line of thought in resource allocations and rationing forced on some regions by centralized planning in medicine - such as the "fair innings" argument in the UK, used to justify moving resources away from medical provision to the old.

"To be clear, in that sort of situation it is the centrally planned, command and control Soviet-style institutions of clinical medicine that are the problems - rationing and fierce arguments over who should feed from the trough are only symptoms. These are outgrowths of the other line item that walks hand in hand with egalitarianism: the urge to power. Egalitarian ideals cannot be enacted without the power to force people to do what they would not otherwise have done: along this road lies socialism, fascism, communism. Any flavor of authoritarianism in medicine, as in all other human endeavors, inevitably destroys in the incentives for progress, good service, and quality that exist in a market. It doesn't matter how good the original intentions were, the end result is never in doubt; only how long it takes to destroy the wealth and progress that previously existed.

"In any case, opposition to human life extension based on an assumption that it will create greater inequality is not uncommon. Egalitarians age, suffer, and die just like the rest of us, however, and we are now entering an era in which the research community might develop biotechnologies to reverse aging. Egalitarians thus have a strong incentive to either selectively abandon their convictions or find a way to advocate for work on rejuvenation biotechnology within their philosophies."

WHERE TO FIND DATA ON AGING RESEARCH?

A few pointers can be found in this Fight Aging! post, of interest to those chasing down historical data on the aging research community:

http://www.fightaging.org/archives/2012/10/where-to-find-data-on-aging-research.php

"I was recently asked for pointers on where to look for historical data on aging and longevity research: the number of active biogerontologists, a count of laboratories dedicated to aging research, levels of public and private funding, and other measures that might be taken as proxies for progress (or at least growth in the field). Unfortunately I don't have anything more than the first sketches of a guide to hand: assembling this sort of data for any industry is a fair-sized task. There are plenty of questions without ready answers, especially when it comes to the for-profit side of aging research, where the participants don't tend to publish easily discovered summaries.

"Some obvious starting points exist, however. The International Aging Research Portfolio (IARP), for example, is an initiative that aims to make data on aging research easily available. The present focus there is on funding, but that data can be broken down by laboratory, region, researcher, and date. There are some trend tools to help produce visualizations."

DISCUSSION

The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!

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LATEST HEADLINES FROM FIGHT AGING!

COMPARING LONGEVITY AND DAMAGE RESISTANCE IN BIVALVES
Friday, October 12, 2012
http://www.fightaging.org/archives/2012/10/comparing-longevity-and-damage-resistance-in-bivalves.php
Much like mammals, bivalve molluscs exhibit a very wide range of life spans. At the known outer end stands the arctic quahog at more than four centuries, and much studied in recent years so as to understand the roots of its longevity. That research project is still ongoing, as are similar comparative studies of aging and longevity in a range of other species. Here, researchers compare resistance to various forms of physical stress and damage in different bivalve species. As you might expect from the view of aging put forward earlier today, longer-lived species are more resistant to most forms of damage: "Bivalve molluscs are newly discovered models of successful aging. Here, we test the hypothesis that extremely long-lived bivalves are not uniquely resistant to oxidative stressors (eg, tert-butyl hydroperoxide, as demonstrated in previous studies) but exhibit a multistress resistance phenotype. We contrasted resistance (in terms of organismal mortality) to genotoxic stresses (including topoisomerase inhibitors, agents that cross-link DNA or impair genomic integrity through DNA alkylation or methylation) and to mitochondrial oxidative stressors in three bivalve mollusc species with dramatically differing life spans: Arctica islandica (ocean quahog), Mercenaria mercenaria (northern quahog), and the Atlantic bay scallop, Argopecten irradians irradians (maximum species life spans: more than 500, more than 100, and ~2 years, respectively). With all stressors, the short-lived A i irradians were significantly less resistant than the two longer lived species. Arctica islandica were consistently more resistant than M mercenaria to mortality induced by oxidative stressors as well as DNA methylating agent nitrogen mustard and the DNA alkylating agent methyl methanesulfonate. The same trend was not observed for genotoxic agents that act through cross-linking DNA. In contrast, M mercenaria tended to be more resistant to epirubicin and genotoxic stressors, which cause DNA damage by inhibiting topoisomerases. To our knowledge, this is the first study comparing resistance to genotoxic stressors in bivalve mollusc species with disparate longevities. In line with previous studies of comparative stress resistance and longevity, our data extends, at least in part, the evidence for the hypothesis that an association exists between longevity and a general resistance to multiplex stressors, not solely oxidative stress." In mammals, you might look to the naked mole rat as an analogous species: very resistant to all sorts of biological and cellular damage, and extremely long-lived in comparison to similar sized rodent species.

CONSIDERING LONGEVITY IN TERMS OF DAMAGE VERSUS DAMAGE REPAIR
Friday, October 12, 2012
http://www.fightaging.org/archives/2012/10/considering-longevity-in-terms-of-damage-versus-damage-repair.php
Here is a framework for thinking about aging and longevity: various forms of low-level biological damage accrue as a result of the operation of metabolism, degrading organs and tissues and ultimately causing death. Where natural selection favors longer-lived individuals, mechanisms will evolve to repair, minimize, or resist the effects of this damage. So aging is driven by damage, but genetic programs interact with that damage, evolved to try to do something about it. Thus we could expect to be able to manipulate life span either by repairing damage or by altering the programs. The former approach should produce far more effective means of healthy life extension, however, including rejuvenation of the old. In comparison, and from what we've seen so far in longevity science, modestly slowing aging is about the best we can expect from the near future of genetic and metabolic alterations. "In spite of exciting new insights into regulatory mechanisms that modulate the aging process, the proximal cause of aging remains one of the unsolved big problems in biology. An evolutionary analysis of aging provides a helpful theoretical framework by establishing boundary conditions on possible mechanisms of aging. The fundamental insight is that the force of natural selection diminishes with age. This does not preclude senescence (age-related decrease in individual fitness) from occurring in natural populations. Senescence can develop because some genes have non-separable, but typically different or opposite, functions in reproductive-age and in old individuals. Such genes, selected according to their "youthful" function, may thus impose a distinct senescent phenotype in old age. In general, however, unless a controversial formulation of group selection is invoked, traits that would become manifest only in old age cannot evolve. This precludes the evolutionary emergence of aging programs, which have been sometimes postulated to exist in analogy to developmental and other biological programs. (By the same token, selective pressure that diminishes with age would also prevent extreme longevity from evolving, if "extreme" denotes a potential life span much longer than that imposed by extrinsic mortality in a given environment.) This and other arguments against the existence of an aging program have been discussed previously. The evolutionary perspective sketched out above does not specify the mechanisms that underlie aging, but it helps to narrow down the possibilities. As already discussed, an evolved deterministic aging program can be ruled out, perhaps with the exception of specific niche situations. In the absence of adaptive life-curtailing processes driven by a putative aging program, we are left with untargeted pro-aging, destabilizing phenomena which, in principle, may range from purely stochastic to side-effects of "legitimate" biochemical pathways. These destabilizing forces are counteracted by evolved, and genetically controlled, longevity assurance (or repair/maintenance) processes. The interplay of these countervailing forces determines the life span. While I have previously presented my detailed interpretation of this model, its central tenets bear repeating: (a) the destabilizing processes that drive aging are neither evolved nor adaptive; (b) in contrast, longevity assurance mechanisms are under genetic control; © together, these two opposing forces determine life span; (d) the average life span of a species is set by evolving longevity assurance mechanisms so as to optimize reproductive success under environmental conditions typical for that species."

TREATING NEURODEGENERATION BY INCREASING NEURAL PLASTICITY
Thursday, October 11, 2012
http://www.fightaging.org/archives/2012/10/treating-neurodegeneration-by-increasing-neural-plasticity.php
One line of research into treatments for neurodegenerative disorders involves spurring the brain to establish new neural connections to replace those that have been damaged or lost. This seems like an inferior strategy in comparison to trying to identify and remove root causes, one that can only delay the inevitable, but it's nonetheless a fairly entrenched field of work. Here is an example of this sort of research - and note that as for other similar efforts there are hints that an induced increase in neural plasticity would be beneficial for cognitive function in all older individuals: "Researchers have developed a new drug candidate that dramatically improves the cognitive function of rats with Alzheimer's-like mental impairment. Their compound, which is intended to repair brain damage that has already occurred [by] rebuilding connections between nerve cells. [The scientists] have been working on their compound since 1992, when they started looking at the impact of the peptide angiotensin IV on the hippocampus, a brain region involved in spatial learning and short-term memory. ... angiotensin IV, or early drug candidates based on it, were capable of reversing learning deficits seen in many models of dementia. The practical utility of these early drug candidates, however, was severely limited because they were very quickly broken down by the body and couldn't get across the blood-brain barrier. Five years ago, [the scientists] designed a smaller version of the molecule [called] Dihexa. Not only is it stable but it can cross the blood-brain barrier. An added bonus is it can move from the gut into the blood, so it can be taken in pill form. The researchers tested the drug on several dozen rats treated with scopolamine, a chemical that interferes with a neurotransmitter critical to learning and memory. Typically, a rat treated with scopolamine will never learn the location of a submerged platform in a water tank, orienting with cues outside the tank. After receiving the [drug], however, all of the rats did, whether they received the drug directly in the brain, orally, or through an injection. [The researchers] also reported similar but less dramatic results in a smaller group of old rats. In this study the old rats, which often have difficulty with the task, performed like young rats. While the results were statistically valid, additional studies with larger test groups will be necessary to fully confirm the finding."

WORKING THYROID CELLS CREATED FROM STEM CELLS
Thursday, October 11, 2012
http://www.fightaging.org/archives/2012/10/working-thyroid-cells-created-from-stem-cells.php
Nature here notes progress towards tissue engineering of replacement thyroid glands and a demonstration of the ability to repair the thyroid in situ: "The thyroid is the latest in a growing list of body parts that can now be 'fixed' in mice, with the potential to treat diseases from diabetes to Parkinson's ... Progress has been very rapid over the past decade. In recent years we've seen a number of very important studies in which mouse stem cells have been converted to a desired cell type that has then been shown to be functional in vivo, and to confer benefits in mouse models of human diseases. [Researchers] first genetically engineered embryonic stem cells to express two proteins - NKX2-1 and PAX8 - that are expressed together only in the thyroid. When these cells were grown in Petri dishes in the presence of thyroid-stimulating hormone, they turned into thyroid cells. Thyroid cells, however, have to be organized into a particular three-dimensional shape before they can work. They need to form small, spherical follicles containing a cavity in which iodide - a component of some hormones produced in the thyroid gland - can be concentrated before being absorbed and used for hormone synthesis. Remarkably, the stem-cell-derived thyroid cells spontaneously grouped into follicles similar to those in an intact thyroid gland [and] the follicles were able to trap iodide and synthesize thyroid hormones. The next step was to see how these follicles would function in live mice, and to assess their potential to correct hypothyroidism. This condition was induced in mice with an injection of radioactive iodine that accumulated in their thyroid glands, causing the tissue to wither away. Four weeks later, once hypothyroidism had been established, the mice received a graft of stem-cell-derived thyroid follicles. Out of nine mice treated in this way, eight showed complete rescue - their thyroid hormones returned to normal levels."

COMPLICATIONS IN DEVELOPING DRUGS TO SLOW AGING
Wednesday, October 10, 2012
http://www.fightaging.org/archives/2012/10/complications-in-developing-drugs-to-slow-aging.php
Trying to safely slow down aging, usually by developing drugs to replicate some of the metabolic and epigenetic alterations caused by calorie restriction or exercise, is an immensely complicated undertaking. Success will be slow in coming, and the end result will be of little use for those already old - so other than an increase in the understanding of how metabolism and aging relate to one another, we should not expect this field of research to contribute much to the bottom line of our own longevity. Nonetheless, this is the mainstream of research into longevity science and where most of the money goes. That state of affairs will have to change in favor of a focus on the more practical path of repairing biochemical damage associated with aging, with the aim of creating biotechnologies that can reverse the root causes of aging and thus bring about some degree of rejuvenation. Here is an example of the sort of complications that arise when attempting to adjust metabolism. Interventions that are beneficial at one point in life may be harmful at others, and may further interact poorly with one another to produce a net harmful effect even though they are individually beneficial: "We tested the effects of a Class I histone deacetylase inhibitor (HDAcI) (sodium butyrate, NaBu) on the longevity of normal- and long-lived strains of Drosophila melanogaster. We report that this HDAcI has mixed effects in the normal-lived Ra strain in that it decreases mortality rates and increases longevity when administered in the transition or senescent spans, but decreases longevity when administered over the health span only or over the entire adult lifespan. It has dose-dependent effects when administered over the entire larval+adult life span. Only deleterious effects are noted when administered by either method to the long-lived La strain. This apparently contradictory set of results is, however, what would be expected if the gene regulatory mechanisms affected by NaBu were those intimately involved in inducing gene expression patterns characteristic of a healthy senescence. Thus "mid- to late-life" drugs may have different stage-specific effects on different genomes of a model organism. A different HDAcI (suberoylanilide hydroxamic acid, SAHA) administered to the normal-lived strain showed similar late-life extending effects, suggesting that this is not an isolated effect of one drug."

COMMENTARY ON FGF SIGNALING AND STEM CELL AGING
Wednesday, October 10, 2012
http://www.fightaging.org/archives/2012/10/commentary-on-fgf-signaling-and-stem-cell-aging.php
You'll recall that researchers recently demonstrated that they could slow or reverse stem cell decline with age by manipulating FGF2 - in the satellite cell population that maintains muscle tissue, at least. Based on their work, the researchers proposed that stem cell aging involves issues with dormancy and recuperation. Because of certain changes in signaling in the supporting stem cell niche, stem cell populations in old muscles are not able to remain dormant sufficiently well to maintain their numbers and functionality. Here is a commentary on this research, placing it into the context of other ongoing investigations into the causes of stem cell decline with aging and consequent loss of tissue integrity: "Gradual declines in tissue homeostasis, function, and regenerative ability are hallmarks of the aging process. Tissue-specific adult stem cells are the primary components of tissue regeneration and homeostasis. Therefore, an attractive theory to explain the age-associated decline in these processes centres around the effects of aging on stem cell function. The current debate focuses on the very nature of how stem cells age. Is the decline in stem cell function with age a cell autonomous change that happens due to the cumulative detrimental effects of DNA damage, epigenetic changes, or metabolic and mechanical stresses over time? Or is it an environmentally induced process whereby a perfectly functional stem cell is instructed to behave in a dysfunction manner by an aging niche or systemic milieu? A recent [study] proposes a unique mechanism whereby a signal from the aged niche causes a cell autonomous and persistent change in the ability of a stem cell to maintain the quiescent state, which, over time, leads into impaired tissue regenerative capacity. ... aged satellite cells display an increased propensity to [leave quiescence, enter] the cell cycle and to undergo apoptotic cell death. ... What is particularly intriguing about environmental theories of stem cell aging is that they imply that the functional changes that occur in stem cells as they age are potentially reversible when the cells are placed in a 'young' environment. This report also touches on another issue that is commonly debated: the role of stem cell number in the effects of aging on tissue function and regeneration. The reported effects of aging on stem cell number vary widely across different stem cell populations but also within the satellite cell literature. [The authors here] report reduced satellite cell numbers in aged animals and attribute that decline to the functional changes they describe: [increases] in cycling and cell death. They propose that functional changes of aged satellite cells, which have previously been shown to impair muscle regeneration, are further exacerbated by declining stem cell numbers. It will be interesting to determine if the maintenance of stem cell number can overcome their functional deficits to prevent an age-related decline in regenerative potential. "

CONVERTING SUPPORTING BRAIN CELLS INTO NEW NEURONS
Tuesday, October 9, 2012
http://www.fightaging.org/archives/2012/10/converting-supporting-brain-cells-into-new-neurons.php
Spurring the brain to produce new neurons more rapidly than it ordinarily does may be a useful form of therapy for a range of conditions - and also quite possibly something you'd want turned on as a matter of course, if it manifests the same sort of benefits to cognitive health as are produced by drugs that induce greater neural plasticity. Here, researchers note an alternative to manipulating stem cell populations into building new neurons - instead work to convert some of the supporting cells in the brain into neurons: ""This work aims at converting cells that are present throughout the brain but themselves are not nerve cells into neurons. The ultimate goal we have in mind is that this may one day enable us to induce such conversion within the brain itself and thus provide a novel strategy for repairing the injured or diseased brain." The cells that made the leap from one identity to another are known as pericytes. Those cells, found in close association with the blood vessels, are important for keeping the blood-brain barrier intact and have been shown to participate in wound healing in other parts of the body. ... Further testing showed that those newly converted neurons could produce electrical signals and reach out to other neurons, providing evidence that the converted cells could integrate into neural networks. "While much needs to be learnt about adapting a direct neuronal reprogramming strategy to meaningful repair in vivo, our data provide strong support for the notion that neuronal reprogramming of cells of pericytic origin within the damaged brain may become a viable approach to replace degenerated neurons.""

LUNG HEALTH AND BRAIN FUNCTION
Tuesday, October 9, 2012
http://www.fightaging.org/archives/2012/10/lung-health-and-brain-function.php
There is a fair amount of research linking general health with the pace at which brain function declines with age: the less robust you are, the more likely you are to get dementia. We can look at the structural integrity and level of age-related decline in blood vessels in the brain as one possible mechanism to link such things as exercise and fitness to brain health, but there are undoubtedly others. Here researchers look at links between lung health and brain function. Lung health, at least in the way it was measured in this study, may be a good marker for the sort of general robustness that both allows for and is improved by exercise: "Researchers used data from a Swedish study of aging that tracked participants' health measures for almost two decades. An analysis of the data with statistical models designed to show the patterns of change over time determined that reduced pulmonary function can lead to cognitive losses, but problems with cognition do not affect lung health. The study sample consisted of 832 participants between ages 50 and 85 who were assessed in up to seven waves of testing across 19 years as part of the Swedish Adoption/Twin Study of Aging. ... Lung function was measured in two ways: forced expiratory volume, or how much air a person can push out of the lungs in one second, and forced vital capacity, the volume of air that is blown out after a deep inhalation. "The logical conclusion from this is that anything you could do to maintain lung function should be of benefit to fluid cognitive performance as well. Maintaining an exercise routine and stopping smoking would be two primary methods. Nutritional factors and minimizing environmental exposure to pollutants also come into play." Though this study does not explain what a loss of pulmonary function does to the brain, the researchers speculated that reduced lung health could lower the availability of oxygen in the blood that could in turn affect chemicals that transmit signals between brain cells."

AN EXAMPLE OF PRESENT STEM CELL THERAPY TRIALS
Monday, October 8, 2012
http://www.fightaging.org/archives/2012/10/an-example-of-present-stem-cell-therapy-trials.php
The range of stem cell therapies now moving from the lab to the clinic - via the slow, expensive, and largely unnecessary regulatory process of clinical trials - are a long way advanced from the state of the art even as recently as a decade ago. Use of a patient's own cells, engineered and manipulated to improve the chances of a successful outcome, is the new standard. As I've noted in the past, the stem cell research community must solve the issue of age-related decline in stem cell function in order to build effective therapies, as most of the medical conditions that need this sort of regenerative treatment only occur in the old: "Canadian heart-attack survivors will get first crack at an experimental therapy that's moving into clinical trials early next year. The treatment is believed to be the first in the world to test the ability of a patient's own stem cells, genetically engineered to have extra-strong healing powers, to repair damaged tissue caused by a heart attack. To date, more than 2,000 heart-attack survivors, mostly in Europe, have received experimental injections of stem cells, often ones taken from their own bone marrow. However, the overall degree of improvement in the patients' heart function has been disappointingly modest. That has led some researchers to think the stem-cell system itself might age and lose its effectiveness in older people. To solve this problem, [researchers have] come up with a way to turn back the biological clock of aging stem cells by genetically reprogramming them to have stronger healing properties. The theory is that these younger, more potent stem cells could grow enough new blood vessels to improve, if not fully restore, the heart's ability to pump blood. In fact, previous studies have suggested that stem-cell therapy can still improve a patient's quality of life even if the overall improvement to heart function is incremental. "There's less development of heart failure, less hospital readmission, less bypass (surgery) and better survival. The data suggest you don't need to fully normalize. You just need to stabilize to such a degree that you're unlikely to go down that slippery slope.""

THE GLENN FOUNDATION FUNDS ANOTHER NEW AGING RESEARCH LAB
Monday, October 8, 2012
http://www.fightaging.org/archives/2012/10/the-glenn-foundation-funds-another-new-aging-research-lab.php
In recent years the Glenn Foundation for Medical Research has established a number of laboratories focused on aging research, building and funding an infrastructure to help grow and sustain this scientific community. The Foundation has donated modestly to SENS research to reverse aging in the past, but these laboratories are firmly in the mainstream of biogerontology. The researchers involved typically investigate mechanisms of aging and ways to slow aging only - this being the slow, hard road ahead that will never lead to methods of rejuvenation. Here is news of the latest: "Under a new $3 million grant from the Glenn Foundation for Medical Research, Princeton University researchers will study the biology of aging and healthspan. The grant will establish the Paul F. Glenn Laboratories for Aging Research at Princeton under the leadership of Coleen Murphy, associate professor of molecular biology and the Lewis-Sigler Institute for Integrative Genomics. The funding will support pioneering collaborative work by faculty members in neuroscience, computer science, computational biology, physics and mathematics on the biological mechanisms that control the aging process. "While great progress has been made in the identification of general longevity regulators, most aging research is focused on late-life physical or biochemical characteristics, such as loss of movement or death," said Murphy, whose cutting-edge research on age-related declines in memory and reproductive ability has received support from several important sources. "Early aging has not been as well studied. I believe that careful quantification of behavioral characteristics will allow us to better analyze these early declines as well as to assess therapeutic improvements.""

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Posted 21 October 2012 - 06:47 PM

FIGHT AGING! NEWSLETTER
October 22nd 2012

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

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CONTENT

- Putting Aside What You'd Rather Be Doing Because You're Dying
- On Chronic Inflammation in Aging
- Considering the Brain
- Discussion
- Latest Headlines from Fight Aging!
    - Spermidine Levels Measured in Centenarians
    - A Small Step Towards Tissue Engineered Kidneys
    - More on Young Blood and Old Mice
    - More Robust Data on the Effect of Mitochondrially Targeted Antioxidants on Fly Life Span
    - The Plasticity of Life Span
    - Overexpression of FGF21 Extends Life in Mice
    - Dopamine and Memory Decline in Aging
    - Another Glenn Foundation Lab Established
    - Commenting on the Late Life Plateau in Aging
    - Investigating Natural Bladder Regeneration in Rats

PUTTING ASIDE WHAT YOU'D RATHER BE DOING BECAUSE YOU'RE DYING

The costs of degenerative aging are all around us, so omnipresent that they are taken for granted. But costs they are, nonetheless:

http://www.fightaging.org/archives/2012/10/putting-aside-what-youd-rather-do-because-youre-dying.php

"Many dubious arguments are fielded in support of aging and involuntary death: every status quo, no matter how terrible, gathers its supporters. This is one of the deeper flaws inherent in human nature, the ability to mistake what is for the most desirable of what is possible. A hundred thousand deaths each and every day and the suffering of hundreds of millions is the proposal on the table whenever anyone suggests that human aging should continue as it is.

"Massive campaigns of giving and social upheaval have been founded on the backs of a hundredth of this level of death and pain - but the world has a blindness when it comes to aging. Such is the power of the familiar and the long-standing: only heretics seek to overturn it, no matter how horrid and costly it is.

"Nonetheless, this is an age of biotechnology in which aging might be conquered. There are plans and proposals, set forth in some detail, and debate over strategy in the comparatively small scientific community focused on aging research. So arguments over whether the development of means of rejuvenation should take place at all, reserved for philosophers and futurists in the past, now have concrete consequences: tens of millions of lives and untold suffering whenever progress is delayed. It should always be feared that a society will somehow turn to block or impede research into therapies for aging - worse and more outright crimes have been committed in the past by the members of so-called civilized cultures.

"One of the arguments put forward in favor of a continuation of aging and mass death is that without the threat of impending personal extinction we'd collapse into stagnation and indolence. As the argument goes, only death and an explicitly limited future gives us the incentive to get anything done, and so all progress depends upon aging to death. I state the proposition crudely, but this is the essence of the thing, flowery language or no.

"This is a terribly wrong way of looking at things: it denies the existence of desire independent of need. It casts us as nothing more than some form of Skinner box, unable to act on our own. This is another example of the way in which many humans find it hard to look beyond what is to see what might be: we live in a state of enforced urgency because we are all dying, because the decades of healthy life are a time of frantic preparation for the decline and sickness that comes later. It is normal, the everyday experience, for all of us to know we are chased by a ticking clock, forced to put aside the things that we would rather do in favor of the things that we must do. We cannot pause, cannot follow dreams, cannot stop to smell the roses.

"Some people seem to manage these goals, but only the lucky few - and then only by twining what they would like to do with what they must do. It's hard to achieve that end, and it is really nothing more than an ugly compromise even when obtained. Yet like so much of what we are forced into by the human condition, it is celebrated. One more way in which what is triumphs over what might be in the minds of the masses.

"Given many more healthy years of life in which to do so, we would lead quite different lives. Arguably better lives, not diverted by necessity into a long series of tasks we do not want to undertake, carried out for the sake of what will come. We could follow desire rather than need: work to achieve the aims that we want to achieve, not those forced on us. Because of aging and death, we are not free while we are alive - and in any collection of slaves there are those who fear the loss of their chains. The longer they are enslaved, the less their vision of freedom. Sadly, in the mainstream of our culture, it is those voices that speak the loudest."

ON CHRONIC INFLAMMATION IN AGING

Researchers believe that chronic inflammation plays an important role in the pace of aging, and that the biology of long-lived mutant mice adds more confirming evidence in support of this view:

http://www.fightaging.org/archives/2012/10/on-inflammation-in-mouse-longevity-mutants.php

"The last 200 years of industrial development along with the progress in medicine and in various public health measures had significant effect on human life expectancy by doubling the average longevity from 35-40 to 75-80. There is evidence that this great increase of the lifespan during industrial development is largely due to decreased exposure to chronic inflammation throughout life. There is strong evidence that exposure of an individual to past infections and the levels of chronic inflammation increase the risk of heart attack, stroke and even cancer.

"During normal aging of rodents and humans there is increased insulin resistance, disruption of metabolic activities and decline of the function of the immune system. All of these age related processes promote inflammatory activity, causing long term tissue damage and systemic chronic inflammation. However, studies of long living mutants and calorie restricted animals show decreased pro-inflammatory activity with increased levels of anti-inflammatory adipokines such as adiponectin. At the same time, these animals have improved insulin signaling and carbohydrate homeostasis that relate to alterations in the secretory profile of adipose tissue including increased production and release of anti-inflammatory adipokines.

"This suggests that reduced inflammation promoting healthy metabolism may represent one of the major mechanisms of extended longevity in long-lived mutant mice and likely also in the human."

CONSIDERING THE BRAIN

A couple of posts from the past week touch on the brain, and efforts to both preserve and understand its workings:

http://www.fightaging.org/archives/2012/10/a-long-discussion-on-what-exactly-needs-to-be-preserved-in-a-stored-brain-in-order-to-preserve-the-mind.php

"But even under the most optimistic of scenarios, such as those in which the SENS program for rejuvenation biotechnology is fully funded starting tomorrow, billions will age to death before the research community can develop the first therapies capable of meaningful rejuvenation. There is something that can be done to address this issue, for all that almost as little effort is made here as for ways to cure aging: long-term preservation of the dead, accomplished in ways that prevent destruction of the fine structures in the brain that store the mind.

"At present, the only way to preserve your mind on death is through cryonics, or low-temperature storage with vitrification of tissue. Legal obstacles make it harder than it needs to be to obtain a good preservation, and as noted above the long-standing cryonics industry is a thin thread rather than the mighty river of effort it would be in a more just and sane world. Billions have died since cryonics became a viable commercial product, of which only a few hundred have been successfully preserved.

"They can wait out the coming decades, wait out the development of medical nanotechnologies that can reverse the processes of cryopreservation. Time is on their side in this age of rapid progress, assuming that the living community of enthusiasts and professionals can continue to ensure a long-term continuity of service.

"A possible future alternative to cryopreservation is plastination, a different methodology for fixing a cell's structure all the way down to the finest details. No organizations analogous to the cryonics industry yet exists to offer plastination services, but that may only be a matter of time. Competition is healthy in any field of human endeavor."

http://www.fightaging.org/archives/2012/10/of-interest-the-human-brain-project.php

"The brain, with its billions of interconnected neurons, is without any doubt the most complex organ in the body and it will be a long time before we understand all its mysteries. The Human Brain Project proposes a completely new approach. The project is integrating everything we know about the brain into computer models and using these models to simulate the actual working of the brain. Ultimately, it will attempt to simulate the complete human brain. The models built by the project will cover all the different levels of brain organisation - from individual neurons through to the complete cortex. The goal is to bring about a revolution in neuroscience and medicine and to derive new information technologies directly from the architecture of the brain.

"The Human Brain Project will impact many different areas of society. Brain simulation will provide new insights into the basic causes of neurological diseases such as autism, depression, Parkinson's, and Alzheimer's. It will give us new ways of testing drugs and understanding the way they work. It will provide a test platform for new drugs that directly target the causes of disease and that have fewer side effects than current treatments. It will allow us to design prosthetic devices to help people with disabilities. The benefits are potentially huge. As world populations grow older, more than a third will be affected by some kind of brain disease. Brain simulation provides us with a powerful new strategy to tackle the problem."

DISCUSSION

The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!

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LATEST HEADLINES FROM FIGHT AGING!

SPERMIDINE LEVELS MEASURED IN CENTENARIANS
Friday, October 19, 2012
http://www.fightaging.org/archives/2012/10/spermidine-levels-measured-in-centenarians.php
Spermidine has been noted to boost autophagy and promote greater longevity to some degree in laboratory animals. Its activities are in the process of being advanced by some researchers as candidate drug mechanisms for slowing aging. Given that, it makes sense for researchers to investigate spermidine levels in longer lived individuals to see if there is any association: "Polyamines (putrescine, spermidine and spermine) are a family of molecules deriving from ornithine, through a decarboxylation process. They are essential for cell growth and proliferation, stabilization of negative charges of DNA, RNA transcription, translation and apoptosis. Recently, it has been demonstrated that exogenously administered spermidine promotes longevity in yeasts, flies, worms and human cultured immune cells. Here, using a cross-sectional observational study, we determined whole-blood polyamines levels from 78 sex-matched unrelated individuals divided into three age groups: group 1 (31-56 years, N=26, mean age: 44.6±6.07), group 2 (60-80 years, N=26, mean age: 68.7±6.07) and group 3 (90-106 years, N=26, mean age: 96.5±4.59). Polyamines total content is significantly lower in group 2 and 3 compared to group 1. Interestingly, this reduction is mainly attributable to the lower putrescine content. Group 2 displays the lowest levels of spermidine and spermine. On the other hand, [nonagenarians and] centenarians (group 3) display significant higher median relative percentage content of spermine with respect to total polyamines, compared to the other groups. For the first time we report polyamines profiles from whole blood of healthy [nonagenarians and] centenarians, and our results confirm and extend previous findings on the role of polyamines in determining human longevity. However, although we found an important correlation between polyamines levels and age groups, further studies are warranted to fully understand the role of polyamines in determining life-span. Also, longitudinal and nutritional studies might suggest potential therapeutic approaches to sustain healthy aging and to increase human life-span."

A SMALL STEP TOWARDS TISSUE ENGINEERED KIDNEYS
Friday, October 19, 2012
http://www.fightaging.org/archives/2012/10/a-small-step-towards-tissue-engineered-kidneys.php
Tissue engineers have been inching closer to building a kidney from stem cells in the past couple of years. Here is a recent example of the ongoing work in this field: "Investigators can produce tissues similar to immature kidneys from simple suspensions of embryonic kidney cells, but they have been unsuccessful at growing more mature kidney tissues in the lab because the kidneys' complicated filtering units do not form without the support of blood vessels. Now, from suspensions of single kidney cells, [researchers] have for the first time constructed "organoids" that can be integrated into a living animal and carry out kidney functions including blood filtering and molecule reabsorption. Key to their success was soaking the organoids in a solution containing molecules that promote blood vessel formation, then injecting these molecules into the recipient animals after the organoids were implanted below the kidneys. The organoids continued to mature and were viable for three to four weeks after implantation."

MORE ON YOUNG BLOOD AND OLD MICE
Thursday, October 18, 2012
http://www.fightaging.org/archives/2012/10/more-on-young-blood-and-old-mice.php
Some of the effects of aging are driven by signaling changes in important parts of our biochemistry - such as in stem cell niches, collections of cells that provide necessary support to the stem cells that maintain and repair tissue. Niches increasingly act to suppress the stem cells they contain in response to rising levels of cellular and other damage connected to aging. The stem cells themselves also suffer damage, and this evolved response is likely a way to minimize the risk of cancer at the cost of maintaining tissues, but the declining function of the stem cells so far seems to be far more a property of signals from the niche. In the course of investigating this and similar effects, researchers have been moving blood between young and old mice. Transfusions and joining the bloodstreams of young and old mice are a way to change the signaling environment in order to see what the effects are. The outcome is that a range of measures of aging are reversed: "Experiments on mice have shown that it is possible to rejuvenate the brains of old animals by injecting them with blood from the young. ... blood from young mice reversed some of the effects of ageing in the older mice, improving learning and memory to a level comparable with much younger animals. [Researchers] connected the circulatory systems of an old and young mouse so that their blood could mingle. This is a well-established technique used by scientists to study the immune system called heterochronic parabiosis. When [researchers] examined the old mouse after several days, [they] found several clear signs that the ageing process had slowed down. The number of stem cells in the brain, for example, had increased. More important, [they] found a 20% increase in connections between brain cells. One of the main things that changes with ageing are these connections, there are a lot less of them as we get older. That is thought to underlie memory impairment - if you have less connections, neurons aren't communicating, all of a sudden you have [problems] in learning and memory. ... the young blood most likely reversed ageing by topping up levels of key chemical factors that tend to decline in the blood as animals age. Reintroduce these and [all] of a sudden you have all of these plasticity and learning and memory-related genes that are coming back."

MORE ROBUST DATA ON THE EFFECT OF MITOCHONDRIALLY TARGETED ANTIOXIDANTS ON FLY LIFE SPAN
Thursday, October 18, 2012
http://www.fightaging.org/archives/2012/10/more-robust-data-on-the-effect-of-mitochondrially-targeted-antioxidants-on-fly-life-span.php
In recent years a few research groups have been working on a class of antioxidant compounds that can be ingested but nonetheless target themselves to mitochondrial in our cells. These compounds extend life in laboratory animals, probably by soaking up reactive free radical compounds emitted by mitochondria in the course of their operation, and thus preventing some of the damage that mitochondria cause to themselves. This damage is significant in aging, one of the root causes of degeneration and age-related disease. It is worth noting that all of the commonly available antioxidant compounds you can buy and ingest do nothing for life span or health, according to many, many studies. They don't target mitochondria, and in fact probably even cause some harm by blocking hormetic processes that use free radical signaling to boost repair mechanisms in tissue. Here is a paper providing more data on the effects of the best known class of mitochondrially targeted antioxidant: "Previously, extremely low [concentrations] of the mitochondria-targeted plastoquinone derivative SkQ1 (10-(6'-plastoquinonyl) decyltriphenylphosphonium) were shown to prolong the lifespan of male and female Drosophila melanogaster by about 10%. Using long-term monitoring of SkQ1 effects on the Drosophila lifespan, we analyzed different integral parameters of Drosophila survival and mortality under SkQ1 treatment. Meta-analysis was used to evaluate the average SkQ1 effect measured in terms of standard deviation. The effect appeared to be 0.25 for females and 0.18 for males. The SkQ1 effects on the Drosophila lifespan were reproducible over six years and showed no relationship to fluctuations in the mean lifespan of the w ( 1118 ) line used in the experiments, methods of preparation and administration of the drug, seasons, or calendar years. Adding SkQ1 to fly food was associated with a reduction in early mortality and a decrease in random variation in lifespan. [The data] indicated that feeding flies SkQ1 reduced the rate of fall of fly vitality and, consequently, slowed aging. These findings indicated that the SkQ1 effect on lifespan was associated with both elevation of life quality and slowing of aging."

THE PLASTICITY OF LIFE SPAN
Wednesday, October 17, 2012
http://www.fightaging.org/archives/2012/10/the-plasticity-of-life-span.php
We live longer than our ancestors thanks to our greater wealth and more advanced technology: risk of death is reduced at all ages, the level of damage suffered due to infectious disease and other causes is lowered throughout life, and inroads made into means of alleviating age-related disease. When it comes to effects across a life span, however, our extended lives are so far largely incidental, a side effect of improvements in medicine and quality of life that were introduced to satisfy other, more short-term goals. This shows that aging and life span is very plastic - it can be changed, and is very readily changed. On the other hand, it tells us next to nothing about what lies ahead, as the rejuvenation biotechnology of the future will be an entirely different beast from the medicine of the past. Only now is the research community deliberately trying to manipulate the processes of aging, or repair the biological damage that causes degeneration. Given this shift in what is possible, projecting past trends to the future is unwise: the deliberately engineered changes in longevity of tomorrow will not look like the incidental benefits that slowed aging yesterday. Here is an article on recent research that seeks to quantify the degree of improvement in human life expectancy that has occurred in recent centuries - you might want to look at the paper itself since it is open access. "It's said that life is short. But people living in developed countries typically survive more than twice as long as their hunter-gatherer ancestors did, making 72 the new 30, according to new research. Most of the decline in early mortality has occurred in the past century, or four generations, a finding that calls into question traditional theories about aging. But there's a larger message from the research: Our estimates about the limits of human lifespans may be too low. The study findings "make it seem unlikely that there is a looming wall of death ... which kills off individuals at a certain age" because of genetic mutations that build up as we age. For example, hunter-gatherer humans were about 100 times more likely to die before age 15 than today's residents of Japan and Sweden. And the study says hunter-gatherers were as likely to die at age 30 as Japanese people are at age 72. But the human lifespan didn't grow gradually over thousands of years. The big jump occurred after 1900 in what the study authors call a "rapid revolutionary leap." In the big picture, the research challenges the idea that genetic mutations over a lifetime prevent humans from living very long ... Without changing our genetic code at all, we have all of this improvement in mortality at these ages where these mutations should kill us off. And we got all this improvement without 'fixing' any of these mutations that are predicted to cause our bodies to break down in various ways."

OVEREXPRESSION OF FGF21 EXTENDS LIFE IN MICE
Wednesday, October 17, 2012
http://www.fightaging.org/archives/2012/10/overexpression-of-fgf21-extends-life-in-mice.php
An enormously complex web of genes and protein machinery controls the operation of metabolism, a layered nest of interactions and feedback loops. It is thus possible for many different genetic alterations to extend life by working through the same basic mechanism. The example here involving fibroblast growth factor 21 is a newly discovered change that seems to work through a known life extension method involving suppression of growth hormone, used in the past to extend life by 60-70% in mice. "Restricting food intake has been shown to extend lifespan in several different kinds of animals. In our study, we found transgenic mice that produced more of the hormone fibroblast growth factor-21 (FGF21) got the benefits of dieting without having to limit their food intake. Male mice that overproduced the hormone had about a 30 percent increase in average life span and female mice had about a 40 percent increase in average life span. FGF21 seems to provide its health benefits by increasing insulin sensitivity and blocking the growth hormone/insulin-like growth factor-1 signaling pathway. FGF21 is a hormone secreted by the liver during fasting that helps the body adapt to starvation. It is one of three growth factors that are considered atypical because they behave like hormones. ... Previous research has found that FGF21 can reduce weight in obese mice. The mice that overproduced FGF21 in this latest study were lean throughout their lives and remained lean even while eating slightly more than the wild-type mice. The hormone does have some downsides: FGF21 overproducers tended to be smaller than wild-type mice and the female mice were infertile. While FGF21 overproducers had significantly lower bone density than wild-type mice, the FGF21-abundant mice exhibited no ill effects from the reduced bone density."

DOPAMINE AND MEMORY DECLINE IN AGING
Tuesday, October 16, 2012
http://www.fightaging.org/archives/2012/10/dopamine-and-memory-decline-in-aging.php
Parkinson's disease is caused by excessive loss of cells in the small population of dopamine-generating neurons. This is an exaggerated version of a loss that we all suffer due to the wear and tear of aging: many age-related conditions are of this nature, aggravated or more rapidly occuring versions of the same damage that everyone suffers. So all people lose some of the cells that generate the neurotransmitter dopamine, just not enough for that loss to become a named and known medical condition. But even this more modest loss of dopamine neurons causes functional decline in the brain, as researchers here demonstrate - with the intent to show that drugs that deliver dopamine to the brain could at least partially compensate for this decline: "Activation of the hippocampus is required to encode memories for new events (or episodes). Observations from animal studies suggest that, for these memories to persist beyond 4-6 hours, a release of dopamine generated by strong hippocampal activation is needed. This predicts that dopaminergic enhancement should improve human episodic memory persistence also for events encoded with weak hippocampal activation. Here, using pharmacological functional MRI (fMRI) in an elderly population in which there is a loss of dopamine neurons as part of normal aging, we show this very effect. The dopamine precursor levodopa led to a dose-dependent (inverted U-shape) persistent episodic memory benefit for images of scenes when tested after 6 hours, independent of whether encoding-related hippocampal fMRI activity was weak or strong (U-shaped dose-response relationship). This lasting improvement even for weakly encoded events supports a role for dopamine in human episodic memory consolidation, albeit operating within a narrow dose range."

ANOTHER GLENN FOUNDATION LAB ESTABLISHED
Tuesday, October 16, 2012
http://www.fightaging.org/archives/2012/10/another-glenn-foundation-lab-established.php
Following on from last week's news, it seems the Glenn Foundation for Medical Research is establishing a brace of new laboratories for the study of aging, joining those formed a few years back. Which is to say that the Foundation is reinforcing some of the existing leading lights in aging and longevity science, and in the process of delivering sizable grants is setting up new, named research centers. This time it's the turn of researchers at the Albert Einstein College of Medicine: " Albert Einstein College of Medicine of Yeshiva University has received a $3 million grant from the Glenn Foundation for Medical Research to establish the Paul F. Glenn Center for the Biology of Human Aging Research. The grant will fund research to translate recent laboratory and animal discoveries into therapies to slow human aging. "Paul F. Glenn has been a visionary in aging research for more than 30 years," said Ana Maria Cuervo, M.D., Ph.D., co-director of the new center, the Robert and Renee Belfer Chair for the Study of Neurodegenerative Diseases, and professor of developmental and molecular biology, of anatomy and structural biology and of medicine at Einstein. "Some of us got to know him when we were still graduate students and he came to scientific conferences to see the data as it was being developed. Paul's personal approach to science has made a big difference to many of us in the field of aging research and has contributed to the career development of many young investigators." The funding, in the form of pilot and feasibility study grants, is targeted to several specific research projects: uncovering the genetic and epigenetic mechanisms that protect humans against aging and age-related diseases, testing the effectiveness of the first-generation pro-longevity therapies, and developing novel preventive and therapeutic interventions against cellular aging in humans." Cuervo, you might recall, led the demonstration of reversal of lysosomal decline in the aging liver a few years back, making old mouse livers function as well as when young.

COMMENTING ON THE LATE LIFE PLATEAU IN AGING
Monday, October 15, 2012
http://www.fightaging.org/archives/2012/10/commenting-on-the-late-life-plateau-in-aging.php
One fairly standard definition for aging is an increase in mortality rate over time. You are said to age if you become increasingly likely to die in any given interval of time. There is an interesting twist, however: researchers have shown that in short-lived species such as flies there appears to be a point in very late life at which mortality rate stops increasing - i.e. aging, by this definition, ceases. There is some debate as to what this tells us, and how useful in might be in terms of informing aging research or practical applications of biotechnology to extend life. For example, the evidence for any such late-life plateau for mortality rates in humans is tenuous to non-existent. Does it even exist outside very short-lived species? Here is a further commentary on late-life plateaus in mortality rate and evolutionary considerations of aging: "Too often, aging is thought of as an inevitable accumulation of damage to cells, as something common to all organisms and across all adult ages, or as a physiological process. These ways of thinking about aging limit aging research. We should instead understand aging as an evolutionarily derived condition, dependent entirely on the pattern of the force of natural selection. In late adult life, the forces of natural selection no longer differentiate between age classes. At these late ages, there is no effective force of natural selection. This leads to a corresponding absence of consistent changes in fecundity and mortality. One prediction of the evolutionary theories is that other fitness characters, such as male virility, should also stabilize in late life. Following the virility of 1000 individual male D. melanogaster, I found that, as expected, male virility also reached a plateau in late life. This result conforms to the predictions of the evolutionary theories of late life. Late life is therefore a period in which mortality, fecundity, and virility all plateau. ... These results suggest that late life physiology is distinct from that of aging, and that the absence of change in the effective forces of selection in late life, leads to paradoxical transitions in physiology as cohorts enter late life. From these results, I infer that the periods of aging and late life are different physiologically as a result of the very different ways in which they experience selective forces."

INVESTIGATING NATURAL BLADDER REGENERATION IN RATS
Monday, October 15, 2012
http://www.fightaging.org/archives/2012/10/investigating-natural-bladder-regeneration-in-rats.php
Important things remain to be learned of the regenerative capacity of various mammal species - such as the way in which rats can regrow large sections of the bladder. Researchers investigate mechanisms of natural regeneration with an eye to finding ways to reproduce exceptional examples of regrowth in human biochemistry. Here, scientists suggest that regeneration of the bladder in rodents is a better avenue of investigation than the well known regeneration of the liver that even we humans are capable of: "Subtotal cystectomy (STC; surgical removal of ~75% of the rat urinary bladder) elicits a robust proliferative response resulting in complete structural and functional bladder regeneration within 8-weeks. ... Although regeneration per se occurs throughout the animal kingdom, there are large disparities in the degree of regeneration observed between species (e.g., amphibian versus mammalian) let alone amid organs (e.g., liver versus kidney). The extensive attention focused on regenerative medicine is understandable given the enormous potential for repair and/or replacement of old, damaged or diseased cells, tissues and organs; such as the diseased and dysfunctional bladders that are the subject of this report. The liver is very efficient in repairing or regenerating its mass, which occurs as a direct result of the proliferation of all the existing cells from the remaining liver remnant, but is mainly driven by mature hepatocytes, which will re-enter the cell cycle to restore the liver. The entire process, which is usually referred to as regeneration, is completed within a couple weeks, depending upon the mammalian species. However, the process is more accurately termed compensatory hyperplasia. These well established observations regarding liver re-growth stand in contrast to rodent bladder regeneration, which occurs over a longer time frame (8 weeks rather than 2 weeks), and moreover, results in a regenerated bladder that structurally and functionally is essentially identical to the native bladder which it replaced. More specifically, the bladder capacity and bladder wall thickness (as well as the presence of all three layers; urothelium, muscularis propria and lamina propria) of the regenerated bladder are indistinguishable from the previous native bladder, and moreover, the animals are entirely continent. To our knowledge, bladder regeneration therefore holds a unique position with respect to its regenerative potential, as there is no other mammalian organ capable of this type of regeneration."

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Posted 28 October 2012 - 03:42 PM

FIGHT AGING! NEWSLETTER
October 29th 2012

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

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CONTENT

- Breaking the Wheel of Time
- What Happened to Protofection?
- Broadening Study of Mitochondrially Targeted Compounds
- Discussion
- Latest Headlines from Fight Aging!
    - Gut Microbes in Aging
    - The Cost of Smoking
    - Reporting on the 2012 Singularity Summit
    - A Report from the Alcor-40 Conference
    - Persistent Infection Harms Long Term Health and Life Expectancy
    - Simulating the Grandmother Effect
    - Generating Cells to Treat Vascular Disease
    - Exercise Beneficial for the Aging Brain
    - More on Establishing an Australian Cryonics Provider
    - Debates in the Mainstream of Aging Research

BREAKING THE WHEEL OF TIME
http://www.fightaging.org/archives/2012/10/breaking-the-wheel-of-time.php

Mortality determines society. By this I mean that the function describing mortality rate by age in humans acts as a filter to determine the sort of societies that can exist and support themselves. A high mortality rate reduces the range of societies that can exist. The mechanisms at play in this relationship are economic in the broadest sense: a mix of population growth, division of labor, effectiveness in recording and transmitting knowledge, time preference, establishment of sufficient capital for more than just subsistence living. Consider the difference between the late paleolithic era and classical Greek civilization, for example, and think on why they are different.

In terms of mortality, the immediately noticeable difference between the classical era and prehistory is an upsurge in the number of people who reached old age - a reduction in the omnipresent violence between small groups, and a marginal improvement in medicine. As a general rule you don't find the bones of old people in early human archaeology: so few of them made it past 40 as to be close to absent entirely as a class. Mortality rates in classical Greek and early Roman times were horrific by modern standards, but enormously improved over those of prehistory.

Thus as a consequence there were both old people and a certain expectation of reaching old age - which means a rise in planning ahead and an increase in available capital. A longer vision breaks through destructive cycles of economic behavior that take place on shorter timescales. As one example, people cultivate their property more effectively if they think that it must last for longer under their stewardship, more readily resisting short-term gains that come at the cost of long-term gains. This incentive has operated throughout human history, whenever average life spans rose. A later example can be seen in the simultaneous rise of life span and economic well-being in 17th and 18th century England:

"If life cycle inspiration was present in rural England in the 18th century, farmers who were becoming aware that old people were gradually living for longer periods must have been more concerned about their own means of subsistence in the future. This may have been an important stimulus to reduce consumption, increase savings and take into account longer horizons."

Various destructive cycles of poverty to wealth to poverty exist for all time scales of human behavior and all population densities. A greater expected span of life doesn't make them go away entirely, but it does mean that more people will be around to suffer the consequences of ill-thought action - and as a result, endeavor to understand and avoid the acts that lead to suffering they see in others. Don't eat your own seed corn; be the ant rather than the grasshopper; don't cut down the whole forest; engage in trade rather than slavery; shun destruction in favor of construction; allow the merchant class to exist; and so forth. You might see the commonality here: it is restraining the urge to obtain short-term gains that harm the prospects for long-term gain.

One important thing to note is that all historical progress in expanding the range of possible human societies has come about without greatly altering the maximum human life span. It was possible to live to more than a century without modern medicine and in the presence of pervasive disease and violence - that outcome was just enormously unlikely for any given individual. Improved mortality rates led to a growth in the number of old people and their influence.

I submit that this largely unchanged outer limit to life span is why we can look back on thousands of years of politics to see the same patterns repeated over and again. Regions rise and fall. Empires form and decline. Countries become wealthy and then poor. Democracies slide into authoritarianism. Currencies are steadily debased and destroyed. Known and enumerated forms of governance arise over and again, and fail in the same ways each time. The patterns repeat because throughout history expectations regarding the outer limits of personal stewardship and responsibility remained set at something less than a century. It is that span of time that drives choices made between cultivating future growth versus squandering it for present advantage - and even drives whatever incentive exists to understand that you are taking one of those paths rather than the other.

After all, economics as a professional body of knowledge and theory only really evolved into the forms we'd recognize today in the wake of 17th to 18th century gains in longevity, after the rise and fall of physiocracy as a flawed means to explain the wealth or poverty of nations and how that related to human behavior.

Just as paleolithic hunter-gatherer groups were stuck in their own limited range of sustainable human societies, their choices and cultural evolution over time driven by high mortality rates at all ages and the near absence of elders, so are we also stuck in our own, larger range of possible societies. Our present span of life limits us to what we see. Where wealth, freedom, and the rule of law necessary to create wealth arise, they corrode over time as successive generations forget how and why their good fortune came about: they eat their own seed corn. We can see this happening in the US, somewhere past the mid-point of the process, and all somewhat analogous to the decline of the Roman Republic, at least insofar as root causes are considered: successful republics have a way of falling into empire and authoritarian rule, accompanied by massive military and welfare spending. Bread, circuses, and the legions.

All humans of our maximum life span and adult mortality rates low enough to allow for societies of cities and writing have found themselves trapped within the wheel of time I described above: the rise and fall of polities that takes place over centuries, poverty to wealth to poverty, or tribes to civilization to tribes. It is the consequence of our dominant short-termisms; where our time preference fails the test; where we squander our own potential.

The human condition has been bounded in this way for a very long time indeed, since the first cities arose more than 6,000 years ago, but it will not continue for much longer. In this age of biotechnology the transition from age-bounded life spans of a century to accident-bounded life spans of thousands of years will happen in the course of mere decades. Entire populations will stop dying as therapies capable of repairing the cellular and molecular damage of aging become widely available. Degenerative aging will become a controlled medical condition, warded and defeated like smallpox and others in the past century.

The wheel of time will be broken. Those who stand at the beginning and the height of empire will be the very same individuals who must also stand at its decline: their horizons will extend, and so the shape of empire will be quite different, if it comes about at all. How will this play out, this grand restructuring of all the incentives that lurk at the base of human societies? What new forms of society will emerge as possibilities given widespread radical life extension? These are open questions: the changes to human life span that lie ahead are dramatically different in character to those that have occurred in the past. The gulf in mortality and life span that likely lies between us and the humanity of the 22nd century is far greater than that separating paleolithic hunter-gatherers from the classical Greeks. Further, it will occur in a comparative eyeblink - a single generation will stand with one foot in each world.

Yet the wheel of time will be broken, and this seems to me to be a good thing.

WHAT HAPPENED TO PROTOFECTION?
http://www.fightaging.org/archives/2012/10/what-happened-to-protofection.php

Mitochondria are a roving herd of power plants that exist in every cell, storing energy in chemical form for use in powering cellular processes. They are the remnants of symbiotic bacteria-like organisms, and so bear their own DNA that encodes much of the protein machinery needed for their operation. Unfortunately, this mitochondrial DNA (usually abbreviated as mtDNA) sits right next to processes that generate reactive byproducts, and is far less protected than the DNA in the cell nucleus. It becomes damaged over time in ways that spiral out to harm the cell, harm surrounding tissue, and ultimately cause some fraction of degenerative aging.

Thus fixing mitochondrial DNA damage is an important line item for any future rejuvenation toolkit. Seven years ago, there was an unofficial claim of the ability to replace mitochondrial DNA in a laboratory animal using a methodology known as protofection. There has not been a great deal of progress on this front since then however: to the best of my knowledge, no-one else has managed to replicate that result. Yet that research group and others continue to work on the mechanisms used: so what's going on here?

At its heart, protofection is a cargo delivery method, and the cargo consists of gene sequences to be inserted into mitochondria - such as extra copies of important genes that tend to get damaged, causing mitochondrial dysfunction. The delivery mechanism is a protein assembled of various parts that enable it to (a) cross cell membranes, (b) be transported into the interior of mitochondria within the cell, and © participate in the normal processes of DNA replication. Thus a cargo of mitochondrial genes attached to this basic assembly will be carried to mitochondria and then added to the mitochondrial DNA that is already present.

This delivery protein is known of late as recombinant human mitochondrial transcription factor A (rhTFAM) ... In recent years, it seems that the core protofection research group has dropped the use of rhTFAM as a carrier and are instead focused on exploring how it might be used in and of itself, without any cargo, as a therapy for mitochondrial conditions. It so happens that rhTFAM boosts mitochondrial activity in some ways, and progressive mitochondrial dysfunction is implicated in a range of age-related conditions, especially in the brain. Even marginal therapies here could have meaningful market value.

You might look on this as one of the more subtle ways in which the present US regulatory structure for medical research and development distorts the undertaking of science. The FDA only permits clinical applications for specific named conditions, and thus anything other than the development of treatments for late-stage disease becomes either too expensive or outright forbidden. Treatment of aging falls into the latter category, as aging is not recognized as a medical condition that should be treated. So research efforts that might have some application to aging are sidelined into the development of marginal therapies for one specific disease, often type 2 diabetes, rather than what are arguably far more important applications.

BROADENING STUDY OF MITOCHONDRIALLY TARGETED COMPOUNDS
http://www.fightaging.org/archives/2012/10/broadening-study-of-mitochondrially-targeted-compounds.php

Mitochondria, the cell's herd of bacteria-like power plants, occupy an important position in processes of aging, metabolism, and many age-related conditions. Mitochondria produce damaging reactive oxidative molecules as a side-effect of their operation, and these can cause all sorts of havoc - such as by damaging mitochondrial DNA in ways that can propagate throughout the mitochondrial population of a cell, causing it to run awry and harm surrounding tissue. This happens ever more often as we age, and is one of the principle contributions to degenerative aging.

It is worth noting that a greater ability of mitochondria to resist this sort of self-inflicted oxidative damage is theorized to explain much of the longevity of many species that are unusually long-lived for their size - such as bats, naked mole-rats, and so forth.

Thus the researcher community is increasingly interested in finding ways to target therapies to mitochondria: to slow oxidative damage, fix that damage, repair other issues such as genetic disorders in mitochondrial DNA, or alter mitochondrial operation as a way of manipulating cellular behavior and metabolic processes. Building such a therapy usually means attaching a payload molecule to a delivery molecule or particle that will be (a) taken up by a cell, passing through the cell membrane, and then (b) swallowed by a mitochondrion within the cell, passing through that mitochondrion's membranes.

A range of different research groups are working on varied forms of delivery technology. Compare, for example, the repurposed protein machinery of rhTFAM with various plastinquione compounds or polymer nanoparticles. Or, more deviously, genetic engineering that makes a cell nucleus produce and export proteins to that cell's mitochondria. There are many others.

Diversity is a good thing - though of course not all of these strategies are equal in the sort of interventions that they can support. There is a world of difference between introducing more antioxidants into the mitochondria so as to blunt their creation of damaging, reactive byproducts and introducing new genes to repair damage to mitochondrial DNA. The former only gently slows the inevitable, while the latter reverses and repairs the harm done.

DISCUSSION

The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!

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LATEST HEADLINES FROM FIGHT AGING!

GUT MICROBES IN AGING
Friday, October 26, 2012
http://www.fightaging.org/archives/2012/10/gut-microbes-in-aging.php
Microbes in the digestive system seem to have some influence on aging, insofar as they interact with the immune system, epigenetic regulation of nearby tissues, and so forth. In effect they act almost like an additional organ or biological system. Researchers are very much in the early stages of trying to understand how microbial life in the body fits in to the bigger picture of metabolism and aging - which is already very complex, and likely to become more so: "The ageing process affects the human gut microbiota phylogenetic composition and its interaction with the immune system. Age-related gut microbiota modifications are associated with immunosenescence and inflamm-ageing in a sort of self-sustaining loop, which allows the placement of gut microbiota unbalances among both the causes and the effects of the inflamm-ageing process. Even if, up to now, the link between gut microbiota and the ageing process is only partially understood, the gut ecosystem shows the potential to become a promising target for strategies able to contribute to the health status of older people. In this context, the consumption of pro/prebiotics may be useful in both prevention and treatment of age-related pathophysiological conditions, such as recovery and promotion of immune functions ... Moreover, being involved in different mechanisms which concur in counteracting inflammation, such as down-regulation of inflammation-associated genes and improvement of colonic mucosa conditions, probiotics have the potentiality to be involved in the promotion of longevity."

THE COST OF SMOKING
Friday, October 26, 2012
http://www.fightaging.org/archives/2012/10/the-cost-of-smoking.php
There are numerous ways in which lifestyle choices can damage long-term health and lower life expectancy, but smoking remains one of the more effective, on a par with becoming obese: "The Life Span Study (LSS) was initiated in 1950 to investigate the effects of radiation, tracking over 100,000 people. However, most received minimal radiation exposure, and can therefore provide useful information about other risk factors. Surveys carried out later obtained smoking information for 68,000 men and women, who have now been followed for an average of 23 years to relate smoking habits to survival. The younger a person was when they started smoking the higher the risk in later life. Older generations did not usually start to smoke until well into adult life, and usually smoked only a few cigarettes per day. In contrast, Japanese born more recently (1920-45) usually started to smoke in early adult life, much as smokers in Britain and the USA. These differences in smoking habits are reflected in the mortality patterns. Smokers born before 1920 lost just a few years. In contrast, men born later (1920-45) who started to smoke before age 20 lost nearly a decade of life expectancy, and had more than double the death rate of lifelong non-smokers, suggesting that more than half of these smokers will eventually die from their habit. Results on the few women who had smoked since before age 20 were similar. In addition to studying the risk of smoking, the researchers were able to examine the benefits of stopping. As elsewhere, those who stopped smoking before age 35 avoided almost all the excess risk among continuing smokers, and even those who stopped around age 40 avoided most of it."

REPORTING ON THE 2012 SINGULARITY SUMMIT
Thursday, October 25, 2012
http://www.fightaging.org/archives/2012/10/reporting-on-the-2012-singularity-summit.php
Videos of the presentations given at this year's Singularity Summit have yet to emerge online, but while we're waiting here is a report on the event: "Kurzweil took the stage on Saturday afternoon to deliver the summit's keynote address. "The singularity is near," he began quietly, a grin slowly spreading across his face. "No, it isn't here yet, but it's getting nearer," he said to laughs and applause. He spoke extemporaneously for over an hour, his presentation a mix of statistics, time series graphs, personal anecdotes, and predictions. Computing ability and technological innovation have been increasing exponentially over the past few decades, he argued, alongside similar increases in life expectancy and income. "All progress stems from the law of accelerating returns," he proclaimed. He discussed his latest project - an attempt to reverse-engineer the human brain. "Intelligence is at the root of our greatest innovations: genetics, nanotechnology, and robotics. Once we master artificial intelligence, unimaginable new frontiers will open up." After his talk, a man stood up and looked Kurzweil in the eye. "I'm in my 60s like you," he said, his voice faltering. "Do you think we'll make it?" It took me a few seconds to realize they were talking about immortality and I felt chills in that moment. "Life expectancy tables are based on what happened in the past," responded Kurzweil without skipping a beat. "In 25 years, we'll be able to add one year of life for every year that passes. We have a very good chance of making it through."" I should note that I believe Kurzweil's timelines for rejuvenation biotechnology are only possible if $300 million or more in dedicated research funding turns up at the SENS Foundation's front door tomorrow, thereby ensuring a good shot at demonstrating rejuvenation in old laboratory mice by the mid-2020s. As things stand progress towards the necessary technologies is far slower - not because it cannot be done, but because there is comparatively little interest in doing it, and therefore little funding. One of the deep puzzles of our age is how a multi-billion-dollar "anti-aging" industry, full of enthusiasm but providing nothing that significantly impacts aging, can exist alongside the near absence of interest in funding research that will produce therapies capable of reversing the progression of aging. There are strange tides at work in the psychology surrounding aging and longevity.

A REPORT FROM THE ALCOR-40 CONFERENCE
Thursday, October 25, 2012
http://www.fightaging.org/archives/2012/10/a-report-from-the-alcor-40-conference.php
Members of the cryonics community gathered for the Alcor-40 conference last week. Here is a report on the event: "I was expecting some excellent talks on the current state of cryonics technology, from the particulars of preservation via vitrification with powerful cryoprotectants, to the pragmatics of transitioning a recently deceased body from the site of death to Alcor's facilities. And the talks on these topics were indeed worthwhile, giving me faith that, in spite of quite limited funding for research and operations, Alcor is steadily improving all dimensions of their practice. Alcor's new CEO Max More started in the position fairly recently, and from what I can tell he's been doing a very professional job. What surprised me was the depth of the talks on longevity science and neuroscience. One definitely got the feeling that cryonics is not nearly as marginalized as it was a decade ago or even five years ago, and is now accepted as a reasonable pursuit by a rapidly increasing subset of the scientific community. Of course, this is part of a larger trend of the gradual mainstreaming of transhumanist technologies. AGI and nanotechnology, for example, were laughed at by most academics in relevant fields just 10-20 years ago. Now they are much more broadly acknowledged as valid and important pursuits, though there are still differences in vision between the maverick advocates and the interested folks in the academic mainstream."

PERSISTENT INFECTION HARMS LONG TERM HEALTH AND LIFE EXPECTANCY
Wednesday, October 24, 2012
http://www.fightaging.org/archives/2012/10/persistent-infection-harms-long-term-health-and-life-expectancy.php
The decline of the immune system is an important component of aging, and one of the causes of that decline is persistent infection by common herpesviruses such as cytomegalovirus (CMV). This is near harmless in the short term, but over time more and more of the limited repertoire of immune cells are devoted to the futile attempt to clear out CMV - and ever less are left free to tackle other threats. One possible solution is to destroy the CMV-specialized immune cells to free up space. This is a very plausible goal, given advances in targeted cell killing technologies emerging from the cancer research community. But here, scientists measure the cost of CMV infection in laboratory animals - more motivation for research groups that might be trying to build a therapy: "Persistent CMV infection has been associated with immune senescence. To address the causal impact of lifelong persistent viral infection on immune homeostasis and defense, we infected young mice systemically with HSV-1, murine CMV, or both viruses and studied their T cell homeostasis and function. Herpesvirus(+) mice exhibited increased all-cause mortality compared with controls. Upon Listeria-OVA infection, 23-mo-old animals that had experienced lifelong herpesvirus infections showed impaired bacterial control and CD8 T cell function, along with distinct alterations in the T cell repertoire both before and after Listeria challenge, compared with age-matched, herpesvirus-free controls. Herpesvirus infection was associated with reduced naive CD8 T cell precursors above the loss attributable to aging. ... To our knowledge, this study for the first time causally links lifelong herpesvirus infection to all-cause mortality in mice and to disturbances in the T cell repertoire, which themselves correspond to impaired immunity to a new infection in aging."

SIMULATING THE GRANDMOTHER EFFECT
Wednesday, October 24, 2012
http://www.fightaging.org/archives/2012/10/simulating-the-grandmother-effect.php
We humans are long-lived for our size when compared with other mammals. One possible explanation is the grandmother hypothesis, suggesting that evolutionary selection favored survival to increasing age because older members of a social group can increase the survival chances of their grandchildren. As for all hypotheses there are arguments against it, but here researchers have created simulations to support the concept: "The simulations indicate that with only a little bit of grandmothering -- and without any assumptions about human brain size - animals with chimpanzee lifespans evolve in less than 60,000 years so they have a human lifespan. Female chimps rarely live past child-bearing years, usually into their 30s and sometimes their 40s. Human females often live decades past their child-bearing years. The findings showed that from the time adulthood is reached, the simulated creatures lived another 25 years like chimps, yet after 24,000 to 60,000 years of grandmothers caring for grandchildren, the creatures who reached adulthood lived another 49 years - as do human hunter-gatherers. Based on earlier research, the simulation assumed that any newborn had a 5 percent chance of a gene mutation that could lead to either a shorter or a longer lifespan. The simulation begins with only 1 percent of women living to grandmother age and able to care for grandchildren, but by the end of the 24,000 to 60,000 simulated years, the results are similar to those seen in human hunter-gatherer populations: about 43 percent of adult women are grandmothers. The new study found that from adulthood, additional years of life doubled from 25 years to 49 years over the simulated 24,000 to 60,000 years. The competing "hunting hypothesis" holds that as resources dried up for human ancestors in Africa, hunting became better than foraging for finding food, and that led to natural selection for bigger brains capable of learning better hunting methods and clever use of hunting weapons. Women formed "pair bonds" with men who brought home meat. Many anthropologists argue that increasing brain size in our ape-like ancestors was the major factor in humans developing lifespans different from apes. But the new computer simulation ignored brain size, hunting and pair bonding, and showed that even a weak grandmother effect can make the simulated creatures evolve from chimp-like longevity to human longevity."

GENERATING CELLS TO TREAT VASCULAR DISEASE
Tuesday, October 23, 2012
http://www.fightaging.org/archives/2012/10/generating-cells-to-treat-vascular-disease.php
Much of the stem cell research community is engaged in determining the recipes needed to create large numbers of specific types of cell for specific therapeutic uses. There are a few hundred different types of cell in the human body, so you'll periodically see announcements such as this as successes are achieved: "A new approach for generating large numbers of circulatory system cells, known as vascular endothelial cells (VECs), from human amniotic-fluid-derived cells (ACs) is reported ... The strategy, which shows promise in mice, opens the door to establishing a vast inventory of VECs for promoting organ regeneration and treating diverse vascular disorders. VECs line the entire circulatory system, including the heart and blood vessels, and they help to control blood pressure, promote the formation of new blood vessels, and support the regeneration and repair of injured organs. A wide range of vascular diseases stem from dysfunctions in VECs, so generating healthy cells for transplantation in patients would represent an attractive treatment strategy. But past stem cell strategies have fallen short: VECs derived from stem cells are unstable and tend to convert to nonvascular cells, and they do not increase rapidly in number, limiting their potential for clinical use. To overcome these limitations, [researchers] developed a safe approach for producing a large number of stable VECs from amniotic cells, which are extracted during routine amniocentesis procedures and thus represent a steady source of cells. To reprogram amniotic cells into mature and functional VECs, called rAC-VECs, the researchers turned specific genes on and off using members of the E-twenty-six family of transcription factors - proteins that bind DNA and are important for VEC development. The rAC-VECs resembled human adult VECs in that they expressed the normal set of vascular-specific genes. When rAC-VECs were transplanted into the regenerating livers of mice, they formed stable, normal, and functional blood vessels."

EXERCISE BENEFICIAL FOR THE AGING BRAIN
Tuesday, October 23, 2012
http://www.fightaging.org/archives/2012/10/exercise-beneficial-for-the-aging-brain.php
Regular exercise, much like calorie restriction, has a beneficial effect on near all measures of aging in humans - though unlike calorie restriction it doesn't increase maximum life span in laboratory animals. Here is a reminder that decline in brain function is slowed by exercise: "The new research included about 700 people living in the United Kingdom who all had brain scans when they reached the age of 73. Three years earlier, at age 70, the study participants were questioned about the leisure and physical activities they engaged in. People in the study who reported being the most physically active tended to have larger brain volumes of gray and normal white matter, and physical activity was linked to less brain atrophy. Regular exercise also appeared to protect against the formation of white matter lesions, which are linked to thinking and memory decline. [In another study, researchers] recruited 120 older inactive adults with no evidence of dementia. ... Half began a modest exercise routine that included walking at a moderate pace for 30 to 45 minutes, three times a week. The other half did stretching and toning exercises. A year later, MRI brain scans showed that a key region of the brain involved with memory, known as the hippocampus, was slightly larger in the walking group, while it has shrunk slightly in the non-aerobic stretching group. "The old view is that as we get older our brains become less malleable and less able to change. The new view is that it remains plastic even very late in life. We were able to show positive change after just one year of moderate-intensity physical activity.""

MORE ON ESTABLISHING AN AUSTRALIAN CRYONICS PROVIDER
Monday, October 22, 2012
http://www.fightaging.org/archives/2012/10/more-on-establishing-an-australian-cryonics-provider.php
The small cryonics industry provides a method of low-temperature storage after death, with the aim of preserving the fine structure in brain tissue that stores the data of the mind. Cryopreserved people can wait out the development of sufficiently advanced applications of molecular nanotechnology that are capable of restoring them to active life. Over the decades since the first cryonics providers were established the industry has not grown greatly, but it is nonetheless the only option other than the grave available to the billions who will die prior to the advent of biotechnologies to reverse aging. In a better world, cryonics providers would be as commonplace as funeral homes and near everyone would be preserved. But there are only a small number of active organizations: a couple in the US, a more recently launched project in Russia, and a few others in various stages of early development. At present it looks like an initiative to launch a cryonics provider in Australia is nearing fruition. Here is a recent article on this effort: "Milton first heard about cryonics as a kid, through reading science fiction, but only became seriously interested four years ago, while researching life-extension techniques. One night he attended a meeting of the Cryonics Association of Australasia (CAA) in a cafe in the city, where he met Peter Tsolakides, a retired manager for ExxonMobil, the oil company. At the meeting, both men were disappointed to discover that there was no cryonics facility in Australia. If you wanted to get frozen, you had to go to the USA. This is not impossible - the Cryonics Institute, in Michigan, has six Australians in cryopreservation, and the Alcor Life Extension Foundation, in Arizona, has two - but it is certainly inconvenient. You either had to be aware you were on the way out and get on a plane, quickly, or wait till you had de-animated and have someone, usually an obliging member from CAA, pack you in ice and mail you over. Either way, it was a logistical nightmare, and so Milton and Tsolakides decided to start a local operation. That was in 2009. Since then, Stasis has recruited 11 investors, each of whom has agreed to put in $50,000. This money will fund the construction of the facility, which should be complete by 2014, and pay for the investors' cryonic suspension, when the time comes. Milton, who works from home, spends his time liaising with NSW Health, which has been "very supportive", and, more recently, scouting for suitable land sites. "We are currently looking for a couple of acres in regional NSW - Yass, Wagga Wagga, Goulburn ... It has to be a low-risk area for natural disasters, like bushfires, earth tremors or flooding, and it needs to be somewhere with reliable power, sealed access and liquid nitrogen delivery routes, because liquid nitrogen is essential.""

DEBATES IN THE MAINSTREAM OF AGING RESEARCH
Monday, October 22, 2012
http://www.fightaging.org/archives/2012/10/debates-in-the-mainstream-of-aging-research.php
The most important strategic debate in aging science is over how to go about producing therapies for aging. The present dominant camp believes that only minimal progress is possible in the near term, and that altering the operation of metabolism is one of the few viable methods: they are aiming to gently slow aging, such as by replicating some of the beneficial changes that occur in calorie restriction. The minority position in this debate looks to build therapies capable of true rejuvenation, reversal of aging by repairing the cellular and molecular damage that causes aging. This is a path that should prove no harder, will produce far better results, but yet remains unpopular in the research community. If we want to see meaningful progress towards engineered longevity in our lifetimes, it is the path that will have to win out, however. The mainstream position has its own internal debates over strategy, as a recent article illustrates, while taking a swipe at the repair-based approach along the way: "In the current issue of Scientific American, author Katherine Harmon takes a brief look at two schools of thought in the field of human lifespan expansion science. One group believes lifespan can be extended by limiting diseases one at a time. Focusing on the top two, cancer and heart disease, they beleive will go a long way. "If we can focus on the major causes of death - cancer, cardiovascular disease - if we can really conquer those diseases and replace parts of the body if they wear out, that is the best possible outcome," gerontologist Sarah Harper is quoted as saying. The other group believes the actual underlying aging pathway itself can be slowed. This camp is represented by Dr . S. Jay Olshanksy at the University of Chicago. He believes that even if diseases are eliminated, cells and organs will age and degenerate and people will still age and die, perhaps some number of fixed years later. Olshansky is said with colleagues to be launching a "Manahttan-style project to slow aging" whose primary goal is to extend healthy lifespan by seven years in the next decade or two. Since disease risk doubles every seven years, slowing aging by seven years will reduce diseases by half. The aim of this group is to find compounds that slow aging. No specific mention was made in the article of Dr. Aubrey de Grey and his SENS Foundation and his premise that age-related damage can be fixed and aging reversed and halted. His efforts are derided by associating one his quotes that the first person to live to 150 has already been born to "pseudoscience backwater, swamped with snake oil and short-lived hopes."" The snake oil abounds amidst the lies and frauds of the "anti-aging" market of course, but it's simple laziness to associate serious scientific efforts like SENS with snake oil salesmen just because both groups say that they want to greatly extend healthy life.

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Posted 04 November 2012 - 04:41 PM

FIGHT AGING! NEWSLETTER
November 5th 2012

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

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CONTENT

- Considering Strategy in Aging Research
- A Review of "The Singularity"
- Not All Longevity Manipulations Play Nice Together
- A Possible Metabolic Signature of Biological Age in Mice
- Discussion
- Latest Headlines from Fight Aging!
    - Investigating the Mechanisms of Cellular Senescence
    - Creating Myelin-Producing Cells to Order
    - Promoting Remyelination by Blocking Hyaluronidase
    - Deepening the Puzzle
    - Considering Antagonistic Pleiotropy
    - More Mitochondrially Targeted Antioxidant Results
    - Exercise Improves Cognitive Function
    - Cartilage From Induced Pluripotent Stem Cells
    - Commenting on the Utility of AGE-Breakers
    - Histone Deacetylase Inhibitors Preserve Function in Aging Axons

CONSIDERING STRATEGY IN AGING RESEARCH
http://www.fightaging.org/archives/2012/10/more-considerations-of-strategy-in-aging-research.php

The research community has as many opinions as researchers when it comes to how best to proceed with lengthening healthy human life spans. There are some clearly identifiable camps, however, such as slowing aging by manipulating metabolism versus reversing aging by repairing the damage that causes degeneration. Here are some thoughts on these camps and some of their subdivisions from Aubrey de Grey of the SENS Foundation:

The September 2012 issue of Scientific American includes a commentary contrasting two approaches to combating aging. Like almost all general-audience piece, and despite the best efforts of most experts in the field, it highlights the goal of life extension rather than stressing that any longevity benefits will be a side effect of health benefits ... The value of the article, though diminished thereby, is still substantial, in that it provides a clear description of the contrast between the "combat one disease at a time" approach generally taken by geriatricians and the holistic "combat aging itself" approach favored by most biogerontologists.

As those readers familiar with my work will know, I view both such approaches as highly unlikely to deliver substantial postponement of age-related ill health in the remotely foreseeable future, but not for the reasons generally given by the proponents of the other approach. Geriatricians reject combating of "aging itself" because they don't generally view aging as a medical condition at all, but instead merely view chronological age as a risk factor for various types of ill health. Biogerontologists, conversely, reject the "one disease at a time" approach because they believe that there will always be something - the very same "aging itself," of course - that will be a source of exponentially accelerating ill health however many specifics are defeated.

The SENS perspective is that it is inaccurate and misleading to draw a sharp distinction between "aging itself" and the specific aspects of age-related ill health, first because where one draws that distinction is arbitrary - Are foam cells atherosclerosis yet, for example? Are fatty streaks? - and second because the lifelong changes that drive ill health, and thus hold the the only logical claim to be lumped under the term "aging," are themselves not aspects of any meaningful unitary process, but are instead relatively independent processes occurring as side-effects of different aspects of metabolism.

A REVIEW OF "THE SINGULARITY"
http://www.fightaging.org/archives/2012/10/a-review-of-the-singularity.php

A documentary film entitled The Singularity is the latest in a line of works from recent years to examine the near future of technology and its implications: a convergence of biotechnology, ever-increasing computing power, and molecular nanotechnology means that we will become capable of engineering ourselves to much the same degree as we presently choose to engineer our surroundings. Why would we stick with the flaky, error-prone, and short-lived evolved version of human biology when far better and more cost-effective replacements can be built? Here is a short review:

Doug Wolens' latest documentary captures the argument between the two sides. The Singularity takes the form of a series of intercut interviews, with animations illustrating various points ... Wolens' subjects include, unsurprisingly, people like Kurzweil himself, roboticist Cynthia Breazeal, and gerontologist Aubrey de Grey. But Wolens also interviews people not normally associated with the speculative edge of artificial intelligence and biomolecular engineering, such as Richard A. Clarke, the former chief counterterrorism advisor to the U.S. National Security Council, and the current U.S. secretary of defense, Leon Panetta.

While The Singularity doesn't cover a great deal of ground that's new to anyone already familiar with the concept, it does provide crisp snapshots of the current state of the debate and many of the main players.

NOT ALL LONGEVITY MANIPULATIONS PLAY NICE TOGETHER
http://www.fightaging.org/archives/2012/11/not-all-longevity-manipulations-play-nice-together.php

One of the pleasant aspects of the repair approach to intervention in aging, such as that proposed in the Strategies for Engineered Negligible Senescence (SENS), is that all distinct forms of repair therapy can reasonably be expected to complement one another. Undergo a procedure to fix mitochondrial damage or break down an AGE such as glucospane, for example, and you are better off. Undergo both therapies and you will gain a commensurately greater benefit.

Unfortunately, this expectation of complementary therapies is very much not the case when it comes to attempts to slow down aging by genetic, epigenetic, or other metabolic manipulation. Metabolism is enormously complex, and even the well-studied phenomenon of calorie restriction isn't yet fully understood in terms of how the machinery of genes, proteins, and controlling signals all ties together to increase life span and improve health. Varied methods of extending life by slowing aging often turn out to operate on different portions of the same mechanism, or to be harmful when used together even though they are beneficial on their own.

One thing often tried by research groups that discover a novel way of slowing aging in laboratory animals is to try out the new method in calorie restricted animals: will the effects on life span complement one another and thus lead to a greater extension of life than is the case for either method on its own? Few presently known genetic alterations or other methods of slowing aging produce more than a 30% life extension in mice, and the standing record is 60-70% for growth hormone deficient mice - so at this point in time, it seems unlikely that any new life span record will be set through slowing aging without employing some complementary combination of techniques.

That this hasn't yet happened suggests that we shouldn't hold out much hope for the next five to seven years - there has, after all, been a lot of experimentation in mice over the past decade, and especially since the record set using growth hormone deficient mice. Unfortunately purely negative results don't tend to be published as often as positive results, so it's not a straightforward matter to find out which combinations of the various known methods to slow aging in mice have been tried only to fail.

A POSSIBLE METABOLIC SIGNATURE OF BIOLOGICAL AGE IN MICE
http://www.fightaging.org/archives/2012/11/a-possible-metabolic-signature-of-biological-age-in-mice.php

A low-cost, reliable method of measuring biological age is greatly sought after by the research community. People and laboratory animals age at different rates - by which I mean that they accumulate damage and changes characteristic of aging at different rates. Thus two individuals of the same species and same chronological age might have different biological ages thanks to life style, environment, access to medicine, and so forth.

Some interventions, such as calorie restriction, can slow the pace at which an individual ages, but measuring this slowing is a challenging process. Biological age is a simple concept at the high level, but finding a quick and reliable way to actually measure it has yet to happen. Thus while researchers would like to have rapid answers as to how effective any given method of slowing aging might be, they must wait and run long-lasting studies. The bottom line measure for any slowing of aging is to wait for the individuals in question to live out their lives and thus measure by effect on life span. Even in short-lived mice this can require years and thus a great deal of money. In longer-lived animals, ourselves included, it is simply impractical to run the necessary studies.

When it comes to the forthcoming generation of therapies capable of limited rejuvenation - by repairing some of the damage that causes degenerative aging - the situation is much the same, as is the need for a quick and easy measure of biological age. A therapy that actually produces some degree of rejuvenation should make a laboratory animal biologically younger than peers with the same chronological age. But how to measure that change without employing the lengthy and expensive wait-and-see approach?

Given the present state of affairs, any quick measure of biological age will speed research, making it very much faster and cheaper to assess varied means of extending healthy life. Some experiments that would presently require a year or more could be conducted in a few weeks or months: apply the therapy and evaluate the resulting changes in measures of biological age.

Several lines of research look promising when it comes to yielding a way to reliably and consistently evaluate biological age. One involves measurement of DNA methylation levels, and despite initial setbacks it may yet prove possible to tease out a useful measure from changes in the dynamics of telomere length. There are others. Here, for example, is a recent paper in which researchers present a method based on measurement of metabolite levels.

DISCUSSION

The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!

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LATEST HEADLINES FROM FIGHT AGING!

INVESTIGATING THE MECHANISMS OF CELLULAR SENESCENCE
Friday, November 2, 2012
http://www.fightaging.org/archives/2012/11/investigating-the-mechanisms-of-cellular-senescence.php
Senescent cells are those that have left the cell cycle without being destroyed, either by the immune system or by one of the processes of programmed cell death. They remain active, however, exhibiting what is termed a senescence-associated secretory phenotype (SASP): these cells secrete all sorts of chemical signals that prove harmful to surrounding tissues and the body as a whole - through promotion of chronic inflammation, for example. The number of senescent cells in tissue grows with age, and this increase in numbers is one of the root causes of aging. Researchers have demonstrated benefits in mice through destroying senescent cells without harming other cells. Regular targeted destruction of senescent cells could be the basis for therapies that remove this contribution to degenerative aging. Any other approach would require understanding more about SASP and how to control or reverse the unpleasant effects of senescence - and here is an example of this sort of research, aimed at identifying controlling mechanisms with an eye to building therapies to reduce SASP: "With advancing age, senescent cells accumulate in tissues and the SASP-elicited proinflammatory state is believed to have a complex influence on age-related conditions. For example, two major SASP factors, IL-6 and IL-8, together with other SASP factors, attract immune cells to the tissue in which senescent cells reside; depending on the tissue context, this immune surveillance can promote processes such as wound healing, the resolution of fibrosis, and tumor regression. At the same time, SASP factors can compromise the integrity of the ECM, thus facilitating cancer cell migration. In addition, the systemic proinflammatory phenotype seen in the elderly is believed to affect a broad range of age-related pathologies, including diabetes, cancer, neurodegeneration and cardiovascular disease and contributes to an age-related decline of the adaptive immune system (immunosenescence). Despite the great potential impact of the SASP on the biology of senescence and aging, the mechanisms that regulate SASP are poorly understood. ... Here, we report the identification of NF90 as an RNA-binding protein that binds to numerous mRNAs encoding SASP factors (collectively named SASP mRNAs) and coordinately influences their post-transcriptional fate in a senescence-dependent manner. In young, early-passage, proliferating fibroblasts, high NF90 levels contributed to the repression of SASP factor production. This repression was elicited mainly via reduction in SASP factor translation ... By contrast, in senescent cells NF90 levels were markedly reduced, which allowed increased expression of numerous SASP factors. Our results are consistent with a role for NF90 as a coordinator of the inhibition of SASP factor production in early-passage, proliferating fibroblasts; in senescent cells, the lower levels of NF90 lead to SASP de-repression, permitting higher expression of SASP factors"

CREATING MYELIN-PRODUCING CELLS TO ORDER
Friday, November 2, 2012
http://www.fightaging.org/archives/2012/11/creating-myelin-producing-cells-to-order.php
Myelin sheaths the axons of nerve cells, but the integrity of this sheathing degrades with age. Transplants of neural stem cells can be used to encourage myelin formation, and researchers are exploring this approach as a therapy for conditions involving more profound myelin loss. There is always a demand in this sort of research for better and cheaper ways to obtain cells that have the desired effect. It is not trivial, for example, to isolate the right sort of neural stem cell, or establish a protocol for producing these cells from embryonic or induced pluripotent stem cells. A great deal of stem cell research these days involves the discovery of chemical signals, growth environments, and other necessary items to guide the growth of specific cell types. Here is an example for myelin-forming cells, which will no doubt contribute to the next round of research and development of cell therapies aimed at regrowth of myelin: "Researchers have unlocked the complex cellular mechanics that instruct specific brain cells to continue to divide. This discovery overcomes a significant technical hurdle to potential human stem cell therapies; ensuring that an abundant supply of cells is available to study and ultimately treat people with diseases. "One of the major factors that will determine the viability of stem cell therapies is access to a safe and reliable supply of cells. This study demonstrates that - in the case of certain populations of brain cells - we now understand the cell biology and the mechanisms necessary to control cell division and generate an almost endless supply of cells." The study focuses on cells called glial progenitor cells (GPCs) that are found in the white matter of the human brain. These stem cells give rise to two cells found in the central nervous system: oligodendrocytes, which produce myelin, the fatty tissue that insulates the connections between cells; and astrocytes, cells that are critical to the health and signaling function of oligodendrocytes as well as neurons. One of the barriers to moving forward with human treatments for myelin disease has been the difficulty of creating a plentiful supply of necessary cells, in this case GPCs. Scientists have been successful at getting these cells to divide and multiply in the lab, but only for limited periods of time, resulting in the generation of limited numbers of usable cells. ... Overcoming this problem required that [researchers] master the precise chemical symphony that occurs within stem cells, and which instructs them when to divide and multiply, and when to stop this process and become oligodendrocytes and astrocytes."

PROMOTING REMYELINATION BY BLOCKING HYALURONIDASE
Thursday, November 1, 2012
http://www.fightaging.org/archives/2012/11/promoting-remyelination-by-blocking-hyaluronidase.php
Myelin is the material sheathing axons in nerve cells. A number of conditions involve loss of myelin, such as multiple sclerosis (MS), but loss of myelin integrity occurs to a lesser degree for all of us as we age, and is thought to contribute to the characteristic cognitive decline of later years. Thus research into ways to regenerate myelin sheathing has broad potential application and is worth keeping an eye on: "We have identified a whole new target for drugs that might promote repair of the damaged brain in any disorder in which demyelination occurs. Any kind of therapy that can promote remyelination could be an absolute life-changer for the millions of people suffering from MS and other related disorders. In 2005, [researchers] discovered that a sugar molecule, called hyaluronic acid, accumulates in areas of damage in the brains of humans and animals with demyelinating brain and spinal cord lesions. Their findings at the time [suggested] that hyaluronic acid itself prevented remyelination by preventing cells that form myelin from differentiating in areas of brain damage. The new study shows that the hyaluronic acid itself does not prevent the differentiation of myelin-forming cells. Rather, breakdown products generated by a specific enzyme that chews up hyaluronic acid - called a hyaluronidase - contribute to the remyelination failure. This enzyme is highly elevated in MS patient brain lesions and in the nervous systems of animals with an MS-like disease. The research team [found] that by blocking hyaluronidase activity, they could promote myelin-forming cell differentiation and remyelination in the mice with the MS-like disease. Most significantly, the drug that blocked hyaluronidase activity led to improved nerve cell function. The next step is to develop drugs that specifically target this enzyme."

DEEPENING THE PUZZLE
Thursday, November 1, 2012
http://www.fightaging.org/archives/2012/11/deepening-the-puzzle.php
One of the many oddities in the way in which the public at large approaches aging is captured by the existence of a thriving "anti-aging" marketplace, full of people selling fake silver bullets and fraudulent potions, alongside a pervasive lack of interest in scientific research aimed at extending human life, and outright rejection of the goal of extending human life in many quarters. One would think that a market claiming to sell ways to turn back the clock - or at least disguise the fact that the clock is ticking - could not thrive without interest in the supposed goal of their products, yet there is little manifestation of that interest when it comes to actually, really doing something about slowing or reversing aging, rather than just throwing money at faking it. Here is another data point to add to the existence of the "anti-aging" marketplace when trying to understand what is going on here: "A study [finds] that in 2011 spending on medications for aging conditions - such as mental alertness, sexual dysfunction, menopause, aging skin and hair loss - ranked third in annual prescription-drug costs of the commercially insured, surpassed only by the cost of treating diabetes and high cholesterol. The research found that among these insured individuals use of drugs to treat the physical impact associated with normal aging was up 18.5 percent and costs increased nearly 46 percent from 2006 to 2011. Increased use of these drugs was even more pronounced for the Medicare population (age 65+), up 32 percent from 2007 to 2011. The largest utilization jump among Medicare beneficiaries was from 2010 to 2011, up more than 13 percent and outpacing increases in the use of drugs for diabetes, high cholesterol and high blood pressure combined."

CONSIDERING ANTAGONISTIC PLEIOTROPY
Wednesday, October 31, 2012
http://www.fightaging.org/archives/2012/10/considering-antagonistic-pleiotropy.php
Antagonistic pleiotropy describes a situation in which a gene provides both benefit and drawback under different circumstances. In evolutionary considerations of aging the usual context for this situation is that a gene is selected because it provides competitive advantages in youth, when reproduction is taking place, and then becomes harmful later in life when evolutionary pressure is much reduced. Here researchers take a measure of the prevalence of this phenomenon in yeast: "The genes responsible for inherited diseases are clearly bad for us, so why hasn't evolution, over time, weeded them out and eliminated them from the human genome altogether? Part of the reason seems to be that genes that can harm us at one stage of our lives are necessary and beneficial to us at other points in our development. [Researchers now] report that antagonistic pleiotropy is very common in yeast, a single-celled organism used by scientists to provide insights about genetics and cell biology. "In any given environment, yeast expresses hundreds of genes that harm rather than benefit the organism, demonstrating widespread antagonistic pleiotropy. The surprising finding is the sheer number of such genes in the yeast genome that have such properties. From our yeast data we can predict that humans should have even more antagonistic pleiotropy than yeast." Yeast has about 6,000 genes, about 1,000 of which are essential - eliminate any of them and the organism dies. [Researchers] worked with a set of 5,000 laboratory strains of yeast in which one non-essential gene had been deleted from each strain. [They] grew all 5,000 strains together in a single test tube and compared the growth rates of each strain. This side-by-side comparison allowed them to determine which genes were beneficial (increased growth rate) and which ones were harmful (decreased growth rate) under the six environmental conditions. The researchers found that for each of the six conditions, on average, the yeasts expressed about 300 genes that slowed their growth and were therefore classified as harmful. Deleting those genes resulted in more rapid growth. But many of the genes that were harmful under one set of environmental conditions proved to be beneficial under another, demonstrating widespread antagonistic pleiotropy."

MORE MITOCHONDRIALLY TARGETED ANTIOXIDANT RESULTS
Wednesday, October 31, 2012
http://www.fightaging.org/archives/2012/10/more-mitochondrially-targeted-antioxidant-results.php
The mitochondria in our cells generate damaging oxidative byproducts as a result of their operation, and that is the first step in a long process that contributes to degenerative aging. Researchers have shown that localizing antioxidants to the mitochondria can reduce this damage and thus modestly slow aging and extend life in laboratory animals. Most antioxidants do not find their way to mitochondria, however, and have no effect on long term health or aging. Thus there has been some interest in recent years in designing compounds that do localize to mitochondria. One research group works on the mitochondrially targeted antioxidant SkQ1 and related compounds, and these scientists continue to conduct a range of studies in laboratory animals: "Here we evaluated the effect of the mitochondria-targeted antioxidant SkQ1 on markers of aging in the old OXYS rats, a unique animal model of accelerated senescence and age-related diseases, as well as normal Wistar rats. ... we compared effects of SkQ1 [on] age-dependent decline in blood levels of leukocytes, growth hormone (GH), insulin-like growth factor-1 (IGF-1), testosterone, dehydroepiandrosterone (DHEA). Our results indicate that when started late in life, treatment with SkQ1 [not] only prevented age-associated hormonal alterations but partially reversed them. These results suggest that supplementation with low doses of SkQ1, even in chronologically and biologically aged subjects seem to be a promising strategy to maintain health and retard the aging process."

EXERCISE IMPROVES COGNITIVE FUNCTION
Tuesday, October 30, 2012
http://www.fightaging.org/archives/2012/10/exercise-improves-cognitive-function.php
Following on from a recent post on exercise and the aging brain, here is yet another study to show that improvements in cognitive function can be brought about by regular exercise and its consequent effects on body composition, metabolism, and other line items. Use it or lose it, as they say: "A regular exercise routine can make you fitter than ever - mentally fit. In a new study, previously sedentary adults were put through four months of high-intensity interval training. At the end, their cognitive functions - the ability to think, recall and make quick decisions - had improved significantly. Blood flow to the brain increases during exercise. The more fit you are, the more that increases. The pilot [study] looked at adults, average age 49, who were overweight and inactive. [Researchers] measured their cognitive function with neuropsychological testing, as well as their body composition, blood flow to the brain, cardiac output and their maximum ability to tolerate exercise. The subjects then began a twice-a-week routine with an exercise bike and circuit weight training. After four months - not surprising - their weight, body mass index, fat mass and waist circumference were all significantly lower. Meanwhile, their capacity to exercise (measured by VO2 max) was up 15 per cent. Most exciting, [cognitive function] had also increased, based on follow-up testing. These improvements were proportional to the changes in exercise capacity and body weight. Essentially, the more people could exercise, and the more weight they lost, the sharper they became."

CARTILAGE FROM INDUCED PLURIPOTENT STEM CELLS
Tuesday, October 30, 2012
http://www.fightaging.org/archives/2012/10/cartilage-from-induced-pluripotent-stem-cells.php
Induced pluripotent stem cells (IPSCs) are reprogrammed cells - such as those obtained from a skin sample - and are similar to embryonic stem cells in the sense that it should be possible to generate any form of cell from them. They offer the capacity to easily generate unlimited numbers of patient-specific cells, or build tissue and organ structures from scratch. Each type of tissue or cell requires different chemical instructions, growth environments, and technical strategies to be discovered and then refined, however - and there are a few hundred types of cell in the human body. Here, researchers report on progress on generating cartilage from IPSCs: "[Researchers have] engineered cartilage from induced pluripotent stem cells that were successfully grown and sorted for use in tissue repair and studies into cartilage injury and osteoarthritis. ... [This] suggests that induced pluripotent stem cells, or iPSCs, may be a viable source of patient-specific articular cartilage tissue. Articular cartilage is the shock absorber tissue in joints that makes it possible to walk, climb stairs, jump and perform daily activities without pain. But ordinary wear-and-tear or an injury can diminish its effectiveness and progress to osteoarthritis. Because articular cartilage has a poor capacity for repair, damage and osteoarthritis are leading causes of impairment in older people and often requires joint replacement. One challenge the researchers sought to overcome was developing a uniformly differentiated population of chondrocytes, cells that produce collagen and maintain cartilage, while culling other types of cells that the powerful iPSCs could form. To achieve that, the researchers induced chondrocyte differentiation in iPSCs derived from adult mouse fibroblasts by treating cultures with a growth medium. They also tailored the cells to express green fluorescent protein only when the cells successfully became chondrocytes. As the iPSCs differentiated, the chondrocyte cells that glowed with the green fluorescent protein were easily identified and sorted from the undesired cells. The tailored cells also produced greater amounts of cartilage components, including collagen, and showed the characteristic stiffness of native cartilage, suggesting they would work well repairing cartilage defects in the body."

COMMENTING ON THE UTILITY OF AGE-BREAKERS
Monday, October 29, 2012
http://www.fightaging.org/archives/2012/10/commenting-on-the-utility-of-age-breakers.php
Advanced glycation endproducts (AGEs) are a class of undesirable metabolic byproduct. The level of AGEs in the body rises with age and causes harm through a variety of mechanisms, such as by excessively triggering certain cellular receptors or gluing together pieces of protein machinery by forming crosslinks, thus preventing them from carrying out their proper function. In past years a number of efforts were undertaken to develop drugs that can safely break down at least some forms of AGE. Early promising candidates in laboratory animals failed in humans because the most harmful forms of AGE are different for short-lived versus long-lived mammals - so what benefits a rat isn't of much utility for we humans. So far little progress has been made towards a therapy for the dominant type of AGE in humans, glucosepane, sad to say, as there is comparatively little interest in this field of research. Here is a recent paper commenting on the potential utility of AGE-beaker drugs: "Reducing sugars can react nonenzymatically with the amino groups of proteins to form Amadori products. These early glycation products undergo further complex reactions, such as rearrangement, dehydration, and condensation, to become irreversibly cross-linked, heterogeneous fluorescent derivatives, termed advanced glycation end products (AGEs). The formation and accumulation of AGEs have been known to progress in a normal aging process and at an accelerated rate under diabetes. Nonenzymatic glycation and cross-linking of proteins not only leads to an increase in vascular and myocardial stiffness, but also deteriorates structural integrity and physiological function of multiple organ systems. Furthermore, there is accumulating evidence that interaction of AGEs with a cell-surface receptor, receptor for AGEs (RAGE), elicits oxidative stress generation and subsequently evokes inflammatory, thrombogenic, and fibrotic reactions, thereby being involved in atherosclerosis, diabetic microvascular complications, erectile dysfunction, and pancreatic β-cell apoptosis. Recently, AGE cross-link breakers have been discovered. Therefore, removal of the preexisting AGEs by the breakers has emerged as a novel therapeutic approach to various types of diseases that develop with aging. This article summarizes the potential clinical utility of AGE cross-link breakers in the prevention and management of age- and diabetes-associated disorders."

HISTONE DEACETYLASE INHIBITORS PRESERVE FUNCTION IN AGING AXONS
Monday, October 29, 2012
http://www.fightaging.org/archives/2012/10/histone-deacetylase-inhibitors-preserve-function-in-aging-axons.php
Epigenetics has become an important component of the study of aging: how genetic regulation changes in response to cellular and molecular damage. One of the mechanisms of this regulation is the acetylation of histones: researchers evaluate the way in which this changes with aging, leading to changes in gene expression, altered levels of key protein machinery in tissues, and changes in the operation of biological systems in the body. Some research groups are in search of epigenetic alterations that might be reversed through therapy to produce beneficial effects: "Aging increases the vulnerability of aging white matter to ischemic injury. Histone deacetylase (HDAC) inhibitors preserve young adult white matter structure and function during ischemia by conserving ATP and reducing excitotoxicity. In isolated optic nerve from 12-month-old mice, deprived of oxygen and glucose, we show that pan- and Class I-specific HDAC inhibitors promote functional recovery of axons. This protection correlates with preservation of axonal mitochondria. The cellular expression of HDAC 3 in the central nervous system (CNS), and HDAC 2 in optic nerve considerably changed with age, expanding to more cytoplasmic domains from nuclear compartments, suggesting that changes in glial cell protein acetylation may confer protection to aging axons. Our results indicate that manipulation of HDAC activities in glial cells may have a universal potential for stroke therapy across age groups."

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Posted 11 November 2012 - 02:18 PM

FIGHT AGING! NEWSLETTER
November 12th 2012

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

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CONTENT

- More Researchers Should Talk About Bold Goals in Human Longevity
- The Greatest Instance of the Broken Window Fallacy
- Regenerative Medicine Timelines from Anthony Atala
- Many Longevity Manipulations Appear to Work Via Insulin Signaling
- Discussion
- Latest Headlines from Fight Aging!
    - Work on Better Understanding Oxidative Damage in Aging
    - Towards Tissue Engineered Large Intestines
    - Lower Vitamin D Levels Correlated to Human Longevity
    - Hypothesizing a Link Between Taste Receptors and Longevity
    - Some Visible Signs of Aging Reflect Biological Age
    - Quantifying Gains in Life Expectancy Correlated With Exercise
    - Compression of Morbidity Through Physical Activity
    - The Mechanism of Blind Mole Rat Cancer Immunity
    - Lifestyle Choices and the Pace of Age-Related Memory Decline
    - Another Example of a Mitochondrially Targeted Antioxidant

MORE RESEARCHERS SHOULD TALK ABOUT BOLD GOALS IN HUMAN LONGEVITY
http://www.fightaging.org/archives/2012/11/more-researchers-should-speak-openly-of-bold-goals-in-extending-the-healthy-human-lifespan.php

It's been a good few years since Aubrey de Grey first put forward his view of the political and social processes that inhibit progress in longevity science: the short summary is that a sort of logjam is created and sustained by the silence of researchers. When scientists don't talk openly about bold goals in their field then there can be no broad public support for funding of those goals, and conservative funding organizations will assign resources to other projects. There are many players in the grand game of scientific progress, but it ultimately falls to the researchers to define the bounds of the possible in the public eye, and it is their pronouncements - or lack thereof - that set the limits of what can be easily funded.

When researchers sit back and say nothing, or restrict themselves to visions of incremental gain when far more is possible, then progress suffers. There are many reasons as to why members of the aging research community were for decades very reluctant to talk about extending human life at all: fear of being associated with the fraudulent "anti-aging" marketplace, the normal reluctance to place a flag far out on the field even in an age of radical change, and so forth. Until very recently, the ethos of aging research was observation and little more, amounting to a stifling of research into extending the healthy human life span. Who can say how much of an opportunity was lost? Certainly the chance to build an aging research community with the same breadth and eagerness to produce measurable results as the cancer research community; that opportunity was squandered, and that task still lies ahead.

The old attitudes have largely thawed, however, in the face of a combination of persistent advocacy (such as that of the Methuselah Foundation and supporters) and many demonstrations of extended healthy life in laboratory animals. It has been welcome, these past few years, to see more researchers willing to step up to the plate to talk in public about radical life extension and pushing the boundaries of what can be achieved through biotechnology.

THE GREATEST INSTANCE OF THE BROKEN WINDOW FALLACY
http://www.fightaging.org/archives/2012/11/the-greatest-instance-of-the-broken-window-fallacy.php

We as a species are defined by our ability to create: given time we will build new wonders from all the matter we can lay our hands on. The true legacy of every generation is the new advances they create in technology - that progress in creation is the only thing likely be recalled in the distant future. Yet despite a history of creation piled upon creation, the urge to destroy is also strong; a certain love of destruction seems a hardwired part of human nature. See the broken window fallacy, for example, which is the 19th century formulation of an ancient truth: that people look upon the consequences of destruction selectively, and call it beneficial.

"Suppose it cost six francs to repair the [window broken by a child], and you say that the accident brings six francs to the glazier's trade - that it encourages that trade to the amount of six francs - I grant it; I have not a word to say against it; you reason justly. The glazier comes, performs his task, receives his six francs, rubs his hands, and, in his heart, blesses the careless child. All this is that which is seen. ... It is not seen that as [the owner of the window] has spent six francs upon one thing, he cannot spend them upon another. It is not seen that if he had not had a window to replace, he would, perhaps, have replaced his old shoes, or added another book to his library. In short, he would have employed his six francs in some way, which this accident has prevented."

The lesson of the broken window is that destruction is never beneficial. It is a cost, and that cost must be paid at the expense of some other benefit. This lesson is needed: the broken window fallacy was widespread two centuries ago and remains so now. You will hear commentary after every natural disaster suggesting that the resulting expenditures on repair will benefit the economy, for example.

What is the greatest ongoing disaster, the cause of the greatest destruction? The answer is degenerative aging. Aging destroys human capital: knowledge, skills, talents, the ability to work, the ability to create. It does so at a ferocious rate, a hundred thousand lives a day, and all that they might have accomplished if not struck down. If translated to a dollar amount, the cost is staggering - even shifts in life expectancy have gargantuan value. And why shouldn't they? Time spent alive and active is the basis of all wealth.

It is unfortunate, but many people advocate for the continuation of aging, for relinquishment of efforts to build medicines to extend health life. Among these are people who welcome aging and death because to their eyes it gives a young person the chance to step into a role vacated by an older person. This is another form of the broken window, however: the advocate for aging looks only at the young person, and dismisses what the older person might have done were they not removed from the picture by death or disability. So too, any apologism for aging based on clearing out the established figures because it provides a greater opportunity for younger people to repeat the same steps, follow the same paths, relearn the same skills, redo the same tasks ... these arguments are the broken window writ large.

Vast wealth and opportunity bleeds into the abyss on a daily basis, destroyed because the people who embody that wealth and opportunity decay and die. We would all be wealthier by far given the medical means to prevent these losses. In your thoughts on aging, don't ignore the vast invisible costs - the work never accomplished, the wonders never created, because those who could have done so never had the chance. The enforced absence of the age-damaged, the frail, the disabled, and the dead is in and of itself a form of damage; the loss of their skills and knowledge is something that must be repaired. That requires work and resources that might have gone to new creations, rather than catching up from loss.

So this continues, and the perpetual devotion of resources to repair and recover from the losses of death and disability is a great ball and chain shackled to our ability to create progress. But most people don't think of at all - it is invisible to them. Nonetheless, the costs of aging that we labor under are so vast that the introduction of ways to rejuvenate the old will lead to an blossoming of wealth and progress the likes of which has never before been seen.

REGENERATIVE MEDICINE TIMELINES FROM ATHONY ATALA
http://www.fightaging.org/archives/2012/11/regenerative-medicine-timelines-from-anthony-atala.php

Anthony Atala is one of the present luminaries of tissue engineering, or at least that part of the field focused on building replacement organs and pseudo-organs - the latter being tissue structures that are not exactly the same as what they replace, but still get the job done, such as the substitute bladder tissue manufactured by Tengion. Atala is also on the SENS Foundation research advisory board, and so can be seen to look favorably on the agenda of engineering longer healthy human life spans.

I notice that a recent article has Atala giving some thoughts on timelines for organ regrowth, which you might compare to similar thoughts from another figure in the field, and to speculative timelines for the use of animal organs, such as those grown in engineered chimeras. Researchers are usually fairly reticent to put times and timelines on the table in public, for all the obvious reasons, so I think it worth taking note when they do:

Right now, more than 116,000 people are on the U.S. organ transplant waiting list. But what if they could just regrow their own livers, hearts, and kidneys, even 3-D print them? Anthony Atala, the director of the Wake Forest Institute for Regenerative Medicine, is working to make that a reality. Speaking today at Ciudad de las Ideas, an annual conference about big ideas held in Puebla, Mexico, and sponsored by Grupo Salinas, Atala asked, "If a salamander can do it, why can't we?"

So how long until regenerative medicine can make the agonizingly long transplant waiting list a thing of the past? Within the next decade, Atala predicts, "we will see partial replacements of [some] organs - not the entire replacement, but many times that's all we need." Of course, [the] regulatory process will have to be carried out before there is widespread use of regenerated organs. Atala notes that the average drug takes 15.5 years to be approved in the United States, and regenerative medicine is neither drug nor medical device, but a combination thereof, which makes approval even more complicated.

MANY LONGEVITY MANIPULATIONS APPEAR TO WORK VIA INSULIN SIGNALING
http://www.fightaging.org/archives/2012/11/many-longevity-manipulations-seem-to-work-through-insulin-signaling.php

There are many ways to manipulate a single protein or gene in lower animals in order to modestly slow aging and extend life, and new ones are discovered on a regular basis. This process of discovery tends to proceed more rapidly for short-lived laboratory species like flies and nematode worms, where evaluating alterations in life span requires less time and fewer resources. Thus more and more diverse studies can be conducted within a given budget in comparison to, say, work in mice.

So: genes can be mutated via genetic engineering, or removed, or doubled up. An individual protein produced from a genetic blueprint can be created more rapidly so as to boost its presence in cells or its production dialed back to lower levels. This is not an exhaustive list. Any of these possibilities can be targeted to specific cell types or portions of anatomy, if so desired. There are far more combinations to tinker with than the research community has capacity for, so researchers tend to work in areas that have already demonstrated some promise, or where the maps of function and interaction between protein machinery are better understood.

Even seemingly trivial functions in the metabolism of lower animals are enormously complex in their details. Anything of the subsystems involved in how food is converted into something that cells can use for energy, for example, or how body temperature is regulated. These evolved systems make use of overlapping feedback loops that might involve dozens or hundreds of proteins, and any given protein might be promiscuously involved in several quite different systems; if our biology teaches us anything it is that evolution favors the reuse of existing materials. A great example is p53, which shows up as a player in many of the central, crucial processes of cellular biology.

Alter the amount of a protein in circulation and that ripples out through all the networks of protein machinery that it is in involved with. You can't flip any switch in isolation. This diversity of components in every biological system is one of the reasons why there are seemingly so many different ways to alter life span in lower animals. There might be only a few important networks of proteins tightly coupled to determination of life span, such as that involved in the calorie restriction response, but within each network there are possibly dozens of proteins that can be tweaked to produce some form of beneficial effect on the whole - and of course varying degrees of side-effects.

So when researchers uncover yet another life extending methodology, they must then chase cause and effect through networks of interacting protein machineries until they get to something that looks familiar - which they usually do. One very well studied area is the network of insulin and insulin-like growth factor (IGF) signaling, and as is the case for increased autophagy, many diverse longevity enhancing alterations touch on this machinery.

DISCUSSION

The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!

______________________________

LATEST HEADLINES FROM FIGHT AGING!

WORK ON BETTER UNDERSTANDING OXIDATIVE DAMAGE IN AGING
Friday, November 9, 2012
http://www.fightaging.org/archives/2012/11/work-on-better-understanding-oxidative-damage-in-aging.php
Oxidative stress is a term you'll see a lot when reading the literature of aging research. The more reactive oxidant compounds there are in a cell, the more they will react with important proteins, modifying them and thus causing cellular machinery to run awry or require repair. Aging is characterized by rising levels of oxidative stress, caused by things such as increased presence of metabolic byproducts that are ever more inefficiently removed, accumulating damage to mitochondria, and so forth. This is still something of a high level picture, however, and there is still a lot of room left for researchers to expand the understanding of how exactly oxidative damage progresses, or how it contributes to specific manifestations of aging, such as increased cellular senescence. Hence we see work of this nature: "Protein damage mediated by oxidation, protein adducts formation with advanced glycated end products and with products of lipid peroxidation, has been implicated during aging and age-related diseases, such as neurodegenerative diseases. Increased protein modification has also been described upon replicative senescence of human fibroblasts, a valid model for studying aging in vitro. However, the mechanisms by which these modified proteins could impact on the development of the senescent phenotype and the pathogenesis of age-related diseases remain elusive. In this study, we performed in silico approaches to evidence molecular actors and cellular pathways affected by these damaged proteins. A database of proteins modified by carbonylation, glycation, and lipid peroxidation products during aging and age-related diseases was built and compared to those proteins identified during cellular replicative senescence in vitro. Common cellular pathways evidenced by enzymes involved in intermediate metabolism were found to be targeted by these modifications, although different tissues have been examined. ... An important outcome of the present study is that several enzymes that catalyze intermediate metabolism, such as glycolysis, gluconeogenesis, the citrate cycle, and fatty acid metabolism have been found to be modified. These results indicate a potential effect of protein modification on the impairment of cellular energy metabolism. Future studies should address this important issue by combining metabolomics and targeted proteomic analysis during cellular and organismal aging."

TOWARDS TISSUE ENGINEERED LARGE INTESTINES
Friday, November 9, 2012
http://www.fightaging.org/archives/2012/11/towards-tissue-engineered-large-intestines.php
Last year a research group demonstrated that they could build tissue engineered sections of small intestine in mice. That same group is also working on producing structures of the large intestine using human cells, and here is an update on their progress: "[Researchers] have for the first time grown tissue-engineered human large intestine. ... Our aim is exact replacement of the tissue that is lacking. There are many important functions of the large intestine, and we can partially compensate for that loss through other medical advances, but there are still patients for whom this technology might be revolutionary if we can cross the translational hurdles. This is one of the advances that brings us toward our goal. The human tissue-engineered colon includes all of the required specialized cell types that are found in human large intestine. The research team grew the tissue-engineered large intestine from specific groups of cells, called organoid units that were derived from intestinal tissue normally discarded after surgery. The organoid units grew on a biodegradable scaffold. After 4 weeks, the human tissue-engineered colon contained the differentiated cell types required in the functioning colon, and included other key components including smooth muscle, ganglion cells, and components of the stem cell niche. ... This proof-of-concept experiment is an important step in transitioning tissue-engineered colon to human therapy."

LOWER VITAMIN D LEVELS CORRELATED TO HUMAN LONGEVITY
Thursday, November 8, 2012
http://www.fightaging.org/archives/2012/11/lower-vitamin-d-levels-correlated-to-human-longevity.php
This research result is noted because it stands in opposition to the present consensus on vitamin D and long term health in humans; the evidence to date supports a correlation between higher levels of vitamin D, a lower risk of age-related disease, and a longer life expectancy. But here we see the opposite result. This sort of outright contradiction is usually indicative of some greater complexity under the hood yet to be outlined and understood - and there's certainly no shortage of complexity in metabolism: "Low levels of 25(OH) vitamin D are associated with various age-related diseases and mortality, but causality has not been determined. We investigated vitamin D levels in the offspring of nonagenarians who had at least one nonagenarian sibling; these offspring have a lower prevalence of age-related diseases and a higher propensity to reach old age compared with their partners. We [assessed] vitamin D levels, [dietary] vitamin D intake and single nucleotide polymorphisms (SNPs) associated with vitamin D levels. We included offspring (n = 1038) of nonagenarians who had at least one nonagenarian sibling, and the offsprings' partners (n = 461; controls) from the Leiden Longevity Study. The offspring had significantly lower levels of vitamin D (64.3 nmol/L) compared with controls (68.4 nmol/L), independent of possible confounding factors. ... Compared with controls, the offspring of nonagenarians who had at least one nonagenarian sibling had a reduced frequency of a common variant in the CYP2R1 gene, which predisposes people to high vitamin D levels; they also had lower levels of vitamin D that persisted over the 2 most prevalent genotypes. These results cast doubt on the causal nature of previously reported associations between low levels of vitamin D and age-related diseases and mortality."

HYPOTHESIZING A LINK BETWEEN TASTE RECEPTORS AND LONGEVITY
Thursday, November 8, 2012
http://www.fightaging.org/archives/2012/11/hypothesizing-a-link-between-taste-receptors-and-longevity.php
Since calorie intake has a comparatively large impact on natural variations in life expectancy, any genetic difference that systematically reduces calorie intake in some way should be correlated with increased longevity. So how about differences in the genes that determine taste? Here researchers search for signs of that correlation: "Several studies have shown that genetic factors account for 25% of the variation in human life span. On the basis of published molecular, genetic and epidemiological data, we hypothesized that genetic polymorphisms of taste receptors, which modulate food preferences but are also expressed in a number of organs and regulate food absorption processing and metabolism, could modulate the aging process. Using a tagging approach, we investigated the possible associations between longevity and the common genetic variation at the three bitter taste receptor gene clusters on chromosomes 5, 7 and 12 in a population of 941 individuals ranging in age from 20 to 106 years from the South of Italy. We found that one polymorphism, rs978739, situated 212 bp upstream of the TAS2R16 gene, shows a statistically significant association with longevity. In particular, the frequency of A/A homozygotes increases gradually from 35% in subjects aged 20 to 70 up to 55% in centenarians. These data provide suggestive evidence on the possible correlation between human longevity and taste genetics." Given the broad role of this gene, the correlation with longevity may or may not have anything to do with a tendency to reduce calorie intake through differences in food preference.

SOME VISIBLE SIGNS OF AGING REFLECT BIOLOGICAL AGE
Wednesday, November 7, 2012
http://www.fightaging.org/archives/2012/11/some-visible-signs-of-aging-reflect-biological-age.php
As one might expect, some of the easily measurable, more visible signs of aging tend to reflect a correspondingly greater risk of age-related conditions. Aging is a body-wide process, after all. Different people age at modestly different rates, predominantly due to lifestyle choices involving diet and exercise these days, now that the burden of infectious disease is greatly reduced. Genetic differences do contribute to some degree, but appear to be more important in survival at old age. The aim of any meaningful advance in longevity science is to make all of these natural differences irrelevant, washed out by the benefits of therapies that can slow or reverse various aspects of degenerative aging: "In a new study, those who had three to four aging signs - receding hairline at the temples, baldness at the head's crown, earlobe crease, or yellow fatty deposits around the eyelid (xanthelasmata) - had a 57 percent increased risk for heart attack and a 39 percent increased risk for heart disease. ... "The visible signs of aging reflect physiologic or biological age, not chronological age, and are independent of chronological age." Researchers analyzed 10,885 participants 40 years and older (45 percent women) in the Copenhagen Heart Study. Of these, 7,537 had frontoparietal baldness (receding hairline at the temples), 3,938 had crown top baldness, 3,405 had earlobe crease, and 678 had fatty deposits around the eye. In 35 years of follow-up, 3,401 participants developed heart disease and 1,708 had a heart attack. Individually and combined, these signs predicted heart attack and heart disease independent of traditional risk factors. Fatty deposits around the eye were the strongest individual predictor of both heart attack and heart disease. Heart attack and heart disease risk increased with each additional sign of aging in all age groups and among men and women. The highest risk was for those in their 70s and those with multiple signs of aging."

QUANTIFYING GAINS IN LIFE EXPECTANCY CORRELATED WITH EXERCISE
Wednesday, November 7, 2012
http://www.fightaging.org/archives/2012/11/quantifying-gains-in-life-expectancy-correlated-with-exercise.php
In recent years a number of studies have tried to put numbers to the gains in life expectancy that might accompany exercise. Here is another: "In pooled data from six prospective cohort studies, the researchers examined associations of leisure-time physical activity of a moderate to vigorous intensity with mortality. They analyzed data from more than 650,000 subjects and followed subjects for an average of ten years - analyzing over 82,000 deaths. Participation in a low level of leisure time physical activity of moderate to vigorous intensity, comparable to up to 75 min of brisk walking per week, was associated with a 19 percent reduced risk of mortality compared to no such activity. Assuming a causal relationship, which is not specifically demonstrated in this research, this level of activity would confer a 1.8 year gain in life expectancy after age 40, compared with no activity. For those who did the equivalent to 150 min of brisk walking per week - the basic amount of physical activity currently recommended by the federal government - the gain in life expectancy was 3.4 years. Participants faring best were those who were both normal weight and active: among normal weight persons who were active at the level recommended by the federal government, researchers observed a gain in life expectancy of 7.2 years, compared to those with a BMI of 35 or more who did no leisure time physical activity." You might compare these results to those obtained from a study of highly trained athletes and work examining jogging and life expectancy.

COMPRESSION OF MORBIDITY THROUGH PHYSICAL ACTIVITY
Tuesday, November 6, 2012
http://www.fightaging.org/archives/2012/11/compression-of-morbidity-through-physical-activity.php
Compression of morbidity is a hypothesis suggesting that advances in medical science are causing, or will cause, a compression of the terminal period of frailty, illness, and disability at the end of life, squeezing it into an ever-shorter fraction of the overall human life span. In colloquial use compression of morbidity is often spoken of as a practical goal by medical researchers who do not wish to talk openly about extending human life for political or funding reasons. There is data to support the existence of compression of morbidity with respect to the effects of lifestyle choices on longevity, such as exercise. When it comes to advances in medical science, however, it seems unlikely that gains in life expectancy will forever lag behind gains in health. Consider aging in terms of accumulated damage, for example: if we find ways to repair that damage, then the overall life expectancy will increase, just as it does for any complex machine that is better maintained. In any case, here is an example of present data supporting a compression of morbidity through increased physical activity: ""Active aging" connotes a radically nontraditional paradigm of aging which posits possible improvement in health despite increasing longevity. The new paradigm is based upon postponing functional declines more than mortality declines and compressing morbidity into a shorter period later in life. This paradigm (Compression of Morbidity) contrasts with the old, where increasing longevity inevitably leads to increasing morbidity. We have focused our research on controlled longitudinal studies of aging. The Runners and Community Controls study began at age 58 in 1984 and the Health Risk Cohorts study at age 70 in 1986. We noted that disability was postponed by 14 to 16 years in vigorous exercisers compared with controls and postponed by 10 years in low-risk cohorts compared with higher risk. Mortality was also postponed, but too few persons had died for valid comparison of mortality and morbidity. With the new data presented here, age at death at 30% mortality is postponed by 7 years in Runners and age at death at 50% (median) mortality by 3.3 years compared to controls. Postponement of disability is more than double that of mortality in both studies. These differences increase over time, occur in all subgroups, and persist after statistical adjustment."

THE MECHANISM OF BLIND MOLE RAT CANCER IMMUNITY
Tuesday, November 6, 2012
http://www.fightaging.org/archives/2012/11/the-mechanism-of-blind-mole-rat-cancer-immunity.php
Blind mole rats, like naked mole rats, do not appear to suffer from cancer - an aspect of their biology that probably drives more research interest at the moment than their exceptional longevity. The cancer suppression mechanism in naked mole rats has been explored in recent years, but here researchers discover that blind mole rats have evolved a different method of achieving the same end: "Blind mole rats and naked mole rats - both subterranean rodents with long life spans - are the only mammals never known to develop cancer. Three years ago, [researchers] determined the anti-cancer mechanism in the naked mole rat. Their research found that a specific gene - p16 - makes the cancerous cells in naked mole rats hypersensitive to overcrowding, and stops them from proliferating when too many crowd together. "We expected blind mole rats to have a similar mechanism for stopping the spread of cancerous cells. Instead, we discovered they've evolved their own mechanism." [The researchers] made their discovery by isolating cells from blind mole rats and forcing them to proliferate in culture beyond what occurs in the animal. After dividing approximately 15-20 times, all of the cells in the culture dish died rapidly. The researchers determined that the rapid death occurred because the cells recognized their pre-cancerous state and began secreting a suicidal protein, called interferon beta. The precancerous cells died by a mechanism which kills both abnormal cells and their neighbors, resulting in a "clean sweep." [The next step is] to find out exactly what triggers the secretion of interferon beta after cancerous cells begin proliferating in blind mole rats. "Not only were the cancerous cells killed off, but so were the adjacent cells, which may also be prone to tumorous behavior. While people don't use the same cancer-killing mechanism as blind mole rats, we may be able to combat some cancers and prolong life, if we could stimulate the same clean sweep reaction in cancerous human cells.""

LIFESTYLE CHOICES AND THE PACE OF AGE-RELATED MEMORY DECLINE
Monday, November 5, 2012
http://www.fightaging.org/archives/2012/11/lifestyle-choices-and-the-pace-of-age-related-memory-decline.php
Longitudinal studies generally show the anticipated results when it comes to physical activity and age-related decline - if you are more active, you tend to exhibit a slower pace of decline. Education, intelligence, and wealth are also correlated with longer life and slower onset of frailty and disability, but unlike physical activity it is less clear as to what the root causes of these correlations might be: "[Data on] one thousand nine hundred fifty-four healthy participants aged 35 to 85 at baseline from the Betula Project [was used] to reveal distinct longitudinal trajectories in episodic memory over 15 years and to identify demographic, lifestyle, health-related, and genetic predictors of stability or decline. Memory was assessed according to validated episodic memory tasks in participants from a large population-based sample. ... Of 1,558 participants with two or more test sessions, 18% were classified as maintainers and 13% as decliners, and 68% showed age-typical average change. More educated and more physically active participants, women, and those living with someone were more likely to be classified as maintainers, as were carriers of the met allele of the catechol-O-methyltransferase gene. Less educated participants, those not active in the labor force, and men were more likely to be classified as decliners, and the apolipoprotein E ɛ4 allele was more frequent in decliners."

ANOTHER EXAMPLE OF A MITOCHONDRIALLY TARGETED ANTIOXIDANT
Monday, November 5, 2012
http://www.fightaging.org/archives/2012/11/another-example-of-a-mitochondrially-targeted-antioxidant.php
Mitochondria, the powerplants of the cell, generate damaging reactive oxygen species as a side-effect of their operation. Unfortunately, they are vulnerable to those very same reactive compounds, and some forms of resulting damage to proteins and genes can create dysfunctional cells that contribute to degenerative aging. The longer you live, the more of these dysfunctional cells you have, and the larger their harmful effects. This contribution to aging can be modestly slowed by use of antioxidants targeted to the mitochondria, as they will soak up some fraction of the oxidants generated before they cause damage. It is also the case that the effects of mitochondrial damage could be reversed entirely by some form of repair or replacement technology, and that would be a far better outcome. Nonetheless, a number of research groups are working on targeted antioxidants, compounds that are very different from generic antioxidants sold in stores. Ingested antioxidants that you can buy today do nothing for this issue of mitochondrial damage, and are arguably a net negative for long-term health because they interfere with the signaling processes that produced increased cellular maintenance in response to exercise or other forms of mild stress. Here is news of a recent addition to the research groups working on mitochondrially targeted antioxidants: "[Researchers] have designed a compound that suppresses symptoms of [Huntington's] disease in mice. The compound is a synthetic antioxidant that targets mitochondria, an organelle within cells that serves as a cell's power plant. Oxidative damage to mitochondria is implicated in many neurodegenerative diseases including Alzheimer's, Parkinson's, and Huntington's. The scientists administered the synthetic antioxidant, called XJB-5-131, to mice that have a genetic mutation that triggers Huntington's disease. The compound improved mitochondrial function and enhanced the survival of neurons. It also inhibited weight loss and stopped the decline of motor skills, among other benefits. In short, the Huntington's mice looked and behaved like normal mice. Defending mitochondria from reactive oxygen species is a tall order. That's because mitochondria are both the main target of these molecules, and a cell's primary source of them. In other words, mitochondria produce the very thing that damages them. Researchers have studied whether dietary supplements of natural antioxidants such as vitamin E and coenzyme Q can mitigate the harmful effects of reactive oxygen species on mitochondria. Natural antioxidants don't target specific tissue within the body, however. And they've been shown to yield only marginal benefits in human clinical trials. These lackluster results have driven scientists to develop synthetic antioxidants that specifically target mitochondria. A few years ago, [researchers] synthesized an antioxidant called XJB-5-131 that zeroes in on bacterial membranes, which are very similar to mitochondrial membranes. The scientists first injected Huntington's mice with XJB-5-131 and tested the mice's motor skills. ... We saw improvements across the board. The difference was amazing. XJB prevented the onset of weight loss and the decline in motor skills. Next, the researchers removed neurons from the Huntington's mice and cultured the cells in the presence of XJB-5-131. They found that XJB-5-131 significantly improved the survival of neuronal cultures compared to untreated neuronal cultures. [Researchers] studied the impacts of the compound on the mice's mitochondrial DNA. They discovered that XJB-5-131 dramatically lowered the number of lesions on the DNA, which is a sign of oxidative damage. They also tallied the number of mitochondrial DNA copies, which plummets in diseased mice. This number was restored back to normal in XJB-treated mice."

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#37 Marios Kyriazis

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Posted 11 November 2012 - 08:36 PM

Good information and summary of many promising subjects

#38 reason

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Posted 18 November 2012 - 07:39 PM

FIGHT AGING! NEWSLETTER
November 19th 2012

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

______________________________

CONTENT

- More Thoughts on Regenerative Medicine Timelines
- Investigating the Agelessness of Hydra
- Mining for Longevity Genes
- Discussion
- Latest Headlines from Fight Aging!
    - The State of Bioprinting
    - Molecular Tweezers Versus Alzheimer's Disease
    - Eliminating Metastasis in Melanoma
    - Investigating a Longevity-Related Mitochondrial Polymorphism
    - Injectable, Compressible, Shaped Tissue Scaffold
    - Humanity+ 2012 Conference, December 1st in San Francisco
    - Digging Deeper into Zebrafish Brain Regeneration
    - SENS Foundation Hiring a Telomere Biology Research Lead
    - "Successful Aging" Seems a Little Ridiculous as a Concept
    - The Goal of Lifelong Perfect Health

MORE THOUGHTS ON REGENERATIVE MEDICINE TIMELINES
http://www.fightaging.org/archives/2012/11/more-thoughts-on-regenerative-medicine-timelines.php

Dr. Brooks Edwards [is the] deputy director of the Mayo Clinic Center for Regenerative Medicine and director of the Mayo Transplant Center. [His] goal, before retiring from Mayo, is to be able to treat most of those patients with regenerative strategies, so they don't have to wait for a catastrophe to happen to a healthy person to become an organ donor, he said.

"We're going to have strategies to repopulate cells in the heart for patients with heart failure to restore them to normal cardiac function, we're going to have regenerative medicine strategies to be able to restore diseased liver to healthy liver by re-growing a liver from the recipient," he said. "We're going to have regenerative medicine strategies for patients with chronic lung disease that could avoid lung transplant."

Those treatments are not available now, said Edwards, who is 55. "But I think when you talk about five- and ten-year horizon, I think some of these things are going to become reality and we're going to look back at the current era and say, 'can you imagine that they had to wait for a deceased donor to treat that patient with heart failure?'" he said.

INVESTIGATING THE AGELESSNESS OF HYDRA
http://www.fightaging.org/archives/2012/11/investigating-the-agelessness-of-hydra.php

Hydra are one of the few ageless species, or at least a good candidate for such: researchers have watched populations age for years with no signs of increased mortality rates or declining pace of reproduction. One might view these creatures as an incremental step up from bacteria or yeast: multicellular animals that can reproduce asexually via budding, and which are extremely proficient at regeneration.

One line of thought regarding the agelessness of hydra is that they simply consistently and relentlessly renew all the tissues in their body, which is accomplished by having very many stem cells that don't decline over time. Hydra might follow a strategy of eliminating the inevitable buildup of malformed proteins, aggregate waste products, and similar damage in individual cells by (a) sacrificing and then replacing damage-bearing cells, and (b) using the bacterial approach of moving as much damage as possible into one of the two daughter cells produced in any cell division. Since a hydra has no brain, any cell can be sacrificed at any time so long as it is replaced with an equivalent new cell - the whole organism can be replaced completely over any arbitrarily short period of time provided it can find the metabolic resources to do so.

There's nothing magical about making cell lineages last essentially forever. All bacteria do it, and even complex organisms like we humans are capable of it. There is, for example, the process that ensures that the first cells of a human child are biologically young and free from damage even though the parents bear decades worth of accumulated damage in their cells. It's also possible that hydra use an aggressive repair and renewal process of this nature, either when they bud or on an ongoing basis.

Aging doesn't happen because it has to, aging happens because it's almost always advantageous from an evolutionary perspective - that we age is an example of the success of the gene built upon the pain, suffering, and death of the individual who bears it. Though apparently this isn't the case for hydra, and many other types of life that are closer to what we might think of as self-replicating machines rather than populations of individual entities. One might argue that the big downside of individual entityhood is the need for brain cells that store data, and thus cannot simply be replaced at arbitrary times. Or perhaps one might argue that a necessary precondition for individual entityhood is a loss of the processes of aggressive regeneration and tissue replacement such that a thing like a brain might be able to evolve in the first place.

In any case, not everything that the aging research community works on is both interesting and potentially useful when it comes to intervening in human aging. Ongoing research into the biology of hydra is certainly interesting, but I'm dubious that we'll find anything that can inform us of a way out of our present predicament, the one in which we are aging to death. We and the hydra live in very different worlds, with very different requirements for success.

MINING FOR LONGEVITY GENES
http://www.fightaging.org/archives/2012/11/mining-for-longevity-genes.php

he intricate, reactive, self-regulating machinery of our cells is built from proteins. Those proteins are specified by the blueprints known as genes, coiled up in each cell nucleus. The operation of our metabolism proceeds as a dance of networks of related proteins, feedback loops and signaling cascades in which the amount of a given protein produced at any given time can rise and fall in response to the rise and fall of other levels of production. The full scope of how variations in metabolism and its response to environment and lifestyle can affect the pace of aging is a staggeringly complex system, and as yet poorly understood.

Still, researchers seek to fully understand metabolism and aging; this goal has broader support than any other in aging research. There are more researchers chasing that understanding at any given time than there are working on ways to intervene in the aging process. A post from last week took a look at one way in which that research can progress: given an established mutation or other single-gene or single-protein change that extends life, scientists then follow the effects of that change through the network of interactions that it impacts, in search of a greater understanding of the system as a whole.

This is a time-worn and well proven methodology in all sciences: if you want to understand how something works then change one small part of it and carefully watch what happens next. Repeat as necessary.

There are other ways in which a knowledge of protein networks and existing longevity genes can be used to further research. For example, the catalog of what is known today can be mined in order to guide the process of uncovering more of the relationship between aging and the operation of metabolism. In any given network of genes where one can be altered to increase longevity, it is to be expected that there may be others. The proteins produced by these genes existing in an interconnected system, and it is probably the case that you can change the behavior of such a system by intervening at more than one point.

Here is an example of this approach: "Intricate and interconnected pathways modulate longevity ... Because biological processes are often executed by protein complexes and fine-tuned by regulatory factors, the first-order protein-protein interactors of known longevity genes are likely to participate in the regulation of longevity. Data-rich maps of protein interactions have been established for many cardinal organisms such as yeast, worms, and humans. We propose that these interaction maps could be mined for the identification of new putative regulators of longevity. For this purpose, we have constructed longevity networks in both humans and worms. We reasoned that the essential first-order interactors of known longevity-associated genes in these networks are more likely to have longevity phenotypes than randomly chosen genes."

DISCUSSION

The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!

______________________________

LATEST HEADLINES FROM FIGHT AGING!

THE STATE OF BIOPRINTING
Friday, November 16, 2012
http://www.fightaging.org/archives/2012/11/the-state-of-bioprinting.php
The developing technology of bioprinting, producing tissue structures using inkjet or other print technologies, has a promising future: "Desktop 3-D printers can already pump out a toy trinket, gear set or even parts to make another printer. Medical researchers are also taking advantage of this accelerating technology to expand their options for regenerative medicine. Researchers have made great strides in coaxing cells to grow over artificial, porous scaffolds that can then be implanted in the body to replace hard tissue, such as bone. ... But now, instead of relying on poured molds, foam designs or donated biological materials, researchers can print custom scaffold structures with biocompatible, biodegradable polymers. ... These methods have allowed us to develop very complex scaffolds which better mimic the conditions inside the body. ... Engineers can carefully control the minute, internal structures of these porous scaffolds to best promote cellular growth. And these new printing methods also allow quick and cheap experiments that test various one-off designs. Advancing bio-printing technologies can also be used for the biological material itself. Like color printing, biomaterial printing can switch among different organic materials as well as produce gradients and blending. Inkjet printing is preferred for depositing cells themselves, and as a demonstration of this in the 1980s an unmodified HP desktop printer was used to print out collagen as well as tissuelike structures. Printing, however, is tough on cells. Some studies have successfully kept more than 95 percent of cells intact through the process, but others have not done as well - losing more than half from damaged membranes. The future of bio-printing may be the combination of these approaches - printing both highly specific scaffolds and cell structures. Recent research has shown that stem cell fate can be controlled by the surfaces onto which the cells are printed."

MOLECULAR TWEEZERS VERSUS ALZHEIMER'S DISEASE
Friday, November 16, 2012
http://www.fightaging.org/archives/2012/11/molecular-tweezers-versus-alzheimers-disease.php
A range of age-related conditions are characterized by a buildup or clumping of harmful proteins, and research tends to focus first on ways to safely break down these compounds. Here researchers are testing a new candidate method of breaking down the beta amyloid and tau associated with Alzheimer's disease: "Last March, researchers at UCLA reported the development of a molecular compound called CLR01 that prevented toxic proteins associated with Parkinson's disease from binding together and killing the brain's neurons. Building on those findings, they have now turned their attention to Alzheimer's disease, which is thought to be caused by a similar toxic aggregation or clumping, but with different proteins, especially amyloid-beta and tau. And what they've found is encouraging. Using the same compound, which they've dubbed a "molecular tweezer," in a living mouse model of Alzheimer's, the researchers demonstrated for the first time that the compound safely crossed the blood-brain barrier, cleared the existing amyloid-beta and tau aggregates, and also proved to be protective to the neurons' synapses - another target of the disease - which allow cells to communicate with one another. Even though synapses in transgenic mice with Alzheimer's may shut down and the mice may lose their memory, upon treatment, they form new synapses and regain their learning and memory abilities. ... For humans, unfortunately, the situation is more problematic because the neurons gradually die in Alzheimer's disease. That's why we must start treating as early as possible. The good news is that the molecular tweezers appear to have a high safety margin, so they may be suitable for prophylactic treatment starting long before the onset of the disease."

ELIMINATING METASTASIS IN MELANOMA
Thursday, November 15, 2012
http://www.fightaging.org/archives/2012/11/eliminating-metastasis-in-melanoma.php
Arguably metastasis is what makes cancer so dangerous: that a single malignant tumor of any size can seed further tumors throughout the body; that a diaspora of metastasized cells is exceedingly hard to eliminate once let lose. If metastasis could be blocked many forms of cancer would become tractable and far less threatening, which is a fair-sized step towards a robust cure for cancer - very much needed as a part of any package of biotechnologies aimed at greatly extending healthy human life. Thus it is promising to see signs of early progress along these lines: "In laboratory experiments, scientists have eliminated metastasis, the spread of cancer from the original tumor to other parts of the body, in melanoma by inhibiting a protein known as melanoma differentiation associated gene-9 (mda-9)/syntenin. ... With further research, the approach used by the scientists could lead to targeted therapies that stop metastasis in melanoma and potentially a broad range of additional cancers. [Researchers] found that Raf kinase inhibitor protein (RKIP) interacted with and suppressed mda-9/syntenin. Mda-9/syntenin [was] shown in previous studies to interact with another protein, c-Src, to start a series of chemical reactions that lead to increased metastasis. ... Prior research suggests that RKIP plays a seminal role in inhibiting cancer metastasis, but, until now, the mechanisms underlying this activity were not clear. Now that the researchers have demonstrated the ability of RKIP to inhibit mda-9/syntenin-mediated metastasis, they are focusing their attention on developing small molecules imitating RKIP that could be used as new treatments for melanoma."

INVESTIGATING A LONGEVITY-RELATED MITOCHONDRIAL POLYMORPHISM
Thursday, November 15, 2012
http://www.fightaging.org/archives/2012/11/investigating-a-longevity-related-mitochondrial-polymorphism.php
Mitochondrial function is important in determining life span, and mitochondrial damage is one of the root causes of aging. Thus life span differences between similar species may to a large degree reflect differences in the damage resistance of mitochondria, and a number of studies in recent years have shown that some human mitochondrial haplogroups - which represent characteristic variations in mitochondrial DNA - can be correlated with increased longevity. The way in which mitochondria become damaged involves the production of reactive oxygen species (ROS) in the course of generating fuel to power the cell that contains them. Here researchers show that a longevity-associated difference in mitochondrial DNA reduces the pace of ROS production - which fits nicely with the present understanding of the role of mitochondria in aging: "Mitochondrial DNA (mtDNA) is highly polymorphic, and its variations in humans may contribute to individual differences in function. [Researchers] found a strikingly higher frequency of a C150T transition in the D-loop of mtDNA from centenarians and twins of an Italian population. The C150T transition is a polymorphism associated with several haplogroups. To determine whether haplogroups that carry the C150T transition display any phenotype that may be advantageous for longevity, we analyzed cybrids carrying or not the C150T transition. These cybrids were obtained by fusing cytoplasts derived from human fibroblasts with human mtDNA-less cells. We have found no association of respiratory capacity, mtDNA level, mitochondrial gene expression level, or growth rate with the presence of the C150T transition. However, we have found that the cybrids with haplogroups that include the C150T transition have in common a lower reactive oxygen species (ROS) production rate than the haplogroup-matched cybrids without that transition. Thus, the lower ROS production rate may be a factor in the increased longevity associated with [these] haplogroups."

INJECTABLE, COMPRESSIBLE, SHAPED TISSUE SCAFFOLD
Wednesday, November 14, 2012
http://www.fightaging.org/archives/2012/11/injectable-compressible-shaped-tissue-scaffold.php
Biodegradable scaffolds are an important part of tissue engineering, providing a way to hold cells in place and shape their growth in three dimensions, breaking down gradually as the new tissue builds its own supporting extracellular matrix. Here an intriguing advance in scaffold technology is noted: "Bioengineers [have] developed a gel-based sponge that can be molded to any shape, loaded with drugs or stem cells, compressed to a fraction of its size, and delivered via injection. Once inside the body, it pops back to its original shape and gradually releases its cargo, before safely degrading. "The simplest application is when you want bulking. If you want to introduce some material into the body to replace tissue that's been lost or that is deficient, this would be ideal. In other situations, you could use it to transplant stem cells if you're trying to promote tissue regeneration, or you might want to transplant immune cells, if you're looking at immunotherapy." Consisting primarily of alginate, a seaweed-based jelly, the injectable sponge contains networks of large pores, which allow liquids and large molecules to easily flow through it. [Researchers] demonstrated that live cells can be attached to the walls of this network and delivered intact along with the sponge, through a small-bore needle. [The] team also demonstrated that the sponge can hold large and small proteins and drugs within the alginate jelly itself, which are gradually released as the biocompatible matrix starts to break down inside the body. Normally, a scaffold like this would have to be implanted surgically. Gels can also be injected, but until now those gels would not have carried any inherent structure; they would simply flow to fill whatever space was available. [Researchers] pushed pink squares, hearts, and stars through a syringe to demonstrate the versatility and robustness of their gel."

HUMANITY+ 2012 CONFERENCE, DECEMBER 1ST IN SAN FRANCISCO
Wednesday, November 14, 2012
http://www.fightaging.org/archives/2012/11/humanity-2012-conference-december-1st-in-san-francisco.php
This year's Humanity+ conference is near: "The Humanity+ conference in San Francisco takes place on December 1-2, 2012 at Seven Hills Conference Center at San Francisco State University. ... Revolving around the theme "Writing the Future", the conference will explore the world of media and communicating Transhumanism. ... Speakers include multi-award winning science fiction author Kim Stanley Robinson, acclaimed biomedical gerontologist Aubrey de Grey, designer and theorist Natasha Vita-More, futurist Jamais Cascio, science fiction author David Brin, philosopher and proactionary principle advocate Max More, national best selling author Sonia Arrison, artificial general intelligence researcher Ben Goertzel, and more. "Writing the Future" focuses on communicating how emerging and converging sciences and technologies are the tools for designing our future, based on the advances in robotics, nanotechnology, artificial intelligence, human enhancement, brain-computer integration, regenerative medicine, and radical life extension. The future and its many narratives, both written and spoken, are is created by people of the present. In many cases, notably the biomedical realm, the intrinsic costs of pioneering technological research mean that the rate of progress is strongly influenced by public enthusiasm for its goals. This creates a dilemma, in that the public are often ambivalent (at best) concerning such goals, even when by any rational standards they should not be. Should those involved in such work therefore understate their goals when writing proposals and addressing a general audience, making them less "scary" and thereby attracting funds to make initial progress?"

DIGGING DEEPER INTO ZEBRAFISH BRAIN REGENERATION
Tuesday, November 13, 2012
http://www.fightaging.org/archives/2012/11/digging-deeper-into-zebrafish-brain-regeneration.php
Zebrafish, like a number of lower animals, are far better at regenerating lost tissue than mammals. In recent years, researchers have been investigating the mechanisms by which this superior regeneration works. It is possible that mammals such as we humans still have the necessary machinery, but it is turned off - or if we have lost it, that there is a way to recapture some of that loss through genetic engineering or other advanced medicine. But first, far more must be learned of the way in which regeneration proceeds in species like the zebrafish: "The secret to zebrafish's remarkable capacity for repairing their brains is inflammation ... Neural stem cells in the fish's brains express a receptor for inflammatory signaling molecules, which prompt the cells to multiply and develop into new neurons. Zebrafish, like many other vertebrates, are able to regenerate a variety of body tissues, including their brains. In fact [mammals] are the ones that seem to have lost this ability - they are kind of the odd ones out. [Given] the therapeutic potential of neuron regeneration for patients with brain or spinal injuries, [we'd] like to figure out if we can somehow reactivate this potential in humans. Last year, [researchers] discovered that radial glial stem cells are responsible for producing new neurons during brain regeneration in zebrafish. But they didn't know what prompted these cells to spring into action. Inflammation seemed a good candidate, [as] it arises as an immediate response to injury. [Researchers] introduced Zymosan A - an immunogenic factor derived from yeast - into the brains of zebrafish to induce inflammation in the absence of injury. They found that, just like brain injury, Zymosan A induced significant glial cell proliferation and new neuronal growth. In fish with suppressed immune responses, however, brain injury did not induce regeneration, further suggesting a role for inflammation."

SENS FOUNDATION HIRING A TELOMERE BIOLOGY RESEARCH LEAD
Tuesday, November 13, 2012
http://www.fightaging.org/archives/2012/11/sens-foundation-hiring-a-telomere-biology-research-lead.php
OncoSENS is the cancer-related project in the Strategies for Engineered Negligible Senescence (SENS). In typically ambitious fashion the plan is to remove the ability of humans to generate cancer by blocking all processes that can lengthen telomeres, as telomere lengthening is a function that all cancers must abuse in order to bypass normal limits on cell replication. No other commonality between all cancers is presently known, and this blocking of telomere lengthening looks very likely to work, but for my money I'd prefer a more traditional approach to building robust cancer therapies - or perhaps adapting the mechanisms by which mole rats render themselves immune to cancer. The reason for this preference is that a person unable to lengthen telomeres would, at a minimum, require replacement of all stem cell populations once a decade or so - and if you miss that procedure, you will decline pretty quickly with many of the symptoms of an accelerated aging condition. The SENS Foundation is presently hiring for a research group lead position in the OncoSENS project; pass it on to anyone you know who might be interested: "SENS Research Foundation is hiring for our research center located in Mountain View, CA. We are seeking a team lead for our OncoSENS group to work both on established projects and new independent research geared towards understanding the genetic mechanisms of telomerase-independent telomere elongation; for example, see the project Identifying and Disrupting Mediators of ALT. Research is focused on developing therapies against cancers that maintain their replicative potential using alternative lengthening of telomeres (ALT), and more generally the mission of the Foundation, toward overcoming the diseases and disabilities of aging. Qualified candidates will have a Ph.D. in the chemical/biological sciences. Duties will include bench work, management of a small team of lab researchers, the preparation of grant proposals, internal and external progress reports, individual and collaborative publication. The project lead will develop, interpret and implement standards, procedures, and protocols for the OncoSENS research program and may collaborate on determining strategic directions in the research program."

"SUCCESSFUL AGING" SEEMS A LITTLE RIDICULOUS AS A CONCEPT
Monday, November 12, 2012
http://www.fightaging.org/archives/2012/11/successful-aging-seems-a-little-ridiculous-as-a-concept.php
As I've pointed out in the past, the concept of "successful aging" looks more and more awkward and ill-thought the closer you examine it. At the high level the idea is connected to compression of morbidity, pushing disability and frailty further out into old age without extending life - but are these things even possible as goals for medical science? It seems likely not: either you extend life or you don't; either you treat aging by slowing its progression or reversing it or you don't. Aging itself is by definition a degenerative medical condition that causes pain, suffering, and death - so the idea of aging successfully seems a contradiction in terms at best, and at worst a sort of propaganda intended to deliberately cloud the issue of what should be done by the medical research community: "Increasing longevity is one of the great achievements of our civilization, but it has also given rise to discussion about good and successful aging. The concept of successful aging has attracted much debate, but there is still no universally accepted definition or standard measurement tool for it. The Encyclopedia of Aging defines successful aging as survival (longevity), health (lack of disabilities), and life satisfaction (happiness). It appears that the main sources of difficulty lay in the ambiguity of the meaning of "success," in the complexity of the aging process, the rapid changes taking place in society, and the changing characteristics of the older population. Discussions on successful aging have taken two main perspectives: one defines successful aging as a state of being, while the other understands it as a process of adaptation, described as doing the best with what one has. Studies taking the adaptation approach have often found that older people themselves feel they are aging successfully, even though traditional quantitative models say otherwise. Successful aging as a state of being, then, is an objective measurable condition at a certain point in time, demonstrating the positive extreme of normal aging. The most influential model of successful aging as a state of being was introduced by Rowe and Kahn, who characterize "success" as absence of disease and disability, maintained physical and mental functioning, and active engagement with life. Many studies and definitions take the view that successful aging is possible only among individuals without disease and impairment. Obviously such categorizations are likely to exclude most older people, typically the oldest-old, from the possibility of successful aging."

THE GOAL OF LIFELONG PERFECT HEALTH
Monday, November 12, 2012
http://www.fightaging.org/archives/2012/11/the-goal-of-lifelong-perfect-health.php
A short Slate article here looks at some comments made by Aubrey de Grey on the goals and outcomes of rejuvenation biotechnology research: ""I do not like to use the word immortality. It gives a very bad, a wrong impression about my work. I work on health. I am interested in ensuring that people will stay completely youthful, like young adults, for as long as they live," he said at a press conference at Ciudad de las Ideas, an annual conference about big ideas held in Puebla, Mexico. de Grey is the founder of the SENS Foundation, a nonprofit that, among other things, is funding projects intended to cure aging, if not dying. His goal: that everyone may stay a health 29 for as long as they may live. "It is quite likely that there will be a big side effect of doing that, which is that people will live a lot longer, but that is just a side effect," he says. Let's say that de Grey's research pans out - whether it's in the next 20 years, as he hopes may be possible; in the next 40, which he thinks is likely; or not for the next 100, which could happen "if we are unlucky or if we do not try hard enough." How would lifelong health change the way we live? ... "I think that actually society will be very different but ... mostly in ways that it is already moving as a result of technology, including health technologies, that are happening already," he says. "We see today many more people having multiple careers, moving from one to another; having multiple long-term partnerships one after another; generally much more equality between ages; people having partners that are very far distance from them in age. These things I think will simply continue to progress.""

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Posted 25 November 2012 - 09:00 PM

FIGHT AGING! NEWSLETTER
November 26th 2012

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

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CONTENT

- Increased Longevity in Mice by Removing Cardiotrophin 1
- Some Answers in Aging Science are Not Worth the Effort
- Removing Large and Unnecessary Costs Imposed Upon Medicine
- Insufficiently Terrified of Aging or Too Terrified of Aging?
- Discussion
- Latest Headlines from Fight Aging!
    - Vacuole Changes as a Contributing Cause of Yeast Cell Aging
    - Improvements in Printed Cartilage Scaffolds
    - Towards an Understanding of Why Dopamine Neurons Are Vulnerable in Parkinson's Disease
    - Looking at Immune Function in Long-Lived Clk1 Mutant Mice
    - Treating Spine Injury in Dogs via Stem Cell Transplant
    - Telomere Length and Life Expectancy in Warblers
    - Aging is Global, So Expect Correlations
    - An Example of Stem Cell Researchers Tackling Aging
    - Astrocytes as a Potential Target for Alzheimer's Therapies
    - Intuition, Mortality Rate, and Life Expectancy

INCREASED LONGEVITY IN MICE BY REMOVING CARDIOTROPHIN 1
http://www.fightaging.org/archives/2012/11/increased-longevity-in-mice-by-removing-cardiotrophin-1.php

Here is an question to think on while you recover from the excesses of the recent holiday: should we expect there to be, in humans, mice, or other species, many simple genetic alterations that are unambiguously beneficial for the individual, yet which evolution did not select for? Another way of looking at this question: why is it that there exist a range of ways to engineer slightly-genetically-altered mice that are stronger, healthier, and longer-lived than the standard wild variants?

The classical answer to this question suggests that these improvements come with fitness costs in the wild, or - more subtly - have the effect of dramatically reducing ability to survive under some rare combination of environmental circumstances. This is obviously the case when you look at mice lacking growth hormone, which live 60-70% longer than their peers, but are absolutely unfit for life in the wild due to their small size and, more importantly, issues with maintaining body temperature due to that small size. But for unambiguously all-round beneficial mutations like myostatin knockout, one has to think harder about how this could be a disadvantage.

Here is another example of a mutation that everyone would want for their offspring, should it turn out to work much the same way in humans: the absence of CT-1 is associated with decreased arterial fibrosis, stiffness, and senescence and increased longevity in mice likely through downregulating apoptotic, senescence, and inflammatory pathways. CT-1 may be a major regulator of arterial stiffness with a major impact on the aging process. ... CT-1-null mice displayed a 5-month increased median longevity compared with wild-type mice.

I look forward to the day on which one can take a flight across the Pacific as a medical tourist, drop into a reputable clinic, and have a few genetic alterations done: myostatin, cardiotrophin 1, and others that arise and are shown to have no downsides for people living in a society with access to modern medicine.

SOME ANSWERS IN AGING SCIENCE ARE NOT WORTH THE EFFORT
http://www.fightaging.org/archives/2012/11/some-answers-in-aging-science-are-not-worth-the-effort.php

Considerations of cost versus benefit drive all human action. With this in mind, and when considering the field of aging research, I'd contend that a fair number of the better defined lines of research are not worth the time and resources likely required to reach definitive results. By better defined I mean here research that can be expressed as a concise and narrow question (e.g. "why are naked mole-rats immune to cancer?") rather than research that is as much about finding the questions in the first place (e.g. attempting to establish a coherent big picture in the progression of Alzheimer's disease), or about gathering data for later use in other people's attempts to answer questions (e.g. whole genome sequencing of various species).

The well-known difference in longevity between human genders is a good example of a constrained and defined question in aging research: why do women live longer than men? It is also, to my mind, a great example of a question with an answer that isn't worth the cost involved in obtaining it. Research to date reveals this to be an inordinately complex issue, possessing all the signs of requiring a great deal of time and money to make any headway towards definitive answers. That is the cost side of the cost-benefit consideration. On the benefit side, we might think that the best possible benefit resulting from a definitive answer to the question "why do women life longer than men?" is something like five to seven years of life - that being the additional life expectancy enjoyed by women in wealthier regions of the world, and which might conceivably be captured by men given an exact methodology to do so. Which is not to say that this outcome could be engineered as a practical matter even if the cause of the difference was known in certainty - for example if it turns out to be, say, some many-headed web of fundamental interactions between metabolism and the genetics of being male, something that must be worked around rather than just altered.

Trying to safely alter metabolism with minimal side-effects is a complex and expensive business, a realm akin to traditional drug discovery processes, where billions can be spent with ease while only marginal benefits resulting. When it comes to slowing aging via metabolic and genetic manipulation, working through this drug discovery process, the mainstream research community believes there is little hope for significant progress towards longer human lives in the next few decades.

My point here is that a goal wherein the research community has no great hope of rapid progress, and which has every sign of being enormously expensive to pursue, and which can only at best somewhat point the way towards a possible gain of up to five years or so of healthy life in half the population is not a goal that merits a full-court press and singular attention - or at least not where better alternatives exist. Insofar as human aging goes, there is no shortage of better alternatives at this point. The aging research community should look to bolder plans, better and more beneficial ways to spend their time: work with far bigger potential gains. This is an age of revolution in the capabilities of biotechnology, a time for great leaps ahead in intervening in the aging process, not a time to be tinkering in the sandbox of fiddling questions.

REMOVING LARGE AND UNNECESSARY COSTS IMPOSED UPON MEDICINE
http://www.fightaging.org/archives/2012/11/removing-large-and-unnecessary-costs-imposed-upon-medicine.php

Insofar as politics goes, I'm against it. Both in the sense of a support for market anarchism as a desirable form of society and in the sense that what we see in the political sphere of our increasingly centralized societies today is reprehensible and destructive. There is control for the sake of control, ever-greater burdens imposed on builders of new technology, and progress in medicine is slowed for the personal aggrandizement of bureaucrats and those who line their pockets. When power accumulates to any group in society, and that group stands unopposed by peers, then it inevitably becomes corrupt.

The cartel of modern politics as practiced in countries like the US is the source of large and unnecessary costs put upon progress in medical technology - and this is a big problem for those of us who want to live longer, healthier lives. We stand at the dawn of an age in which aging might be treated as a medical condition, in which therapies could be designed to slow or reverse aging. But medicine and medical research labor beneath heavy regulation: the modern guilds like the AMA that seek to reduce supply; the agencies like the FDA that have few incentives to approve new medicines, yet seek ever-greater authority over all forms of treatment; the regulation and nationalization of medical services and insurance that severs customers from prices, and replaces markets with central planning after the Soviet model.

From a practical standpoint people of my views, being a minority, can do little but think of the vast benefits that might be realized should the present political costs imposed on progress in medicine suddenly evaporate. There are few opportunities to do more than that - we paw at the glass and stare longingly at the products on the other side, as it were. Human societies follow certain paths, and most lead away from individual freedoms of the sort needed for rapid progress in technology. Sad but true.

We can see a modest fraction of what might be achieved by stripping away regulation, guilds, and central planning by comparing progress in medicine over the past twenty years with progress in computing and software. Consider what computers and their role in everyday life would look like if it had always been the case that introducing a new machine or new software package meant spending years and $100 million to pass a bureaucratic one-size-fits-all process - and where radical new designs required a decade of expensive lobbying to be added to the list of what is permitted.

Yet this is exactly where things stand with medicine, at a time in which it is more important than it has ever been for progress to occur as rapidly as possible. A hundred thousand lives are lost every day to degenerative aging, and we might do something about that in the years ahead - but the therapies will emerge far more slowly than they would in a society that was more free and open than ours.

INSUFFICIENTLY TERRIFIED OF AGING OR TOO TERRIFIED OF AGING?
http://www.fightaging.org/archives/2012/11/insufficiently-terrified-of-aging-or-too-terrified-of-aging.php

It is my hope that, if asked, most people would agree that degenerative aging is not a pleasant, beneficial thing to look forward to. It is a looming years-long tunnel of varying forms of increasing suffering, expense, loss of dignity, and disability. You wouldn't volunteer for the consequences of aging if they were optional. Everyone knows what's coming. Everyone gets a close-up preview of what will happen, in all its painful details via family, media, stories, the common currencies of education. No adult is truly ignorant of where aging leads and what its costs are.

Any yet, and yet. The masses carry on and for the most part put all thoughts of future suffering to one side - even as the young interact with old people day in and day out, and even as those old people live out their lives. The folk who look at degenerative aging and suggest, seriously, with reference to sound science, that perhaps we can and should do something about it are in a tiny minority. Further, they are often castigated for that view, as if it is something that shouldn't be brought out in polite company.

Living in fear of being dead is of debatable rationality, but living in fear of chronic pain and suffering seems eminently rational to me. You'd be terrified if a random thug could credibly threaten you with half the physical harm that aging is capable of. Fear is a great motivator, but unfortunately far from reliable in what it motivates people to do: the various shadings of fear are well characterized by a loss of analysis and control.

So people blithely walk towards degenerative aging and its suffering, and the vast majority choose to do nothing to try to fight against that future. Is that because they have too little fear of what lies ahead, or because they are too terrified to even bring out the topic for introspection, debate, and planning?

I have become perhaps one of the least qualified people to answer that sort of question. I am so far removed from the years in which I didn't think much on the topic, or had only ordinary thoughts about aging, that I have no insight left into what it was like or why I thought that way. The more I learn about rejuvenation biotechnology and the longer I spend observing the world while favoring the defeat of aging, the less I understand prevalent attitudes, and the more of a mystery it all becomes: the concurrent acknowledgement and aversion of degenerative aging; the existence of a vibrant "anti-aging" marketplace next to a lack of support for real longevity science; the signs of fear next to the signs of complacency.

DISCUSSION

The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!

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LATEST HEADLINES FROM FIGHT AGING!

VACUOLE CHANGES AS A CONTRIBUTING CAUSE OF YEAST CELL AGING
Friday, November 23, 2012
http://www.fightaging.org/archives/2012/11/vacuole-changes-as-a-contributing-cause-of-yeast-cell-aging.php
The type of vacuole found in yeast cells is somewhat analogous to the lysosome that we animals possess in that it is involved in breaking down waste products and recycling broken cellular components (via the process of autophagy) that would otherwise harm the cell. It is an agent of cellular housekeeping, in other words. There the similarities end, however, as the vacuole performs many other vital tasks that the more specialized lysosome does not. So here, researchers show that they can extend life in yeast by reversing a change that occurs in the vacuole. Because the vacuole has many more tasks than the lysosome, it's not immediately clear that this has any application to our biology of aging, however. It is still worth keeping an eye on this research as we know that decline in lysosomal function (and thus of cellular housekeeping) is important in animal aging. You might recall, for example, that researchers managed to reverse the age-related loss of liver function in mice by finding a way to keep lysosomal function running at youthful rates. Similarly, reversing the root causes of lysosomal decline is on the SENS agenda - to be achieved by breaking down the build up of metabolic waste products that accumulate in lysosomes and cause them to malfunction. "Normally, mitochondria [in yeast] are beautiful, long tubes, but as cells get older, the mitochondria become fragmented and chunky. The changes in shape seen in aging yeast cells are also observed in certain human cells, such as neurons and pancreatic cells, and those changes have been associated with a number of age-related diseases in humans. The vacuole - and its counterpart in humans and other organisms, the lysosome - has two main jobs: degrading proteins and storing molecular building blocks for the cell. To perform those jobs, the interior of the vacuole must be highly acidic. [Researchers] found that the vacuole becomes less acidic relatively early in the yeast cell's lifespan and, critically, that the drop in acidity hinders the vacuole's ability to store certain nutrients. This, in turn, disrupts the mitochondria's energy source, causing them to break down. Conversely, when [researchers] prevented the drop in vacuolar acidity, the mitochondria's function and shape were preserved and the yeast cells lived longer. Until now, the vacuole's role in breaking down proteins was thought to be of primary importance. We were surprised to learn it was the storage function, not protein degradation, that appears to cause mitochondrial dysfunction in aging yeast cells. ... The unexpected discovery prompted [the researchers] to investigate the effects of calorie restriction, which is known to extend the lifespan of yeast, worms, flies and mammals, on vacuolar acidity. They found that calorie restriction - that is, limiting the raw material cells need - delays aging at least in part by boosting the acidity of the vacuole."

IMPROVEMENTS IN PRINTED CARTILAGE SCAFFOLDS
Friday, November 23, 2012
http://www.fightaging.org/archives/2012/11/improvements-in-printed-cartilage-scaffolds.php
Cartilage is a deceptively complex tissue to build, due to the small-scale structure that determines its mechanical and load-bearing properties - getting that structure right has proven to be a challenge. Researchers have nonetheless been making progress towards this goal in recent years, and the lessons learned will be carried forward to other tissue engineering projects: "The printing of three-dimensional tissue has taken a major step forward with the creation of a novel hybrid printer that simplifies the process of creating implantable cartilage. [The] printer is a combination of two low-cost fabrication techniques: a traditional ink jet printer and an electrospinning machine. In this study, the hybrid system produced cartilage constructs with increased mechanical stability compared to those created by an ink jet printer using gel material alone. The constructs were also shown to maintain their functional characteristics in the laboratory and a real-life system. The key to this was the use of the electrospinning machine, which uses an electrical current to generate very fine fibres from a polymer solution. Electrospinning allows the composition of polymers to be easily controlled and therefore produces porous structures that encourage cells to integrate into surrounding tissue. The constructs [were] inserted into mice for two, four and eight weeks to see how they performed in a real life system. After eight weeks of implantation, the constructs appeared to have developed the structures and properties that are typical of elastic cartilage, demonstrating their potential for insertion into a patient."

TOWARDS AN UNDERSTANDING OF WHY DOPAMINE NEURONS ARE VULNERABLE IN PARKINSON'S DISEASE
Thursday, November 22, 2012
http://www.fightaging.org/archives/2012/11/towards-an-understanding-of-why-dopamine-neurons-are-vulnerable-in-parkinsons-disease.php
The most visible signs of Parkinson's disease are caused by the progressive destruction of a comparatively small population of dopamine-generating neurons in the brain. But why these cells? A full answer to that question might lead to ways to block progression of the condition: "Neuroinflammation and its mediators have recently been proposed to contribute to neuronal loss in Parkinson's, but how these factors could preferentially damage dopaminergic neurons has remained unclear until now. [Researchers] were looking for biological pathways that could connect the immune system's inflammatory response to the damage seen in dopaminergic neurons. After searching human genomics databases, the team's attention was caught by a gene encoding a protein known as interleukin-13 receptor alpha 1 chain (IL-13Ra1), as it is located in the PARK12 locus, which has been linked to Parkinson's. IL-13rα1 is a receptor chain mediating the action of interleukin 13 (IL-13) and interleukin 4 (IL-4), two cytokines investigated for their role as mediators of allergic reactions and for their anti-inflammatory action. With further study, the researchers made the startling discovery that in the mouse brain, IL-13Ra1 is found only on the surface of dopaminergic neurons. "This was a 'Wow!' moment." The scientists set up long-term experiments using a mouse model in which chronic peripheral inflammation causes both neuroinflammation and loss of dopaminergic neurons similar to that seen in Parkinson's disease. The team looked at mice having or lacking IL-13Ra1 and then compared the number of dopaminergic neurons in the brain region of interest. The researchers expected that knocking out the IL-13 receptor would increase inflammation and cause neuronal loss to get even worse. Instead, neurons got better. If further research confirms the IL-13 receptor acts in a similar way in human dopaminergic neurons as in mice, the discovery could pave the way to addressing the underlying cause of Parkinson's disease. Researchers might, for instance, find that drugs that block IL-13 receptors are useful in preventing loss of dopaminergic cells during neuroinflammation."

LOOKING AT IMMUNE FUNCTION IN LONG-LIVED CLK1 MUTANT MICE
Thursday, November 22, 2012
http://www.fightaging.org/archives/2012/11/looking-at-immune-function-in-long-lived-clk1-mutant-mice.php
Reducing expression of clk1 (known as Mclk1 in mice) is one of the few known single-gene alterations that can slow aging enough to extend life in mice by as much as 30%. First impressions were that it works by altering mitochondrial function - and regular readers will know by now that mitochondria and the the pace of their self-inflicted damage is very important in aging and longevity. There is some debate as to how exactly this works in the case of clk-1, however, as the way in which it changes metabolic processes isn't self-evidently beneficial given what is known today. A fair amount of wading through complexity to gain a better understanding of mammalian biochemistry still needs to happen. Few single gene alterations change only one thing, and clk-1 reduction has all sorts of other knock-on effects in metabolism and biological systems. Researchers here are working their way through what it does to the immune system, and how that might be beneficial even though it doesn't at first look that way: "The immune response is essential for survival by destroying microorganisms and pre-cancerous cells. However, inflammation, one aspect of this response, can result in short- and long-term deleterious side-effects. Mclk1+/− mutant mice can be long-lived despite displaying a hair-trigger inflammatory response and chronically activated macrophages as a result of high mitochondrial [reactive oxygen species] generation. Here we ask whether this phenotype is beneficial or simply tolerated. We used models of infection [and] found that Mclk1+/− mutants mount a stronger immune response, control bacterial proliferation better, and are resistant to cell and tissue damage resulting from the response, including fibrosis and types of oxidative damage that are considered to be biomarkers of aging. Moreover, these same types of tissue damage were found to be low in untreated 23 months-old mutants. ... Mclk1+/− mutants thus display an association of an enhanced immune response with partial protection from age-dependent processes and from pathologies similar to those that are found with increased frequency during the aging process. This suggests that the immune phenotype of these mutants might contribute to their longevity. We discuss how these findings suggest a broader view of how the immune response might impact the aging process."

TREATING SPINE INJURY IN DOGS VIA STEM CELL TRANSPLANT
Wednesday, November 21, 2012
http://www.fightaging.org/archives/2012/11/treating-spine-injury-in-dogs-via-stem-cell-transplant.php
A pleasant example of what can sometimes be achieved with even comparatively crude autologous stem cell therapies: "Scientists have reversed paralysis in dogs after injecting them with cells grown from the lining of their nose. The pets had all suffered spinal injuries which prevented them from using their back legs. The [team] is cautiously optimistic the technique could eventually have a role in the treatment of human patients. The study is the first to test the transplant in "real-life" injuries rather than laboratory animals. [The] dogs had olfactory ensheathing cells from the lining of their nose removed. These were grown and expanded for several weeks in the laboratory. Of 34 pet dogs on the proof of concept trial, 23 had the cells transplanted into the injury site - the rest were injected with a neutral fluid. Many of the dogs that received the transplant showed considerable improvement and were able to walk on a treadmill with the support of a harness. None of the control group regained use of its back legs. The researchers say the transplanted cells regenerated nerve fibres across the damaged region of the spinal cord. This enabled the dogs to regain the use of their back legs and coordinate movement with their front limbs. The new nerve connections did not occur over the long distances required to connect the brain to the spinal cord. [In] humans this would be vital for spinal injury patients who had lost sexual function and bowel and bladder control. ... This is not a cure for spinal cord injury in humans - that could still be a long way off. But this is the most encouraging advance for some years and is a significant step on the road towards it."

TELOMERE LENGTH AND LIFE EXPECTANCY IN WARBLERS
Wednesday, November 21, 2012
http://www.fightaging.org/archives/2012/11/telomere-length-and-life-expectancy-in-warblers.php
Researchers are making better progress of late in finding ways to use changes in telomere length that occur with aging as a marker for biological age and life expectancy - though it remains an open question as to whether telomere shortening is a cause of aging versus a secondary consequence of causes of aging. You might look at work in mice published earlier this month, for example. Or moving to birds, a few years back researchers noted that pace of telomere shortening over time correlated with lifespan differences between species. Here researchers consider telomere length in a species of warbler: "[Researchers] studied the length of chromosome caps - known as telomeres - in a 320-strong wild population of Seychelles Warblers on a small isolated island. ... Over time these telomeres get broken down and become shorter. When they reach a critical short length they cause the cells they are in to stop functioning. This mechanism has evolved to prevent cells replicating out of control - becoming cancerous. However the flip side is that as these zombie cells build up in our organs it leads to their degeneration - aging - and consequently to health issues and eventually death. Telomeres help safeguard us from cancer but result in our aging. We wanted to understand what happens over an entire lifetime, so the Seychelles Warbler is an ideal research subject. They are naturally confined to an isolated tropical island, without any predators, so we can follow individuals throughout their lives, right through to old age. We investigated whether, at any given age, their telomere lengths could predict imminent death. We found that short and rapidly shortening telomeres were a good indication that the bird would die within a year. We also found that individuals with longer telomeres had longer life spans overall. It used to be thought that telomere shortening occurred at a constant rate in individuals, and that telomere length could act as an internal clock to measure the chronological age of organisms in the wild. However while telomeres do shorten with chronological age, the rate at which this happens differs between individuals of the same age. This is because individuals experience different amounts of biological stress due to the challenges and exertions they face in life. Telomere length can be used as a measure of the amount of damage an individual has accumulated over its life. We saw that telomere length is a better indicator of life expectancy than chronological age - so by measuring telomere length we have a way of estimating the biological age of an individual - how much of its life it has used up."

AGING IS GLOBAL, SO EXPECT CORRELATIONS
Tuesday, November 20, 2012
http://www.fightaging.org/archives/2012/11/aging-is-global-so-expect-correlations.php
The body is a web of overlapping systems, many of which depend upon one another for effective function. If one system begins to weaken, so do many others. Degenerative aging is a global affair, occurring throughout the body, and so we should not be surprised to find strong correlations between specific forms of age-related decline in many different organs. That doesn't necessarily mean that there is anything profound hiding behind such an association - cells are accumulating damage in all tissues, body-wide systems such as blood vessel elasticity and the immune system are progressively failing, and so decline is everywhere: "Decreased kidney function is associated with decreased cognitive functioning in areas such as global cognitive ability, abstract reasoning and verbal memory. [This] is the first study describing change in multiple domains of cognitive functioning in order to determine which specific abilities are most affected in individuals with impaired renal function. [Researchers] examined longitudinal data, five years apart, from 590 people. They wanted to see how much kidney function had changed over that time period, and whether it was associated with how much cognitive functioning had changed. They were interested in the overall change, but also in specific abilities such as abstract reasoning and verbal memory. "The brain and kidney are both organs that are affected by the cardiovascular systems. They are both affected by things like blood pressure and hypertension, so it is natural to expect that changes in one organ are going to be linked with changes in another.""

AN EXAMPLE OF STEM CELL RESEARCHERS TACKLING AGING
Tuesday, November 20, 2012
http://www.fightaging.org/archives/2012/11/an-example-of-stem-cell-researchers-tackling-aging.php
Much of the output of the regenerative medicine and tissue engineering fields will be of greatest use to old people: repair and replacement of worn, damaged, and diseased tissue. Unfortunately the cellular environment in an old body works to suppress stem cell activity, and this seems to be a more important factor in the decline of regenerative capacity than age-related damage to stem cells themselves, or the size of the stem cell population. This is perhaps an evolved response to rising levels of cellular damage, and works to suppress cancer risk - but at the cost of an accelerated decline in organ and tissue function. From a practical standpoint, this means that the stem cell research community must learn to control and reverse specific aspects of aging in order for their therapies to have the best possible effect. Otherwise they are throwing good stem cells into an environment that will suppress their activity. This roadblock is actually a good thing: this field of research is very well funded, and thus we all benefit as they find out that aging is in their way. Here is an example of the sort of exploratory early-stage work taking place today: "This study investigated whether cytokine enhancement of a biodegradable patch could restore cardiac function after surgical ventricular restoration (SVR) even when seeded with cells from old donors. ... SVR can partially restore heart size and improve function late after an extensive anterior myocardial infarction. However, 2 limitations include the stiff synthetic patch used and the limited healing of the infarct scar in aged patients. We [placed cytokines onto] porous collagen scaffolds. We seeded human mesenchymal stromal cells from young or old donors into the scaffolds, with or without growth factors. The patches were characterized and used for SVR in a rat model of myocardial infarction. Cardiac function was assessed. In vitro results showed that cells from old donors grew slower in the scaffolds. However, the presence of cytokines modulated the aging-related p16 gene and enhanced cell proliferation, converting the old cell phenotype to a young phenotype. In vivo studies showed that 28 days after SVR, patches seeded with cells from old donors did not induce functional recovery as well as patches seeded with young cells. However, cytokine-enhanced patches seeded with old cells exhibited preserved patch area, prolonged cell survival, and augmented angiogenesis, and rats implanted with these patches had better cardiac function. The patch became an elastic tissue, and the old cells were rejuvenated."

ASTROCYTES AS A POTENTIAL TARGET FOR ALZHEIMER'S THERAPIES
Monday, November 19, 2012
http://www.fightaging.org/archives/2012/11/astrocytes-as-a-potential-target-for-alzheimers-therapies.php
The brain is made up of far more than just neurons; its functions and complex structures require the support of a wide range of specialized cells types. Prominent amongst these supporting cells are the astrocytes. You might recall research from a few months back that indicated a role for age-related changes in astrocytes in the progression of Alzheimer's disease. Following on from that, researchers here report on the use of gene therapy to target astrocytes and potentially reduce the scope of any harmful behavior: "Astrocytes are the most abundant cell type in the brain and play a critical role in maintaining healthy nervous tissue. In Alzheimer's disease (AD) and most other neurodegenerative disorders, many astrocytes convert to a chronically "activated" phenotype characterized by morphologic and biochemical changes that appear to compromise protective properties and/or promote harmful neuroinflammatory processes. Activated astrocytes emerge early in the course of AD and become increasingly prominent as clinical and pathological symptoms progress, but few studies have tested the potential of astrocyte-targeted therapeutics in an intact animal model of AD. Here, we used adeno-associated virus (AAV) vectors containing the astrocyte-specific Gfa2 promoter to target hippocampal astrocytes [in] mice. AAV-Gfa2 vectors drove the expression of VIVIT, a peptide that interferes with [a signaling pathway] shown by our laboratory and others to orchestrate biochemical cascades leading to astrocyte activation. After several months of treatment with Gfa2-VIVIT, [the] mice exhibited improved cognitive and synaptic function, reduced glial activation, and lower amyloid levels. The results confirm a deleterious role for activated astrocytes in AD and lay the groundwork for exploration of other novel astrocyte-based therapies."

INTUITION, MORTALITY RATE, AND LIFE EXPECTANCY
Monday, November 19, 2012
http://www.fightaging.org/archives/2012/11/intuition-mortality-rate-and-life-expectancy.php
Here is a short post with graphs on the relationship between mortality rates and life expectancy: "I read a few weeks ago about a study where vitamin D supplementation reduced all-cause mortality rates by 6%. How many years would that add to life expectancy? I wondered. 6% of a 75-year life span would mean 4½ extra years, I thought, naïvely. I pulled up a mortality table (from the Social Security Admin) and did the calculation in a spreadsheet. The two lines were barely distinguishable. A 6% drop in mortality only increases life expectancy by 7 months. If the death rate did not increase with age, then it would be true that subtracting 6% from mortality would add about 6% to life expectancy. That's where the intuition came from about 4½ years. But with a death rate that increases with age, you "have to work a lot harder" to get an improvement in life expectancy. And in reality, the mortality curve doesn't just rise with age - it rises at an accelerating rate. Once I had set up the spreadsheet, it's easy enough to ask the general question: How much does life expectancy improve for a given change in mortality? The answer I found was: very slowly. ... To add just 5 years to life expectancy, we would need to slash the mortality rate by more than 40%. This is a counter-intuitive statistic - and a discouraging one. There is another perspective: [in] medical research, we are working piecemeal to chip away at the mortality rate from one disease and another. But if the fundamental rate of aging can be slowed, this will push the curve not down but to the right. This will have as much benefit as many decades of progress in cancer and heart disease."

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Posted 02 December 2012 - 06:05 PM

FIGHT AGING! NEWSLETTER
December 3rd 2012

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

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CONTENT

- Reminder: Eurosymposium on Healthy Aging, December 12th
- A Bioprinting Infographic
- The Lifespan Observations Database
- Associations Between Reduced Thyroid Function and Longevity
- Discussion
- Latest Headlines from Fight Aging!
    - A Protein Map for Mitochondrial Function
    - A Method of Determining Lobster Age
    - Kynurenine-Tryptophan Metabolism and Fly Longevity
    - Rejuvenation in the Jellyfish Turritopsis Dohrnii
    - Visceral Fat Associated With Decreased Bone Strength
    - Mild Early Hypoxia Produces Life-long Benefits in Rats
    - Reducing Alzheimer's Progression By Blocking Cytokines
    - FGF21 as Calorie Restriction Mimetic
    - Dihydrolipoamide Dehydrogenase as Longevity Gene

REMINDER: EUROSYMPOSIUM ON HEALTHY AGING, DECEMBER 12TH
http://www.fightaging.org/archives/2012/11/a-reminder-the-eurosymposium-on-healthy-ageing-will-be-held-in-brussels-on-december-12th.php

A few weeks from now, Heales, the Healthy Life Extension Society will host a Eurosymposium on Healthy Ageing in Brussels, Belgium. Heales sets its claim as the largest European longevity advocacy group: "Heales is the largest non-profit organisation in Continental Europe promoting and advocating scientific research into longevity and biogerontology (the science of aging). We are a group of biologists, biochemists, medical doctors and diverse other professions throughout Europe."

The December symposium will be a three day affair, and you may recognize some of the names in the program - noted folk from the longevity science community. The presentation abstracts make for good reading, and there is still time to register online if you plan to be in that part of the world later this month. From the symposium website:

"Having followed the evolution of the European Innovation Partnership on Active and Healthy Ageing we have reached the conclusion that biology of ageing needs to be highlighted more clearly as an important solution. Innovations based on biology of ageing can contribute to improve healthy life in a very significant way and we want to address this message to the European Union through this conference.

"In this conference, we will let scientists explain how their research contributes or can contribute to extend the healthy lifespan of European citizens; we will put scientists, entrepreneurs, medical doctors and other key actors together to build the business of long term health, towards a living Europe rather than a dying Europe. We hope that policy makers and people who work for the European Union will be interested and will further help biology of aging reach concrete implementations."

A BIOPRINTING INFOGRAPHIC
http://www.fightaging.org/archives/2012/11/a-bioprinting-infographic.php

Bioprinting is one of the many applications of 3D printing, a family of automation technologies for building three-dimensional structures from a blueprint. Living tissue is only different from other forms of automated fabrication by virtue of being much more complicated and somewhat more fragile. On the other hand, cells in a structure can self-assemble to some degree if the initial printed structure, chemical signals, and types of cell used are close enough to the final goal. So the challenges in printing tissue - and eventually in printing organs - are focused on trying to produce structures sufficiently close to living tissue for the cells involved to finish up on their own and close the gap. Creating a sufficiently comprehensive network of blood vessels to allow printed tissue to sustain itself is a big issue, for example.

At the end of this road, not so many years away, lies the goal of organ printing: producing complex organs for transplant on demand, grown from a patient's own cells. What effect this will have on life span remains to be seen, but on its own it is unlikely to be as large as we would like: probably incremental rather than revolutionary. You might look on it more in the way of taking conventional medicine for organ damage to the next level: expanding the number of people who can be treated, increasing the success rate of treatments, but suffering from many of the same limitations when it comes to the ability to successfully treat very elderly and frail people. There will probably be modest incidental benefits to life expectancy, just as there are for most broad improvements in medical technology. But you can have organs replaced as much as you like, and still age to death if there is no way to treat mitochondrial damage, build up of aggregates, aging in the brain, and so forth.

Surgery is never a desirable thing to have happen to you, especially if you are frail enough to need a transplant. This is one of the reasons why I suspect that stem cell medicine will ultimately gravitate to methods for inducing repair, regeneration, and rejuvenation in situ. They will either manipulate existing stem cells or infuse cultured stem cells taken from the patient, but these will be minimally invasive procedures that produce little to no trauma in the way that a transplant does.

THE LIFESPAN OBSERVATIONS DATABASE
http://www.fightaging.org/archives/2012/11/the-lifespan-observations-database.php

Over the years a great many studies have been conducted using laboratory animals with the aim of recording changes in life span that result from drugs, genetic alterations, and environmental conditions. The shorter-lived and less costly to maintain the species, the more studies there are - probably thousands for nematode worms, for example.

If you feel like browsing through the stacks to gain an impression of the work that has taken place over the past few decades, allow me to point you to the Lifespan Observations Database, which "collects published lifespan data across multiple species." It isn't a complete reference, but contains thousands of entries.

ASSOCIATIONS BETWEEN REDUCED THYROID FUNCTION AND LONGEVITY
http://www.fightaging.org/archives/2012/11/the-association-of-reduced-thyroid-function-with-longevity.php

The thyroid gland carries out a number of important functions, responding to changing conditions by varying its production of thyroid hormones that alter the behavior of metabolism elsewhere in the body. The behavior of the thyroid changes with age, but in a sufficiently subtle and varying manner to make its role in aging a challenging thing to study. Nonetheless, there is at this point enough data to conclude that some forms of reduced thyroid function tend to associate with increased longevity in a number of species.

This also ties in with other lines of research. Calorie restriction, for example, reduces thyroid hormone levels in the course of extending life and improving health. A predisposition to low thyroid hormone levels appear to be inherited in long-lived families. And so forth. Here is a short and very readable open access review paper that looks at thyroid function in the context of aging and longevity.

DISCUSSION

The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!

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LATEST HEADLINES FROM FIGHT AGING!

A PROTEIN MAP FOR MITOCHONDRIAL FUNCTION
Friday, November 30, 2012
http://www.fightaging.org/archives/2012/11/a-protein-map-for-mitochondrial-function.php
Mitochondria and the damage they accumulate as a result of their operation are important in the process of degenerative aging. Further, declining mitochondrial function is a feature in many age-related conditions. Many researchers focus their studies on mitochondrial function, differences in mitochondria between species and how that determines life span, alterations in mitochondrial operation that occur in connection with life-extending interventions in laboratory animals, and similar areas. These days that often involves producing a great deal of data for later analysis: "In efforts to understand what influences life span, cancer and aging, scientists are building roadmaps to navigate and learn about cells at the molecular level. To survey previously uncharted territory, a team of [researchers] created an "atlas" that maps more than 1,500 unique landmarks within mitochondria that could provide clues to the metabolic connections between caloric restriction and aging. The map, as well as the techniques used to create it, could lead to a better understanding of how cell metabolism is re-wired in some cancers, age-related diseases and metabolic conditions such as diabetes. "It's really a dynamic atlas for regulatory points in mitochondrial function - there are many interesting avenues that other scientists can follow up on. It could take years for researchers to understand what it all means, but at least now we have a list of the most important players." [The scientists] conducted earlier research on the mitochondrial protein Sirt3, where they suggested a link between Sirt3 and the benefits of caloric restriction in situations such as the prevention of age-related hearing loss. The new research [more] broadly identifies pathways in mitochondria that could be behind the rewiring of metabolism. Their work uncovered regulatory processes that maintain mitochondrial health, control cells' ability to metabolize fat and amino acids, as well as stimulate antioxidant responses."

A METHOD OF DETERMINING LOBSTER AGE
Friday, November 30, 2012
http://www.fightaging.org/archives/2012/11/a-method-of-determining-lobster-age.php
Lobsters are one of the small number of species that might be ageless, or at the very least age very slowly and exhibit little to no decline until very late life. There is little money for aging research in lobsters, however: until now researchers possessed no way to accurately determine the age of a lobster, and no good estimate as to average or maximum life span in these species. This new development should hopefully lead to a better grasp of the degree to which lobsters do or do not age, and pin down numbers for life span: " For the first time, scientists have figured out how to determine the age of a lobster - by counting its rings, like a tree. Nobody knows how old lobsters can live to be; some people estimate they live to more than 100. Scientists already could tell a fish's age by counting the growth rings found in a bony part of its inner ear, a shark's age from the rings in its vertebrae and a scallop or clam's age from the rings of its shell. But crustaceans posed a problem because of the apparent absence of any permanent growth structures. It was thought that when lobsters and other crustaceans molt, they shed all calcified body parts that might record annual growth bands. [Researchers] took a closer look at lobsters, snow crabs, northern shrimp and sculptured shrimp. They found that growth rings, in fact, could be found in the eyestalk - a stalk connected to the body with an eyeball on the end - of lobsters, crabs and shrimp. In lobsters and crabs, the rings were also found in the so-called "gastric mills," parts of the stomach with three teeth-like structures used to grind up food."

KYNURENINE-TRYPTOPHAN METABOLISM AND FLY LONGEVITY
Thursday, November 29, 2012
http://www.fightaging.org/archives/2012/11/kynurenine-tryptophan-metabolism-and-fly-longevity.php
Metabolism is a very complex set of overlapping mechanisms, feedback loops, and networks of protein interactions. So even if there are only a few core methods of extending life by altering metabolism in a species, we should expect to see scores of different ways to trigger some or all of that alteration - and with widely varying side-effects. This is one of the present challenges facing those researchers who focus on how metabolism and genes determine natural variations in longevity: mapping it all for any one species is a vast task. Here is one example of ongoing research drawn from among the many ways to make flies live longer: "Up-regulation of kynurenine (KYN) pathway of tryptophan (TRP) was suggested as one of the mechanisms of aging and aging-associated disorders. Genetic and pharmacological impairment of TRP - KYN metabolism resulted in prolongation of life span in Drosophila models. Minocycline, an antibiotic with anti-inflammatory, antioxidant and neuroprotective properties independent of its antibacterial activity, inhibited KYN formation from TRP. Since minocycline is the only FDA approved for human use medication with inhibitory effect on TRP - KYN metabolism, we were interested to study minocycline effect on life- and health-spans in Drosophila model. Minocycline prolonged mean, median and maximum life span of wild-type Oregon Drosophila melanogaster of both genders [and] might be a promising candidate drug for anti-aging intervention. [The] role of TRP - KYN metabolism in the mechanisms of minocycline-effect on life- and health-span might be elucidated by the future assessment of minocycline effects in Drosophila mutants naturally or artificially knockout for genes impacting the key enzymes of KYN pathway of TRP metabolism."

REJUVENATION IN THE JELLYFISH TURRITOPSIS DOHRNII
Thursday, November 29, 2012
http://www.fightaging.org/archives/2012/11/rejuvenation-in-the-jellyfish-turritopsis-dohrnii.php
Aging has evolved despite its terrible effects on the individual because over the long run it is highly effective in the evolutionary competition that takes place in most ecological niches - any amount of hardship and pain can be selected for if it means that genes are more effectively propagated. There are exceptions, however, in the form of successful species that do not appear to age; especially in the case of lower animals we can find life histories that look nothing like our own. Take the hydra, for example, or here the tiny jellyfish Turritopsis dohrnii: "[An individual Turritopsis dohrnii appears to reverse its life cycle], growing younger and younger until it reached its earliest stage of development, at which point it began its life cycle anew. ... We now know [that] the rejuvenation of Turritopsis dohrnii and some other members of the genus is caused by environmental stress or physical assault. We know that, during rejuvenation, it undergoes cellular transdifferentiation, an unusual process by which one type of cell is converted into another - a skin cell into a nerve cell, for instance. But we still don't understand how it ages in reverse. There are several reasons for our ignorance, all of them maddeningly unsatisfying. There are, to begin with, very few specialists in the world committed to conducting the necessary experiments. ... The genus, it turns out, is extraordinarily difficult to culture in a laboratory. It requires close attention and an enormous amount of repetitive, tedious labor; even then, it is under only certain favorable conditions, most of which are still unknown to biologists, that a Turritopsis will produce offspring."

VISCERAL FAT ASSOCIATED WITH DECREASED BONE STRENGTH
Wednesday, November 28, 2012
http://www.fightaging.org/archives/2012/11/visceral-fat-associated-with-decreased-bone-strength.php
Visceral fat is strongly associated with most common age-related conditions and frailties, and mice have been shown to live longer if you remove their visceral fat. Maintaining excess fat tissue appears to be bad for you in many ways: more disability, more disease, a shorter life expectancy. So it's no surprise to see research results like this: "Visceral, or deep belly, obesity is a risk factor for bone loss and decreased bone strength in men. [Not] all body fat is the same. Subcutaneous fat lies just below the skin, and visceral or intra-abdominal fat is located deep under the muscle tissue in the abdominal cavity. Genetics, diet and exercise are all contributors to the level of visceral fat that is stored in the body. Excess visceral fat is considered particularly dangerous, because in previous studies it has been associated with increased risk for heart disease. [Researchers] evaluated 35 obese men with a mean age of 34 and a mean body mass index (BMI) of 36.5. The men underwent CT of the abdomen and thigh to assess fat and muscle mass, as well as very high resolution CT of the forearm and a technique called finite element analysis (FEA), in order to assess bone strength and predict fracture risk. ... FEA can determine where a structure will bend or break and the amount of force necessary to make the material break. In the study, the FEA analysis showed that men with higher visceral and total abdominal fat had lower failure load and stiffness, two measures of bone strength, compared to those with less visceral and abdominal fat. There was no association found between age or total BMI and bone mechanical properties. "We were not surprised by our results that abdominal and visceral fat are detrimental to bone strength in obese men. We were, however, surprised that obese men with a lot of visceral fat had significantly decreased bone strength compared to obese men with low visceral fat but similar BMI.""

MILD EARLY HYPOXIA PRODUCES LIFE-LONG BENEFITS IN RATS
Wednesday, November 28, 2012
http://www.fightaging.org/archives/2012/11/mild-early-hypoxia-produces-life-long-benefits-in-rats.php
Hormesis is the process by which a little stress or damage actually improves health. It spurs greater repair, growth, and regeneration than would otherwise have taken place, with the net effect being positive. This is an example with life-long benefits: "Whereas brief acute or intermittent episodes of hypoxia have been shown to exert a protective role in the central nervous system and to stimulate neurogenesis, other studies suggest that early hypoxia may constitute a risk factor that influences the future development of mental disorders. We therefore investigated the effects of a neonatal "conditioning-like" hypoxia on the brain and the cognitive outcomes of rats until 720 days of age (physiologic senescence). We confirmed that such a short hypoxia led to brain neurogenesis within the ensuing weeks, along with reduced apoptosis in the hippocampus. During aging, previous exposure to neonatal hypoxia was associated with enhanced memory retrieval scores specifically in males, better preservation of their brain integrity than controls, reduced age-related apoptosis, larger hippocampal cell layers, and higher expression of glutamatergic and GABAergic markers. These changes were accompanied with a marked expression of synapsin proteins, mainly of their phosphorylated active forms which constitute major players of synapse function and plasticity. Thus, early non-injurious hypoxia may trigger beneficial long term effects conferring higher resistance to senescence in aged male rats, with a better preservation of cognitive functions."

REDUCING ALZHEIMER'S PROGRESSION BY BLOCKING CYTOKINES
Tuesday, November 27, 2012
http://www.fightaging.org/archives/2012/11/reducing-alzheimers-progression-by-blocking-cytokines.php
Researchers here demonstrate a much reduced progression of the signs of Alzheimer's disease in mice by altering immune signaling: "Alzheimer's disease is one of the most common causes of dementia. [The] accumulation of particular abnormal proteins, including amyloid-ß (Aβ) among others, in patients' brains plays a central role in this disease. [Researchers] were able to show that turning off particular cytokines (immune system signal transmitters) reduced the Alzheimer's typical amyloid-ß deposits in mice with the disease. As a result, the strongest effects were demonstrated after reducing amyloid-ß by approximately 65 percent, when the immune molecule p40 was affected, which is a component of the cytokines interleukin (IL)-12 and -23. Follow-up experiments [showed] that substantial improvements in behavioral testing resulted when mice were given the antibody blocking the immune molecule p40. This effect was also achieved when the mice were already showing symptoms of the disease. Based on the current [study], the level of p40 molecules is higher in Alzheimer's patients' brain fluid, which is in agreement with a recently published [study] demonstrating increased p40 levels in blood plasma of subjects with Alzheimer's disease. The significance of the immune system in Alzheimer's research is the focus of current efforts. [Researchers] suspect that cytokines IL-12 and IL-23 themselves are not causative in the pathology, and that the mechanism of the immune molecule p40 in Alzheimer's requires additional clarification."

FGF21 AS CALORIE RESTRICTION MIMETIC
Tuesday, November 27, 2012
http://www.fightaging.org/archives/2012/11/fgf21-as-calorie-restriction-mimetic.php
Boosting levels of fibroblast growth factor 21 (FGF21) has been shown to extend life in mice. Here, researchers classify it as a calorie restriction mimetic treatment: "Dietary or caloric restriction (DR or CR), typically a 30-40% reduction in ad libitum or "normal" nutritional energy levels, has been reported to extend lifespan and healthspan in diverse organisms, including mammals. Although the lifespan benefit of DR in primates and humans is unproven, preliminary evidence suggests that DR confers healthspan benefits. A serious effort is underway to discover or engineer DR mimetics. The most straightforward path to a DR mimetic requires a detailed understanding of the molecular mechanisms that underlie DR and related lifespan-enhancing protocols. Increased expression of FGF21, a putative mammalian starvation master regulator, promotes many of the same beneficial physiological changes seen in DR animals, including decreased glucose levels, increased insulin sensitivity, and improved fatty acid/lipid profiles. Ectopic over-expression of FGF21 in transgenic mice (FGF21-Tg) extends lifespan to a similar extent as DR in a recent study. FGF21 may achieve these effects by attenuating GH/IGF1 signaling. Although FGF21 expression does not increase during DR, and therefore is unlikely to mediate DR, it does increase during short-term starvation in rodents which is a critical component of alternate day fasting, a DR-like protocol that also increases lifespan and healthspan in mammals. Various drugs have been reported to induce FGF21 [but] of these, only metformin has been reported to extend lifespan in mammals, and the extent of benefit is less than that seen with ectopic FGF21 expression. Perhaps the most parsimonious explanation is that high, possibly unphysiological, levels of FGF21 are needed to achieve maximum life- and healthspan benefits and that sufficiently high levels are not achieved by the identified FGF21 inducers. More in-depth studies of the effects of FGF21 and its inducers on longevity and healthspan are warranted."

DIHYDROLIPOAMIDE DEHYDROGENASE AS LONGEVITY GENE
Monday, November 26, 2012
http://www.fightaging.org/archives/2012/11/dihydrolipoamide-dehydrogenase-as-longevity-gene.php
It's no longer remarkable for researchers to discover ways to alter genes or the level of proteins produced through gene expression that extend life in laboratory animals. Many new interventions of this sort are discovered every year, and most go largely unremarked now. With the falling cost and increasing capacity of DNA sequencing and related biotechnologies it is becoming ever easier to find new connections or poke and prod at DNA and protein machinery in living organisms. That trend speeds the pace of progress in this field, and here is a recent example: "Mit mutations that disrupt function of the mitochondrial electron transport chain can, inexplicably, prolong Caenorhabditis elegans lifespan. In this study we use a metabolomics approach to identify an ensemble of mitochondrial-derived α-ketoacids and α-hydroxyacids that are produced by long-lived Mit mutants but not by other long-lived mutants or by short-lived mitochondrial mutants. We show that accumulation of these compounds is dependent upon concerted inhibition of three α-ketoacid dehydrogenases that share dihydrolipoamide dehydrogenase (DLD) as a common subunit, a protein previously linked in humans with increased risk of Alzheimer's disease. When the expression of DLD in wild type animals was reduced using RNA interference we observed [that] as RNAi dosage was increased lifespan was significantly shortened but, at higher doses, it was significantly lengthened, suggesting DLD plays a unique role in modulating length of life."

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#41 reason

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Posted 09 December 2012 - 02:35 PM

FIGHT AGING! NEWSLETTER
December 10th 2012

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

______________________________

CONTENT

- Is Funding the Only Roadblock for Longevity Science?
- The Duty to Extend the "Biological Warranty Period"
- Nature Outlook: Ageing
- At Some Point Soon, Mouth Bacteria Will Be Defeated
- Discussion
- Latest Headlines from Fight Aging!
    - PGC-1 alpha-4 Spurs Muscle Growth
    - Being Older is Very Positive, Being Aged is Not
    - A Brief Look at Retinal Implants
    - Stem Cells and Scaffolds to Regrow the Cornea
    - Trialing Regenerative Medicine for Heart Failure
    - First Generation Stem Cell Therapies Moving Through Trials
    - Diastolic Dysfunction Correlates With AGE Levels
    - An Interview With a KrioRus Director
    - Considering NF-κB in Aging
    - Reviewing the Online Human Aging Genomics Resources

IS FUNDING THE ONLY ROADBLOCK FOR LONGEVITY SCIENCE?
http://www.fightaging.org/archives/2012/12/is-funding-the-only-roadblock-standing-in-the-way-of-greatly-extending-healthy-human-life-spans.php

I was asked this question a few weeks back: is money the only real obstacle standing between us and good odds of greatly extending the healthy human life span within the next 20-30 years? The answer I gave was this: yes, yes it is is. A hundred times yes - a shortage of money is the central and only limiting factor to progress in slowing and reversing aging.

The world as a whole does not suffer from a shortage of money, of course. (If anything, the situation quite the opposite, sadly). When I say that money is a challenge, I mean that at present only a tiny faction of the optimal - or even somewhat adequate - research funds flow into the best projects in aging and longevity science. The field of aging research is as a whole underfunded in comparison to its importance, and a great deal of that funding is consistently misallocated - at least when seen from the perspective of someone who wants to produce concrete results in terms of years gained and lives saved. Very little of it goes to longevity science.

Nonetheless, clear research plans exist to address aging, such as the Strategies for Engineered Negligible Senescence (SENS) that aims to reverse its causes. The way ahead is known in great detail, the root causes of aging at the cellular and molecular level are so well specified at this point that proof or disproof by example lies within a handful of years, were suitable research programs funded. By that I mean go ahead and reverse or repair a root cause of aging in mice, then see what happens. That, however, takes money. Perhaps a billion dollars of it and ten years if a crash program was put together.

There are of course any number of other challenges I could point to - goals and line items that lie between the present and a possible future in which we will all live far longer in good health. For example, take the need to grow a longevity research community to rival the cancer research institution in energy and fundraising prowess. Or the need for SENS and related work on rejuvenation to win dominance over slowing aging by metabolic manipulation as the approach most favored by biogerontologists. Or the need to attract high net worth philanthropic donors and conservative funding institutions to the field. Or the need to make the public more aware of what progress could be achieved, and more demanding of that progress. I could go on. Yet these all boil down to money: sufficient funding will solve all of these challenges, as they will be flattened beneath a weight of money.

Consider this: if a few hundred million dollars fell upon the SENS Foundation today, and was spent aggressively, in five years the Foundation could be the leading US center for aging research. (For comparison, note that the Buck Institute draws an annual budget of a little less than $40 million, and the NIH itself budgets around $2.5 billion dollars a year, mostly spent on matters that have little to no impact on extending human life). That much money attracts more funding, opens doors, draws researchers, provides a megaphone for public speaking, and shifts the balance of interest and strategy in the way research is conducted in the field.

The bottom line: a section of the research community knows how to go about creating a good shot at reversing aging within a few decades. Only a trickle of money is flowing in their direction, and it is that level of funding that limits their progress. So the bootstrapping approach continues: get a little money, do the work, show positive results, leverage those results to gain more interest and more funding, repeat. This is a slow business, however, and will remain so until greater funding and interest in longevity science is achieved.

So money matters, is the limiting factor to progress, and will continue to be so until it is not.

Since we're talking about money, I should note that the year is coming to a close. This is traditionally a time to make charitable donations. If you want to have an impact on the future, then consider donating to help fund the active development of rejuvenation biotechnology or advocacy for longevity science. See the Take Action! page here at Fight Aging! for suggested charitable causes, such as the SENS Foundation, Methuselah Foundation, or New Organ initiative.

THE DUTY TO EXTEND THE "BIOLOGICAL WARRANTY PERIOD"
http://www.fightaging.org/archives/2012/12/the-duty-to-extend-the-biological-warranty-period.php

A couple of months back, I pointed out the first pair of posts in a series entitled "the Duty to Extend the Biological Warranty Period." In this Fight Aging! post, you'll find links to the full series. An except follows:

"For over the past decade now I have taught undergraduate and graduate students on ethical issues pertaining to life extension and aging and I am always struck by how easily and quickly intelligent people can convince themselves that it is better to accept the rate of aging selected for by the blind process of evolution through natural selection than by a rate humans consciously influence to expand the opportunities for health by reducing and delaying many of the afflictions of senescence.

"The objections I have heard over the years range from a concern that reducing mortality could reduce our appreciation of life, to concerns that it would be boring to be married to the same person for longer and a concern that promoting the health of the elderly would make things worse for the employment of younger generations (a sentiment I find is more common among my undergraduate students who have anxieties about finding employment and paying off their student debts).

"Most of these objections can be dispensed with when one makes the benefits of age retardation more concrete. Adding 2 or 3 decades to the human lifespan, for example by a pill that mimics the effects of caloric restriction, would mean a delay of cancer, heart disease, stroke, AD, etc. When framed in that light the concerns typically raised against life extension begin to sound less compelling, even ridiculous. Would living with a lower risk of death from cancer, stroke or heart disease decrease our appreciation of living? If so, then is that a reason to promote smoking, obesity and an inactive lifestyle? Is it desirable that we increase the job prospects of today's younger adults by ensuring their parents' generation are afflicted with stroke or heart disease a decade or two earlier? Is increasing the risk of morbidity and mortality a fair and reasonable strategy for tackling societal problems like unemployment? No, of course not. But much work must be done to persuade people to think rationally about such issues rather than be governed by their knee jerk reactions to such cases."

NATURE OUTLOOK: AGEING
http://www.fightaging.org/archives/2012/12/nature-outlook-ageing.php

Humans are the longest lived primates, with life expectancy in some developed nations surpassing 80 years. Of course, that doesn't stop us wanting more time. Research into the mechanisms of ageing is yielding insights, many of them diet-related, into how we might not only live longer but also stay healthier as we do.

While researchers wait for statistical proof of the diet's effects in primates, some people have elected to go on the diet anyway. CRONies - the label adopted by those on a diet of Caloric Restriction with Optimal Nutrition - voluntarily eat 30% fewer calories than recommended by the US Department of Agriculture. That can be as low as 1,400 calories a day for men, and 1,120 for women.

Fontana, who studies the CRONies, says most of the health benefits seen in animals on the caloric restriction diet also appear in humans. He says that people who started caloric restriction in middle age and stayed with the regimen for eight years have a "fantastic" cardiometabolic profile. He adds that he has seen subjects in their late 70s with the blood pressure of teenagers.

AT SOME POINT SOON, MOUTH BACTERIA WILL BE DEFEATED
http://www.fightaging.org/archives/2012/12/at-some-point-soon-mouth-bacteria-will-be-defeated.php

The modern age of antibiotics didn't do a great deal to combat the inexorable processes that contribute to tooth decay and gum disease, as it things turned out. One might have thought so at the outset: bacteria in the mouth are causing issues, we're developing all sorts of enormously improved methods of killing bacteria, ergo tooth decay and commonplace gum disease like gingivitis and should soon be a thing of the past. Alas not so, however - nothing is straightforward in the world of medicine. As one consideration, many of the hundreds of bacterial species in the mouth are actually beneficial.

In recent years, there has been some progress towards more sophisticated solutions. These include methods of sabotaging key mechanisms in problem bacterial species so as to leave other bacteria unharmed, or of targeting bacteria by their surface chemistry or other markers. I suspect that the next generation will very rarely visit dentists, as much of the need for regular dental services will be removed by products based on this and similar sorts of research. Here is one example of laboratory work in progress:

Porphyromonas gingivalis, the bacterium responsible for many cases of periodontitis, acts to "hijack" a receptor on white blood cells called C5aR. The receptor is part of the complement system, a component of the immune system that helps clear infection but can trigger damaging inflammation if improperly controlled. By hijacking C5aR, P. gingivalis subverts the complement system and handicaps immune cells, rendering them less able to clear infection from the gum tissue. As a result, numbers of P. gingivalis and other microbes rise and create severe inflammation. According to a study published [last year], mice bred to lack C5aR did not develop periodontitis.

[The] researchers synthesized and administered a molecule that blocks the activity of C5aR, to see if it could prevent periodontitis from developing. They gave this receptor "antagonist," known as C5aRA, to mice that were then infected with P. gingivalis. The C5aRA injections were able to stave off inflammation to a large extent, reducing inflammatory molecules by 80 percent compared to a control, and completely stopping bone loss. And when the mice were given the antagonist two weeks after being infected with P. gingivalis, the treatment was still effective, reducing signs of inflammation by 70 percent and inhibiting nearly 70 percent of periodontal bone loss.

DISCUSSION

The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!

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LATEST HEADLINES FROM FIGHT AGING!

PGC-1 ALPHA-4 SPURS MUSCLE GROWTH
Friday, December 7, 2012
http://www.fightaging.org/archives/2012/12/pgc-1-alpha-4-spurs-muscle-growth.php
Researchers have found a number of potential ways to spur growth of muscle tissue, and some of these might be used in attempts to fend off the loss of muscle mass and strength that occurs with aging - not by fixing the root causes, but by trying to compensate through another mechanism. Here is a recent example: "The protein is an isoform, or slight variant, of PGC-1 alpha, an important regulatory of body metabolism that is turned on by forms of exercise, such as running, that increase muscular endurance rather than size. [A rise in] PGC-1 alpha-4 with exercise increases activity of a protein called IGF1 (insulin-like growth factor 1), which facilitates muscle growth. At the same time, PGC-1 alpha-4 also represses another protein, myostatin, which normally restricts muscle growth. In effect, PGC-1 alpha-4 presses the accelerator and removes the brake to enable exercised muscles to gain mass and strength. Several experiments demonstrated the muscle-enhancing effects of the novel protein. The investigators used virus carriers to insert PGC-1 alpha-4 into the leg muscle of mice and found that within several days their muscle fibers were 60 percent bigger compared to untreated mice. They also engineered mice to have more PGC-1 alpha-4 in their muscles than normal mice who were not exercising. Tests showed that the treated mice were 20 percent stronger and more resistant to fatigue than the controls; in addition, they were leaner than their normal counterparts."

BEING OLDER IS VERY POSITIVE, BEING AGED IS NOT
Friday, December 7, 2012
http://www.fightaging.org/archives/2012/12/being-older-is-very-positive-being-aged-is-not.php
It should be noted that, on balance, everything except physical health becomes better with age. Outside of degenerative aging, becoming older is so good that people are driven to apologism for the fact that aging cripples and kills them - they conflate being old and being aged, seeing two very different things as one, and a certain confusion arises after that point. Consider how much better it will be to be older once we start being able to treat the root causes of the degenerative medical condition called aging. If you're not there yet, consider just how good being older must be in order for people to be able to say they are well off even while their health is crumbling: "The SAGE study included adults between the ages of 50 and 99 years, with a mean age of just over 77 years. In addition to measures which assessed rates of chronic disease and disability, the survey looked at more subjective criteria such as social engagement and participants' self-assessment of their overall health. Participants were asked to rate the extent to which they thought they had "successfully aged," using a 10-point scale and using their own concept of the term. The study found that people with low physical functioning but high resilience, had self-ratings of successful aging similar to those of physical healthy people with low resilience. Likewise, the self-ratings of individuals with low physical functioning but no or minimal depression had scores comparable to those of physically healthy people with moderate to severe depression. "It was clear to us that, even in the midst of physical or cognitive decline, individuals in our study reported feeling that their well-being had improved with age.""

A BRIEF LOOK AT RETINAL IMPLANTS
Thursday, December 6, 2012
http://www.fightaging.org/archives/2012/12/a-brief-look-at-retinal-implants.php
Retinal implants are currently in their earliest stage of development: comparatively crude electrode arrays that provide an alternative to vision rather than restoring it. From here the path to ever more sophisticated systems seems assured, however: "A coming generation of retinal implants that fit entirely inside the eye will use nanoscale electronic components to dramatically improve vision quality for the wearer, according to two research teams developing such devices. Current retinal prostheses, such as Second Sight's Argus II, restore only limited and fuzzy vision to individuals blinded by degenerative eye disease. Wearers can typically distinguish light from dark and make out shapes and outlines of objects, but not much more. The Argus II, the first "bionic eye" to reach commercial markets, contains an array of 60 electrodes, akin to 60 pixels, that are implanted behind the retina to stimulate the remaining healthy cells. The implant is connected to a camera, worn on the side of the head, that relays a video feed. A similar implant, made by Bionic Vision Australia, incorporates just 24 electrodes. With so few electrodes, the amount of visual information transmitted to the brain is limited: text, for example, is difficult to read. Second Sight recently announced a method by which Argus II wearers are able to visualize Braille instead of traditional text. Recognizing this limitation, both Second Sight and Bionic Vision Australia have announced that they are developing next-generation devices with 200-plus electrodes. But arrays of nanoscale electrodes, which are currently being incorporated into new retina devices, could someday give blind people 20/20 vision."

STEM CELLS AND SCAFFOLDS TO REGROW THE CORNEA
Thursday, December 6, 2012
http://www.fightaging.org/archives/2012/12/stem-cells-and-scaffolds-to-regrow-the-cornea.php
One of a number of methods under development to regenerate or rebuild the cornea is outlined here: "Using a combination of techniques known as microstereolithography and electrospinning, the researchers are able to make a disc of biodegradable material which can be fixed over the cornea. The disc is loaded with stem cells which then multiply, allowing the body to heal the eye naturally. "The disc has an outer ring containing pockets into which stem cells taken from the patient's healthy eye can be placed. The material across the centre of the disc is thinner than the ring, so it will biodegrade more quickly allowing the stem cells to proliferate across the surface of the eye to repair the cornea." A key feature of the disc is that it contains niches or pockets to house and protect the stem cells, mirroring niches found around the rim of a healthy cornea. Standard treatments for corneal blindness are corneal transplants or grafting stem cells onto the eye using donor human amniotic membrane as a temporary carrier to deliver these cells to the eye. For some patients, the treatment can fail after a few years as the repaired eyes do not retain these stem cells, which are required to carry out on-going repair of the cornea. Without this constant repair, thick white scar tissue forms across the cornea causing partial or complete sight loss. The researchers have designed the small pockets they have built into the membrane to help cells to group together and act as a useful reservoir of daughter cells so that a healthy population of stem cells can be retained in the eye. "Laboratory tests have shown that the membranes will support cell growth, so the next stage is to trial this in patients in India. One advantage of our design is that we have made the disc from materials already in use as biodegradable sutures in the eye so we know they won't cause a problem in the body. This means that, subject to the necessary safety studies and approval from Indian Regulatory Authorities, we should be able to move to early stage clinical trials fairly quickly.""

TRIALING REGENERATIVE MEDICINE FOR HEART FAILURE
Wednesday, December 5, 2012
http://www.fightaging.org/archives/2012/12/trialing-regenerative-medicine-for-heart-failure.php
Since clinical trials for comparatively simple forms of stem cell therapy seem to be today's topic, here is another example: "Cardio3 BioSciences (C3BS) announced it has received authorization from the Belgian Federal Agency for Medicines and Health Products (FAMHP) to begin its Congestive Heart failure Cardiopoietic Regenerative Therapy (CHART-1) European Phase III trial. [The] therapy, called C3BS-CQR-1, involves taking stem cells from a patient's own bone marrow and [re-programming] those cells so that they go onto becoming heart cells. The cells, known as cardiopoietic cells, are then injected back into the patient's heart through a minimally invasive procedure using a catheter, [with] the aim of repairing damaged tissue and improving heart function and patient clinical outcomes. The trial will recruit a minimum of 240 patients with chronic advanced symptomatic heart failure. The primary endpoint of the trial is a composite endpoint including mortality, morbidity, quality of life, Six Minute Walk Test and left ventricular structure and function at 9 months post-procedure. Studies in additional countries will commence once national regulatory approvals have been received."

FIRST GENERATION STEM CELL THERAPIES MOVING THROUGH TRIALS
Wednesday, December 5, 2012
http://www.fightaging.org/archives/2012/12/first-generation-stem-cell-therapies-moving-through-trials.php
Stem cell therapies based on comparatively uncomplicated transplants of cells - either grown from the patient's own tissue or from donors - are still working their way through trials in the more regulated parts of the world, and will be for years yet. For wider access to these therapies, one has to look to medical tourism and reputable clinics overseas. So far these therapies usually result in modest or better improvements over presently available treatment options. Here is an example: "Critical limb ischemia (CLI) is a vascular disease affecting lower limbs, which is going to become a demanding challenge because of the aging of the population. Despite advances in endovascular therapies, CLI is associated with high morbidity and mortality. Patients without direct revascularization options have the worst outcomes. To date, 25%-40% of CLI patients are not candidates for surgical or endovascular approaches, ultimately facing the possibility of a major amputation. This study aimed to assess the safety and efficacy of autologous bone marrow (BM) [stem cell] transplantation performed in "no-option" patients, in terms of restoring blood perfusion by collateral flow and limb salvage. A multicenter, prospective, not-controlled phase II study for no-option CLI patients was performed. Patients were subjected to intra-arterial infusion of autologous bone marrow and followed for 12 months after the treatment. Sixty patients were enrolled and treated with BM transplantation, showing improvement in objective and subjective measures of perfusion. Furthermore, survival analysis demonstrated improved amputation-free survival rates at 12 months after the treatment."

DIASTOLIC DYSFUNCTION CORRELATES WITH AGE LEVELS
Tuesday, December 4, 2012
http://www.fightaging.org/archives/2012/12/diastolic-dysfunction-correlates-with-age-levels.php
Advanced glycation end-products (AGEs) are a form of metabolic byproduct that build up with age, causing increasing damage through their effects on cellular machinery, which ultimately manifest in harmful conditions such as reduced elasticity in blood vessels and skin. Ways to safely break down the most important forms of AGE would be greatly beneficial - but research aimed at achieving that goal is unfortunately very sparse and poorly funded. Here researchers show that some of the mechanisms of heart failure and decline in heart function correlate with the level of AGEs in the body: "Aging is accompanied by increased vascular and ventricular stiffness, diastolic dysfunction and an increased risk of heart failure. Heart failure, with either reduced or preserved ejection fraction, is associated with abnormalities of myocardial structure and microvasculature including increased fibrosis, cardiomyocyte hypertrophy and reduced microvascular density, and animal models suggest that these abnormalities precede the development of heart failure in older age. In addition, advanced glycation end-products (AGEs) are proposed to contribute to the increased myocardial stiffening of aging by cross-linking collagen and elastin and promoting collagen accumulation, and by promoting inflammation and oxidative stress mediated by the receptor for AGEs (RAGE). Moreover, plasma AGE levels correlate with the severity and prognosis of heart failure and predict all-cause and cardiovascular disease mortality in older adults. We investigated the hypothesis that diastolic dysfunction of aging humans is associated with altered myocardial structure and plasma AGE levels. [We found that] diastolic dysfunction of aging was independent of myocardial structure but was associated with plasma AGE levels."

AN INTERVIEW WITH A KRIORUS DIRECTOR
Tuesday, December 4, 2012
http://www.fightaging.org/archives/2012/12/an-interview-with-a-kriorus-director.php
Igor Artyukhov of the Institute of Biology of Aging is director of research for Russian cryonics provider KrioRus, and here is interviewed by Pravda: "Pravda: If you live forever, then you stop rushing somewhere. You can always take time because it would seem that you will always have time for everything, that you can do everything later. Igor Artyukhov: If you know you'll die anyway, you do not rush either. And most of us, by the way, live by this principle. Few people can write a book, trying to finish it before the end of life. Most of us just live. You can not bring the meaning of life from the outside. People set all goals themselves. If life is long, they will be able to set a lot of goals and reach them. If life is short, people just die. Imagine how much Galois could do, who at age 20 proved an important mathematical theorem. Let us understand one simple thing - there is nothing good either about aging or death. This is something that we have imposed on us by nature, events, our lifestyle. We do not know any laws of nature that could make aging and death inevitable. If we can cope with aging, then we should do it. Many say that it is not like this, they say that it is contrary to the laws of nature. This is incorrect. They mention the second law of thermodynamics, which has nothing to do with aging. Moreover, it turns out that there are ageless creatures in the world. The naked mole rat revealed no signs of aging. This is a tiny animal, the size of a mouse. Maybe we will be able to make man ageless too. Pravda: Old age - this is still weakness. Imagine how young people will suffer, when they are forced to endure endless moods. Igor Artyukhov: Depression is one of the manifestations of senile debility, when a person wants to die soon. It happens that people commit suicide at this age. But this is a manifestation of aging, and we want to fight with it. If we can push aging away, elderly people would stay longer in sober mind, they would feel useful to society. Pravda: How can we make old age not feeble and horrible, but joyful and fulfilling? Igor Artyukhov: Well, you first need to make it come as late as possible. In the words of biologist Ashley Montague, "I want to die young as late as possible." From my point of view, if it were possible not to die, it would be better to do without it. If this is impossible, then we must find a way to postpone death. My mission is to extend the active period of life in perpetuity."

CONSIDERING NF-κB IN AGING
Monday, December 3, 2012
http://www.fightaging.org/archives/2012/12/considering-nf-b-in-aging.php
Researcher have been examining the role of NF-κB in accelerated aging conditions such as Hutchinson-Gilford Progeria Syndrome, and believe that the findings may also be relevant as a basis for therapies to slow the ordinary progression of degenerative aging: "NF-κB transcription factors respond to a large variety of external and internal stress signals, having essential roles in development and tissue http://en.wikipedia....iki/Homeostasis>homeostasis maintenance. The in vivo monitoring of NF-κB activity by using a reporter-based assay revealed that this pathway was constitutively hyperactivated in progeroid mice. Further experiments allowed us to unveil the molecular pathway involved in this aberrant activation. [Our] results indicate that these findings can be extended to normal aging, suggesting that a common accumulation of genetic damage and nuclear envelope alterations with age could be responsible, at least in part, of the abnormal NF-κB activity reported in tissues from advanced aged donors. The accumulation of senescent cells together with the decline in adult stem cell function is a primary cause of the compromise of tissue homeostasis during aging. The primary function of NF-κB activation in this context could be related to the prevention of apoptosis of damaged cells, so that chronic activation of this pathway with the subsequent immunological decline could preclude a proper clearance of senescent and damaged cells. [Experimental data] confirm that NF-κB signaling is active during normal aging, its hyperactivation is associated with the development of accelerated aging and its amelioration retards the aging process. These characteristics support the use of strategies aimed at controlling NF-κB related inflammation as putative rejuvenation strategies during both normal and pathological aging."

REVIEWING THE ONLINE HUMAN AGING GENOMICS RESOURCES
Monday, December 3, 2012
http://www.fightaging.org/archives/2012/12/reviewing-the-online-human-aging-genomics-resources.php
Since online databases on aging research have been a recent topic, here is an open access paper that discusses a set of such databases: "The Human Ageing Genomic Resources (HAGR) is a freely available online collection of research databases and tools for the biology and genetics of ageing. HAGR features now several databases with high-quality manually curated data: (i) GenAge, a database of genes associated with ageing in humans and model organisms; (ii) AnAge, an extensive collection of longevity records and complementary traits for more than 4000 vertebrate species; and (iii) GenDR, a newly incorporated database, containing both gene mutations that interfere with dietary restriction-mediated lifespan extension and consistent gene expression changes induced by dietary restriction. Since its creation about 10 years ago, major efforts have been undertaken to maintain the quality of data in HAGR, while further continuing to develop, improve and extend it. This article briefly describes the content of HAGR and details the major updates since its previous publications, in terms of both structure and content. ... Altogether, we hope that through its improvements, the current version of HAGR will continue to provide users with the most comprehensive and accessible resources available today in the field of biogerontology."

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#42 reason

  • Guardian Reason
  • 1,101 posts
  • 243
  • Location:US

Posted 16 December 2012 - 09:00 PM

FIGHT AGING! NEWSLETTER
December 17th 2012

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

______________________________

CONTENT

- Recommended Charitable Causes in Longevity Science
- Peter Singer on SENS and Radical Life Extension
- The Life-Long Regenerative Capacity of Zebrafish
- Discussion
- Latest Headlines from Fight Aging!
    - A Look at Tissue Engineering Research
    - A Decade in Life Expectancy Gained Since 1970
    - Embryonic Versus Induced Pluripotent Stem Cells
    - The Genetics of Extreme Longevity
    - Seeking Correlations Between Fertility and Longevity in Humans
    - On Targeting Senescent Cells to Treat Aging
    - β-hydroxybutyrate in Calorie Restriction
    - Changing the Behavior of Old Skin Cells
    - Targeting Cancer Stem Cells Via DNA Repair Mechanisms
    - Engineered T Cells Versus Leukemia

RECOMMENDED CHARITABLE CAUSES IN LONGEVITY SCIENCE
http://www.fightaging.org/archives/2012/12/recommended-charitable-causes-in-longevity-science.php

The year heads towards its close again, and it seems somewhat traditional for people to make charitable 501©3 or equivalent donations around this time. I was asked for recommendations a few times in the past month, and here they are:

1) SENS Foundation

At the head of my list is the SENS Foundation, the best organized and most central of the small number of groups working on ways to rejuvenate the old by repairing the cellular and molecular damage that causes aging. The SENS Foundation is a research organization: they put money to work in the laboratory. Given that rejuvenation of the old is the goal, the Strategies for Engineered Negligible Senescence (SENS) is far more attractive as a charitable cause when compared to most aging research. The vast majority of researchers in the field of aging and longevity aim at best to modestly slow aging, if they are even working on the basis for therapies. If we want to see significant progress towards engineered human longevity in our lifetimes, it is very important to support work that credibly aims to do more than simply slow the degenerations of aging a little.

At this point in the ebb and flow of advocacy and research programs, SENS would benefit from a more rapid flow of tangible research results, preferably attractive and easily comprehended by the public at large. Bootstrapping from modest funding to grand funding is a matter of side-by-side progress in advocacy on the one hand and results in the lab on the other - neither can really move too far ahead of the other. The best way to help progress at this time is to donate and persuade others to donate, as money creates results. The SENS Foundation is a very efficient engine for turning philanthropic funds into progress in the best sort of longevity science.

If you know enough about the work under development and which approaches you favor you might even consider calling the SENS Foundation folk to talk about more directed donations - for example, if you are intrigued by the UK-based work on breaking down glucosepane. But for most of us the reason to donate to a trusted organization staffed by smart and knowledgeable folk is because they can do a better job of directing funds to the goal of engineered longevity than we can: they know the researchers, are familiar with who is doing what in which laboratories, and all the tricks of the trade when it comes to stretching funds as far as they can go. You are not going to find a better place to put money if progress towards therapies of human rejuvenation is your goal.

2) New Organ Prize

The New Organ initiative is driven by the folk at the Methuselah Foundation, in alliance with tissue printing company Organovo and a range of other advocates. They are building a crowdsourced research prize to speed development in tissue engineering of complex organs. As you might know, the Methuselah Foundation runs the Mprize for longevity science, and was the umbrella organization for SENS research prior to the formation of the SENS Foundation.

It will likely require decades to move from present day technology demonstrations in growing small amounts of structured tissue to the ability to print functional hearts, livers, and lungs to order. There is plenty of room to accelerate that process - and research prizes have shown their worth in this and many other fields of human endeavor. The faster it goes, the more lives can be saved.

Research prizes offer a purse for specific goals in development, and tend to encourage far more activity in a field than would otherwise take place. A well run prize acts as incentive, beacon, watering hole, loudspeaker, and clearing house for research and development - enlivening the field, drawing attention and funding. If you recall the way in which the Mprize for longevity science grew back when it was the Methuselah Mouse Prize - well, the New Organ Prize something like that, but with the benefit of social networks, modern online donation management services, and a focus on tissue engineering and organ printing.

PETER SINGER ON SENS AND RADICAL LIFE EXTENSION
http://www.fightaging.org/archives/2012/12/peter-singer-on-sens-and-radical-life-extension.php

Aubrey de Grey, Chief Science Officer of SENS Foundation and the world's most prominent advocate of anti-aging research, argues that it makes no sense to spend the vast majority of our medical resources on trying to combat the diseases of aging without tackling aging itself. [In] developed countries, aging is the ultimate cause of 90% of all human deaths; thus, treating aging is a form of preventive medicine for all of the diseases of old age. Moreover, even before aging leads to our death, it reduces our capacity to enjoy our own lives and to contribute positively to the lives of others.

On the other hand, we still need to pose the ethical question: Are we being selfish in seeking to extend our lives so dramatically? And, if we succeed, will the outcome be good for some but unfair to others? People in rich countries already can expect to live about 30 years longer than people in the poorest countries. If we discover how to slow aging, we might have a world in which the poor majority must face death at a time when members of the rich minority are only one-tenth of the way through their expected lifespans.

Whether we can overcome these objections depends on our degree of optimism about future technological and economic advances. De Grey's response to the first objection is that, while anti-aging treatment may be expensive initially, the price is likely to drop, as it has for so many other innovations, from computers to the drugs that prevent the development of AIDS. If the world can continue to develop economically and technologically, people will become wealthier, and, in the long run, anti-aging treatment will benefit everyone. So why not get started and make it a priority now?

De Grey has set up SENS Foundation to promote research into anti-aging. By most standards, his fundraising efforts have been successful, for the foundation now has an annual budget of around $4 million. But that is still pitifully small by the standards of medical research foundations. De Grey might be mistaken, but if there is only a small chance that he is right, the huge pay-offs make anti-aging research a better bet than areas of medical research that are currently far better funded.

THE LIFE-LONG REGENERATIVE CAPACITY OF ZEBRAFISH
http://www.fightaging.org/archives/2012/12/the-life-long-regenerative-capacity-of-zebrafish.php

Zebrafish, like a number of lower animals, have far greater regenerative abilities than we mammals. They can regrow fins and even large portions of some of their major organs. As is the case for salamanders, there is a research community working on understanding the mechanisms of this regeneration, with an eye to seeing whether it can be brought to humans anytime soon. One school of thought suggests that we and other mammals still possess the necessary biological machinery for regeneration of limbs and organs, but it is buried and inactive - after all, just like the fish, we grow from embryos. So there is at least one program for growing limbs and organs hidden in there somewhere.

Nonetheless, it remains to be seen whether it is in fact the case that a mammal can be made to regrow major body structures by following this path of salamanders and fish: there are reasonable arguments to be made for both yes and no, and it's still too early to say which it will turn out to be. There is no necessary reason for limb regeneration in one species to be in any way present but dormant in another, and there is no necessary reason for limb regeneration to be some form of re-running of the initial program of embryonic growth. These could all be different, distinct processes - and for that matter, there could be distinct, different processes of regrowth in different species with these strong regenerative abilities. Biology is always more complex than you'd like it to be.

Putting all this to one side, there is another interesting reason to study regeneration in zebrafish - their ability to regrow tissue and heal wounds doesn't decline all that much with age. From a recent paper:

"Their average lifetime is about 3 years, and recent studies have shown that zebrafish exhibit aging-related degeneration, suggesting the possibility that aging might affect regenerative potential. In order to investigate this possibility, we compared regeneration of the fin and heart after experimental amputation in young (6-12 month old) and old (26-36 month old) fish. Comparison of recovery rate of the caudal fin, measured every two or three days from one day post amputation until 13 days post amputation, show that fins in young and old fish regenerate at a similar rate. In the heart, myocardium regeneration and cardiomyocyte proliferation occurred similarly in the two groups. Our results demonstrate that zebrafish preserve a life-long regenerative ability of the caudal fin and heart."

DISCUSSION

The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!

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LATEST HEADLINES FROM FIGHT AGING!

A LOOK AT TISSUE ENGINEERING RESEARCH
Friday, December 14, 2012
http://www.fightaging.org/archives/2012/12/a-look-at-tissue-engineering-research.php
MIT news here looks at the present state of tissue engineering, with a focus on work that is taking place at their own institution: "In the 1970s and 1980s, tissue engineers began working on growing replacement organs for transplantation into patients. While scientists are still targeting that goal, much of the tissue engineering research [is] also focused on creating tissue that can be used in the lab to model human disease and test potential new drugs. Another near-term goal for tissue engineers is developing regenerative therapies that help promote wound healing. [Healthy cells] sitting adjacent to diseased tissues can influence the biology of repair and regeneration, [which might be achieved via] implantable scaffolds embedded with endothelial cells, which secrete a vast array of proteins that respond to injury. Endothelial cells, normally found lining blood vessels, could help repair damage caused by angioplasty or other surgical interventions; smoke inhalation; and cancer or cardiovascular disease. The implants are now in clinical trials to treat blood-vessel injuries caused by the needles used to perform dialysis in patients with kidney failure. One major challenge for designing implantable organs is that the tissues need to include blood vessels that can connect to the patient's own blood supply. [Researchers] are working on inducing blood vessels to form by growing cells on nanopatterned surfaces, [and] recently developed 3-D liver tissues that include their own network of blood vessels. Though still a long-term goal, being able to regenerate new organs could have a great impact on the future of health care. "It's the kind of thing that can transform society. You can't have a drug that will grow a new liver or a new heart, so this could be huge.""

A DECADE IN LIFE EXPECTANCY GAINED SINCE 1970
Friday, December 14, 2012
http://www.fightaging.org/archives/2012/12/a-decade-in-life-expectancy-gained-since-1970.php
Previous estimates of ongoing gains in life expectancy at birth put it at around a fifth of a year every year. Life expectancy at 60 rises at about half that pace - a tenth of what is needed for actuarial escape velocity. This has been incidental life extension, achieved without any deliberate attempt to tackle aging. New data suggests a slightly higher pace for gains in life expectancy at birth, with a decade gained since 1970. This is probably largely driven by increased wealth and accompanying reductions in childhood mortality: "In the first Global Burden of Disease Study 2010 paper [the] authors present new estimates of life expectancy for the last four decades in 187 different countries. While overall life expectancy is increasing globally, the gap in life expectancy between countries with the highest and lowest life expectancies has remained similar since 1970. The new estimates show that, globally, in 2010 a man's average life expectancy at birth had increased by 11.1 years (19.7%) since 1970, from 56.4 years in 1970, to 67.5 years in 2010. For women, life expectancy increased by 12.1 years (19.8%) during the same period, from 61.2 years in 1970, to 73.3 years in 2010. Deaths in children under five years old have declined by almost 60% since 1970, from 16.4 million deaths in 1970 to 6.8 million in 2010."

EMBRYONIC VERSUS INDUCED PLURIPOTENT STEM CELLS
Thursday, December 13, 2012
http://www.fightaging.org/archives/2012/12/embryonic-versus-induced-pluripotent-stem-cells.php
A review paper here looks over the biochemistry, similarities, and differences between embryonic stem cells and induced pluripotent stem cells, both of which are presently used in the development of new therapies, but the former is far more limited by regulation than the latter: "Embryonic stem cells (ESCs) are derived from the inner cell mass of the blastocysts and are characterized by the ability to renew themselves (self-renewal) and the capability to generate all the cells within the human body. In contrast, inducible pluripotent stem cells (iPSCs) are generated by transfection of four transcription factors in somatic cells. Like embryonic stem cells, they are able to self-renew and differentiate. Because of these features, both ESCs and iPSCs, are under intense clinical investigation for cell-based therapy. Since the first isolation of human Embryonic Stem Cells (ESCs) huge interest has developed in the scientific and clinical communities and in the public in general because of their therapeutic potential. In particular, attention has focused on their potential use in cell-based therapy for diseases that are refractory to conventional treatments, such as neurodegenerative diseases and immunodeficiency, because of their ability to be programmed into new mature differentiated cells of all lineages. Although our knowledge of the molecular mechanisms that control the self-renewal and differentiation of stem cells has grown considerably during the past decade, we still need more basic research in order to understand the molecular mechanisms that regulate proliferation, survival and differentiation of stem cells particularly after transplantation and in the pathological environment."

THE GENETICS OF EXTREME LONGEVITY
Thursday, December 13, 2012
http://www.fightaging.org/archives/2012/12/the-genetics-of-extreme-longevity.php
An open access review of the New England Centenarian Study: "The New England Centenarian Study (NECS) was founded in 1994 as a longitudinal study of centenarians to determine if centenarians could be a model of healthy human aging. Over time, the NECS along with other centenarian studies have demonstrated that the majority of centenarians markedly delay high mortality risk-associated diseases toward the ends of their lives, but many centenarians have a history of enduring more chronic age-related diseases for many years, women more so than men. However, the majority of centenarians seem to deal with these chronic diseases more effectively, not experiencing disability until well into their nineties. Unlike most centenarians who are less than 101 years old, people who live to the most extreme ages, e.g., 107+ years, are generally living proof of the compression of morbidity hypothesis. That is, they compress morbidity and disability to the very ends of their lives. Various studies have also demonstrated a strong familial component to extreme longevity and now evidence particularly from the NECS is revealing an increasingly important genetic component to survival to older and older ages beyond 100 years. It appears to us that this genetic component consists of many genetic modifiers each with modest effects, but as a group they can have a strong influence."

SEEKING CORRELATIONS BETWEEN FERTILITY AND LONGEVITY IN HUMANS
Wednesday, December 12, 2012
http://www.fightaging.org/archives/2012/12/seeking-correlations-between-fertility-and-longevity-in-humans.php
The results from this paper suggests that efforts to find any correlation between fertility and longevity in humans will be challenging, as in most data sets it will be swamped by associations with wealth, use of medical technologies to control fertility, and so forth: "The disposable soma theory proposes a trade-off between fertility and longevity but existing findings on this association have been mixed. This study used data from 15,622 twins born between 1901 and 1925 ascertained from the population-based Swedish Twin Registry to test the child-longevity association and whether it is accounted for by individual-level factors or by genetic and environmental factors shared by family members. Based on survival analysis, both women and men with children had significantly longer survival relative to the childless, with a slightly higher relative advantage in men. Adjustments for demographic factors and cotwin fertility did not mediate the parenting-survival association, indicating that this association is attributable to individual-level factors associated with fertility rather than family-level environmental or genetic factors shared by cotwins. These results, derived from a large, population-based sample, are inconsistent with the disposable soma theory as applied to modern human populations."

ON TARGETING SENESCENT CELLS TO TREAT AGING
Wednesday, December 12, 2012
http://www.fightaging.org/archives/2012/12/on-targeting-senescent-cells-to-treat-aging.php
Senescent cells accumulate with age, disrupting the tissues they are in, promoting inflammation, and undertaking a range of other bad behavior. Their presence is one of the causes of degenerative aging, and thus targeting them for destruction or reversal of their senescent state is a priority in longevity science: "Research has revealed that the presence of senescent cells is worse than one might think. These cells assume a special secretory form (SASP) in which they release various chemical signals that harm the health of nearby cells. In a domino effect they then damage their neighbors further accelerating the aging process. A breakthrough study earlier this year showed that using specialized genetic methods to remove senescent cells throughout the lifespan of rats reduced signs of aging in the animals. The current state of the science review article [is] written by two of the scientists who performed that study. In the paper they describe how senescent cells lead to aging in many tissues in the body. They further point out that aging of tissue is the reason for the development of diseases. "Therapeutic intervention in normal aging may prevent comorbidity and delay mortality in the elderly," they write. "In this way, targeting of senescent cells during the course of normal aging would be a preventative strategy rather than a treatment." It is also pointed out that senescent stem cells may poison stem cell niches reducing the ability to regenerate and rejuvenate tissue so that removing them there could have diffuse age reducing benefit. Of course the big question is how senescent cells could be regularly removed from all over and within the human body other than embedding programmable genes before birth like was done in lab rats. The answers remain vague but the authors offer an idea, and some hope: "If a common signature is identified for senescent cells in vivo, strategies to alleviate these effects with compounds or drugs, whether by dampening the SASP profile or by completely removing the senescent cells, can begin to be elucidated.""

β-HYDROXYBUTYRATE IN CALORIE RESTRICTION
Tuesday, December 11, 2012
http://www.fightaging.org/archives/2012/12/-hydroxybutyrate-in-calorie-restriction.php
Here is one research result among the many generated by scientists investigating the biochemistry of calorie restriction, seeking after a greater understanding of how it improves health and extends life: "[Researchers] examined the role of the compound β-hydroxybutyrate (βOHB), a so-called "ketone body" that is produced during a prolonged low-calorie or ketogenic diet. While ketone bodies such as βOHB can be toxic when present at very high concentrations in people with diseases such as Type I diabetes, Dr. Verdin and colleagues found that at lower concentrations, βOHB helps protect cells from "oxidative stress" - which occurs as certain molecules build to toxic levels in the body and contributes to the aging process. "Over the years, studies have found that restricting calories slows aging and increases longevity - however the mechanism of this effect has remained elusive. Here, we find that βOHB - the body's major source of energy during exercise or fasting - blocks a class of enzymes that would otherwise promote oxidative stress, thus protecting cells from aging." The researchers found that calorie restriction spurs βOHB production, which blocked the activity of a class of enzymes called histone deacetylases, or HDACs. Normally HDACs keep a pair of genes, called Foxo3a and Mt2, switched off. But increased levels of βOHB block the HDACs from doing so, which by default activates the two genes. Once activated, these genes kick-start a process that helps cells resist oxidative stress."

CHANGING THE BEHAVIOR OF OLD SKIN CELLS
Tuesday, December 11, 2012
http://www.fightaging.org/archives/2012/12/changing-the-behavior-of-old-skin-cells.php
The visible signs of skin aging are reflected by a similar loss of elasticity and function in important tissues inside the body, driven by declining function in stem cells that support these tissues, a steep growth in the number of senescent cells that hamper maintenance of tissue integrity, the accumulation of AGEs - largely glucosepane - and the other mechanisms that cause aging. These root causes must be dealt with, but comparatively few scientists are trying to tackle them directly. The more usual research focuses on ways to try to patch over consequences by making use of other mechanisms - somewhat akin to trying to deal with a broken dam by bailing rather than fixing the holes. Here researchers manage to reverse a fraction of the effects of skin aging: "[The] extracellular matrix, or ECM, acts like the scaffold that skin cells roost in. It's made of tiny fibrils of collagen, produced by the cells (fibroblasts). Over time, as skin ages, the ECM becomes fragmented, which causes cells to lose their connections to that scaffold - and the lack of support accelerates their decline further. The same thing may happen in other types of tissue. [Scientists] injected the skin of 21 volunteers in their 80s with a filler often used cosmetically to reduce facial wrinkles. The filler bolsters the ECM, filling in the spaces left by aging. The researchers did not receive funding from the product's manufacturer, nor did they get input on the design or results from the company. Rather, they were using the product as a way to increase the mechanical forces within the volunteers' skin. The result: over three months, the fibroblasts began expressing collagen-related genes, producing more collagen, and connecting better to the ECM. The entire layer of skin grew thicker, and more blood vessels, which nourished the cells were seen. "Fragmentation of the extracellular matrix plays an important role in skin aging, but by altering the matrix using an external filler and increasing the internal pressure, we've shown that we can essentially trigger a signal for cells to wake up. This shows that skin cells in elderly people have the capacity to respond robustly in a very positive way to alterations in the mechanical property of their environment. We still need to know more about how cells sense their environment, but in general it appears we have made a real difference in the structural integrity of skin.""

TARGETING CANCER STEM CELLS VIA DNA REPAIR MECHANISMS
Monday, December 10, 2012
http://www.fightaging.org/archives/2012/12/targeting-cancer-stem-cells-via-dna-repair-mechanisms.php
The next generation of cancer therapies will involve ways to target and destroy cancer cells with far greater precision than is possible through presently available treatments, leading to highly effective therapies with few side effects. One branch of this research and development effort involves targeting cells by characteristic differences in surface chemistry, but there are many others. This is one recent example: "In a series of experiments in mice with cancer and in cancer cells, [researchers] have shown that they can block the process by which leukemia stem cells repair themselves by targeting a particular protein, RAD52, which the cells depend on to fix genetic mistakes. The findings may lead to a new strategy to help overcome drug resistance that hinges on cancer stem cells gone awry. In chronic myeloid leukemia (CML), an enzyme called ABL1 goes into overdrive because of a chromosomal mix-up that occurs in bone marrow stem cells that are responsible for the generation of all blood components. The genes ABL1 and BCR become fused and produce a hybrid BCR-ABL1 enzyme that is always turned on. This overactive BCR-ABL1 protein drives the excessive production of white blood cells that is the hallmark of CML. In CML cells, the BCR-ABL1 protein shuts down the main DNA repair system and leukemia cells have to rely on a backup pathway for repair. Previous experiments in mice bone marrow cells lacking RAD52, a key protein in the backup system, showed that its absence abrogated the development of CML, proving that CML DNA repair depended on RAD52. [Researchers] then used an "aptamer," a peptide that mimicked the area where the RAD52 protein binds to DNA, to see the effects of blocking RAD52 from binding to DNA. The investigators found that when the aptamer was added to BCR-ABL1-positive bone marrow cells, RAD52 was prevented from binding to DNA and the leukemic bone marrow cells accumulated excessive double-strand breaks and eventually died. The aptamer had no effect on normal cells. "With this treatment in hand, we eventually hope to generate a small molecule inhibitor with which we will be able to target leukemia patients based on their oncogenic profiles. We've started to use microarrays to look at the expression profiles of the DNA repair genes in other cancers, and based on these profiles, predicted if they would be sensitive to [this] approach.""

ENGINEERED T CELLS VERSUS LEUKEMIA
Monday, December 10, 2012
http://www.fightaging.org/archives/2012/12/engineered-t-cells-versus-leukemia.php
The positive results of a cancer immunotherapy trial are noted here: "Nine of twelve leukemia patients who received infusions of their own T cells after the cells had been genetically engineered to attack the patients' tumors responded to the [therapy]. Two of the first three patients treated with the [protocol] remain healthy and in full remissions more than two years after their treatment, with the engineered cells still circulating in their bodies. The findings reveal the first successful and sustained demonstration of the use of gene transfer therapy to turn the body's own immune cells into weapons aimed at cancerous tumors. The protocol for the new treatment involves removing patients' cells through an apheresis process similar to blood donation, and modifying them in [a] vaccine production facility. Scientists there reprogram the patients' T cells to target tumor cells through a gene modification technique using a HIV-derived lentivirus vector. The vector encodes an antibody-like protein, called a chimeric antigen receptor (CAR), which is expressed on the surface of the T cells and designed to bind to a protein called CD19. The modified cells are then infused back into the patient's body following lymphodepleting chemotherapy. Once the T cells start expressing the CAR, they focus all of their killing activity on cells that express CD19, which includes [tumor] cells, and normal B cells. All of the other cells in the patient that do not express CD19 are ignored by the modified T cells, which limits systemic side effects typically experienced during traditional therapies. In addition to initiating the death of the cancer cells, a signaling molecule built into the CAR also spurs the cell to produce cytokines that trigger other T cells to multiply - building a bigger and bigger army until all the target cells in the tumor are destroyed."

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Posted 23 December 2012 - 10:10 PM

FIGHT AGING! NEWSLETTER
December 24th 2012

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

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CONTENT

- 2012 Holiday Newsletter from the SENS Research Foundation
- From the Methuselah Foundation: 2012, the Year in Review
- Overexpression of BubR1 Extends Life in Mice
- Years of Life Gained Through Leisure-Time Activity
- An Introduction to What's Going On Inside Long-Lived Mice
- Discussion
- Latest Headlines from Fight Aging!
    - A Report From the Eurosymposium on Healthy Aging
    - Using Immune Cells to Deliver Cancer-Killing Viruses
    - Treating ALS With Neural Stem Cell Transplants
    - Removing Cellular Garbage to Treat Neurodegenerative Disease
    - Life is Change, and a Longer Life Means More Change
    - We Owe it to Our Ancestors to Pursue Greater Longevity
    - Immune Therapy Versus Brain Tumors
    - Digging Deeper into Nematode Longevity via Loss of Germ Cells
    - The International Longevity Alliance
    - Inducing the Formation of a New Biological Pacemaker

2012 HOLIDAY NEWSLETTER FROM THE SENS RESEARCH FOUNDATION
http://www.fightaging.org/archives/2012/12/2012-holiday-newsletter-from-the-sens-research-foundation.php

SENS Research Foundation's mission is to transform the way the world researches and treats the diseases of aging. As another holiday season approaches, we would like to share the progress that we have made with you. Our projects on lysosomal aggregates and mitochondrial mutations at our Mountain View, California research center have advanced steadily over the last year. We have also launched a major new project on the alternative lengthening of telomeres.

Meanwhile, we continued to expand our extramural programs, conducted in collaboration with such elite university partners as Harvard, Yale, Cambridge, and Berkeley. Our development work has also made great strides. You will soon see the results of a complete logo and website design overhaul, and the world-class animations that we have commissioned to visualize the individual strands of SENS.

All that said, you can be sure that the challenge we face remains daunting. Not a single one of the conditions that cause so much suffering and claim so many lives across the world - Alzheimer's, heart disease, and diabetes, to name a few - has yet been cured. We believe that the greatest promise to not simply treat but eradicate age-related disease lies in the use of regenerative medicine: the rejuvenation biotechnology approach.

Unfortunately, despite the increasingly large amount of data indicating the effectiveness of this approach, research on "damage repair" therapies remains largely neglected.
As a nonprofit research charity, we depend on your generosity to drive this critical work. Our level of funding determines how many new scientific projects we can sponsor, how loudly we can broadcast our message, and how many students we can educate about the SENS platform. We have come a long way with your help so far, and have many more steps that we can take.

FROM THE METHUSELAH FOUNDATION: 2012, THE YEAR IN REVIEW
http://www.fightaging.org/archives/2012/12/from-the-methuselah-foundation-2012-the-year-in-review.php

n the spirit of the season, we've been looking back on the last year at Methuselah Foundation and appreciating everything we have to be thankful for. And we want you to know that you're at the top of the list. Without our many donors, colleagues, partners, and friends, we could never do what we do. We're so grateful for your ongoing support, and we'd like to thank you for believing so fervently, like we do, in the enormous promise of regenerative medicine for extending healthy human life.

Thanks to your generosity, Methuselah made significant progress in 2012 on our flagship project, the New Organ Prize. We launched a beta website at neworgan.org and kicked off our first campaign to raise $100,000 and inspire 100 people to become "New Organizers." We quadrupled the size of our online community at facebook.com/neworganprize. We're collaborating with the gifted filmmaker Michael Marantz (The Future is Ours) on a video highlighting regenerative medicine as a lasting solution to the organ crisis. We've been working with tissue engineering pioneers like Dr. Anthony Atala, Dr. Paolo Macchiarini, and Dr. Gabor Forgacs to beging shaping prize rules and criteria. And as we enter December, we're only $20,000 away from reaching our $100,000 goal for New Organ in 2012.

The field of regenerative medicine is truly coming of age, with growing public interest and more press coverage during the past six months than at any time we can remember. We even saw a Nobel Prize in Medicine this year for Dr. Shinya Yamanaka and Dr. John Gurdon's work on pluripotent stem cells. From all of us at the Methuselah Foundation, happy holidays, and thank you once again for everything you do. We're looking forward to sharing an even brighter 2013 with you.

OVEREXPRESSION OF BUBR1 EXTENDS LIFE IN MICE
http://www.fightaging.org/archives/2012/12/less-bubr1-accelerates-aging-but-more-bubr1-appears-to-slow-the-progression-of-aging.php

Biologists report that genetically engineered mice that make extra BubR1 are less prone to cancer. For example, they found that when they exposed normal mice to a chemical that causes lung and skin tumors, all of them got cancer. But only 33% of those overexpressing BubR1 at high levels did. They also found that these animals developed fatal cancers much later than normal mice - after about 2 years, only 15% of the engineered mice had died of cancer, compared with roughly 40% of normal mice.

The animals that overexpressed BubR1 at high levels also lived 15% longer than controls, on average. And the mice looked veritably Olympian on a treadmill, running about twice as far - 200 meters rather than 100 meters - as control animals. All of this left [researchers] thinking that BuBR1's life-extending effects aren't due to only its ability to prevent cancer, although that's not yet certain.

BubR1 overexpression markedly reduced aneuploidy (a state of having an abnormal number of chromosomes), which causes birth defects. Other results showed these mice were protected from muscle fiber deterioration, that they were better performers in treadmill tests, that they had much reduced levels of renal sclerosis, intestinal fibrosis and tubular atrophy - all signs of aging. They also showed higher cardiac-stress tolerance and resistance to age-related retinal atrophy.

YEARS OF LIFE GAINED THROUGH LEISURE TIME ACTIVITY
http://www.fightaging.org/archives/2012/12/years-of-life-gained-due-to-leisure-time-physical-activity.php

Data from the National Health and Nutrition Examination Survey (2007-2010); National Health Interview Study mortality linkage (1990-2006); and U.S. Life Tables (2006) were used to estimate and compare life expectancy at each age of adult life for inactive (no moderate to vigorous physical activity); somewhat-active (some moderate to vigorous activity); and active ([more] moderate to vigorous activity) adults. Analyses were conducted in 2012.

Somewhat-active and active non-Hispanic white men had a life expectancy at age 20 years that was ∼2.4 years longer than that for the inactive men; this life expectancy advantage was 1.2 years at age 80 years. Similar observations were made in non-Hispanic white women, with a higher life expectancy within the active category of 3.0 years at age 20 years and 1.6 years at age 80 years. In non-Hispanic black women, as many as 5.5 potential years of life were gained due to physical activity. Significant increases in longevity were also observed within somewhat-active and active non-Hispanic black men; however, among Hispanics the years-of-life-gained estimates were not significantly different from 0 years gained.

The estimates in the present study for non-Hispanic white men aged 20 years [suggest] that 2.6 hours [of overall life expectancy] are gained per hour of moderate activity and 5.2 hours were gained per hour of vigorous activity accrued in adulthood.

AN INTRODUCTION TO WHAT'S GOING ON INSIDE LONG-LIVED MICE
http://www.fightaging.org/archives/2012/12/an-introduction-to-whats-going-on-inside-long-lived-mice.php

The remarkable extension of longevity in mice lacking GH or GH receptors appears to be due to multiple interacting mechanisms including reduced activation of growth-promoting pathways, greater stress resistance, reduced inflammation, increased reservoir of pluripotent stem cells, and improved genome maintenance.

Data summarized in this article indicate that alterations in energy metabolism and improved insulin control of carbohydrate homeostasis have to be added to this list. In fact, these metabolic adaptations may represent key features of the "longevous" phenotype of these animals and important mechanisms of the extension of both healthspan and lifespan in GH-related mutants.

Importantly, many of the metabolic features of long-lived mutant mice described in this article have been associated with extended human longevity. Comparisons between centenarians and elderly individuals from the same population and between the offspring of exceptionally long-lived people and their partners indicate that reduced insulin, improved insulin sensitivity, increased adiponectin, and reduced pro-inflammatory markers consistently correlate with improved life expectancy.

DISCUSSION

The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!

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LATEST HEADLINES FROM FIGHT AGING!

A REPORT FROM THE EUROSYMPOSIUM ON HEALTHY AGING
Friday, December 21, 2012
http://www.fightaging.org/archives/2012/12/a-report-from-the-eurosymposium-on-healthy-aging.php
The Eurosymposium on Healthy Aging took place in Brussels earlier this month, a gathering of researchers and advocates for longevity science. The presentations were recorded and videos have been posted to Youtube. I encourage you to browse. Here is a report on the event: "Theoretical questions of longevity were covered in the first day, including such themes as the general overviews of ageing theories, molecular damage in ageing, mitochondria and autophagy. The general panel on causes, mechanisms, and interventions in aging, featured Drs. Aubrey de Grey, David Gems, Kris Verburgh, and Diana Van Heemst, and was moderated by Sven Bulterijs of HEALES. The second day featured an inspiring plethora of promising potential interventions for increasing healthy longevity: genetics of aging and centenarians research, nutritional and pharmacological interventions in aging, biomedical interventions such as repair of damaged mitochondria, destruction of senescent cells, use of telomerase to extend health span, remediation of the Alzheimer's disease, and regenerative medicine, including both cell material and computational aspects. The main subject of the third day was the political and social promotion of research into the biology of aging and healthy longevity. Discussion groups were formed and tentative suggestions made for increasing funding for life extension research, improving public opinion of life extension, and scientific positioning of life-extension."

USING IMMUNE CELLS TO DELIVER CANCER-KILLING VIRUSES
Friday, December 21, 2012
http://www.fightaging.org/archives/2012/12/using-immune-cells-to-deliver-cancer-killing-viruses.php
A successful demonstration of a novel form of immune therapy is noted in this article, and described in a recently published paper: "An experimental "Trojan-horse" cancer therapy has completely eliminated prostate cancer in experiments on mice. [The] team hid cancer killing viruses inside the immune system in order to sneak them into a tumour. [After] chemotherapy or radiotherapy is used to treat cancer, there is damage to the tissue. This causes a surge in white blood cells, which swamp the area to help repair the damage. "We're surfing that wave to get as many white blood cells to deliver tumour-busting viruses into the heart of a tumour." [Researchers] blood samples and extract macrophages, a part of the immune system which normally attacks foreign invaders. These are mixed with a virus which, just like HIV, avoids being attacked and instead becomes a passenger in the white blood cell. In the study, the mice were injected with the white blood cells two days after a course of chemotherapy ended. At this stage each white blood cell contained just a couple of viruses. However, once the macrophages enter the tumour the virus can replicate. After about 12 hours the white blood cells burst and eject up to 10,000 viruses each - which go on to infect, and kill, the cancerous cells. At the end of the 40-day study, all the mice who were given the Trojan treatment were still alive and had no signs of tumours. By comparison, mice given other treatments died and their cancer had spread."

TREATING ALS WITH NEURAL STEM CELL TRANSPLANTS
Thursday, December 20, 2012
http://www.fightaging.org/archives/2012/12/treating-als-with-neural-stem-cell-transplants.php
Many of the early forms of stem cell therapy involve cell transplants, and seem to produce benefits without those transplanted cells creating replacements for lost native cells. Instead the newcomers are improving the local environment and issuing signals that allow greater survival and repair among the native cell populations. Here is an example of the type: "Promising new research provides evidence that amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, may be treatable using neural stem cells. A consortium of researchers at multiple institutions [have] shown that neural stem cells, when transplanted into the spinal cord of a mouse model with familial ALS, slow disease onset and progression while improving motor function, breathing and survival time compared to untreated mice. Neural stem cells are the precursors of all brain cells. They can self-renew, making more neural stem cells, and differentiate, becoming nerve cells or other brain cells. These cells can also rescue malfunctioning nerve cells and help preserve and regenerate brain tissue. But they've never before been studied extensively in a good model of adult ALS. In 11 independent studies [researchers] transplanted neural stem cells into the spinal cord of a mouse model of ALS. The transplanted neural stem cells benefited the mice with ALS by preserving the health and function of the remaining nerve cells. Specifically, the neural stem cells promoted the production of protective molecules that spared remaining nerve cells from destruction. They also reduced inflammation and suppressed the number of toxin-producing and disease-causing cells in the host's spinal cord."

REMOVING CELLULAR GARBAGE TO TREAT NEURODEGENERATIVE DISEASE
Thursday, December 20, 2012
http://www.fightaging.org/archives/2012/12/removing-cellular-garbage-to-treat-neurodegenerative-disease.php
Improving the ability of cells to clear out garbage is a potential therapy for a wide range of conditions - probably including aging itself, as the failure of garage clearance mechanisms related to the lysosome contributes to degenerative aging. In past years researchers have noted that calorie restriction seems to boost garbage clearance and the cellular recycling known as autophagy, while making autophagy more efficient has been used to rejuvenate liver function in old mice. Here researchers are tinkering with garbage clearance in the brain as a way to treat neurodegenerative conditions, many of which seem to involve a buildup of unwanted and harmful compunds inside cells: "[Researchers] found that the issue in amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) is the inability of the cell's protein garbage disposal system to "pull out" and destroy TDP-43, a powerful, sometimes mutated gene that produces excess amounts of protein inside the nucleus of a nerve cell, or neuron. The way to rev up protein disposal is to add parkin - the cell's natural disposal units - to brain cells. In this study, [researchers] demonstrated in two animal experiments that delivering parkin genes to neurons slowed down ALS pathologies linked to TDP-43. [The] study further demonstrates that clumps known as "inclusions" of TDP-43 protein found inside neuron bodies in both disorders do not promote these diseases, as some researchers have argued. What happens in both diseases is that this protein, which is a potent regulator of thousands of genes, leaves the nucleus and collects inside the gel-like cytoplasm of the neuron. In ALS, also known as Lou Gehrig's disease, this occurs in motor neurons, affecting movement; in FTD, it occurs in the frontal lobe of the brain, leading to dementia. "Our study suggests TDP-43 in the cell cytoplasm is deposited there in order to eventually be destroyed - without contributing to disease - and that TDP-43 in the nucleus is causing the damage. Because so much protein is being produced, the cell can't keep up with removing these toxic particles in the nucleus and the dumping of them in the cytoplasm. There may be a way to fix this problem." [Researchers] found that parkin "tags" TDP-43 protein in the nucleus with a molecule that takes it from the nucleus and into the cytoplasm of the cell. "This is good. If TDP-43 is in the cytoplasm, it will prevent further nuclear damage and deregulation of genetic materials that determine protein identity, We think parkin is tagging proteins in the nucleus for destruction, but there just isn't enough parkin around - compared with over-production of TDP-43 - to do the job.""

LIFE IS CHANGE, AND A LONGER LIFE MEANS MORE CHANGE
Wednesday, December 19, 2012
http://www.fightaging.org/archives/2012/12/life-is-change-and-a-longer-life-means-more-change.php
Change is coming, more of it in the next few decades than has taken place in the past few centuries: progress is accelerating. We are the species that builds and changes - but inside we still carry the evolved instincts of the ape, and he greatly dislikes change, no matter whether or not it is positive. How much of opposition to human life extension is predicated on fear of change? ""Wouldn't you eventually get bored?" Like clockwork, the question arises when I tell someone quixotically, arrogantly, that I plan on living forever. From the limited perspective of 20 years, even the prospect of living another six or seven decades in full color can be impossible to envisage. Hedging, I answer that assuming a world where radical life extension is possible, there will be no telling as to how different the human experience will be from what we know. Returning to the original question - in essence: "Why choose to live forever if forever really just means eternal boredom and senescence?" - it's apparent that living forever would mean something other than continuing as our current selves. Technology futurists are reasonably certain that at some point in the next century, we'll be enmeshed in networks of artificial intelligence, bodily modified beyond immediate recognition, and confronted with a new set of identity questions, societal challenges, and existential ambitions. If I'm fortunate enough to make it to 150, I expect to find a world where caring about ethnic politics in the Middle East, wearing university colors, impressing girls, and investigating my ancestral origins won't be of much, if any, use. In other words, I expect that I'll need to invent a new self for a radically new world. More than anything I can imagine, it'll be a tall order. We have good evolutionary reason to love ourselves to death rather than contemplate being completely reconfigured. It's a daunting prospect to imagine, but it's anything but boring."

WE OWE IT TO OUR ANCESTORS TO PURSUE GREATER LONGEVITY
Wednesday, December 19, 2012
http://www.fightaging.org/archives/2012/12/we-owe-it-to-our-ancestors-to-pursue-greater-longevity.php
In the past I've discussed whether or not we are obliged to future generations, morally bound to work on making their world a better place by producing rejuvenation biotechnologies. Here, it is suggested that we are obliged to past generations - that we owe much to their efforts to improve the human condition and should thus continue to do the same, as a sign of respect at the very least: "Humanity has braved the weather many times over the millennia, surviving long enough to invent language, an earth-shattering breakthrough in their time. Language to them was as big of a game changing breakthrough than the internet is to the world now. We pushed on through famines and wars, the cold, the heat, the wild. We figured out how to harness fire. We learned how to farm so we could live in greater abundance. That gave rise to more free time to invent and explore, and led us through progressions like the bronze and iron ages. This in turn enabled so many other things eventually leading up through times like the great industrial age. Humanity exponentially shifted a gear soon after, and moved on through the technology revolution. The struggle and strife and hardship and toil that has been gone through to get us here is deeper than I can imagine. I try sometimes, as many of you might also, and its horrifying. The world is filled with graveyards; the soil is drenched in blood, sweat and tears. The dreams realized and the dreams shattered echo across the millennia and eons. If we could have collected all the hardship on video to play it in a huge montage then I imagine it might kill us from strife. We owe this to them, we owe the creation of indefinite life spans to them. They have brought us through all that to this great cusp of destiny. We grab the baton, on the ground work that our ancestors put down for us, with their blood coursing through our veins. [They] had to die for us to be here. They had to give us all that they did and then die so that we may have what we have. We don't have what we have because it magically appeared here. We have it because they toiled and died for us to have it. We cannot pilfer it and waste the opportunity, we have to keep pioneering existence, we have to keep building, we have to keep pushing the boundaries, because that is the wage they earned."

IMMUNE THERAPY VERSUS BRAIN TUMORS
Tuesday, December 18, 2012
http://www.fightaging.org/archives/2012/12/immune-therapy-versus-brain-tumors.php
Cancer immunotherapy technology demonstrations continue to roll in. This one is representative of what is taking place in many laboratories these days: "Using an artificial protein that stimulates the body's natural immune system to fight cancer, a research team [has] engineered a lethal weapon that kills brain tumors in mice while sparing other tissue. If it can be shown to work in humans, it would overcome a major obstacle that has hampered the effectiveness of immune-based therapies. The protein is manufactured with two arms - one that exclusively binds to tumor cells and another that snags the body's fighter T-cells, spurring an attack on the tumor. In six out of eight mice with brain tumors, the treatment resulted in cures. "This work represents a revival of a somewhat old concept that targeting cancer with tumor-specific antigens may well be the most effective way to treat cancer without toxicity. But there have been problems with that approach, especially for brain tumors. Our therapeutic agent is exciting, because it acts like Velcro to bind T-cells to tumor cells and induces them to kill without any negative effects on surrounding normal tissues. One of the major advantages is that this therapy can be given intravenously, crossing the blood-brain barrier. When we gave the therapy systemically to the mice, it successfully localized to the tumors, treating even bulky and invasive tumors in the central nervous system.""

DIGGING DEEPER INTO NEMATODE LONGEVITY VIA LOSS OF GERM CELLS
Tuesday, December 18, 2012
http://www.fightaging.org/archives/2012/12/digging-deeper-into-nematode-longevity-via-loss-of-germ-cells.php
If you remove germ cells from nematode worms or flies they live longer. Researchers continue to investigate the mechanisms involved: "The gonad is well known to be important for reproduction but also affects animal life span. Removal of germ cells - the sperm and egg producing cells - increases longevity of the roundworm Caenorhabditis elegans. However, the underlying molecular mechanisms were a mystery. [The] roundworm Caenorhabditis elegans is a commonly used model organism in the field of ageing research. It develops from an egg to adult through four larval stages. These developmental stages are controlled by a developmental clock. [Researchers] used a laser to remove the germ cells. They found that the remaining gonadal cells trigger production of a steroid hormone called dafachronic acid. Dafachronic acid activates so-called microRNAs, which work as tiny molecular switches causing changes in gene expression that promote longevity. Interestingly, this same steroid hormone-microRNA switch was previously shown [to] be part of the developmental clock. Thus, the loss of the germ cells ultimately causes the worm to use developmental timers to put in motion a life-prolonging programme."

THE INTERNATIONAL LONGEVITY ALLIANCE
Monday, December 17, 2012
http://www.fightaging.org/archives/2012/12/the-international-longevity-alliance.php
This past year, efforts have started in the longevity science community to form single-issue political parties in Russia and some European Union countries. This is a long-standing form of advocacy in that part of the world, where political systems are structured in such a way that having a formal party - even if small - opens the door to reaching more people with your message. Successful examples from past years include the Green Party and the Pirate Party. The various newly-founded longevity party initiatives have a unified banner organization called the International Longevity Alliance. That group recently launched their website: "The International Longevity Alliance promotes the social struggle against the deteriorative aging process and for healthy and productive longevity for all, through scientific research, technological development, medical treatment, public health and education measures, and social activism. We believe that this goal can be achieved through broad public cooperation and support, from all nations and all walks of life. Hence, the International Longevity Alliance promotes the creation and international cooperation of social activist and advocacy groups from across the world. Advocacy Groups within the International Longevity Alliance have been initiated in more than 30 countries. Currently we are in the process of official registration as a non-profit, non-governmental international public association. Several options for registration are considered, mainly in the US and EU, that would ensure the optimal and egalitarian international cooperation. Petitions in support of research of aging and longevity are being promoted in the EU, US and Russia."

INDUCING THE FORMATION OF A NEW BIOLOGICAL PACEMAKER
Monday, December 17, 2012
http://www.fightaging.org/archives/2012/12/inducing-the-formation-of-a-new-biological-pacemaker.php
Researchers demonstrate the ability to guide heartbeats by introducing pacemaker cells: "A human heart is made up of billions of cells, but researchers say fewer than 10,000 are responsible for controlling the heartbeat. Age and disease can lead to problems such as the heart pumping too fast or too slow - and it can even stop completely, in what is known as a cardiac arrest. A team of [researchers] tried to restore the heart's own ability to dictate the beat by creating new pacemaker cells. They used a virus to infect heart muscle cells with a gene, called Tbx18, which is normally active when pacemaker cells are formed during normal development in an embryo. When heart cells were infected with the virus they became smaller, thin and tapered as they acquired the "distinctive features of pacemaker cells." When the virus was injected into a region of the hearts of seven guinea pigs, five later had heartbeats which originated from their new pacemaker. [Researchers expect] the same method to work in the human heart as they used a human gene, Tbx18, to generate the effect. "It opens up the tantalising possibility of using cell therapy to restore normal heart rhythm in people who would otherwise need electronic pacemakers. However, much more research now needs to be done to understand if these findings can help people with heart disease in the future.""

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Posted 30 December 2012 - 05:08 PM

FIGHT AGING! NEWSLETTER
December 31st 2012

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

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CONTENT

- Longevity Research: Donate Now or Donate Later?
- Compression of Morbidity Versus Increasing Longevity
- From the Russian End of the Longevity Science Community
- An Interview With Stephen Valentine
- An Update on Organovo
- Discussion
- Latest Headlines from Fight Aging!
    - The Emergence of Biogerontology as a Discipline
    - Considering the Business of Regenerative Medicine
    - Reviewing Mitochondrial Activity and Longevity
    - Using Stem Cell Transplants to Boost Neurogenesis
    - Blocking miR-15 Boosts Regenerative Capacity in the Heart
    - Progress in Therapies for Retinitis Pigmentosa
    - Further Commentary on Hydra Longevity
    - Suppressing the Inflammasome in Alzheimer's
    - Repairing Blindness Due to Corneal Limbal Stem Cell Deficiency
    - Health Extension Salons, Bay Area and Expanding

LONGEVITY RESEARCH: DONATE NOW OR DONATE LATER?
http://www.fightaging.org/archives/2012/12/longevity-research-donate-now-or-donate-later.php

Life is a sequence of decisions involving time and resources: how much, how long, now, or later? Everything from choosing a career to deciding whether to reach for the salt passes through the engine in your mind that weighs costs and time. In this, helping to further the advance of longevity science is the same as any other human endeavor. We choose when to support research, we try to pick the best research to support based on likely outcomes, and we choose how much support to give.

I've debated the money axis ad nauseam, so let us do something different and look at the time axis for a change. You could choose to donate resources today to an organization like the SENS Research Foundation, one that funds the most promising projects in the laboratory, or you could wait to donate in some future year. Some arguments to either side:

Donating Later

On balance, I am likely to have more resources to donate later. If I soundly invest what I would have donated now, it will most likely be worth more in later years. This is not a certainty, but a reasonable expectation.

The cost of life science research is falling dramatically. If I donate the same amount later, more can be accomplished, and more rapidly, than now.

Donating Now

Work that isn't accomplished today will have to be accomplished tomorrow. It may be faster and cheaper to complete that research project if we start twenty years from now, but what if we could be long done by then, even though today's progress is slow and expensive by comparison? Every year shaved from the time taken to develop new medicines means many lives saved.

If you don't use money when you have it, it has a way of vanishing amid life's slings and arrows. Not donating today easily turns into not donating at all. Just as "paying yourself first" is the way to enforce savings in spite of your worse nature, so maintaining a steady stream of donations today is the way to ensure that you actually make a difference.

Without providing support now, a range of researchers and organizations that can make best use of your resources will not emerge to accept later donations. Growth in the sciences is as much about establishing institutions that have authority and continuity as anything else. Funds here and now are needed for all of their functions: drawing new researchers into the field; bringing respect to the field; communicating to the public; educating students. No great research community, dedicated to a cause, arises spontaneously from nothing. Years or decades of steadily increasing funds and incremental progress are required.

Donating now encourages other people to donate very soon. It is a form of persuasion, granting legitimacy in other people's eyes to the project you favor. When you do not donate now, you miss the chance to persuade others now.

In Conclusion

Donate now. Unless you find yourself in the rare and envious position of knowing in certainty that a stupendous pile of money will fall upon your bank account in years to come. In which case, donate both now and after that fortunate event.

Over the years I have watched many people churning their way through the energetic startup community of the US West Coast, putting off many things in their lives because of the conviction that they would have time and much money to deal with them later. Among the ways to wealth, it is true that doing a good job of starting a company (and a good job of being networked while doing it) is the best shot at success - but best is a far way from a sure thing, or even a good chance. I can assure you that most of the people involved in that world do not end up wealthy enough to have justified putting off anything.

The same, at a more sedate pace, applies to the rest of us. Tomorrow is what we build today. If we set down no bricks, there will be no wall.

COMPRESSION OF MORBIDITY VERSUS INCREASING LONGEVITY
http://www.fightaging.org/archives/2012/12/compression-of-morbidity-versus-increasing-longevity.php

Back in the Fight Aging! archives, you'll find a post on breaking out historical data on increases in human longevity into two components: firstly an increase in the average years lived, and secondly a reduction in early mortality - that more people are reaching ever closer to the average. This second statistical behavior is often presented as compression of morbidity, with the goal being to reduce the time spent in ill health at the end of life.

There is some debate over whether compression of morbidity is in any way a realistic or even useful goal for medical science, as opposed to aiming for increased human longevity through repair and reduction in the ongoing damage that causes aging. If you consider aging in terms of reliability theory, for example, it seems dubious that one could engineer the machineries of human life to last a set time and then fall apart very rapidly at the end - at least not without deliberately making it fall apart at the end. If all you are doing is consistently removing damage, then you extend the length of life, but don't do much about the time taken to fall apart when you stop repairing damage.

In any case, here is a recent paper that revisits this structural decomposition of increased longevity. The researchers here suggest that it is longevity, not compression of morbidity, that is the important factor:

In low-mortality countries, life expectancy is increasing steadily. This increase can be disentangled into two separate components: the delayed incidence of death (i.e. the rectangularization of the survival curve) and the shift of maximal age at death to the right (i.e. the extension of longevity).

We studied the secular increase of life expectancy at age 50 in nine European countries between 1922 and 2006. The respective contributions of rectangularization and longevity to increasing life expectancy are quantified with a specific tool.

For men, an acceleration of rectangularization was observed in the 1980s in all nine countries, whereas a deceleration occurred among women in six countries in the 1960s. These diverging trends are likely to reflect the gender-specific trends in smoking. As for longevity, the extension was steady from 1922 in both genders in almost all countries. The gain of years due to longevity extension exceeded the gain due to rectangularization. This predominance over rectangularization was still observed during the most recent decades.

FROM THE RUSSIAN END OF THE LONGEVITY SCIENCE COMMUNITY
http://www.fightaging.org/archives/2012/12/from-the-russian-end-of-the-longevity-science-community.php

Right now one can't come to the hospital and say, "doctor, I've got a problem, I am aging." People would laugh at such a patient, however this is the best kind of patient, the smartest one, one who cares about his future and wants to prevent the upcoming illnesses and frailty.

Let's say you touched the light of truth and decide to convince people of the need to spend their resources on radical life extension. First, please accept my admiration - what you think - is the most important task for you, for me and for all the people on the planet. Now your goal is to convey a simple message to your buddies to live - good and bad die. Here you will find a shock, most people do not agree with this rather obvious postulate. The overwhelming majority stand against their own immediate death, but insist on the fact that the after-life is beautiful and that man should not argue with nature in the matter of aging.

There is another school in transhumanism, which states that people need to talk about a more moderate view of prevention of age-related diseases and healthy aging, and then most people will agree to help. In my view, this agreement is not worth anything, because for one it has not yet gained any great success, but more importantly it does not lead to scientific experiments aimed at radical life extension. I believe that you first need to attract people who want to live a long time, who want to live come what may. Then you deliver the motivation, a way to wake up such a man. You have the most wonderful news for him that ever he heard: "You have a chance not to die!"

AN INTERVIEW WITH STEPHEN VALENTINE
http://www.fightaging.org/archives/2012/12/an-interview-with-stephen-valentine.php

No one's claiming that human reanimation is within our grasp yet, although the Cryonics Institute claims that insects, vinegar eels and human brain tissue (not to mention human embryos, as shown by the growing success of IVF treatment) have been stored at liquid nitrogen temperature, at which point all decay ceases, and then revived fully.

"No one's saying, 'Hey, we cryopreserved a dog and brought it back,'" says Stephen. "The breakthroughs come at a slow, slow pace, but the advantage with being cryopreserved is that you have time. If they can work it out in 100 or 200 years, you're not going anywhere. You're on ice for a while..."

The early part of the procedure is now certainly feasible, thanks to a process called vitrification. Before, one of the main stumbling blocks to freezing bodies was the damage caused to tissue by ice crystals (think about how inferior a steak that's been in the freezer tastes: that's because of molecular damage caused by crystallisation).

Not surprisingly, Stephen is optimistic. "Many scientists are saying that this is going to be considered the century of immortality," he says. [Meanwhile], he insists that life-preservation is not just for the elite few. "This is no exclusive club," he says. "It's affordable to anybody, because it can be paid for through life insurance. Most people around the world can do it if they want."

Irritated that doubters still see life extension as a crackpot notion, Stephen points out that every major scientific breakthrough in history was once deemed unthinkable. "When Christiaan Barnard did the first heart transplant in 1967 in South Africa, they thought the guy was an unethical monster," he says. "Today, thousands of heart transplants take place every year and - rightly - no one questions the moral or ethical issues of it."

The international cryonics community certainly has no shortage of widely celebrated scientists on its side. Marvin Minsky, the pioneer of artificial intelligence, is a supporter; Ray Kurzweil, the author and inventor, has signed up with for preservation with Alcor; molecular nanotechnologist K Eric Drexler is an advocate; as are prominent stem-cell researcher Michael West and Aubrey de Grey, a prominent gerontologist (the scientific study of ageing).

AN UPDATE ON ORGANOVO
http://www.fightaging.org/archives/2012/12/an-update-on-organovo-1.php

Organovo is the organ printing company that was partially funded in the early days with an investment from the Methuselah Foundation - an investment that the Foundation has done well by so far. In turn, the Organovo founders are noteworthy supporters of the crowdfunded New Organ Prize that the Foundation is working on these days.

Organovo has engineered a good position for itself even though the technologies it works on will take another decade or two to arrive at maturity. The research community won't be printing organs next year, but between here and the arrival of printed organs somewhere in the 2020s there are many commercially viable products that build upon one another: tissue for research, machinery for laboratories, and so forth.

DISCUSSION

The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!

______________________________

LATEST HEADLINES FROM FIGHT AGING!

THE EMERGENCE OF BIOGERONTOLOGY AS A DISCIPLINE
Friday, December 28, 2012
http://www.fightaging.org/archives/2012/12/the-emergence-of-biogerontology-as-a-discipline.php
Here is a review paper that looks back at the recent history of biogerontology as a field of study, noting the struggle with long-held perceptions of fraud associated with the intersection of aging and medicine: "Through archival analysis this article traces the emergence, maintenance, and enhancement of biogerontology as a scientific discipline in the United States. At first, biogerontologists' attempts to control human aging were regarded as a questionable pursuit due to: perceptions that their efforts were associated with the long history of charlatanic, anti-aging medical practices; the idea that anti-aging is a "forbidden science" ethically and scientifically; and the perception that the field was scientifically bereft of rigor and scientific innovation. The hard-fought establishment of the National Institute on Aging, scientific advancements in genetics and biotechnology, and consistent "boundary work" by scientists, have allowed biogerontology to flourish and gain substantial legitimacy with other scientists and funding agencies, and in the public imagination. In particular, research on genetics and aging has enhanced the stature and promise of the discipline by setting it on a research trajectory in which explanations of the aging process, rather than mere descriptions, have become a central focus. Moreover, if biogerontologists' efforts to control the processes of human aging are successful, this trajectory has profound implications for how we conceive of aging, and for the future of many of our social institutions."

CONSIDERING THE BUSINESS OF REGENERATIVE MEDICINE
Friday, December 28, 2012
http://www.fightaging.org/archives/2012/12/considering-the-business-of-regenerative-medicine.php
Looking back at past commercial development in medicine is a fair way to manage expectations for present efforts to bring therapies to the clinic. The short version of the story is that there are certainly cycles in which expectations outpace results, but those results arrive in the end: "Like many advanced technologies, the field of regenerative medicine has gone from boom to nearly bust to boom again in the span of just 30 years. Today, there are over 55 regenerative medicine products on the market focused on diverse therapeutic areas, including repair of skin/soft tissue, wound care, cardiology, oncology, and diabetes. Thirty years in, regenerative medicine has truly "come of age," the result of a tenacious pursuit to translate groundbreaking research into therapeutic products and overcome initial setbacks that almost derailed this critical new medical approach. Yet while the past decade's focus on scientific advances and business fundamentals has propelled regenerative medicine forward, I believe this is just the start. By reflecting on the successes and lessons learned over the past three decades, we can begin to chart a roadmap for the future that will help to ensure that regenerative medicine continues to deliver important new treatments for patients, while creating sustainable value for shareholders. From its origins in the mid-1980s, regenerative medicine was greeted with the kind of extreme excitement that has accompanied other potential breakthroughs, including monoclonal antibodies and RNA interference. By the year 2000, more than a decade after the first companies were formed, regenerative medicine companies were valued at over $2.6 billion, TIME named tissue engineering one of the hottest jobs for the 21st century, and Barron's predicted it would become a $100 billion industry. A few years later, the bubble had burst, and company valuations plummeted to a tenth of their year 2000-high. Several factors contributed to these setbacks. First, like many new medical advances, expectations far exceeded reality. Investors and the media saw incredible promise in early research, and unrealistic timelines were set for when a product could be on the market. Second, the initial regenerative medicine products to reach the market had limited commercial success, as the few companies in the space had not yet understood all that was required to achieve both clinical and commercial success. From a scientific perspective, the field was poised to deliver, but it had not yet developed the regulatory, business, and commercial expertise required for long-term success. In the wake of these setbacks, there came a clear understanding of what was needed to propel regenerative medicine forward and strike the appropriate balance between promise and reality. When I joined Organogenesis in 2003, the company was emerging from bankruptcy and a dissolved commercial partnership with big pharma. In the decade since, I have experienced firsthand the rebirth of our company, and on a larger scale, of the regenerative medicine field itself. Our path over the past decade has taught us several lessons about what it will take to succeed in this space going forward."

REVIEWING MITOCHONDRIAL ACTIVITY AND LONGEVITY
Thursday, December 27, 2012
http://www.fightaging.org/archives/2012/12/reviewing-mitochondrial-activity-and-longevity.php
Mitochondria are the power plants of your cells, responsible for creating the energy stores that are used to power cellular operations. Mitochondrial composition is an important determinant of longevity, and accumulating mitochondrial damage - self-inflicted in the course of the operation of metabolism - is one of the root causes of aging. Here researchers review what is know of mitochondrial decline in aging, and the ways in which mitochondrial function can be altered to extend life in laboratory animals: "For decades, aging was considered the inevitable result of the accumulation of damaged macromolecules due to environmental factors and intrinsic processes. Our current knowledge clearly supports that aging is a complex biological process influenced by multiple evolutionary conserved molecular pathways. With the advanced age, loss of cellular homeostasis severely affects the structure and function of various tissues, especially those highly sensitive to stressful conditions like the central nervous system. In this regard, the age-related regression of neural circuits and the consequent poor neuronal plasticity have been associated with metabolic dysfunctions, in which the decline of mitochondrial activity significantly contributes. Interestingly, while mitochondrial lesions promote the onset of degenerative disorders, mild mitochondrial manipulations delay some of the age-related phenotypes and, more importantly, increase the lifespan of organisms ranging from invertebrates to mammals. Here, we survey the insulin/IGF-1 and the TOR signaling pathways and review how these two important longevity determinants regulate mitochondrial activity. Furthermore, we discuss the contribution of slight mitochondrial dysfunction in the engagement of pro-longevity processes and the opposite role of strong mitochondrial dysfunction in neurodegeneration."

USING STEM CELL TRANSPLANTS TO BOOST NEUROGENESIS
Thursday, December 27, 2012
http://www.fightaging.org/archives/2012/12/using-stem-cell-transplants-to-boost-neurogenesis.php
Failing neural plasticity, the ability of the brain to adapt and continue creating new neurons, seems to be important in aging. Here researchers investigate the ability of some forms of stem cell transplant to boost the pace of http://en.wikipedia....ki/Neurogenesis>neurogenesis, the creation of neurons: "Neurogenesis occurs throughout life but significantly decreases with age. Human umbilical cord blood mononuclear cells (HUCB MNCs) have been shown to increase the proliferation of neural stem cells (NSCs) in the dentate gyrus (DG) of the hippocampus and the subgranular zone of aging rats, but it is unclear which fraction or combination of the HUCB MNCs are responsible for neurogenesis. To address this issue, we examined the ability of HUCB MNCs [to] increase proliferation of NSCs. [We] injected HUCB cells intravenously in young and aged [rats] and examined proliferation in the DG at 1 week and 2 weeks postinjection. HUCB-derived [cells] increased NSC proliferation at both 1 and 2 weeks while also enhancing the density of dendritic spines at 1 week and decreasing inflammation at 2 weeks postinjection. Collectively, these data indicate that a single injection of HUCB-derived T cells induces long-lasting effects and may therefore have tremendous potential to improve aging neurogenesis."

BLOCKING MIR-15 BOOSTS REGENERATIVE CAPACITY IN THE HEART
Wednesday, December 26, 2012
http://www.fightaging.org/archives/2012/12/blocking-mir-15-boosts-regenerative-capacity-in-the-heart.php
One important outgrowth of stem cell research is the search for ways to manipulate existing cell populations into greater feats of regeneration. Eventually, it would be hoped, the research community can gain sufficient control over cells in the body so as not to need stem cell transplants at all. Meanwhile scientists are uncovering advances such as this one: "Researchers have pinpointed a molecular mechanism needed to unleash the heart's ability to regenerate, a critical step toward developing eventual therapies for damage suffered following a heart attack. Researchers found that hearts of young rodents mounted a robust regenerative response following myocardial infarction, but this restorative activity only occurs during the first week of life. They then discovered that a microRNA called miR-15 disables the regenerative capacity after one week, but when miR-15 is blocked, the regenerative process can be sustained much longer. Further research will be needed to optimize the ways in which medical scientists, and eventually clinicians, may be able to control this regenerative process. "This may well be the beginning of a new era in heart regeneration biology. Our research provides hope that reawakening the regenerative capacity of adult mammalian hearts is within reach.""

PROGRESS IN THERAPIES FOR RETINITIS PIGMENTOSA
Wednesday, December 26, 2012
http://www.fightaging.org/archives/2012/12/progress-in-therapies-for-retinitis-pigmentosa.php
Therapies for several forms of degenerative blindness have been under development for some years. Here is news of progress towards trials for two of them: "Two recent experimental treatments - one involving skin-derived induced pluripotent stem (iPS) cell grafts, the other gene therapy - have been shown to produce long-term improvement in visual function in mouse models of retinitis pigmentosa (RP). Researchers tested the long-term safety and efficacy of using iPS cell grafts to restore visual function in a mouse model of RP. [The] cells were administered, via injection directly underneath the retina, when the mice were five days old. The iPS cells assimilated into the host retina without disruption, and none of the mice receiving transplants developed tumors over their lifetimes, the researchers reported. The iPS cells were found to express markers specific to retinal pigmented epithelium (the cell layer adjacent to the photoreceptor layer), showing that they had the potential to develop into functional retinal cells. Using electroretinography, a standard method for measuring retinal function, the researchers found that the visual function of the mice improved after treatment and the effect was long lasting. In the [other] study, the [researchers] tested whether gene therapy could be used to improve photoreceptor survival and neuronal function in mice with RP caused by a mutation to a gene called phosphodiesterase-alpha (Pde6α) - a common form of the disease in humans. To treat the mice, the researchers used adeno-associated viruses (AAV) to ferry correct copies of the gene into the retina. The AAV were administered by a single injection in one eye, with the other eye serving as a control. When the mice were examined at six months of age (over one-third of the mouse lifespan), photoreceptor cells were found in the treated eyes but not in the untreated eyes, the researchers reported. More important, the treated eyes showed functional visual responses, while the untreated eyes had lost all vision."

FURTHER COMMENTARY ON HYDRA LONGEVITY
Tuesday, December 25, 2012
http://www.fightaging.org/archives/2012/12/further-commentary-on-hydra-longevity.php
Last month the popular press was doing its normal breathless job of failing to adequately understand and present the facts in relation to research into aging and longevity. In this case it related to recent research into hydra. These small water creatures may be ageless, or at least age very slowly, and are certainly very competent when it comes to regeneration from injury, but that's about as far as it goes - it seems unlikely that profound advances immediately applicable to humans lurk in hydra biology. Instead this is the standard slow gathering of new knowledge, adding to the grand picture of the evolution of aging, longevity, and the plethora of individual mechanisms that contribute to these traits. Here is a short open access commentary on the recent hydra research: "Clues to the role of FOXO3A in controlling longevity may be available through the comparative study of organisms which show no sign of aging. One of the very few examples of animals which appear to be truly immortal is the freshwater polyp Hydra. Much of Hydra's remarkable immortality can be traced back to the asexual mode of reproduction by budding which requires a tissue consisting of stem cells with continuous self-renewal capacity. [Hydra's] stem cells indeed continuously proliferate and generate eternal lineages. How? This question has been plaguing some of us since the late 1980s. In the new study, a literally immortal model organism was induced to both stem cell senescence and immune senescence by altering the expression level of a single gene, the longevity factor FoxO. The data suggest that FoxO has ancient roles in controlling stem cell behavior that may underlie longevity. The findings have captured the imagination of the popular press, and raised the skeptic's eyebrows. What lessons can actually be learned from the Hydra study? What does this mean for understanding human longevity? First, the Hydra results have moved the longevity-enabling FOXO3A gene from reported association to possible functions, corroborating and extending beyond previous observations in C. elegans and Drosophila. Second, the link between FoxO and components of the innate immune system is of particular interest since aging processes in humans are known to result in impairment of both innate and adaptive immunity ("immunosenescence") as well as in a pro-inflammatory status ("inflammaging"). Third, the Hydra study strengthens the earlier described role of FOXO3A in human stem cell maintenance and regulation. This hypothesis warrants further investigation and indicates another plausible mechanism through which FOXO3A variation may exert its effect on longevity. Attempts to extend the lessons learnt from Hydra to more complex organisms including humans will be challenging. However, the recent study is a proof of principle that investigations in Hydra stem cells hold promise. The more we learn about the role of FoxO in Hydra, the better we will understand how the gene and its variants contribute to longevity in humans."

SUPPRESSING THE INFLAMMASOME IN ALZHEIMER'S
Tuesday, December 25, 2012
http://www.fightaging.org/archives/2012/12/suppressing-the-inflammasome-in-alzheimers.php
Inflammation is an important process in the progression of Alzheimer's disease, and researchers have been turning their attention to ways to manipulate inflammation as a form of treatment: "The complex named "NLRP3 inflammasome" is composed of several proteins and plays a key role in the immune system. It resembles a fire alarm sensor that triggers a chain reaction when activated. As a result, immune cells are mobilized and substances that foster inflammation are released. This process can be triggered by infections, which are subsequently suppressed by the immune response. However, in the case of Alzheimer's disease, the activation of the molecular alarm may have negative consequences: nerve cells are damaged and die. Ultimately, this leads to the loss of brain function and mental capabilities in humans. The researchers collected a comprehensive chain of evidences: they examined both the brains of deceased Alzheimer patients and of mice who exhibited behavioural disorders that are typically associated with Alzheimer's disease. The researchers found an activated form of the NLRP3 inflammasome in both cases. Looking at another group of mice, the scientists examined possibilities for suppressing inflammatory reactions. To achieve this, they removed the genes that trigger production of the NLRP3 inflammasome. Therefore, these mice were no longer able to synthesize the protein complex. As a result, the animals developed only relatively mild symptoms of the disease. Moreover, their brains showed only reduced amounts of the damaging plaques."

REPAIRING BLINDNESS DUE TO CORNEAL LIMBAL STEM CELL DEFICIENCY
Monday, December 24, 2012
http://www.fightaging.org/archives/2012/12/repairing-blindness-due-to-corneal-limbal-stem-cell-deficiency.php
Here is an example of a stem cell therapy that is just a little advanced over established medical techniques - in effect just a more sophisticated and cost-effective version of a tissue transplant: "A variety of things can cause [corneal limbal stem cell deficiency], including chemical and thermal burns to the corneas, which are the glass "domes" over the coloured part of our eyes. But it's also thought that microbial infections and wearing daily wear contact lenses for too long without properly disinfecting them can lead to the disease, too. Since a corneal transplant was not an option for Binns, his doctors at Toronto Western Hospital proposed something new: a limbal stem cell transplant. The limbus is the border area between the cornea and the whites of the eye where the eye normally creates new epithelial cells. Since Binns' limbus was damaged, doctors hoped that giving him healthy limbal cells from a donor would cause healthy new cells to grow over the surface. While the treatment is available in certain centres around the U.S., Binns became the first patient to try the treatment at a new program at Toronto Western Hospital. Though Binns knew he'd need to take anti-rejection drugs, he decided the procedure was worth a try. Just like with an organ transplant, Binns' doctors had to find a healthy match. It turned out his younger sister, Victoria, was the ideal candidate for the job. In the operating room, doctors removed the scar tissue on Taylor's eyes, then took some healthy stem cells from Victoria's eyes and stitched them to the surface of Binns' eyes. "Within a month he could see 20/40. His last visit he was 20/20 and 20/40." Researchers are also working on using stem cells from deceased donors and even using limbal stem cells from a patient's own eyes. While that would require growing the cells in a lab to force them to multiply, it would also mean that patients might be able to skip anti-rejection drugs."

HEALTH EXTENSION SALONS, BAY AREA AND EXPANDING
Monday, December 24, 2012
http://www.fightaging.org/archives/2012/12/health-extension-salons-bay-area-and-expanding.php
The Health Extension salons are an ongoing series of meetups in the Bay Area for people interested in supporting and advancing longevity science, associated with the energetic technology entrepreneur community there. This sort of initiative is important, as grassroots efforts associated with this community have a way of growing and getting things done. There are a number of presentation videos at the meetup site from previous events, and you might consider helping out if you are in the area: "The Health Extension community is committed to information sharing and collaborative action to extend healthy and happy human lifespans to 123 years and beyond. Our members are scientists, entrepreneurs and social influencers dedicated to fixing the degenerative cellular processes that cause deadly human diseases. This community began in early 2012 as informal meet-ups in the home of Joe and Lisa Betts-La Croix. Our 100+ members now meet monthly at Y Combinator HQ in Mountain View, California with plans to launch salons and other projects in Los Angeles and New York in 2013."

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Posted 06 January 2013 - 07:50 PM

FIGHT AGING! NEWSLETTER
January 7th 2013

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

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CONTENT

- Looking Back at 2012
- Instructing Scar Tissue to Change Itself into Healthy Tissue
- Why Not Infuse a Person With Many, Many, Many Immune Cells?
- Vision and Efforts Made to Live Longer
- Discussion
- Latest Headlines from Fight Aging!
    - Dopamine Receptor Variant Associated With Longevity
    - UCP1 Extends Longevity Via Hormesis?
    - TFP5 Shows Promise for Treating Alzheimer's Disease
    - Does Lichen Age?
    - A French Interview with Aubrey de Grey
    - Reduced Frataxin Expression Extends Life in Nematodes
    - In Search of the Roots of Heat Shock Hormesis
    - A New Record For Human Male Longevity
    - Early Growth Rate and Aging
    - Reviewing the Mechanisms of Muscle Atrophy

LOOKING BACK AT 2012
http://www.fightaging.org/archives/2012/12/looking-back-at-2012.php

That was 2012: another year closer to both the grave and the rejuvenation biotechnology to keep us out of it. This is very much a race, but one in which we can all do our part to help the right horse win. Research runs on money and popularity - but mostly money. Every little bit helps.

Follow the link above to read a long Fight Aging! post that reviews the more noteworthy events and research results from the field of longevity science presented this past year, alongside many links to items of interest.

INSTRUCTING SCAR TISSUE TO CHANGE ITSELF INTO HEALTHY TISSUE
http://www.fightaging.org/archives/2013/01/instructing-scar-tissue-to-change-itself-into-healthy-tissue.php

A cocktail of three specific genes can reprogram cells in the scars caused by heart attacks into functioning muscle cells, and the addition of a gene that stimulates the growth of blood vessels enhances that effect. "The idea of reprogramming scar tissue in the heart into functioning heart muscle was exciting. The theory is that if you have a big heart attack, your doctor can just inject these three genes into the scar tissue during surgery and change it back into heart muscle."

Changing the scar into heart muscle would strengthen the heart. To accomplish this, during surgery, [researchers] transferred three forms of the vascular endothelial growth factor (VEGF) gene that enhances blood vessel growth or an inactive material (both attached to a gene vector) into the hearts of rats. Three weeks later, the rats received either Gata4, Mef 2c and Tbx5 (the cocktail of transcription factor genes called GMT) or an inactive material.

The GMT genes alone reduced the amount of scar tissue by half compared to animals that did not receive the genes, and there were more heart muscle cells in the animals that were treated with GMT. The hearts of animals that received GMT alone also worked better as defined by ejection fraction than those who had not received genes. [The] hearts of the animals that had received both the GMT and the VEGF gene transfers had an ejection fraction four times greater than that of the animals that had received only the GMT transfer.

WHY NOT INFUSE A PERSON WITH MANY, MANY, MANY IMMUNE CELLS?
http://www.fightaging.org/archives/2013/01/why-not-infuse-a-person-with-many-many-many-immune-cells.php

One of the many things that can be accomplished today, but largely isn't due to regulation, is infusion of a large number of immune cells grown from a patient's own cells. Existing immune cells - or even skin cells - can be reprogrammed to form induced pluripotent stem cells, which can then be then expanded in number and redifferentiated into the hunter killer cells that rove the body in search of things to destroy.

So why not look ahead to a range of treatments that involve temporarily endowing a person with twice as many immune cells as he or she normally possesses? Or five times as many, or ten times as many, or more? There may well be a why not, at least one that lies beyond the concern shared with all stem cell treatments, which is controlling these cells well enough to avoid the risk of pluripotent cells slipping through and generating some form of cancer. That why not hasn't surfaced yet, however, and the fastest way to see whether or not it exists is more research, more clinical trials, and more responsible medical tourism.

VISION AND EFFORTS MADE TO LIVE LONGER
http://www.fightaging.org/archives/2013/01/vision-and-efforts-made-to-live-longer.php

The thesis in a post from last month at Overcoming Bias is that futurists, at least those with the vision to see the golden future ahead better than most folk, don't really do that much more to live longer. Which sounds about right from what I've seen. Do people, even those with vision, really care all that much about living longer? Sometimes it looks like the answer is, on average, not so much. At least not enough to make immediate sacrifices in money and time or hard left turns in the course of life.

One might argue that increasing nihilism with age is something fundamental to the human condition. In order to be successful in our evolutionary role, we have to, on balance, manage to be good worker ants even as the day of our demise looms closer. Whatever benefits we are providing to the propagation of our genes when old, benefits that caused human life span to evolve to be much longer than similarly sized mammals, we can only provide them if staying the course. When young, time preference is on your side: the psychology of discounting the future applies just as much to horrible, terrible things as it does to beneficial events. But later in life something has to take its place, some growing sense of acceptance, one of the many long-standing delusions regarding personal immortality, or disinclination to care one way or another.

People don't tend to break down and run around screaming in later life even though, to my mind at least, it seems that there is every justification for it. I don't think that this is a cultural thing per se, though its exact manifestation might be. Somewhere around the time that most people hit their stride in life, they have every incentive and the evolved wherewithall to stop caring about the fact that life is being stolen from them.

Which is something of a problem. You can only help people who want to help themselves, and those folk serious about building biotechnology and new medicine to intervene in the aging process are a tiny minority. Their entire aggregate yearly funding wouldn't stretch to a large building project in a small city. The world turns, and its population, by their actions, just doesn't seem to care all that greatly about aging to death.

It is a puzzle of our time, given that the very same people would already be taking advantage of these technologies were they in common use, the same way as they go to their annual checkups and brush their teeth.

DISCUSSION

The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!

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LATEST HEADLINES FROM FIGHT AGING!

DOPAMINE RECEPTOR VARIANT ASSOCIATED WITH LONGEVITY
Friday, January 4, 2013
http://www.fightaging.org/archives/2013/01/dopamine-receptor-variant-associated-with-longevity.php
This research illustrates one of the many challenges associated with untangling genetic contributions to longevity; some of those genes affect personality traits that are also known to correlate with longevity: "A variant of a gene associated with active personality traits in humans seems to also be involved with living a longer life. [This] derivative of a dopamine-receptor gene - called the DRD4 7R allele - appears in significantly higher rates in people more than 90 years old and is linked to lifespan increases in mouse studies. The variant gene is part of the dopamine system, which facilitates the transmission of signals among neurons and plays a major role in the brain network responsible for attention and reward-driven learning. The DRD4 7R allele blunts dopamine signaling, which enhances individuals' reactivity to their environment. People who carry this variant gene [seem] to be more motivated to pursue social, intellectual and physical activities. The variant is also linked to attention-deficit/hyperactivity disorder and addictive and risky behaviors. "While the genetic variant may not directly influence longevity, it is associated with personality traits that have been shown to be important for living a longer, healthier life. It's been well documented that the more you're involved with social and physical activities, the more likely you'll live longer. It could be as simple as that.""

UCP1 EXTENDS LONGEVITY VIA HORMESIS?
Friday, January 4, 2013
http://www.fightaging.org/archives/2013/01/ucp1-extends-longevity-via-hormesis.php
Uncoupling proteins affect mitochondrial function, altering the balance of energy going to heat versus building ATP molecules to store it for use elsewhere. Like a range of other mitochondrial manipulations, altering levels of uncoupling proteins can extend life in laboratory animals, and here researchers suggest this works via hormesis, causing just enough damage to spur repair mechanisms to greater ongoing effects for a net overall gain: "Ectopic expression of uncoupling protein 1 (UCP1) in skeletal muscle (SM) mitochondria considerably increases lifespan in high fat diet fed UCP1 transgenic (TG) mice in comparison to wildtype (WT). In order to clarify the underlying mechanisms we investigated substrate metabolism as well as oxidative stress damage and antioxidant defense in SM of low fat and high fat fed mice. TG mice [showed] elevated lipid peroxidative protein modifications with no changes in glycoxidation or direct protein oxidation. This was paralleled by an induction of catalase and superoxide dismutase activity, an increased redox signaling (MAPK signaling pathway), and increased expression of stress protective heat shock protein 25. We conclude that increased skeletal muscle mitochondrial uncoupling in vivo does not reduce the oxidative stress status in the muscle cell. Moreover it increases lipid metabolism and reactive lipid-derived carbonyls. This stress induction in turn increases the endogenous antioxidant defense system and redox signaling. All together our data argue for an adaptive role of reactive species as essential signaling molecules for health and longevity."

TFP5 SHOWS PROMISE FOR TREATING ALZHEIMER'S DISEASE
Thursday, January 3, 2013
http://www.fightaging.org/archives/2013/01/tfp5-shows-promise-for-treating-alzheimers-disease.php
A new candidate for building an Alzheimer's therapy shows promise in mice: "When a molecule called TFP5 is injected into mice with disease that is the equivalent of human Alzheimer's, symptoms are reversed and memory is restored - without obvious toxic side effects. "We hope that clinical trial studies in AD patients should yield an extended and a better quality of life as observed in mice upon TFP5 treatment. Therefore, we suggest that TFP5 should be an effective therapeutic compound." To make this discovery, [researchers] used mice with a disease considered the equivalent of Alzheimer's. One set of these mice were injected with the small molecule TFP5, while the other was injected with saline as placebo. The mice, after a series of intraperitoneal injections of TFP5, displayed a substantial reduction in the various disease symptoms along with restoration of memory loss. In addition, the mice receiving TFP5 injections experienced no weight loss, neurological stress (anxiety) or signs of toxicity. The disease in the placebo mice, however, progressed normally as expected. TFP5 was derived from the regulator of a key brain enzyme, called Cdk5. The over activation of Cdk5 is implicated in the formation of plaques and tangles, the major hallmark of Alzheimer's disease."

DOES LICHEN AGE?
Thursday, January 3, 2013
http://www.fightaging.org/archives/2013/01/does-lichen-age.php
There are many candidates for ageless organisms, such as the hydra or the lobster, and some that have been revealed to in fact age in recent years as research costs fall far enough to allow these niche questions to be answered. Bacteria, for example, do age, but that was only conclusively established comparatively recently. Aging is not a large field in comparison to the life science mainstream, which is one of the reasons why there are so many unanswered questions relating to aging in various species. Here is a fairly typical example - a collection of lower species that may or may not age, probably does so in a very different way to higher organisms, and where the process is largely unstudied. "Pale green and vaguely ruffled, like calcified doilies, lichens grow all over the tombstones and the old stone walls that fringe properties in this part of the world. Most people barely notice them. But Dr. Pringle, a mycologist at Harvard, believes they may help answer one of science's greatest questions: Is immortality biologically possible? For eight years, Dr. Pringle, 42, has been returning to this cemetery each fall, to measure, sketch and scrutinize the lichens, which belong to the genus Xanthoparmelia. She wants to know whether they deteriorate with the passage of time, leaving them more susceptible to death. Lichens are not individuals but tiny ecosystems, composed of one main fungus, a group of algae and an assortment of smaller fungi and bacteria. [While] lichens are communities, Dr. Pringle is largely interested in the fungi. Mycologists, the scientists who study fungi - not the most glamorous corridor of biology - have long assumed that many of these organisms don't age.The clear exception is yeast, a single-cell fungus that does senesce and that researchers use as a model to study aging. But most multicellular fungi, the assumption goes, don't senesce. No one has ever proved that, though, or even collected much data."

A FRENCH INTERVIEW WITH AUBREY DE GREY
Wednesday, January 2, 2013
http://www.fightaging.org/archives/2013/01/a-french-interview-with-aubrey-de-grey.php
In the French language press, translated via machine: "[JOL Press]: You are often described as "the man who tries to make us immortal." Immortality, do you believe? [Aubrey de Grey]: I do not agree with this presentation of my research. Sensationalism and this annoys me a lot because it undermines our credibility and affects, therefore, the money we can raise for [the research that] we finance. [JOL Press]: In this case, how would you describe your work? [Aubrey de Grey]: SENS is an association with a research center in California. We drive medical research whose goal is to prevent people from getting sick. One of our projects which we hope to make public soon, revolutionary advances, is to insert a gene [derived from bacteria] in our patients and prevent them from dying from cardiovascular disease - the No. 1 cause of death today. [JOL Press]: You say "soon", you hope when? [Aubrey de Grey]: In time ... there are different approaches to deal with - and destroy - the effects of aging on an individual and we are progressing slowly. We are continuing our experiments. If all goes as we hope, we expect significant gains in the rats of 8 to 10 years, then apply to humans in 20 or 40 years. [JOL Press]: Specifically, what do you mean by "treating aging"? [Aubrey de Grey]: Humans can live healthier, longer. Our approach is to transform the aging process. [JOL Press]: How do you get there? [Aubrey de Grey]: Regenerative medicine aims to repair the effects of damage, to prevent their recurrence. Our goal is to reverse the process, rather than just stop it or slow it down."

REDUCED FRATAXIN EXPRESSION EXTENDS LIFE IN NEMATODES
Wednesday, January 2, 2013
http://www.fightaging.org/archives/2013/01/reduced-frataxin-expression-extends-life-in-nematodes.php
Many of the methods of extending life in laboratory animals involve boosting levels of autophagy, the cellular housekeeping processes that remove damaged components and unwanted proteins. Here is another of them: "Severe mitochondria deficiency leads to a number of devastating degenerative disorders, yet, mild mitochondrial dysfunction in different species, including the nematode Caenorhabditis elegans, can have pro-longevity effects. This apparent paradox indicates that cellular adaptation to partial mitochondrial stress can induce beneficial responses, but how this is achieved is largely unknown. Complete absence of frataxin, the mitochondrial protein defective in patients with Friedreich ataxia, is lethal in C. elegans, while its partial deficiency extends animal lifespan in a p53 dependent manner. In this paper we provide further insight into frataxin control of C. elegans longevity by showing that a substantial reduction of frataxin protein expression is required to extend lifespan, affect sensory neurons functionality, remodel lipid metabolism and trigger autophagy. We find that Beclin and p53 genes are required to induce autophagy and concurrently reduce lipid storages and extend animal lifespan in response to frataxin suppression. Reciprocally, frataxin expression modulates autophagy in the absence of p53. Human Friedreich ataxia-derived lymphoblasts also display increased autophagy, indicating an evolutionarily conserved response to reduced frataxin expression. In sum, we demonstrate a causal connection between induction of autophagy and lifespan extension following reduced frataxin expression."

IN SEARCH OF THE ROOTS OF HEAT SHOCK HORMESIS
Tuesday, January 1, 2013
http://www.fightaging.org/archives/2013/01/in-search-of-the-roots-of-heat-shock-hormesis.php
The heat shock response can induce hormetic benefits: repair and maintenance systems are spurred to greater activity for some time, leading to a healthier, longer-lived organism. Researchers are in search of the pivotal mechanisms of this process, with an eye to targeting them in therapies: ""That which does not kill us, makes us stronger" This famous quote by Friedrich Nietzsche is exemplified by the phenomenon of "hormesis". Exposure of organisms to mild stress fortifies them against subsequent, more severe insults. Yet, the relevant molecular mechanisms remain poorly understood. [Small heat shock proteins, or sHSPs] constitute a diverse family of proteins with multiple roles. Several ageing theories suggest that longevity positively correlates with the ability of the cell and the organism to resist stress. Ageing influences both general and organelle-specific stress response pathways. Distinct experimental approaches have identified proteins that are abundant in long-lived worms. Intriguingly, the most consistently represented subset is the sHSP group, including the HSP-16 family. We propose that HSP-16.1 mediates its protective effect partly by preserving cellular ionic homeostasis, which is perturbed in the stressful context of ageing. How could sHSPs protect under unfavorable conditions? In stressed cells, ATP levels drop significantly leading to fatal aggregation of damaged proteins. sHSPs protect proteins from thermal denaturation and irreversible aggregation in an ATP-independent manner. We propose that sHSPs constitute one of the cell's first lines of defense against cell death."

A NEW RECORD FOR HUMAN MALE LONGEVITY
Tuesday, January 1, 2013
http://www.fightaging.org/archives/2013/01/a-new-record-for-human-male-longevity.php
One of the expected signs of an upward trend in longevity is the setting of new records in maximum human life span, and an increase in the number of people getting closer to that record. The longest documented human life, that of Jeanne Calment, was an unusual statistical outlier, however, so despite progress that record will stand for a while at the current rate of increase in elder life expectancy. On the male side of the house there is no such unusually long-lived individual in the verified records, and the age of the oldest male supercentenarians is indeed inching upward: "[On December 28th] Jiroemon Kiruma has set a world record. At 115 years 253 days he has become the oldest living man in history. The record was previously held by Christian Mortensen who lived to 115 years 252 days. Among supercentenarians being a male is particularly rare. The oldest living person in history was a woman named Jeanne Calment who lived to be 122. Currently there are 64 supercentenarians in the world (those 110 years and old) and only 4 of them are males. Kiruma is also the oldest living person in the world, a record he achieved when Dina Mafredini of Iowa passed away ten days ago. Kiruma has a strong will to live per family members, though presently he is in a hospital suffering from an illness of 10 days duration. His condition is noted to be improving. "His condition has improved, and we're not worried, but the doctors said it would be best if he stayed in the hospital into the new year," said Yasuhiro Kawato a hospital spokesperson. Kimura lives with his grandson's widow Eiko Kimura, and continues to eat three small meals per day, a strategy he has maintained for life. He is conversant and generally cheerful though now spends most of his time in bed. He has also escaped disease."

EARLY GROWTH RATE AND AGING
Monday, December 31, 2012
http://www.fightaging.org/archives/2012/12/early-growth-rate-and-aging.php
From earlier this month, something to think about in the context of reliability theory and life span: "Manipulating growth rates in stickleback fish can extend their lifespan by nearly a third or reduce it by 15 percent. [Researchers] altered the growth rate of 240 fish by exposing them to brief cold or warm spells, which put them behind or ahead their normal growth schedule. Once the environmental temperature was returned to normal, the fish got back on track by accelerating or slowing their growth accordingly. However, the change in growth rate also affected their rate of ageing. While the normal lifespan of sticklebacks is around two years, the slow-growth fish lived for more than 30 percent longer, with an average lifespan of nearly 1000 days. In contrast, the accelerated-growth fish had a lifespan that was 15% shorter than normal. These effects occurred despite all fish reaching the same adult size, and were even stronger when the rate of growth was increased by artificially manipulating the length of daylight the fish were exposed to, 'tricking' their bodies into growing faster to reach their target size before the start of the breeding season. The results of the study are striking. It appears that bodies which grow quickly accumulate greater tissue damage than those that grow more slowly and their lifespan is substantially reduced as a result. The study also demonstrates the surprising ways in which a slight change in environmental conditions in early life can have long-term consequences. These findings are likely to apply to many other species, including humans, since the manner in which organs and tissues grow and age is similar across very different kinds of animal. It has already been documented in humans, for example, that rapid growth in early childhood is associated with a greater risk of developing ailments later in life such as cardiovascular disease in middle or old age, possibly because of the way in which the tissues of a fast-grown heart are laid down."

REVIEWING THE MECHANISMS OF MUSCLE ATROPHY
Monday, December 31, 2012
http://www.fightaging.org/archives/2012/12/reviewing-the-mechanisms-of-muscle-atrophy.php
Muscle mass and strength diminish with age, and researchers are making steady progress into understanding exactly why this is the case. Rejuvenation biotechnologies of the sort proposed in the SENS plan should reverse this decline, but most researchers are looking more narrowly at intervening in secondary mechanisms - patching the problem rather than attacking aging at its roots. "Skeletal muscle is a plastic organ that is maintained by multiple pathways regulating cell and protein turnover. During muscle atrophy, proteolytic systems are activated, and contractile proteins and organelles are removed, resulting in the shrinkage of muscle fibers. Excessive loss of muscle mass is associated with poor prognosis in several diseases, including myopathies and muscular dystrophies, as well as in systemic disorders such as cancer, diabetes, sepsis and heart failure. Muscle loss also occurs during aging. In this paper, we review the key mechanisms that regulate the turnover of contractile proteins and organelles in muscle tissue, and discuss how impairments in these mechanisms can contribute to muscle atrophy. We also discuss how protein synthesis and degradation are coordinately regulated by signaling pathways that are influenced by mechanical stress, physical activity, and the availability of nutrients and growth factors. Understanding how these pathways regulate muscle mass will provide new therapeutic targets for the prevention and treatment of muscle atrophy in metabolic and neuromuscular diseases."

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#46 reason

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Posted 13 January 2013 - 09:36 PM

FIGHT AGING! NEWSLETTER
January 14th 2013

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

______________________________

CONTENT

- Fat and Mortality Rates Again
- Rebuilding an Artery With Stem Cells
- Deuterium and Lifespan in Flies
- Discussion
- Latest Headlines from Fight Aging!
    - Endurance Training Associated With Longer Telomeres
    - Unpublished Reader's Digest Interview on Aging and Longevity
    - Fat Tissue Knockout of Mitochondrial Transcription Factor A is Beneficial, and May Extend Life in Mice
    - Regenerating Hair Cells to Restore Hearing
    - Identifying a Mechanism for Nematode Longevity via Bifidobacteria in the Diet
    - Towards Therapies for Regeneration of Dental Pulp
    - News from the International Longevity Alliance
    - Cell Transplants to Rebuild the Retina
    - Comments on the State of Medical Biotechnology Development
    - Data From the Genetics of Healthy Ageing Project

FAT AND MORTALITY RATES AGAIN
http://www.fightaging.org/archives/2013/01/fat-and-mortality-rates-again.php

I'll preface this post by noting that one should always pay attention to the incentives operating behind any particular piece of news as it makes its way through the cultural landscape. In this case it is news about weight and mortality risk, and the incentive that always seems close to mind here is that, on balance, overweight people like to be told that they are not risking their health and longevity by being overweight. No one enjoys bad news, and bad news about general health always has that implied nagging edge of personal criticism. Good news is so much more welcome.

Thus there has been more press attention than usual given to the latest big metastudy on weight and mortality risk, as it claims that being slightly overweight is better than being of normal weight when it comes to mortality rates. Being obese still shows up as a bad lifestyle choice. The paper is open access and very readable, but here's the press release:

"The researchers found [a] 6 percent lower risk of death for overweight; a 18 percent higher risk of death for obesity (all grades); a 5 percent lower risk of death for grade 1 obesity; and a 29 percent increased risk of death for grades 2 and 3 obesity. The authors note that the finding that grade 1 obesity was not associated with higher mortality suggests that that the excess mortality in obesity may predominantly be due to elevated mortality at higher BMI levels."

I can roll out some of the obvious theorizing myself without trying too hard: average weight is increasing and thus more of the people of normal weight in fact have something wrong with them that causes weight loss and higher mortality; wealth effects and corresponding access to medical services have some relation to weight and are thus distorting the picture; overweight people have higher medical expenditures and are getting value for that expense; and so forth. Many versions of this sort of pseudo-explanation are doing the rounds, including the standard objections to working with BMI as a measure in the first place, as it isn't necessarily a great proxy for visceral fat mass.

Beyond the fact that people want to hear that they are just fine the way they are, the issue here is a collision of large masses of data. On the one side there is a huge, mountainous pile of evidence to show that excess visceral fat is very bad for you. Even a modest amount above a normal weight raises the risk of later age-related disease and shortens your life expectancy. Calorie restriction in humans, which necessitates leanness, is shown to be very, very positive for all measures of health. It goes on.

On the other hand we have this meta-study and other similar items from past years to claim that irrespective of all this data showing that fat is bad for health, people who are slightly overweight still live longer. There are no doubt some researchers out there who see this as an opportunity: how to reconcile these two collections of research. If there is a consensus among scientists with an interest in the field, I'd have to say it looks like one that leans towards the evidence that fat is bad, and therefore something has yet to be explained in the structure or underlying threads of causation in these mortality rate studies.

REBUILDING AN ARTERY WITH STEM CELLS
http://www.fightaging.org/archives/2013/01/cells-derived-from-embryonic-stem-cells-rebuild-an-artery.php

Researchers completely removed the cells that line the inside surface from a segment of artery, and then put cells that had been derived from embryonic stem cells inside the artery. They then connected both ends of the arterial segment to plastic tubing inside a device called a bioreactor which is designed to grow cells and tissues. The scientists then pumped fluid through the artery under pressure as if blood were flowing through it. The outside of the artery was bathed in another fluid to sustain the cells located there.

Three days later, the complex structure of the inner surface was beginning to regenerate, and by 14 days, the inside of the artery had been perfectly restored to its complex natural state. It went from a non-functional tube to a complex fully functional artery. "Just think of what this kind of treatment would mean to a patient who had just suffered a heart attack as a consequence of a damaged coronary artery. And this is the real potential of stem cell regenerative medicine - that is, a treatment with stem cells that regenerates a damaged or destroyed tissue or organ."

DEUTERIUM AND LIFESPAN IN FLIES
http://www.fightaging.org/archives/2013/01/deuterium-and-lifespan-in-flies.php

Every few years research on the effects of deuterium on life span in lower animals surfaces, by way of exposing them to heavy water, D2O rather than H2O. The presence of deuterium rather than hydrogen results in an uptake of deuterium atoms into biological molecules, subtly and slightly changing their behavior. Too much of that and you fall over dead - the mechanisms of life do not have a high tolerance for such tinkering, and heavy water is effectively toxic. At lower levels, however, species such as flies and nematodes live longer as a result of exposure to deuterium.

There is some skepticism and debate amongst various parties regarding the mechanisms by which deuterium uptake extends life span, but it's clear that exposure to heavy water at lower levels does in fact extend life in flies, worms, and so forth. Not too many people are working on this, so there is a lot of room for speculation and a lack of hard evidence that can rule out possibilities such as increased resistance to oxidative damage in important proteins. Given the evidence backing the membrane pacemaker theory of longevity, this is an attractive idea - there is plenty of support for the hypothesis that differences in the proteins that make up cell membranes are responsible for large differences in life span between various otherwise similar species. But robust evidence for the much smaller difference of a little extra deuterium substituted for hydrogen atoms - as opposed to completely different proteins - is lacking.

Hormesis is a possible (and disappointingly ordinary) explanation for this sort of result. Given the range of ways to make flies, worms, and rodents live longer by exposing them to adversity in early life, this almost seems like the first place to be looking. Perhaps lesser degrees of heavy water exposure, entirely separately from any deuterium uptake into proteins, have a hormetic effect, causing enough damage and disarray to spur repair mechanisms into greater efforts and leading to a net gain in life expectancy.

DISCUSSION

The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!

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LATEST HEADLINES FROM FIGHT AGING!

ENDURANCE TRAINING ASSOCIATED WITH LONGER TELOMERES
Friday, January 11, 2013
http://www.fightaging.org/archives/2013/01/endurance-training-associated-with-longer-telomeres.php
Exercise correlates with all sorts of better measures of health, but there is some debate and conflicting evidence on whether more is better past the point of moderate regular exercise. This ties in to questions of causation - to what degree are endurance athletes drawn to their activities because they are already more robust than their peers, for example? "Telomeres are the molecular caps on chromosomes. They shorten with each successive cell division and are thus linked to aging. The shortening rate also varies among people. Shorter telomeres have been linked to increased disease risk as well as shortening of lifespan. Chronic endurance training is at least modestly linked with long lifespan, though there are some controversies about whether it may increase the risk of some heart diseases. In the current study researchers sought to determine if chronic endurance training is associated with telomere length in older aged individuals. To perform the trial they measured the length of telomeres in four groups of individuals: young people and older people who did or did non engage in chronic endurance training. For the endurance training the researchers chose participation in a 58 km cross country ski competition. They found that indeed the older people who were chronic endurance trainers had significantly longer telomeres than moderately active older controls. There was no difference in telomere length in the younger subjects whether they did endurance training or not. There was also an association in older people between VO2 max and telomere length."

UNPUBLISHED READER'S DIGEST INTERVIEW ON AGING AND LONGEVITY
Friday, January 11, 2013
http://www.fightaging.org/archives/2013/01/unpublished-readers-digest-interview-on-aging-and-longevity.php
Over at In Search of Enlightenment you'll find an unpublished interview where the questions somewhat illustrate the point that most people don't look much beyond trivial matters when it comes to aging and longevity. Biotechnology like SENS and similar research projects are given no thought at all in most quarters, and even amongst advocates many favor the snail's pace path of trying to slow aging rather than working to repair its root causes to reverse it. This all means that there is much yet to accomplish in advocacy and education. "The field of research known as biogerontology, which studies the biology of aging, is a truly fascinating, though often misunderstood, area of scientific research. In 2011 the genome of the naked-mole rat was sequenced. This rodent is only the size of a mouse, and one might wonder what the significance of sequencing its genome could possibly be. But the naked-mole rate is the longest living rodent, it has a maximum lifespan exceeding 30 years and an exceptional resistance to cancer. Understanding the biology of this species could help unlock the mystery of healthy aging. A variety of experiments on fruit flies, mice and other species have demonstrated that the rate of aging can be manipulated, either by calorie restriction or by activating particular genes. Such research could eventually lead to the development of a drug that safely mimics the effects of caloric restriction (which delays the onset of disease) or actives the "longevity genes" that help protect against the diseases of late life. The lion's share of funding for medical research is spent on disease research, such as research on cancer, heart disease or Alzheimer's disease. This approach, which I call "negative biology", assumes that the most important question to answer is "what causes disease?". Unfortunately this is a severely limited approach, especially for older populations. Even if you cured all 200+ forms of cancer (and we have not yet eliminated even just one cancer despite investing enormous sums of money for decades now), one of the other diseases of aging would quickly replace cancer as the leading cause of death because most people in late life are vulnerable to multiple diseases. So "positive biology" takes a different intellectual starting point. It assumes that the puzzles of exemplar health are just as important to understand as the development of disease. How can some (very rare) humans live over a century of disease-free life? Understanding these exemplar examples of health might prove to be more significant than trying to understand, treat and cure every specific disease of late life."

FAT TISSUE KNOCKOUT OF MITOCHONDRIAL TRANSCRIPTION FACTOR A IS BENEFICIAL, AND MAY EXTEND LIFE IN MICE
Thursday, January 10, 2013
http://www.fightaging.org/archives/2013/01/fat-tissue-knockout-of-mitochondrial-transcription-factor-a-is-beneficial-and-may-extend-life-in-mice.php
Mitochondrial transcription factor A (TFAM) plays a number of important roles and shows up in connection with protofection research aimed at mitochondrial repair. Separately, researchers observe benefits by removing it from the fat tissue of mice: "Mutations in genes involved in the electron transport chain that cause mitochondrial dysfunction can sometimes paradoxically lead to improved health and/or enhanced longevity. One example is the situation in mice with conditional knockout of the mitochondrial transcription factor A (TFAM) specifically in fat. These F-TFKO mice exhibit mitochondrial dysfunction with increased energy expenditure, but are protected from age- and diet-induced obesity, insulin resistance and hepatosteatosis, despite increased food intake. Mitochondrial DNA (mtDNA) is maternally inherited with multiple copies in each mitochondria. TFAM plays a critical role in maintenance and expression of mtDNA, and reductions of mtDNA copy number usually correlate with reduction of mitochondria content and function. So, how does a reduction in TFAM in fat have this beneficial effect? Upon high fat diet, [the F-TFKO] mice develop a build-up of long chain acyl carnitines in both adipose tissue and the circulation. In addition, markers of oxidative stress are observed at the level of DNA and lipids in adipose tissue of F-TFKO mice on high fat diet, indicating overload of the ROS protection system. Despite this mitochondria stress, the mice remain lean and insulin sensitive even at 10 months of age. Although no formal aging studies have been conducted in these mice, we also noted that by 18 months of age, an age at which the control mice have started to die, the F-TFKO mice are still thriving, suggesting this knockout may be beneficial to aging mice as well."

REGENERATING HAIR CELLS TO RESTORE HEARING
Thursday, January 10, 2013
http://www.fightaging.org/archives/2013/01/regenerating-hair-cells-to-restore-hearing.php
In recent years a number of research groups have been investigating ways to restore the hair cells lost in some forms of deafness. Here is the latest example of success in laboratory mice: "Hair cell loss results from a variety of factors including noise exposure, aging, toxins, infections, and certain antibiotics and anti-cancer drugs. Although hearing aids and cochlear implants can ameliorate the symptoms somewhat, there are no known treatments to restore hearing, because auditory hair cells in mammals, unlike those in birds or fish, do not regenerate once lost. [Here, researchers] demonstrate for the first time that hair cells can be regenerated in an adult mammalian ear by using a drug to stimulate resident cells to become new hair cells, resulting in partial recovery of hearing in mouse ears damaged by noise trauma. This finding holds great potential for future therapeutic application that may someday reverse deafness in humans. The drug had been selected for its ability to generate hair cells when added to stem cells isolated from the ear. It acted by inhibiting an enzyme called gamma-secretase that activates a number of cellular pathways. The drug applied to the cochlea inhibited a signal generated by a protein called Notch on the surface of cells that surround hair cells. These supporting cells turned into new hair cells upon treatment with the drug. Replacing hair cells improved hearing in the mice, and the improved hearing could be traced to the areas in which supporting cells had become new hair cells."

IDENTIFYING A MECHANISM FOR NEMATODE LONGEVITY VIA BIFIDOBACTERIA IN THE DIET
Wednesday, January 9, 2013
http://www.fightaging.org/archives/2013/01/identifying-a-mechanism-for-nematode-longevity-via-bifidobacteria-in-the-diet.php
One line of longevity science involves linking known ways to extend life in laboratory species with known mechanisms of longevity. In nematode worms, for example, it costs comparatively little to create groups with a range of the various genetic alterations shown to extend life in recent years, and then test strategies with those groups. If a strategy for extending life in nematodes doesn't have much effect on a particular long-lived mutant strain, then it's likely that it works through the same underlying mechanism - though of course it's rarely as cut and dried as that: multiple mechanisms and varying degrees of effect can be involved. Here is an example of this sort of work: "Lactobacilli and bifidobacteria are probiotic bacteria that modify host defense systems and have the ability to extend the lifespan of the nematode Caenorhabditis elegans. Here, we attempted to elucidate the mechanism by which bifidobacteria prolong the lifespan of C. elegans. When the nematode was fed Bifidobacterium infantis (BI) mixed at various ratios with the standard food bacterium Escherichia coli strain OP50 (OP), the mean lifespan of worms was extended in a dose-dependent manner. Worms fed BI displayed higher locomotion and produced more offspring than control worms. The growth curves of nematodes were similar regardless of the amount of BI mixed with OP, suggesting that BI did not induce prolongevity effects through caloric restriction. Notably, feeding worms the cell wall fraction of BI alone was sufficient to promote prolongevity. The accumulation of protein carbonyls and lipofuscin, a biochemical marker of aging, was also lower in worms fed BI; however, the worms displayed similar susceptibility to heat, hydrogen peroxide, and paraquat, an inducer of free radicals, as the control worms. As a result of BI feeding, loss-of-function mutants of daf-16, jnk-1, aak-2, tol-1, and tir-1 exhibited a longer lifespan than OP-fed control worms, but BI failed to extend the lifespan of pmk-1, skn-1, and vhp-1 mutants. As skn-1 induces phase 2 detoxification enzymes, our findings suggest that cell wall components of bifidobacteria increase the average lifespan of C. elegans via activation of skn-1, regulated by the p38 MAPK pathway, but not by general activation of the host defense system via DAF-16."

TOWARDS THERAPIES FOR REGENERATION OF DENTAL PULP
Wednesday, January 9, 2013
http://www.fightaging.org/archives/2013/01/towards-therapies-for-regeneration-of-dental-pulp.php
Dental regenerative medicine is closer to commercial application than many other areas of this field: "The traditional root canal procedure involves removing decayed root tissue, or dental pulp, from the tooth's canal and filling that space with gutta percha, an artificial rubber-like substance. With Huang's new approach, the canals that have been cleared would be injected with stem cell tissue to stimulate healthy tissue growth, essentially rebuilding the tooth, and eliminating the need for gutta percha. "Our group has been able to demonstrate that we can isolate stem cells from the pulp tissue, let them expand or grow in culture dishes, seed them onto artificial or natural scaffolding materials, and then insert them into the canal space. Using a small animal model, we were able to demonstrate that we can entirely regenerate pulp tissue in the empty canal space." "The dentin can also be regenerated. The natural function of the pulp tissue is to maintain the homeostasis of the tooth and lay down the dentin structure to sustain the architecture of the tooth." Similar research in other countries has been successful. Testing has now moved to larger animals, including pigs and dogs, and clinical trials on humans could begin in the next 10 years."

NEWS FROM THE INTERNATIONAL LONGEVITY ALLIANCE
Tuesday, January 8, 2013
http://www.fightaging.org/archives/2013/01/news-from-the-international-longevity-alliance.php
Here is news from the newly formed International Longevity Alliance, the umbrella group for the brace of single issue political party initiatives that have arisen in the past year in Europe and Russia: "On January 5, the second general meeting of the leaders and activists of the International Longevity Alliance (ILA) took place. [The] meeting took place in an extremely cooperative and constructive atmosphere. About 18 collaborative projects were initiated right there and then. The exact organizational structure, goals and ways to join the projects will be elaborated and announced soon, in the "Projects" section of the ILA website. To facilitate the collection of knowledge, exchange and distribution of free and accessible information about longevity, a Wikipedia project was initiated. A related item is the Collaborative Knowledge Management project that will provide a repository of information on aging and longevity researchers and research centers, as well as providing linking tools. And yet another form of knowledge collection and sharing will be the creation of Educational Platforms on longevity, for different audiences, lay and more academic. There is an overarching "Linking Researchers" project, initiated to facilitate the interaction with and between researchers in the field. [The] Denigma project will be the main IT platform in the creation of the repository of information on research of aging, and linking of researchers."

CELL TRANSPLANTS TO REBUILD THE RETINA
Tuesday, January 8, 2013
http://www.fightaging.org/archives/2013/01/cell-transplants-to-rebuild-the-retina.php
An example of the sort of work presently taking place aimed at retinal regeneration: "The researchers worked with mice that are blind due to complete loss of the light-sensing photoreceptor cells in their retinas. This is the most relevant mouse model for treating patients who are blind from retinitis pigmentosa. After two weeks, the researchers showed the cells transplanted into the eye had re-formed a full light-detecting layer on the retina and the mice could see. The cells used were mouse 'precursor' cells that are on an initial path towards developing into retinal cells. A pupil constriction test showed that, of the 12 mice that received the cell transplant, 10 showed improved pupil constriction in response to light. This shows that the retinas of the mice were sensing the light once more, and this was being transmitted down the optic nerve to the brain. "We found that if enough cells are transplanted together, they not only become light sensing but they also regenerate the connections required for meaningful vision. Stem cells have been trialled in patients to replace the pigmented lining of the retina, but this new research shows that the light-sensing layer might also be replaced in a similar way. The light-sensing cells have a highly complex structure and we observed that they can resume function as a layer and restore connections after transplantation into the completely blind retina.""

COMMENTS ON THE STATE OF MEDICAL BIOTECHNOLOGY DEVELOPMENT
Monday, January 7, 2013
http://www.fightaging.org/archives/2013/01/comments-on-the-state-of-medical-biotechnology-development.php
Via FuturePundit, some comments on the development of medical biotechnology: "My suspicion: most of the remaining problems that chemical drugs haven't cured or slowed down are problems that chemical drugs can't fix. For most of what goes wrong as we age we need gene therapies, cell therapies, and other techniques that are powerful enough to repair or replace aged tissue. Chemical drugs are just too simple in structure and in potential effects. They can't do much tissue repair. The slow rate of cancer drug testing and the regulatory environment that causes the snail's pace is tragic. [If] I was dying of cancer and had months to live I'd volunteer to take a large dose of an experimental drug to find out its toxicity. If I was really lucky I'd be cured. If I was only moderately lucky the drug would kill me quickly so I wouldn't have to spend months in pain slowly dying. I bet if dying cancer patients were given the choice of whether to risk a fast death due to aggressive testing of new drugs enough would say yes that drug testing could be sped up substantially. The regulators who create this slow drug development environment also place high hurdles in the way of trying stem cell therapies and gene therapies for fatal illnesses. The US FDA has won a court case that gives it broad power to regulate stem cell therapies. Well, FDA regulation basically means "spend hundreds of millions of dollars and spend a decade getting approval". Got a disease that'll kill you 5 or even 10 years from now? Time to get a passport if you don't already have one. When the biotech revolution finally starts arriving with great clinical treatments you'll have to go abroad to get the latest treatments. We need a faster rate of progress in biotechnology."

DATA FROM THE GENETICS OF HEALTHY AGEING PROJECT
Monday, January 7, 2013
http://www.fightaging.org/archives/2013/01/data-from-the-genetics-of-healthy-ageing-project.php
Research into genetic contributions to longevity rolls onwards. APOE remains one of the few genes with variants associated with longevity in many populations. For the rest, it is expected that there are many different contributing variations, different by population, and each only causing a small change in life expectancy. It is still the case that genes are not as important as good lifestyle choices, and neither of those are anywhere near as important as progress in medical technology when it comes to the prospects for living a long life. Here are the results from a recent study that again point to APOE. You might also look at an introduction to gene locations for an overview of how researchers label locations in a chromosome such as 17q12-q22: "Clear evidence exists for heritability of human longevity, and much interest is focused on identifying genes associated with longer lives. To identify such longevity alleles, we performed the largest genome-wide linkage scan thus far reported. Linkage analyses included 2118 nonagenarian Caucasian sibling pairs that have been enrolled in fifteen study centers of eleven European countries as part of the Genetics of Healthy Ageing (GEHA) project. In the joint linkage analyses we observed four regions that show linkage with longevity; chromosome 14q11.2, chromosome 17q12-q22, chromosome 19p13.3-p13.11 and chromosome 19q13.11-q13.32. To fine map these regions linked to longevity, we performed association analysis using [genome-wide association study] data in a subgroup of 1,228 unrelated nonagenarian and 1,907 geographically matched controls. [By] combined modeling of linkage and association we showed that association of longevity with APOEε4 and APOEε2 alleles explain the linkage at 19q13.11-q13.32. In the largest linkage scan thus far performed for human familial longevity, we confirm that the APOE locus is a longevity gene and that additional longevity loci may be identified at 14q11.2, 17q12-q22 and 19p13.3-p13.11. Since the latter linkage results are not explained by common variants, we suggest that rare variants play an important role in human familial longevity."

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#47 reason

  • Guardian Reason
  • 1,101 posts
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  • Location:US

Posted 20 January 2013 - 09:31 PM

FIGHT AGING! NEWSLETTER
January 21st 2013

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

______________________________

CONTENT

- Posters: Aging is a Curable Disease
- People Are Not Good at Being Rational, and That Costs a Great Many Lives
- For How Long Can a Desirable Goal Remain Cheap Without Being Aggressively Pursued?
- Discussion
- Latest Headlines from Fight Aging!
    - Sarcopenia Correlates With Increased Mortality
    - Luminescent Marking of Cellular Senescence
    - Plastination Will Have Its Challenges, Just Like Cryonics
    - More on Sestrins and Longevity
    - Reducing Amyloid Beta Levels in a Mouse Model of Alzheimer's
    - Solvents Increase Life in Nematode Worms
    - Adenine in the Diet Blocks Calorie Restriction Benefits in Flies
    - β-blockers Modestly Extend Mean Life Span in Flies and Mice
    - ROS Production Necessary for Tadpole Tail Regrowth
    - An Estimate of the Worldwide Cost of Dementia

POSTERS: AGING IS A CURABLE DISEASE
http://www.fightaging.org/archives/2013/01/aging-is-a-curable-disease.php

The Russian end of the longevity science advocacy community seems to include a majority of its graphic design folk; certainly they've published a range of attractive, glossy materials in past years. Via Maria Konovalenko here are a couple more items to add to the stack - click through for the full size PDF posters.

PEOPLE ARE NOT GOOD AT BEING RATIONAL, AND THAT COSTS A GREAT MANY LIVES
http://www.fightaging.org/archives/2013/01/people-are-not-good-at-being-rational-and-that-costs-a-great-many-lives.php

This is an old story for regular readers, but I'll restate it anyway: people are dying of aging at a rate of something more than a hundred thousand lives a day. It is a mark of our inventive ongoing engagement with ways and means of death that despite this vast toll, aging still only manages to kill two thirds of us - and that in this era of comparatively advanced medicine, comparative peace, and comparative risk aversion.

Biotechnology is today's revolutionary industry in the making. Costs are falling, capabilities increasing just as dramatically as happened for computers two decades ago. We could be well on the way to removing aging as a cause of death at this point. A detailed plan is in hand, the way forward to achieve the goal of rejuvenation biotechnology is as clear as life science research ever gets, and the cost of an initial demonstration of rejuvenation in mice is ten years and a sum of money that's a rounding error in comparison what is spent on developing new and better ways to kill people.

Here's the thing, though, the point that's enough to make bitter old folk of us all: we're not actually well on the way to removing aging as a cause of death. We could be, but we're not - we're only just getting started at a time when we could be far further ahead, and we're moving slowly when we could be moving far faster. The hard-won funding and solid research programs for SENS and related initiatives are a trickle where a river is needed. You have to start at the start, of course, and every flood of effort started with a few drops back at the beginning. Nonetheless the flood does not yet exist, despite every reason for it to do so: a hundred thousand lives a day, the suffering of hundreds of millions more, and yet it's hard to get anyone to care enough to even think much about the topic, let alone do anything to help stop it from happening.

Where is rationality in all this? It's that the world is an asylum, run by the inmates, that makes people bitter before their time. To a first approximation those with resources build wars and circuses, and sometimes throw a crust to to the few who work on making the human condition better than it was yesterday. Those without resources heartily support this strategy, even while they owe pretty much every affordable comfort to work accomplished by a few centuries of researchers and developers - the tiny crust-fed minorities of their time.

FOR HOW LONG CAN A DESIRABLE GOAL REMAIN CHEAP WITHOUT BEING AGGRESSIVELY PURSUED?
http://www.fightaging.org/archives/2013/01/for-how-long-can-a-desirable-goal-remain-cheap-without-being-aggressively-pursued.php

The costs of life science research are falling rapidly. What was expensive is now cheap: a few bright graduate studies and a small lab can accomplish in six months what would have required an entire institution and the better part of a decade in 1990. This means that, setting aside the incredible burden of regulation, prototyping a major new medical procedure or taking a therapy from theory to working result in laboratory animals has become cheap in comparison to many endeavors. It can cost considerably less to build a focused therapy given a strategy to work with than to construct the laboratory building in which the researchers work, for example - though it is true that the building will not take as long to assemble.

Degenerative aging in particular does not lack for a plan that can lead to effective therapies: the Strategies for Engineered Negligible Senescence (SENS). The likely cost of following through from where we are now to demonstrating the collection of seven to ten different therapies needed to rejuvenate old mice is a billion dollars and a decade or two in which to spend it well. Today funding for these various lines of research runs at a bare few million a year, and a great deal of work and advocacy was required to reach that far.

A billion dollars at a rate of fifty to a hundred million a year is a large sum of money in one sense, but smaller than countless organized projects that take place in the wealthier regions of the world. How much longer can the earnest pursuit of rejuvenation continue to be within the easy grasp of an alliance of any dozen of the world's twelve hundred billionaires and yet not funded to any great level? If shared between such a group, the individual costs wouldn't come close to what these figures invest in order to achieve far less beneficial end goals.

For how long can a brass ring remain hanging unclaimed? The opportunity to build the basis for human rejuvenation biotechnology exists, yet there is no massively funded effort underway to reach that goal. For how long can this state of affairs continue?

DISCUSSION

The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!

______________________________

LATEST HEADLINES FROM FIGHT AGING!

SARCOPENIA CORRELATES WITH INCREASED MORTALITY
Friday, January 18, 2013
http://www.fightaging.org/archives/2013/01/sarcopenia-correlates-with-increased-mortality.php
As might be expected, older people with a greater loss of muscle mass and strength - the condition known as sarcopenia - also tend to exhibit a higher risk of death: "Sarcopenia has been indicated as a reliable marker of frailty and poor prognosis among the oldest individuals. We evaluated the impact of sarcopenia on the risk of all-cause death in a population of frail older persons living in community. We analysed data from the Aging and Longevity Study, a prospective cohort study that collected data on all subjects aged 80 years and older residing in the Sirente geographic area (n = 364). The present analysis was conducted among those subjects who were between 80 and 85 years of age at the time of the baseline assessment (n = 197). The main outcome measure was all-cause mortality over 7-year follow-up. According to the European Working Group on Sarcopenia in Older People (EWGSOP) criteria, the diagnosis of sarcopenia required the documentation of low muscle mass and the documentation of either low muscle strength or low physical performance. [Using] the EWGSOP-suggested criteria, 43 subjects with sarcopenia (21.8%) were identified. During the 7-year follow-up, 29 (67.4%) participants died among subjects with sarcopenia compared with 63 subjects (41.2%) without sarcopenia. After adjusting for potential confounders including age, gender, education, activities of daily living (ADL) impairment, body mass index, hypertension, congestive heart failure, chronic obstructive pulmonary disease, number of diseases, TNF-α, participants with sarcopenia had a higher risk of death for all causes compared with non-sarcopenic subjects."

LUMINESCENT MARKING OF CELLULAR SENESCENCE
Friday, January 18, 2013
http://www.fightaging.org/archives/2013/01/luminescent-marking-of-cellular-senescence.php
Here is news of a research tool for those developing ways to target and destroy senescent cells. A successful method should minimize the contribution of cellular senescence to degenerative aging and thus extend healthy life - this is one of the necessary biotechnologies for human rejuvenation that is closest to actual implementation: "Researchers have long known that the gene, p16INK4a (p16), plays a role in aging and cancer suppression by activating an important tumor defense mechanism called 'cellular senescence'. The [team] has developed a strain of mice that turns on a gene from fireflies when the normal p16 gene is activated. In cells undergoing senescence, the p16 gene is switched on, activating the firefly gene and causing the affected tissue to glow. Throughout the entire lifespan of these mice, the researchers followed p16 activation by simply tracking the brightness of each animal. They found that old mice are brighter than young mice, and that sites of cancer formation become extremely bright, allowing for the early identification of developing cancers. "With these mice, we can visualize in real-time the activation of cellular senescence, which prevents cancer but causes aging. We can literally see the earliest molecular stages of cancer and aging in living mice." The researchers used these mice to make several unexpected discoveries. First, the group was able to track the accumulation of senescent cells in aging mice by assessing how brightly each mouse glowed. Surprisingly, the brightest animals were no more likely to die from spontaneous cancer than dimmer animals of the same age. That is, the number of senescent cells in the mouse did not predict its risk of dying. Another surprise came from the disparities in p16 levels among the mice. The authors studied a large group of genetically identical animals that were all housed in the same way and fed the same diet. However, despite identical genetic and environmental conditions, the brightness of individual mice at any given age was highly variable, suggesting that factors beyond genetics and diet influence aging."

PLASTINATION WILL HAVE ITS CHALLENGES, JUST LIKE CRYONICS
Thursday, January 17, 2013
http://www.fightaging.org/archives/2013/01/plastination-will-have-its-challenges-just-like-cryonics.php
Plastination seems to have the potential to become a viable alternative to cryonics as a long-term storage method for the brains of those who die before the advent of rejuvenation biotechnology. If the fine structure that encodes the data of the mind is preserved, then these individuals can wait indefinitely for the arrival of molecular nanotechnology needed to restore them to life. Cryonics has been around for decades, and has had its challenges, while plastination remains a comparatively new idea - and thus we should expect there to be hurdles to overcome. One of my concerns with room temperature storage of plastinated individuals is the potential for bacteria and bugs than might like to consume the fixative compounds, something that isn't a concern in low-temperature storage. Here is another: " I have always been interested in chemical fixation as a (low cost) alternative for cryonics. In fact, years before all the talk about the "connectome" and "plastination" I spent considerable time exchanging messages with Michael Perry at Alcor about the technical and practical feasibility of chemical brain preservation. But no matter how open minded I tried to be about this approach, I kept running into the same challenges over and over again. The challenge that has concerned me the most is whether a delayed start of chemical brain fixation will produce incomplete distribution of the chemical fixative in the brain because of ischemia-induced perfusion impairment. Thinking about the technical problem of "no-reflow" is not the first thing on the mind of someone who first hears about the idea of using chemical fixatives to preserve the brain. In my case, this concern was not just "theoretical." In my lab I have spent many years looking at the effects of cerebral ischemia on cryopreservation and chemical fixation. Last year we decided to broaden our investigations to delayed chemical fixation and we have not been pleased at what we have observed so far. After 1.5 years of room temperature storage the delayed aldehyde fixed brains are falling apart and continue to decompose. In small animals one might imagine that such perfusion impairment could be overcome by immersing the brains in the fixative instead but human brains are simply too large. By the time that the fixative would have reached the core of the brain, extensive autolysis will have occurred."

MORE ON SESTRINS AND LONGEVITY
Thursday, January 17, 2013
http://www.fightaging.org/archives/2013/01/more-on-sestrins-and-longevity.php
Sestrins have been linked to life span in flies, and here researchers look at the analogs in nematode worms. I've yet to notice similar work for mice, however: "Aging is a process of gradual functional decline leading to death. Reactive oxygen species (ROS) contribute to oxidative stress and cell damage that lead to aging but also serve as signaling molecules. Sestrins are evolutionarily conserved in all multicellular organisms and are required for regenerating hyperoxidized forms of peroxiredoxins and ROS clearance. However, whether sestrins regulate longevity in metazoans is still unclear. Here, we demonstrated that SESN-1, the only sestrin ortholog in Caenorhabditis elegans, is a positive regulator of lifespan. sesn-1 gene mutant worms had significantly shorter lifespans compared to wild-type animals, and overexpression of sesn-1 prolonged lifespan. Moreover, sesn-1 was found to a play key role in defense against several life stressors, including heat, hydrogen peroxide and the heavy metal copper; and sesn-1 mutants expressed higher levels of ROS and showed a decline in body muscle function. [These] results suggest that SESN-1 is required for normal lifespan and its function in muscle cells prevents muscle degeneration over a lifetime."

REDUCING AMYLOID BETA LEVELS IN A MOUSE MODEL OF ALZHEIMER'S
Wednesday, January 16, 2013
http://www.fightaging.org/archives/2013/01/reducing-amyloid-beta-levels-in-a-mouse-model-of-alzheimers.php
This is one of a number of approaches in recent years that has significantly reduced the levels of amyloid beta in the brain in the mouse version of Alzheimer's disease used for research. As for the others, it remains to be seen whether it is a suitable basis for a human therapy. Even if so, like much of the approach of modern medicine for age-related conditions, it isn't addressing causes, only trying to patch over consequences: "One of the main characteristics of Alzheimer's disease is the production in the brain of a toxic molecule known as amyloid beta. Microglial cells, the nervous system's defenders, are unable to eliminate this substance, which forms deposits called senile plaques. [Researchers] identified a molecule that stimulates the activity of the brain's immune cells. The molecule, known as MPL (monophosphoryl lipid A), has been used extensively as a vaccine adjuvant [for] many years, and its safety is well established. In mice with Alzheimer's symptoms, weekly injections of MPL over a twelve-week period eliminated up to 80% of senile plaques. In addition, tests measuring the mice's ability to learn new tasks showed significant improvement in cognitive function over the same period. The researchers see two potential uses for MPL. It could be administered by intramuscular injection to people with Alzheimer's disease to slow the progression of the illness. It could also be incorporated into a vaccine designed to stimulate the production of antibodies against amyloid beta. "The vaccine could be given to people who already have the disease to stimulate their natural immunity. It could also be administered as a preventive measure to people with risk factors for Alzheimer's disease.""

SOLVENTS INCREASE LIFE IN NEMATODE WORMS
Wednesday, January 16, 2013
http://www.fightaging.org/archives/2013/01/solvents-increase-life-in-nematode-worms.php
This result is reminiscent of the demonstration that ethanol produces significant life extension in nematodes - and similarly, one wonders whether it will be confirmed, and if so why it wasn't noted a long time ago. If it is accurate, it casts doubt on a range of life span studies that used the solvents in question. "Lifespan extension through pharmacological intervention may provide valuable tools to understanding the mechanisms of aging and could uncover new therapeutic approaches for the treatment of age-related disease. Although the nematode C. elegans is well known as a particularly suitable model for genetic manipulations, it has been recently used in a number of pharmacological studies searching for compounds with anti-aging activity. These compound screens are regularly performed in amphipathic solvents like dimethyl sulfoxide (DMSO), the solvent of choice for high-throughput drug screening experiments performed throughout the world. In this work, we report that exposing C. elegans to DMSO in liquid extends lifespan up to 20%. Interestingly, another popular amphipathic solvent, dimethyl formamide (DMF), produces a robust 50% increase in lifespan. These compounds work through a mechanism independent of insulin-like signaling and dietary restriction (DR). Additionally, the mechanism does not involve an increased resistance to free radicals or heat shock suggesting that stress resistance does not play a major role in the lifespan extension elicited by these compounds. Interestingly, we found that DMSO and DMF are able to decrease the paralysis associated with amyloid-β(3-42) aggregation, suggesting a role of protein homeostasis for the mechanism elicited by these molecules to increase lifespan."

ADENINE IN THE DIET BLOCKS CALORIE RESTRICTION BENEFITS IN FLIES
Tuesday, January 15, 2013
http://www.fightaging.org/archives/2013/01/adenine-in-the-diet-blocks-calorie-restriction-benefits-in-flies.php
Work continues on finding the mechanisms for longevity induced through calorie restriction. This latest paper seems to be as interesting a step forward in this regard as the establishment of dietary methionine levels as a principle trigger for the health and longevity benefits obtained via calorie restriction. That said, I'd like to see this work repeated in mice before giving it too much weight: "A common thread among conserved life span regulators lies within intertwined roles in metabolism and energy homeostasis. We show that heterozygous mutations of AMP biosynthetic enzymes extend Drosophila life span. The life span benefit of these mutations depends upon increased AMP:ATP and ADP:ATP ratios and adenosine monophosphate-activated protein kinase (AMPK). Transgenic expression of AMPK in adult fat body or adult muscle, key metabolic tissues, extended life span, while AMPK RNAi reduced life span. Supplementing adenine, a substrate for AMP biosynthesis, to the diet of long-lived AMP biosynthesis mutants reversed life span extension. Remarkably, this simple change in diet also blocked the prolongevity effects of dietary restriction. These data establish AMP biosynthesis, adenosine nucleotide ratios, and AMPK as determinants of adult life span; provide a mechanistic link between cellular anabolism and energy sensing pathways; and indicate that dietary adenine manipulations might alter metabolism to influence animal life span."

β-BLOCKERS MODESTLY EXTEND MEAN LIFE SPAN IN FLIES AND MICE
Tuesday, January 15, 2013
http://www.fightaging.org/archives/2013/01/-blockers-modestly-extend-mean-life-span-in-flies-and-mice.php
It is good to see more researchers controlling for calorie restriction effects as a matter of course in their studies on health and life span: "Chronic treatment with β-adrenergic receptor (βAR) agonists increases mortality and morbidity while βAR antagonists (β-blockers) decrease all-cause mortality for those at risk of cardiac disease. Levels of sympathetic nervous system βAR agonists and βAR activity increase with age, and this increase may hasten the development of age-related mortality. Here, we show that β-blockers extend the life span of healthy metazoans. The β-blockers metoprolol and nebivolol, administered in food daily beginning at 12 months of age, significantly increase the mean and median life span of isocalorically fed, male C3B6F1 mice, by 10 and 6.4 %, respectively. Neither drug affected the weight or food intake of the mice, indicating that induced CR is not responsible for these effects, and that energy absorption and utilization are not altered by the drugs. Both β-blockers were investigated to control for their idiosyncratic, off-target effects. Metoprolol and nebivolol extended Drosophila life span, without affecting food intake or locomotion. Thus, βAR antagonists are capable of directly extending the life span of two widely divergent metazoans, suggesting that these effects are phylogenetically highly conserved. Thus, long-term use of β-blockers, which are generally well-tolerated, may enhance the longevity of healthy humans."

ROS PRODUCTION NECESSARY FOR TADPOLE TAIL REGROWTH
Monday, January 14, 2013
http://www.fightaging.org/archives/2013/01/ros-production-necessary-for-tadpole-tail-regrowth.php
Many lower animals are capable of great feats of regeneration, and researchers are working to understand the mechanisms by which this occurs. There is the possibility that the ability to regenerate lost body parts is something that lies dormant in mammals, rather than being completely lost. Finding out whether or not this is the case requires a far better understanding of regeneration than presently exists. Here, researchers investigate the biochemistry of tail regeneration in tadpoles: "It is generally appreciated that frogs and salamanders have remarkable regenerative capacities, in contrast to mammals, including humans. For example, if a tadpole loses its tail a new one will regenerate within a week. In an earlier study, [researchers] identified which genes were activated during tail regeneration. Unexpectedly, that study showed that several genes that are involved in metabolism are activated, in particular those that are linked to the production of reactive oxygen species (ROS) - chemically reactive molecules containing oxygen. [The researchers] were able to show that a marked increase in H2O2 occurs following tail amputation and interestingly, they showed that the H2O2 levels remained elevated during the entire tail regeneration process, which lasts several days. To assess how vital the presence of ROS are in the regeneration process, [the scientists] limited ROS production using two methods. The first was by using chemicals, including an antioxidant, and the second was by removing a gene responsible for ROS production. In both cases the regeneration process was inhibited and the tadpole tail did not grow back. "When we decreased ROS levels, tissue growth and regeneration failed to occur. Our research suggests that ROS are essential to initiate and sustain the regeneration response. We also found that ROS production is essential to activate Wnt signalling, which has been implicated in essentially every studied regeneration system, including those found in humans.""

AN ESTIMATE OF THE WORLDWIDE COST OF DEMENTIA
Monday, January 14, 2013
http://www.fightaging.org/archives/2013/01/an-estimate-of-the-worldwide-cost-of-dementia.php
A research paper here puts forward an estimate for the cost of treating dementia - though the true economic burden must also consider opportunity costs: what might have been accomplished by patients had they not become disabled. Dementia is but one of the many degenerative conditions of aging, of course, and all of the others have their costs as well. The overall cost of aging is staggering, and, sadly, rarely considered. If it was, we might see more effort put towards developing the means to repair and reverse the causes of aging. "The basic design of this study was a societal, prevalence-based, gross cost-of-illness study in which costs were aggregated to World Health Organization regions and World Bank income groupings. The total estimated worldwide costs of dementia were US$604 billion in 2010. About 70% of the costs occurred in western Europe and North America. In such high-income regions, costs of informal care and the direct costs of social care contribute similar proportions of total costs, whereas the direct medical costs were much lower. In low- and middle-income countries, informal care accounts for the majority of total costs; direct social care costs are negligible. Worldwide costs of dementia are enormous and distributed inequitably. There is considerable potential for cost increases in coming years as the diagnosis and treatment gap is reduced. There is also likely to be a trend in low- and middle-income countries for social care costs to shift from the informal to the formal sector, with important implications for future aggregated costs and the financing of long-term care. Only by investing now in research and the development of cost-effective approaches to early diagnosis and care can future societal costs be anticipated and managed."

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Posted 27 January 2013 - 07:41 PM

FIGHT AGING! NEWSLETTER
January 28th 2013

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

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CONTENT

- Natural Death: We Should Be Worried About It
- A Blithe Acceptance of Death and Centralized Control
- On Strengthening the Longevity Research Community
- Discussion
- Latest Headlines from Fight Aging!
- But What About Pushkin?
- Considering Cybernetic Immortality
- On Long-Lived Cancer-Resistant Rodents
- Longer Telomeres, Less Cancer in Calorie Restricted Mice
- More on Central Control and the Acceptance of Death
- Confirming the Importance of Autophagy in Calorie Restriction
- SENS Research Foundation: Reimagine Aging
- Hearing Loss Correlates With Cognitive Decline
- So How Do You Measure Life Span in Fly Studies?
- Using Epigenetics to Search for the Mechanisms of Rheumatoid Arthritis

NATURAL DEATH: WE SHOULD BE WORRIED ABOUT IT
http://www.fightaging.org/archives/2013/01/natural-death-we-should-be-worried-about-it.php

Here is an extract from one of the better responses to the Edge yearly question for 2013, "what should we be worried about?" - with the implication that there are many things we are not worrying enough about. In this case, aging to death:

Even if the probability of quickly finding a technological method to delay or reverse senescence is low, we have been devoting far too little effort to it. After all, no matter what else we might achieve with our work in life, we soon won't be around to enjoy it. There are other problems on the planet to worry about, but none more personally important. And yet, despite this motivation, there is very little money being spent on longevity research. Because there is no history of success, and because of widely held religious beliefs, government won't fund it. And because achieving success will be difficult, and the marketplace is flooded with false claims, industry has little interest in solving the problem. Although the profit could be astronomical, there is no easy path to attain it, unlike for cosmetic improvements. Over a hundred times more money is spent on R&D for curing baldness than for curing aging. We may someday find ourselves with extended lifespans as an unintended side effect of taking a pill that gives us fuller hair.

This absurd situation is typical for high-risk, high-reward research in an area without an established record of success. Even with strong motivation, financial support is nearly nonexistent. Scientists working on life extension often lack for equipment or a livable salary, and risk their careers by conducting oddball research that repeatedly fails. The problems are hard. But even with limited resources, a handful of scientists are devoting their lives to the pursuit, because of what's at stake. Success will require research on a similar scale as the Manhattan Project, but government and industry won't be supporting it. The greatest hope is that private individuals will step forward and fund the research directly, or through organizations established for that purpose. Maybe an eccentric, farsighted billionaire will want a chance at not dying. Or maybe many people will contribute small amounts to make it happen. This is being done, to some extent, and it gives me hope.

Personally, I know I am not so different than other people. I also have a very difficult time accepting mortality. When I think about all who have and will be lost, and my own impending nonexistence, it makes me ill. It's entirely possible that the hope I have for a technological solution to aging and death is biased by my own aversion to the abyss. Being realistic, given our current rate of technological advance, although I'm hopeful that radical life extension will happen before I die, I think it's more likely that I'll just miss it. Either way, whether aging is cured within my lifetime or afterwards, it won't happen soon enough. Good people are suffering and dying, and that needs to change in a way that's never been done before.

A BLITHE ACCEPTANCE OF DEATH AND CENTRALIZED CONTROL
http://www.fightaging.org/archives/2013/01/a-blithe-acceptance-of-death-and-centralized-control.php

We live in an age in which the majority of people blithely accept the suffering and death of aging as a given, an axiom, something of no great consequence to the arrangement of everyday life, and do much the same for the centralized control over lives and activities undertaken by a small, empowered elite. The latter is not a novel situation - see ancient Sparta, for example - but the sheer, pervasive breadth and depth in which it is presently practiced is an invention of the past few hundred years, made possible through great increases in wealth and technology. The Panopticon state is a modern creation, Sparta only its tiniest seed. Aging is aging, of course, and has been with us since the beginning. But both of these things are far from inconsequential, and indeed they shape our lives to a very great degree.

It is an important point that most people consider it unremarkable and entirely ethical to talk of regimenting society, placing widespread strictures on everyday activities and choices. Part of the struggle faced by researchers and advocates focused on lengthening human life stems from the fact that a large portion of the population sees nothing inherently wrong in forcing other people to act or not act as they see fit - or worse in forcing them to suffer and die to a timetable. It's somewhat irrelevant that the reasons for such would-be tyranny are flimsy and illogical. The real horror is that this is considered normal and reasonable.

Prompting this line of thought, earlier today I stumbled over an unusual argument against working to reverse degenerative aging and extend healthy life. At root it appears to suggest that a higher throughput of human lives is better (for nebulous reasons relating to variety of life and culture at any given moment), and since population will tend to fall off with increasing wealth and longevity we should thus refrain from trying to prevent the tremendous suffering and death caused by aging. As I was thinking what to make of this particular example, it occurred to me that in order to put forward this sort of argument, you really have to be very accepting of the present cost of aging: the pain, the death, the loss. It has to be a trivial axiom, something that isn't all that important, if you can focus instead on incrementally steering the variety of culture present in the world. Further, you would also have to be pretty comfortable with the sort of tyranny needed to force the world to relinquish biotechnology and die to a particular arbitrary schedule.

It is an ongoing failure on our part that people can idly - or not so idly as has been the case in past years - make arguments of this nature without being noted as unethical, evil, and morally bankrupt. You can advocate enforcing the deaths of as many people as you like, and for whatever thin reasons, so long as they are old, or so it seems. Few people will think you any less of an upstanding fellow for doing so.

ON STRENGTHENING THE LONGEVITY RESEARCH COMMUNITY
http://www.fightaging.org/archives/2013/01/on-strengthening-the-longevity-research-community.php

Building scientific communities with strong ties to the broader public runs in just the same way as building any community in this day and age - which means very differently to the way things used to be. The internet, open data, and cheap global communication allow a whole new layer of activism and effort by small groups of researchers to stand beside the traditional conferences, funding sources, and institutional relationships. The successful research community of today will be a lot more in touch with the public who stand to benefit from its work, and with the advocates and activists who support progress in the field. You might look at calorie restriction research as an example of strong ties between researchers and advocates, leading to a greater number of human research programs and a greater visibility for calorie restriction as a lifestyle choice. Similarly for aging research: efforts like the Methuselah Foundation and SENS Research Foundation have emerged as much from visionaries and support outside the research community as from the work of those within.

It may be easier to build communities these days, but that doesn't mean it's easy. Effort is definitely involved, along with some measure of fortuitous happenstance, the upkeep of watering holes and initiatives, a need for strong personalities to make and maintain diverse connections, the creation of collaboration tools and outreach programs. The list goes on.

Some of the folk at the International Longevity Alliance are enthused by the idea of building more and better threads to link and strengthen the longevity science community. From their point of view there is much yet to be done in terms of opening up collaboration between research groups and between researchers and interested members of the public. For the moment their efforts center around the Denigma resource database. There is a fair amount of this sort of sentiment in the broader research community these days: towards open publishing, greater transparency, relationships established with philanthropists and supporters in the public. It is the mood of the times, enabled by the falling cost of communication and the increasing capacity of the internet. But mood of the times or not, it still takes people to do the work, bang the drum, build the tools.

DISCUSSION

The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!

______________________________

LATEST HEADLINES FROM FIGHT AGING!

BUT WHAT ABOUT PUSHKIN?
Friday, January 25, 2013
http://www.fightaging.org/archives/2013/01/but-what-about-pushkin.php
From the Russian end of the longevity advocacy community: "A man strives for justice, but the most unjust thing in life is the inevitability of death. Here's a small child, then an adult, he learns, grows up, falls in love, gets married - divorce, have children, he is happy and suffering, dreaming and disappointed, laughing and crying, running, resting, but for all that the fate is death, imminent death due to aging. Monstrous injustice! A man with his life does not deserve death. People put up with this situation, they talk about natural dying, saying that a person must make room. These excuses have the sound of death due to frustration, due to a lack of knowledge about the theoretical possibilities of science, not a desire to act rationally. A person finds it easier to accept death and aging than to begin to act. So the struggle with death and aging: a complex internal decision, the decision to confront the established foundations, the victory of reason over faith and the desire for psychological comfort, the victory over short-term interest. In 20 years it will not matter exactly what you ate today, what color your wallpaper, and where you go to relax - only one thing will be important, how you confronted death in our day. And in a hundred years, nothing that you are or do now will be important if aging is not defeated. "But what about Pushkin? Everyone remembers him!" - Pushkin would love to change places with you, as he is dead while you are alive and can act. The memory of a man is not the man himself. The good works of Pushkin do not help him in any way nor are a compensation for his dying. Conversely, a victory over aging grants a continuation and the opportunity to do many things. Transhumanism is the desire for freedom. Freedom is possibility. Pain, suffering and aging limit our possibilities. Death reduces them to zero. Improving people via the new nano-, bio-, info-technology of the 21st century offers opportunities only dreamed of by philosophers of the past. It is important to take action."

CONSIDERING CYBERNETIC IMMORTALITY
Friday, January 25, 2013
http://www.fightaging.org/archives/2013/01/considering-cybernetic-immortality.php
If the 2045 initiative continues onwards as the founder intends, we're all going to be hearing more about what here is called "cybernetic immortality" - copying the data of the mind to run in machinery that is much more robust and longer-lasting than its biological equivalent. I consider the popularity of this goal (as put forward by Ray Kurzweil, for example) something of an existential threat, insofar as it may drain enthusiasm and allies from work on rejuvenation biotechnology now, and in future decades it may become cheaper to build mind-copies than to finalize the means to reverse and prevent aging in our biological bodies. You don't need to fully understand the brain to copy it given powerful enough computers and scanning tools, and you don't need to understand aging much better than we do today to create rejuvenation biotechnology. There are more than enough people in the world who consider a copy of themselves a suitable continuation to support this sort of technology in preference over medicine for rejuvenation. Today a person can choose to support programs like SENS research on the rejuvenation side or the 2045 group on the mind copying side - it's not just talk, it's a rather important choice between aiming for continued survival of the self or aiming for death while a copy of you survives. "Cybernetic immortality - fantasy or scientific problem? I can answer that right away. It is a scientific problem - of approximately the same type as the problem of people going into outer space, which was proposed by Tsiolkovsky at the turn of the 20th century. Why, despite the support of important scientists (such as V. Turchin, C. Joslyn, R. Kurzweil, A. Bolonkin, B. Bainbridge and others), is this idea rejected by many, or at best treated with skepticism? There are many reasons for this. Firstly: the scale of this super-project, which really does verge on fantasy, is too "overwhelming", for the "average" scientific mindset, which is mundane and cautious, and too dependent on the opinion of the scientific management. Anything is proposed nowadays if financing can be secured for it. I'm not even talking about the colossal growth of false science - charlatans, mages, "miracle-workers". All of this throws a shadow on the idea of cybernetic immortality. Furthermore, we are now only at the approach stage of a solution to this problem, specific steps for its development are in many ways only at discussion level, and creative solutions are required. The eternal idea of immortality has been expressed in myths, legends and religious beliefs. Hence the prejudice that it is not compatible with science. What is the basis for the conviction that the problem of cybernetic immortality is a real scientific problem? It does not contradict the principles of science. In fact, it finds a theoretical basis in them - above all, in the fundamental principle of the iso-functionalism of systems, which essentially heralded the beginning of the computer era. The idea of this principle is that the same complex of functions may be reproduced on substrates with different physical properties. Hence the fundamental possibility to reproduce the functions of a living system and the brain on non-biological substrates, which also fully applies to mental functions."

ON LONG-LIVED CANCER-RESISTANT RODENTS
Thursday, January 24, 2013
http://www.fightaging.org/archives/2013/01/on-long-lived-cancer-resistant-rodents.php
An open access review paper looks at the rise of mole-rats in cancer and aging research: "Most rodents are small and short-lived, but several lineages have independently evolved long lifespans without a concomitant increase in body-mass. Most notable are the two subterranean species naked mole rat (NMR) and blind mole rat (BMR) which have maximum lifespans of 32 and 21 years, respectively. The longevity of these species has sparked interest in the tumor suppression strategies that may have also evolved, because for many rodent species (including mice, rats, guinea pigs, gerbils, and hamsters) tumors are a major source of late-life mortality. Here, we review the recent literature on anti-cancer mechanisms in long-lived rodents. Both NMR and BMR seem to have developed tumor defenses that rely on extra-cellular signals. However, while the NMR relies on a form of contact inhibition to suppress growth, the BMR evolved a mechanism mediated by the release of interferon, and rapid necrotic cell death. Although both organisms ultimately rely on canonical downstream tumor suppressors (pRB and p53) the studies reveal species can evolve different strategies to achieve tumor-resistance. Importantly, studies of these cancer-resistant rodents may benefit human health if such mechanisms can be activated in human cells."

LONGER TELOMERES, LESS CANCER IN CALORIE RESTRICTED MICE
Thursday, January 24, 2013
http://www.fightaging.org/archives/2013/01/longer-telomeres-less-cancer-in-calorie-restricted-mice.php
Here's one of the hundreds of examples to show that the practice of calorie restriction improves near all measures of health and slows near all measures of aging: "To carry out the study, researchers used young mice - just three months old - and reduced their caloric intake by 40% before observing them until the end of their life cycle. "We see that mice that undergo caloric restriction show a lower telomere shortening rate than those fed with a normal diet. These mice therefore have longer telomeres as adults, as well as lower rates of chromosome anomalies." To study the effects of this phenomenon on the health of the mammals, researchers observed the incidence of age-related illnesses like cancer. The mice that had been fed a lower calorie intake showed a reduction in the incidence of cancer. Furthermore, these mice also showed a lower incidence of other age-related illnesses such as osteoporosis, greater glucose uptake or improvements in motor coordination. When the researchers carried out these same experiments with a variety of mice that produce more telomerase - a protein that lengthens telomeres and protects chromosomes - they observed that these mice not only enjoyed better health but also lived up to 20% longer. "We believe that such a significant increase in longevity is due to the protective effect against cancer produced by caloric restriction - incidences fall by 40% if we compare them with the mice that produce more telomerase and have a normal diet - and, added to the presence of longer telomeres, this makes the mice live longer and better." It is calculated that there are currently more than 10,000 people in the world on some form of controlled caloric restriction, so the observation of these individuals will be decisive in discovering the effects of this type of diet on humans."

MORE ON CENTRAL CONTROL AND THE ACCEPTANCE OF DEATH
Wednesday, January 23, 2013
http://www.fightaging.org/archives/2013/01/more-on-central-control-and-the-acceptance-of-death.php
Following on from yesterday's post on the pervasive acceptance of both aging to death and centralized control over society, here is another item that illustrates how state control of medical services and their funding via taxation distorts ethics in the matter of life and death. It quickly becomes acceptable to talk about structuring countless deaths to reduce costs - the power of perverse incentives at work. In industries not so dominated by the state, growth in customer needs and outlays is a boon, an opportunity for growth to meet the challenge, but where the state runs things it inevitably means rationing: the incentives operate to make us all worse off. We become inured to this, disturbingly. So you won't find much outrage in response to this sort of thing, and especially not the relevant sort of outrage - that this is what centralized control over medicine and health brings us to, a complete reversal of the eagerness to serve and develop new products that is the characteristic of a free market. "Past successes in reducing smoking have paid off in slower spending growth on associated medical conditions. Has smoking reduction has also slowed the rate of growth in total health care spending? Maybe, but maybe not. [One] component of outlays declines over time due to a healthier population with lower per capita health care costs. However, another component labeled "Effects of greater longevity on outlays" increases over time as smoking-related deaths are averted and more individuals are alive to collect Social Security and consume federally funded health care. After about twelve years, the longevity effect begins to outweigh the per capita spending effect, and federal outlays are actually increased by the reduced prevalence of smoking brought about by the excise tax! Too bad that not smoking couldn't just keep us healthier without prolonging life! Without this dreaded longevity effect, we could unambiguously claim to be saving money in addition to producing greater health. Seriously though, the narrow question of whether reduced prevalence of smoking saves federal dollars hinges on the number of extended life years. Because some policy-makers will evaluate tobacco control programs on whether they save federal dollars, the delayed-mortality effect of reduced smoking is a negative from this perspective. This perverse result is no knock on the CBO study; it simply answers the question asked and is careful to note that "consequences for the federal budget are only one factor that lawmakers may consider when developing policies to promote health.""

CONFIRMING THE IMPORTANCE OF AUTOPHAGY IN CALORIE RESTRICTION
Wednesday, January 23, 2013
http://www.fightaging.org/archives/2013/01/confirming-the-importance-of-autophagy-in-calorie-restriction.php
Autophagy is the collection of processes used by cells to remove and recycle damaged components and unwanted macromolecules. More housekeeping is a better thing, and increased autophagy is linked to many of the genetic and metabolic alterations shown to extend life in laboratory animals. Here researchers confirm once more the importance of autophagy to the health and longevity benefits induced by calorie restriction: "We have previously shown that autophagy is required for chronological longevity in the budding yeast Saccharomyces cerevisiae. Here we examine the requirements for autophagy during extension of chronological life span (CLS) by calorie restriction (CR). We find that autophagy is upregulated by two CR interventions that extend CLS: water wash CR and low glucose CR. Autophagy is required for full extension of CLS during water wash CR under all growth conditions tested. In contrast, autophagy was not uniformly required for full extension of CLS during low glucose CR, depending on the atg allele and strain genetic background. Leucine status influenced CLS during CR. Eliminating the leucine requirement in yeast strains or adding supplemental leucine to growth media extended CLS during CR. In addition, we observed that both water wash and low glucose CR promote mitochondrial respiration proficiency during aging of autophagy-deficient yeast. In general, the extension of CLS by water wash or low glucose CR was inversely related to respiration deficiency in autophagy-deficient cells. Also, autophagy is required for full extension of CLS under non-CR conditions in buffered media, suggesting that extension of CLS during CR is not solely due to reduced medium acidity. Thus, our findings show that autophagy is: (1) induced by CR, (2) required for full extension of CLS by CR in most cases (depending on atg allele, strain, and leucine availability) and, (3) promotes mitochondrial respiration proficiency during aging under CR conditions."

SENS RESEARCH FOUNDATION: REIMAGINE AGING
Tuesday, January 22, 2013
http://www.fightaging.org/archives/2013/01/sens-research-foundation-reimagine-aging.php
The SENS Research Foundation staff have launched their newly updated website: "If this is your first time visiting our site, welcome. If you've been here before, you're no doubt noticing plenty that is new: an updated site design, a variety of new content, a new logo, and a new organizational name. It all centers around a new tagline: reimagine aging. For a public charity, a tagline can be an enormously powerful thing. Our vision and mission statements remain the primary guides to our planning, but the tag is everywhere, on every business card and letter and web page. More than any other document or phrase, it naturally becomes the daily reminder of who we are and what we are about. Of course we are still "advancing rejuvenation biotechnologies" just as vigorously as when we carried that tagline over the last couple years. We still aim to introduce a new premise for the pharma and biotech industries. And now, our successes in our research, our collaborations, our conferences, and our educational programs have made us increasingly aware of the need to refocus our messaging to people being exposed to us for the first time. So we've consulted with a number of talented and insightful PR folks, and they all offered the same basic advice: "You do a great job of telling people what you do. Now tell them why they should care." That's really the root of the aforementioned changes: we want to do a better job of communicating that, together, we can change the way we think about how to treat age-related disease. We can change the basic research premises that have so far prevented any age-related disease from being eradicated. We can improve medicine in some of the most critical but neglected areas and increase human healthspan. It's quite a bit of change, but it all starts when enough of us reimagine aging."

HEARING LOSS CORRELATES WITH COGNITIVE DECLINE
Tuesday, January 22, 2013
http://www.fightaging.org/archives/2013/01/hearing-loss-correlates-with-cognitive-decline.php
Aging is a global phenomenon, occurring throughout the body, which is why correlations between the pace of different manifestations of degenerative aging are likely to happen and not necessarily linked by anything other than the fundamental causes of aging: "[Researchers] studied 1,984 older adults (average age about 77 years) enrolled in a prospective observational study that began in 1997-1998. A total of 1,162 individuals with baseline hearing loss had annual rates of decline in test scores that measured global and executive function that were 41 percent and 32 percent greater, respectively, than those among individuals with normal hearing. Compared to those individuals with normal hearing, individuals with hearing loss at baseline had a 24 percent increased risk for incident cognitive impairment, according to the study results. "Our results demonstrate that hearing loss is independently associated with accelerated cognitive decline and incident cognitive impairment in community-dwelling older adults," the authors comment. "The magnitude of these associations is clinically significant, with individuals having hearing loss demonstrating a 30 percent to 40 percent accelerated rate of cognitive decline and a 24 percent increased risk for incident cognitive impairment during a six-year period compared with individuals having normal hearing." The authors suggest that, on average, individuals with hearing loss would require 7.7 years to decline by five points on the 3MS (the Modified Mini-Mental State Examination, a commonly accepted level of change indicative of cognitive impairment) compared with 10.9 years in individuals with normal hearing."

SO HOW DO YOU MEASURE LIFE SPAN IN FLY STUDIES?
Monday, January 21, 2013
http://www.fightaging.org/archives/2013/01/so-how-do-you-measure-life-span-in-fly-studies.php
The nuts and bolts of reliably measuring life span in small, numerous laboratory animals like flies and worms are glossed over in most of the materials presented here. It's more complicated and prone to error than anyone would like it to be, and as for all such undertakings a whole field of knowledge and practice has been established over the years. Here's an interesting video presentation from the Journal of Visualized Experiments: "Individual aging is manifest at the population level as an increase in age-dependent mortality, which is often measured in the laboratory by observing lifespan in large cohorts of age-matched individuals. Experiments that seek to quantify the extent to which genetic or environmental manipulations impact lifespan in simple model organisms have been remarkably successful for understanding the aspects of aging that are conserved across taxa and for inspiring new strategies for extending lifespan and preventing age-associated disease in mammals. The vinegar fly, Drosophila melanogaster, is an attractive model organism for studying the mechanisms of aging due to its relatively short lifespan, convenient husbandry, and facile genetics. However, demographic measures of aging, including age-specific survival and mortality, are extraordinarily susceptible to even minor variations in experimental design and environment, and the maintenance of strict laboratory practices for the duration of aging experiments is required. These considerations, together with the need to practice careful control of genetic background, are essential for generating robust measurements. Indeed, there are many notable controversies surrounding inference from longevity experiments in yeast, worms, flies and mice that have been traced to environmental or genetic artifacts. In this protocol, we describe a set of procedures that have been optimized over many years of measuring longevity in Drosophila using laboratory vials."

USING EPIGENETICS TO SEARCH FOR THE MECHANISMS OF RHEUMATOID ARTHRITIS
Monday, January 21, 2013
http://www.fightaging.org/archives/2013/01/using-epigenetics-to-search-for-the-mechanisms-of-rheumatoid-arthritis.php
Rheumatoid arthritis is a malfunction of the immune system, but like many autoimmune diseases, comparatively little progress has been made towards understanding its causes. Here researchers are using epigenetic surveys to attempt to find genes of interest: " One probable factor involves chemical "tags" that attach to DNA sequences, part of a so-called epigenetic system that helps regulate when and how DNA sequences are "read," how they're used to create proteins and how they affect the onset or progress of disease. To complicate matters, [the] attachment of the tags to particular DNA sequences can itself be regulated by genes. "The details of what causes a particular sequence to be tagged are unclear, but it seems that some tagging events depend on certain DNA sequences. In other words, those tagging events are under genetic control." Other tagging events, however, seem to depend on cellular processes and environmental changes, some of which could be the result, rather than the cause, of disease. To tease apart these two types of tagging events, the researchers catalogued DNA sequences and their tagging patterns in the white blood cells of more than 300 people with and without one form of RA. The team then began filtering out the tags that did not appear to affect RA risk. For example, if tags were seen on the same DNA sequence in those with and without RA, it was assumed that the tags at those sites were irrelevant to the cause or development of the disease. Ultimately, the team identified 10 DNA sites that were tagged differently in RA patients and whose tagging seemed to affect risk for RA. Nine of the 10 sites were within a region of the genome known to play an important role in autoimmune diseases, while the 10th was on a gene that had never before been associated with the disease. "Since RA is a disease in which the body's immune system turns on itself, current treatments often involve suppressing the entire immune system, which can have serious side effects. The results of this study may allow clinicians to instead directly target the culpable genes and/or their tags.""

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Posted 03 February 2013 - 09:22 PM

FIGHT AGING! NEWSLETTER
February 4th 2013

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

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CONTENT

- More on the Longevity of Telomerase-Enhanced Mice
- Towards Xenotransplantation of Pig Hearts
- Learning More About SIRT3 in Aging
- Another Brief Detour into Morality
- The Damage Caused by AGEs
- Discussion
- Latest Headlines from Fight Aging!
    - A Podcast Interview With Aubrey de Grey
    - Wrapping Nanoparticles in Cell Membranes
    - Vegetarianism Associated With Lower Risk of Heart Disease
    - A Commentary on Radical Life Extension
    - The View of Mortality as Not Easily Explainable By Common Genetic Variants
    - Foundational Work For Nervous System Repair
    - Magnetic Levitation in Tissue Engineering
    - Advocating Intermittent Fasting
    - Human Brain Simulation Project Funded
    - Altering Eye Cells to Restore Vision

MORE ON THE LONGEVITY OF TELOMERASE-ENHANCED MICE
>http://www.fightaging.org/archives/2013/01/telomerase-enhanced-mice-live-longer-and-longer-still-when-calorie-restricted.php

These past few years, researchers have produced several demonstrations of extended life and reduced cancer rates in mice through the use of various gene therapy combinations involving increased telomerase expression and extra copies of cancer suppression genes such as P53.

The latest update to arrive this month has the researchers trying out calorie restriction (CR) on their transgenic telomerase-enhanced (TgTERT) mice, with a wild-type (WT) control group. Apparently calorie restriction somewhat synergizes with the effects of additional telomerase, and thus calorie restricted TgTERT mice live longer than their ad libitum peers. Beyond that, this is also a study of how calorie restriction impacts telomere dynamics, finding that it delays the characteristic erosion of telomeres with age - which is consistent with the body of research showing calorie restriction to slow almost all other measurable aspects of aging.

The trouble with ascribing causes and mechanisms to calorie restriction is that it does change everything. So autophagy researchers see it boosting autophagy, telomerase researchers see it changing telomere dynamics, fat metabolism researchers see it affecting fat metabolism, and so forth. So far I think that autophagy has a stronger claim than any other mechanism as being the dominant cause of calorie restriction benefits to health and longevity, if only because removal of mechanisms essential to autophagy has been shown to remove those benefits in some laboratory species. But there's still plenty of room for evidence and debate.

TOWARDS XENOTRANSPLANTATION OF PIG HEARTS
http://www.fightaging.org/archives/2013/02/working-on-the-use-decellularization-to-make-pig-hearts-suitable-for-human-transplantation.php

One recent morning, a pig heart hung suspended in a clear homemade tank in the lab built for Taylor and her team. Filled with detergent, the heart had expanded to the size of a large man's fist, excess liquid dripping slowly out its sides. Once the heart is thoroughly cleaned, hard-working human stem cells - immature cells found in our organs and tissues that help repair damage on a daily basis - will bring it to life. "We can take stems cells from bone marrow, blood or fat and place them onto a heart, liver or lung scaffold," Taylor explains. "My motto for a long time has been 'Give nature the tools and get out of the way.' "

Taylor and her team will add stem cells to the heart one of two ways: by inserting a tube in the aorta and letting the cells drip inside, or by injecting the cells with a syringe through the wall of the heart. A heartbeat is perceptible after just a few days. Within a few weeks, the heart is strong enough to pump blood.

Taylor predicts that in the next two years, she and her team will approach the U.S. Food and Drug Administration and ask to do a first-in-human study with the bio-artificial hearts. "Will it be a whole heart? Probably not," Taylor says. "But it could be a cardiac patch or a valve. We might start with a piece to show the safety and efficacy of the technology."

LEARNING MORE ABOUT SIRT3 IN AGING
http://www.fightaging.org/archives/2013/01/learning-more-about-the-role-of-sirt3-in-aging.php

Sirtuins have been a hot topic in aging research - largely undeservedly as it turned out - for some years, the large sums of money flowing into that field of research helping to drive enthusiasm for the slow, expensive road of slowing aging by metabolic manipulation. Most of the relevant research community, those who might be working on SENS or other rejuvenation biotechnologies if the money was there, work towards similar goals. They are producing knowledge rather than applications that can influence human lifespan, and have little expectation of producing anything more than knowledge for decades to come. Knowledge is never useless, but this path is not likely to deliver meaningful extension of human life in time to matter to us, nor is it likely to produce technologies that will help people who are already aged.

There are a number of different sirtuins, and while research initially focused on SIRT1, it is SIRT3 and SIRT6 that have generated the more interesting results in the past couple of years. SIRT3 is the topic for today, a mitochondrial protein - it is noteworthy to see just how many longevity-related genes and proteins are connected to the mitochondria in some way. Calorie restriction is noted to boost levels of SIRT3, and SIRT3 is thought to promote antioxidant activity in cells, reducing damage in the places where oxidants are produced as a side-effect of the operation of metabolism - something that you can't achieve by ingesting antioxidants, I should add.

Here, researchers demonstrate a modest reversal of one small aspect of the breadth of aging biology by boosting levels of SIRT3 in old mice:

"The researchers first observed the blood system of mice that had the gene for SIRT3 disabled. Surprisingly, among young mice, the absence of SIRT3 made no difference. It was only when time crept up on the mice that things changed. By the ripe old age of two, the SIRT3-deficient mice had significantly fewer blood stem cells and decreased ability to regenerate new blood cells compared with regular mice of the same age.

"What is behind the age gap? It appears that in young cells, the blood stem cells are functioning well and have relatively low levels of oxidative stress, which is the burden on the body that results from the harmful byproducts of metabolism. At this youthful stage, the body's normal anti-oxidant defenses can easily deal with the low stress levels, so differences in SIRT3 are less important.

"To see if boosting SIRT3 levels could make a difference, the researchers increased the levels of SIRT3 in the blood stem cells of aged mice. That experiment rejuvenated the aged blood stem cells, leading to improved production of blood cells."

ANOTHER BRIEF DETOUR INTO MORALITY
http://www.fightaging.org/archives/2013/01/another-brief-detour-into-morality.php

Why can't we just focus on the engineering when it comes to aging and our biology? Stuff in our biology is broken, it causes tremendous pain and suffering, not to mention most of the world's deaths, so let's work on fixing it. This seems like a simple enough proposition, one that nobody has issues with when it comes to specific manifestations of aging like heart disease or Alzheimer's. Yet as soon as you talk about fixing the brokenness of aging itself, the very root causes that produce things like heart disease and Alzheimer's, suddenly half of the room wants you to know just how terribly immoral this would be.

We do not live in a rational age. Not that any of the others were any better, but still. We should be better - we have the grand sweep of recorded historical irrationality to look back on and learn from.

Throughout history people have aged and died because they had to, even as they struggled to live and railed against the inevitable, because there was nothing that could be done. Now there is something that can be done: we can build rejuvenation biotechnologies to repair the known causes of aging. That wasn't plausible centuries ago, or even three decades ago, but it's plausible now. The research and development community is not pursuing this goal in any energetic way, however, and there is no great public clamor for greater longevity through medical technology. So one might argue that the defining characteristic of this new age of ours is that its occupants, presented for the first time with the option to choose life, are instead choosing death.

They are choosing death not just for themselves, but for every future individual that might have had the choice to use rejuvenation therapies had the work started now in earnest. A day late is a hundred thousand lives short: aging produces a sweeping, staggering toll of death. More people than you will plausibly meet in a lifetime have died of aging already today. Tomorrow it will happen again, and for every new day until we choose to stop it from happening.

This is the status quo, this avalanche of funerals and pain. Yet those who tell us that it would be immoral to do anything about it often raise up the status quo, the present structure of society, the bounds of what is, as something of greater worth that must be preserved. A mighty god, the system - on a par with the environment and society when it comes to people willing to march themselves and others to death in its name. Grouping individuals and then coming to see only the group, to the point of discarding the individuals as worthless, has been all too familiar this past century - with its fervors, its global wars, and its megadeaths. I don't imagine that it'll be any easier going forward to convince people that saving tens of millions of lives every year is more important than their precious abstractions.

THE DAMAGE CAUSED BY AGES
http://www.fightaging.org/archives/2013/01/a-look-at-some-of-the-biomechanical-damage-caused-by-ages.php

Advanced glycation end-products (AGEs) are perhaps the most frustrating of the mechanisms that cause aging. Frustrating because the overwhelming majority of AGEs are of the same basic type in humans - glucosepane - and all it will take to remove this contribution to aging is a designed molecule that can break down this specific compound without harming the rest of our biology. To my eyes finding that basis for therapy is a goal well within reach of a sensible, $20 million, five year program at this time, or pretty much any time over the last decade. Yet no-one is putting more than a pittance into this research, and no more than a handful of researchers pay any attention. This is why development of a glucosepane AGE-breaker therapy is low in the list of plausible near future advances in rejuvenation biotechnology. Not because it's harder than the rest, far from it, but because no-one with a large budget is trying.

AGE buildup is one of the root causes of aging. Advanced glycation end-products accumulate as a consequence of the ordinary operation of metabolism, and wherever they lurk in the body they gum up important molecular machinery, deliver harmful signals to cells that spur inflammation, and generally cause all sorts of damage and dysfunction. Aging is no more than unrepaired damage, and as you can see, a part of that stems from something that should be very easy to fix in the grand scheme of things.

Yet next to no-one is trying. The SENS Foundation is one of the few groups that does put funding into finding ways to clear glucosepane, but that is still a small amount in the grand scheme of things - certainly nowhere close to millions of dollars yet. You can read a summary at the Foundation website that discusses the science and gives an overview of the current research collaboration.

DISCUSSION

The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!

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LATEST HEADLINES FROM FIGHT AGING!

A PODCAST INTERVIEW WITH AUBREY DE GREY
Friday, February 1, 2013
http://www.fightaging.org/archives/2013/02/a-podcast-interview-with-aubrey-de-grey.php
From a few weeks back, an audio interview with Aubrey de Grey of the SENS Research Foundation: "Anti-aging scientist and biogerontologist Aubrey de Grey told [the host] about his work with the SENS Foundation, an organization he founded with the purpose of defeating aging. According to him, aging is treated as a disease that should be defeated by targeting the 7 cellular activities that cause us to age. Dr. de Grey discussed the science that researchers at SENS are studying to back up the claim that we could live to 1000 years some day soon. "The problem is the funding," de Grey said. "We've been trying to fight what we've described as the pro-aging trance." The pro-aging trance, according to Dr. de Grey, is the social conception we have that death is inevitable. "No one wants to keep cancer, no one wants to keep heart disease, so what would we want to keep aging?" de Grey asks. Part of Aubrey de Grey's work is marketing his ideas and helping to diminish the acceptance society has of death. Citing his long beard which [the interviewer] said looked "like Rasputin's," de Grey said, "This is something my team and I have discussed. It's something that helps me stick in people's minds." [The interviewers] briefly talked about the social, economic, and cultural consequences of a longer life extension. When [the interviewers] pressed de Grey on these issues, Aubrey reiterated that his work is not a "longevity issue, but a health care issue, so stop thinking of it that way please." Aubrey pressed that the key for his scientific success lies in his publicity: getting more exposure and raising money through his foundation."

WRAPPING NANOPARTICLES IN CELL MEMBRANES
Friday, February 1, 2013
http://www.fightaging.org/archives/2013/02/wrapping-nanoparticles-in-cell-membranes.php
Here is another small step on the way towards the creation of artificial cells as medical devices. If you can wrap nanoparticles in cell membranes, then its not hard to see that disguising any arbitrary nanomachinery that way is on the agenda - such as those that can dispense or create proteins, or perform other tasks inside our tissues. " By cloaking nanoparticles in the membranes of white blood cells, [scientists] may have found a way to prevent the body from recognizing and destroying them before they deliver their drug payloads. "Our goal was to make a particle that is camouflaged within our bodies and escapes the surveillance of the immune system to reach its target undiscovered. We accomplished this with the lipids and proteins present on the membrane of the very same cells of the immune system. We transferred the cell membranes to the surfaces of the particles and the result is that the body now recognizes these particles as its own and does not readily remove them." Nanoparticles can deliver different types of drugs to specific cell types, for example, chemotherapy to cancer cells. But for all the benefits they offer and to get to where they need to go and deliver the needed drug, nanoparticles must somehow evade the body's immune system that recognizes them as intruders. The ability of the body's defenses to destroy nanoparticles is a major barrier to the use of nanotechnology in medicine. Systemically administered nanoparticles are captured and removed from the body within few minutes. With the membrane coating, they can survive for hours unharmed. "Being able to use synthetic membranes or artificially-created membrane is definitely something we are planning for the future. But for now, using our white blood cells is the most effective approach because they provide a finished product. The proteins that give us the greatest advantages are already within the membrane and we can use it as-is.""

VEGETARIANISM ASSOCIATED WITH LOWER RISK OF HEART DISEASE
Thursday, January 31, 2013
http://www.fightaging.org/archives/2013/01/vegetarianism-associated-with-lower-risk-of-heart-disease.php
Vegetarianism is associated with health benefits such as reduced risk of age-related disease. It is also associated with carrying less of the visceral fat shown to cause harm to long-term health - which on balance probably means a lower calorie intake. As we all know by now, calorie intake has a disproportionate effect on measures of health. So that would seem to be a more plausible mechanism than, say, reduced dietary intake of AGEs or lower levels of methionine. Here, however, researchers are claiming that differences in body mass index - a not-so-great proxy measure for the amount of body fat - between vegetarians and non-vegetarians are not terribly important in comparison to blood pressure and cholesterol measures. That is not a particularly intuitive result: "The risk of hospitalisation or death from heart disease is 32% lower in vegetarians than people who eat meat and fish, according to a new study. "Most of the difference in risk is probably caused by effects on cholesterol and blood pressure, and shows the important role of diet in the prevention of heart disease." This is the largest study ever conducted in the UK comparing rates of heart disease between vegetarians and non-vegetarians. The analysis looked at almost 45,000 volunteers from England and Scotland enrolled in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Oxford study, of whom 34% were vegetarian. Such a significant representation of vegetarians is rare in studies of this type, and allowed researchers to make more precise estimates of the relative risks between the two groups. The Oxford researchers arrived at the figure of 32% risk reduction after accounting for factors such as age, smoking, alcohol intake, physical activity, educational level and socioeconomic background. Participants were recruited to the study throughout the 1990s, and completed questionnaires regarding their health and lifestyle when they joined. These included detailed questions on diet and exercise as well as other factors affecting health such as smoking and alcohol consumption. Almost 20,000 participants also had their blood pressures recorded, and gave blood samples for cholesterol testing. The volunteers were tracked until 2009, during which time researchers identified 1235 cases of heart disease. This comprised 169 deaths and 1066 hospital diagnoses, identified through linkage with hospital records and death certificates. The researchers found that vegetarians had lower blood pressures and cholesterol levels than non-vegetarians, which is thought to be the main reason behind their reduced risk of heart disease. Vegetarians typically had lower body mass indices (BMI) and fewer cases of diabetes as a result of their diets, although these were not found to significantly affect the results. If the results are adjusted to exclude the effects of BMI, vegetarians remain 28% less likely to develop heart disease."

A COMMENTARY ON RADICAL LIFE EXTENSION
Thursday, January 31, 2013
http://www.fightaging.org/archives/2013/01/a-commentary-on-radical-life-extension.php
Here is a commentary I noticed recently, not entirely positive when it comes radical life extension, but the positive portion is quoted below: "Aging, along with the physical and mental deterioration that characterizes it, is undesirable. Potential economic and social difficulties notwithstanding, living longer and healthier lives is a positive and productive premise. Acceptance of the preceding premise leads to the conclusion that the technology that would facilitate radical life extension ought to be pursued. Dr. Aubrey de Grey, a [biogerontologist] with a formidable beard, offers the argument that it would be morally dubious of us not to develop these technologies and deprive future generations of the benefits therein. To have the ability to develop therapies that lead to longer and healthier lives makes it our responsibility to do so. Policy decisions concerning the adoption and implementation of the policies should be left to those generations in which they are most relevant; it is presumptuous of us to make those decisions for them by not developing these therapies. In his view, it is not only desirable but a moral imperative to give future generations the choice and allow them to decide on implementation. Our hesitation in diverting resources to the development of these therapies is actually condemning future generations to a life span that is far shorter than it could be were we to actively pursue life extension technology. Furthermore, we cannot presume to fully understand the social and political landscape of the future and their priorities - they will be best suited to make a choice and we should allow them to do so. Without going so far as to characterize those opposed to life extension technology as luddites, there is a serious risk of preventing the potential benefits of these technologies from reaching us, or our children, in time. Some people's fear of what may happen if people live ever longer lives is not a basis for pre-emptive policy decisions."

THE VIEW OF MORTALITY AS NOT EASILY EXPLAINABLE BY COMMON GENETIC VARIANTS
Wednesday, January 30, 2013
http://www.fightaging.org/archives/2013/01/the-view-of-mortality-as-not-easily-explainable-by-common-genetic-variants.php
It is likely the case that natural variations in longevity emerge from the interaction of many, many minor genetic differences with lifestyle and other environmental factors. The majority of these contributions to longevity will be tiny, and their presence will vary widely across a population: "Twin studies have estimated the heritability of longevity to be approximately 20-30%. Genome-wide association studies (GWAS) have revealed a large number of determinants of morbidity, but so far, no new polymorphisms have been discovered to be associated with longevity per se in GWAS. We aim to determine whether the genetic architecture of mortality can be explained by single nucleotide polymorphisms (SNPs) associated with common traits and diseases related to mortality. By extensive quality control of published GWAS we created a genetic score from 707 common SNPs associated with 125 diseases or risk factors related with overall mortality. We prospectively studied the association of the genetic score with: (1) time-to-death; (2) incidence of the first of nine major diseases (coronary heart disease, stroke, heart failure, diabetes, dementia, lung, breast, colon and prostate cancers) in two population-based cohorts of Dutch and Swedish individuals (N = 15,039; age range 47-99 years). During a median follow-up of 6.3 years (max 22.2 years), we observed 4,318 deaths and 2,132 incident disease events. The genetic score was significantly associated with time-to-death. The association between the genetic score and incidence of major diseases was stronger. Associations were stronger for individuals dying at older ages. Our findings are compatible with the view of mortality as a complex and highly polygenetic trait, not easily explainable by common genetic variants related to diseases and physiological traits."

FOUNDATIONAL WORK FOR NERVOUS SYSTEM REPAIR
Wednesday, January 30, 2013
http://www.fightaging.org/archives/2013/01/foundational-work-for-nervous-system-repair.php
An example of researchers working on the tools needed to guide cell growth: "The aim of the research was to find a biomaterial able to sustain the population of neural stem cells and to generate new differentiated cells in order to start the development of an implant that allows brain regeneration. Despite recent advances in understanding the mechanisms of nerve injury, tissue-engineering solutions for repairing damage in the central nervous system (CNS) remain elusive, owing to the crucial and complex role played by the neural stem cell (NSC) niche. This zone, in which stem cells are retained after embryonic development for the production of new cells, exerts a tight control over many crucial tasks such as growth promotion and the recreation of essential biochemical and physical cues for neural cell differentiation. The team tested types of polylactic acid (PLA) with different proportions of isomers L and D/L, a biodegradable material allowing neural cell adhesion and growth, as materials for nerve regeneration. They found that one type, PLA with a proportion of isomers of 70/30, maintained the important pools of neuronal and glial progenitor cells in vitro. PLA 70/30 was more amorphous, degraded faster and, crucially, released significant amounts of L-lactate, which is essential for the maintenance and differentiation of neural progenitor cells. The results suggest that the introduction of 3D patterns mimicking the architecture of the embryonic NSC niches on PLA70/30-based scaffolds may be a good starting point for the design of brain-implantable devices. [These] will be able to induce or activate existing neural progenitor cells to self-renew and produce new neurons, boosting the CNS regenerative response in situ."

MAGNETIC LEVITATION IN TISSUE ENGINEERING
Tuesday, January 29, 2013
http://www.fightaging.org/archives/2013/01/magnetic-levitation-in-tissue-engineering.php
Researchers here demonstrate a way to use magnetic levitation to make small pieces of tissue grow more naturally, though one suspects it won't scale to much larger tissue sections. The focus here, as for much of tissue engineering at this time, is to produce tissues as close to the real thing as possible, suitable for testing and research, applications where the small amount is not an issue: "The research is part of an international trend in biomedical engineering to create laboratory techniques for growing tissues that are virtually identical to those found in people's bodies. In the new study, researchers combined four types of cells to replicate tissue from the wall of the bronchiole deep inside the lung. "One of the unique things about the magnetic levitation technology is that it allows us to move cells around and arrange them the way that we want for a particular type of tissue. This is the first time anyone has arranged these four cell types in the same way that they are found in lung tissue." The technology is said to rely on inert, non-toxic magnetic nanoparticles that are inserted into the living cells. Researchers can then use magnets to lift and suspend the cells as they grow and divide. "We conducted a number of tests, and the tissue has the same biochemical signature as native tissue. We also used primary cells rather than engineered cells, which is important for toxicological testing because primary cells provide the closest possible match to native cells." "Bronchiole tissue could solve another problem that's frequently encountered in testing the toxicity of airborne agents. With traditional 2D cultures, it is very difficult to culture cells at the air-liquid interface, which is what you'd prefer for toxicity testing. With our technology, we can easily levitate the bronchiole tissue to the air-liquid interface so that airborne toxins are exposed to the epithelial layer of the tissue, just as it would occur in the lungs.""

ADVOCATING INTERMITTENT FASTING
Tuesday, January 29, 2013
http://www.fightaging.org/archives/2013/01/advocating-intermittent-fasting.php
This pop-sci piece extols the virtues of intermittent fasting, though the author gives it weight over calorie restriction that it doesn't merit at this time. The evidence is much stronger for the benefits of calorie restriction, as it has been studied more extensively. The results for extended longevity in laboratory animals due to intermittent fasting remain mixed, though it certainly seems to produce health benefits: "One of the most important studies in this area was conducted just last year at Salk's Regulatory Biology Laboratory. In an experiment, biologist Satchidananda Panda and colleagues restricted the feeding of mice to - conveniently enough - an 8-hour period each day. The researchers were attempting to study whether obesity and metabolic diseases like diabetes were the result of high-fat diets, or from the disruption of metabolic cycles. To that end, Panda gave the mice lots of fat to eat. In fact, 60% of the calories consumed were derived from fat (which was meant to simulate foods like chips and ice-cream). The researchers also created a control group that ate the same thing, but these mice could eat any time they wanted (interestingly, as nocturnal creatures, they ate half their meals at night, while grazing on the remainders during the day). As for the restricted group, their 8-hour window was at night. One hundred days later, the free-for-all group was a mess. They gained weight, developed high cholesterol, high blood glucose, and experienced liver damage and diminished motor control. But as for the mice who practiced the intermittent fast, they weighed 28% less and showed no signs of adverse health."

HUMAN BRAIN SIMULATION PROJECT FUNDED
Monday, January 28, 2013
http://www.fightaging.org/archives/2013/01/human-brain-simulation-project-funded.php
An early step towards whole brain emulation seems to be underway, though as always funding past what is in hand now remains a question mark: "The European Commission has selected the two research proposals it will fund to the tune of half-a-billion euros each after a two-year, high-profile contest. The Human Brain Project, led by neuroscientist Henry Markram at the Swiss Federal Institute of Technology (EPFL) in Lausanne, plans to simulate everything known about the human brain in a supercomputer - a breathtaking ambition that has been met with some scepticism (See "Brain in a box"). The final winners were selected from a shortlist of six projects as being the most likely to achieve the paradigm-shifting advances they claim. They will now enter the so-called 'ramp-up' phase, each receiving €54 million over 30 months. That represents the last cash available from the EU's expiring 7th Framework Programme of Research. Subsequent phases will be supported under its successor programme, Horizon 2020, though the structure of that programme is still being negotiated and some observers fear that funds may be scaled back."

ALTERING EYE CELLS TO RESTORE VISION
Monday, January 28, 2013
http://www.fightaging.org/archives/2013/01/altering-eye-cells-to-restore-vision.php
An approach to therapy for degenerative blindness that involves reprogramming existing cells rather than introducing new ones: "Doctors may one day treat some forms of blindness by altering the genetic program of the light-sensing cells of the eye. [Working] in mice with retinitis pigmentosa, a disease that causes gradual blindness, the researchers reprogrammed the cells in the eye that enable night vision. The change made the cells more similar to other cells that provide sight during daylight hours and prevented degeneration of the retina, the light-sensing structure in the back of the eye. "We think it may be significantly easier to preserve vision by modifying existing cells in the eye than it would be to introduce new stem cells. A diseased retina is not a hospitable environment for transplanting stem cells. [The] question was, when retinitis pigmentosa is caused by a mutation in a protein only active in rods, can we reduce or stop vision loss by making the cells less rod-like?" The new study focuses on a protein known as Nrl, which influences development of photoreceptors. Cells that make Nrl become rods, while cells that lack the protein become cones. Turning off the Nrl gene in developing mice leads to a retina packed with cone cells. To see if this rod-to-cone change was possible in adult mice, [researchers] created a mouse model of retinitis pigmentosa with an Nrl gene that could be switched on and off by scientists. [In] adult mice, switching off Nrl partially converts the rod cells into cone cells."

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Posted 10 February 2013 - 07:12 PM

FIGHT AGING! NEWSLETTER
February 11th 2013

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

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CONTENT

- Planning to Live to 110
- Final Complexity is Less Relevant Than That of Root Causes
- Towards a Goal That Can Never Be Attained
- The Quest for Reversible Cryopreservation
- Discussion
- Latest Headlines from Fight Aging!
    - An Interview With Judith Campisi
    - Parkinson's Disease as Localized Garbage Catastrophe
    - An Actuarial Overview on Human Longevity and Mortality
    - A Popular Science Article on the Study of the Axolotl
    - Telomere Length as Biomarker of Somatic Redundancy
    - Being Overweight is Harmful at All Ages, In No Way Protective
    - Chromatin and Transposons in Senescent Cells
    - Gene Copy Number Variations Associated With Longevity
    - The Proximal Cause of Aging From the Point of View of the Programmed Aging Camp
    - The First Person to Live to 150 Has Already Been Born

PLANNING TO LIVE TO 110
http://www.fightaging.org/archives/2013/02/planning-to-live-to-110.php

I'll spare you a link to one of the talking heads of the "anti-aging" marketplace discussing her plans to live to 110, and how other folk might, hypothetically, follow along at home. You can find it easily enough via Google if so inclined. It puts me in mind of the following entirely made-up short exchange:

Quote:Me: I hear you are planning to live to 110?
Talking Head: Yes.
Me: So you must be donating handsomely to help fund the SENS research program, which aims to repair the causes of aging, right?
Talking Head: No.
Me: You're not planning this very well at all, then, are you?

People show up every now and again in public forums with talk of planning to live for a long time in good health using nothing more than supplements, diet, and exercise: make all the right lifestyle choices, eat a good diet, don't get fat, be calorie restricted, and so forth. There's even a billionaire who was talking a good game on the topic a couple of years back. Good health practices all raise the odds of living a healthier life, but with present day medical technology those odds don't see you making it to 90, let alone 100 or 110. Living as healthily as possible gives you slim odds - perhaps somewhere a little north of 25% - of celebrating your 90th birthday under present medical capabilities. The odds get worse if you let yourself go. The simple, unfortunate truth of the matter is this: if eating exceedingly well really could let people live to 100 and beyond with any reliability, then this would be well known, and the world population would include thousands upon thousands upon thousands of centenarians.

So plan away, planners. It won't help all that much in achieving any goal related to the number of candles on your cake, though it may well make your life much more pleasant along the way. Good health is a very underrated thing, usually by those who still have it. The only way the planner demographic will reliably hit their high-end life span targets is by benefiting from advances in medical technology, i.e. from the results of actions and initiatives that have absolutely nothing to do with their personal health practices. For the presently older demographic, those advances would have to be of the sort envisaged in the Strategies for Engineered Negligible Senescence (SENS): ways to actually create rejuvenation in the old by addressing the cellular and molecular damage that causes aging.

The bottom line here: if you're planning to live to 110, then you aren't planning very well if those plans don't largely revolve around helping to fund rejuvenation research of the sort pioneered by the SENS Research Foundation. Advances in medicine don't just happen: they require money, advocacy, and hard work. Which of those are you helping out with?

FINAL COMPLEXITY IS LESS RELEVANT THAN THAT OF ROOT CAUSES
http://www.fightaging.org/archives/2013/02/final-complexity-is-less-relevant-than-that-of-root-causes.php

I think we can all agree that, separately, each of aging, cancer, and Alzheimer's disease is a complicated phenomenon. Is cancer more or less complicated than aging, however? Are the likely several different disease processes leading to a similar end presently lumped under the heading of Alzheimer's disease more or less complex than either cancer or aging? I think that arguments could be made for any ordering of the three, though not all of them are good arguments, and anything that fits in this short blog post is going to involve a fair amount of hand-waving. We could compare the funding and researcher man-years devoted to understanding each, for example, or papers published, or some other similar research metric. I suspect that cancer wins by those measures, if we airily assume that greater amounts of funding are led by the fact that there is much more to catalog at the level of genes, proteins, and cellular mechanisms. I don't think that this is a safe assumption.

If we look at the SENS vision of aging, or indeed any damage-based model of how and why we age, we might say that aging is more simple than Alzheimer's, or more simple than any age-related condition. Aging stems from simple root causes, which expand out into massively complex and varied failure modes as damage interacts with damage and systems flail and fail in any number of ways. To draw an analogy, the rust that eats iron structures is a very simple, homogenous thing - a trivial set of a few chemical reactions, easily described, easily prevented. Yet a structure can fail in countless ways due to rust, as the progression and damage caused is stochastic. Which girder or support will be eaten to breaking point first? Similar structures might fail in similar ways more often, perhaps because they allow moisture to linger in the same places.

But you get the point: from simple causes great complexity can arise. The more complex the structure, the greater the number of failure modes that simple forms of damage can cause. We humans are tremendous complex, vast, interlinked arrays of molecular machinery, and in most modern theories of aging the few rusts we are theorized to suffer (some with much more evidence than others) are pretty simple at root. Thus any age-related condition must be more complex than its cause, aging, by virtue of being an end result rather than the cause of that end result. That is one way of looking at it. Another is to view the end state of aging as a whole and measure that complexity - which is obviously also much more complex than the simple processes that gave rise to it.

Does the complexity of the end state of aging matter, however? Or for that matter, the end state of cancer or Alzheimer's disease? This is not an idle question, as it points to the consequences that result from different core philosophies or approaches in medicine and medical research. Do we fix a problem by working to understand its end states and then try to clean up after or block every branching failure mode, or do we aim to remove the root causes and then let our biology try to restore itself?

That is not a question with a correct answer for all times and places: sometimes it isn't enough just to remove a root cause, sometimes the root cause is unknown. It is clear, however, that when it comes to age-related conditions a great deal of modern medicine runs along the lines of being an ever more sophisticated means of sticking a finger into the rapidly eroding hole in the dam, rather than repairing the hole in a way that will last. Consider the widespread efforts to safely remove amyloid beta in Alzheimer's disease, for example: it seems likely that this is not a case of treating root causes, which remain poorly understood at this time, but rather cleaning up the most evident of the biological signatures.

The regulatory structure for medicine and medical research in the US and Europe biases researchers towards the goal of producing what are ultimately less effective treatments for end causes. The system is so set up that the path of least resistance is to research some part of the complex pathology of a late-stage disease, where there is more room to carve out something that can be patented, and then build what are essentially palliative medicines for people who are very sick, having long suffered their particular named condition. Prevention and root causes don't yet get anywhere near as much attention. When it comes to aging itself, it isn't even legal in the US to try to produce and commercialize a clinical therapy that might do some good.

But prevention and root causes are exactly where the attention should be when it comes to aging and age-related diseases. Root causes are simple, end stages are complex: that is reflected in the cost and time required to produce therapies. The way to harness the complexity of our self-repairing biology rather than fight against it is to look to removing causes rather than cleaning up after the spreading tree of secondary and tertiary consequences. This has long been understood by the public and researchers alike when it comes vaccination, poisons, and all sorts of other areas of medicine. Somehow it has gone a little astray in the matter of aging and age-related disease. That must change.

TOWARDS A GOAL THAT CAN NEVER BE ATTAINED
http://www.fightaging.org/archives/2013/02/towards-a-goal-that-can-never-be-attained.php

It is a polite fiction in some parts of the aging research community that the goal of the scientists' work is to improve health in the old without improving longevity. Like all the best polite fictions, it survives because many people have come to actually believe this line. It arose during the period when researchers couldn't talk openly about extending human life without risking their funding and their careers: proposing improvements to health in the old was the way to raise funds when you couldn't talk about extending healthy and overall life span. Sad to say, but the research and funding community was, up until comparatively recently, in the business of discouraging research and researchers who might head in that direction - or at the very least in the business of saying nothing about the matter in public. There is surprisingly little shame evident from those who engaged in those practices back in the day, now that things are somewhat different.

If we look at aging from the high level abstraction of reliability theory, it becomes clear that it should be impossible to improve health without also extending life. Aging is an accumulation of damage, and improving health involves fixing or preventing that damage. The statistics of the way in which any machinery - our bodies included - ages and fails, and the statistics of how long that failure will take to happen, depend on the level of unrepaired damage in the system's component parts. Arguing the opposite side of that position, that is is possible to fix damage without extending life expectancy, is a steep hill to climb: you have to come up with a convincing explanation as to why a human doesn't behave like any other physical system that undergoes limited self-repair - which starts to sound suspiciously like vitalism.

Nonetheless, we still see things like this, buried in the introduction to abstracts from one of last year's conferences: "the true goal of aging research is to increase the health of the elderly, not their longevity." I think it's a problem that a fair proportion of researchers in this field continue to either (a) put forward the proposition that you can improve long-term health without extending life as a matter of fact, or (b) conveniently omit any discussion of extended longevity as a possible goal or result of their work. This is to say nothing of the ethics of actually trying to avoid extending life span in a field where it is a possibility.

THE QUEST FOR REVERSIBLE CRYOPRESERVATION
http://www.fightaging.org/archives/2013/02/the-quest-for-reversible-cryopreservation.php

Much of the talk of low-temperature preservation of tissue here at Fight Aging! directly relates to the cryonics industry: the work of preserving the brains of those who age to death prior to the advent of rejuvenation biotechnology, so that they have some possible chance at a longer life in the future. There is a large mainstream cryobiology industry and research community that shares essentially the same goals when it comes to organs and tissues, although cryobiologists have historically been quite hostile towards cryonics groups. It's the same old story of the conformist mainstream pushing away anyone who is doing something out of the ordinary - yet all bold new technologies and approaches start exactly that way, with a small group moving the boundaries of the possible and the plausible.

In any case, back to the commonalities: both cryobiologists and cryonicists want to produce the means for reversible cryopreservation rather than the presently irreversible methods of vitrification used on the human patients stored at Alcor, the Cryonics Institute, KrioRus, and so forth. Presently irreversible is not forever irreversible, of course, but the cryoprotectant compounds used now are pretty toxic, which adds an additional level of difficulty to the task of restoring patients to life. A reasonable argument is that given that this task requires technologies such as swarms of medical nanorobots, and sufficient control over small-scale biology to be able to repair arrangements of macromolecules within cells, then sequestering toxic molecules along the way shouldn't be a big deal by comparison.

So the cryobiologists want to be able to store organs and other large tissue masses in the same way that we can presently store embryos - in the deep freeze, so that donated organs or organs grown to order can be stored until needed. The cryonics community includes some groups with expertise in this area, such as 21st Century Medicine, and the development of reversible cryopreservation would be one of the potential spin-off technologies that could draw greater funding and interest into cryonics. Follow the link above for more on the present state of work on cryopreservation that is not directly related to the cryonics industry.

DISCUSSION

The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!

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LATEST HEADLINES FROM FIGHT AGING!

AN INTERVIEW WITH JUDITH CAMPISI
Friday, February 8, 2013
http://www.fightaging.org/archives/2013/02/an-interview-with-judith-campisi.php
Scientific American interviews Judith Campisi, a member of the SENS Research Foundation's scientific advisory board and a noted figure in the aging research community. You'll note that her views are fairly conservative, much closer to the mainstream of longevity science than to SENS, however: "[SciAm]: Why is it so hard to figure out what causes aging? [Judith Campisi]: In many ways we already know what causes aging. We just don't know what causes aging in the kind of molecular detail that would allow us to intervene in large meaningful ways. It's not even clear that once we solve those mysteries we will be able to intervene in aging or dramatically extend longevity. I started my career studying cancer. Look at all the things we have learned since the 1970s about how cancers form in the body. And yet, still the best cures we have for most cancers are sledgehammers. Biology is complex - and this is a reality that the public has to come to grips with and our legislators have to come to grips with. I predict aging will follow the same trajectory as cancer research. Why is aging so difficult to figure out? It's because it's a really tough problem. I think it's tougher than cancer. The time has come to really wallow in the complexities. [SciAm]: What would you say is one of the biggest mysteries of aging research? [Judith Campisi]: Why do organisms with remarkable genetic similarity have sometimes remarkable differences in life span? We know that for the most part, many of the processes that go on in the human body also go on in yeast and mice. Yet, yeast live a few days, a mouse lives about three years, and people live for decades. We really do not know what evolution has done to take basically the same genes and produce different life spans. [SciAm]: Is that where the naked mole rat comes in? [Judith Campisi]: Yes. The mystery shows up even in species that are mouselike. The naked mole rat is more related to the mouse than to us - it looks like a mouse. And yet it lives for 30 years, or 10 times longer than a regular mouse. On top of all that, it has signs of oxidative damage that exceeds that of the mouse. Now there are three ideas that scientists have come up with to try to explain why naked mole rats live so long: Maybe oxidative damage doesn't cause aging. Maybe naked mole rats are evolutionary oddities. And then my personal favorite, maybe it's not oxidative damage that is the problem but how the cell responds to the damage. But that's all speculative."

PARKINSON'S DISEASE AS LOCALIZED GARBAGE CATASTROPHE
Friday, February 8, 2013
http://www.fightaging.org/archives/2013/02/parkinsons-disease-as-localized-garbage-catastrophe.php
Alpha-synuclein is associated with Parkinson's disease (PD), and is believed to play a central role in the mechanisms that cause the destruction of dopamine-generating neurons, and thus the pathology of the condition. Here, researchers dig deeper into the processes involved: "Overexpression of a protein called alpha-synuclein appears to disrupt vital recycling processes in neurons, starting with the terminal extensions of neurons and working its way back to the cells' center, with the potential consequence of progressive degeneration and eventual cell death. "This is an important new insight. I don't think anybody realized just how big a role alpha-synuclein played in managing the retrieval of worn-out proteins from synapses and the role of alterations in this process in development of PD." Using a variety of leading-edge imaging technologies, including a new fluorescent tagging technique developed for electron microscopy, [the] scientists created three-dimensional maps of alpha-synuclein distribution both in cultured neurons and in the neurons of mice engineered to over-express the human protein. They found that excess levels of alpha-synuclein accumulated in the presynaptic terminal - part of the junction where axons and dendrites of brain cells meet to exchange chemical signals. "The over-expression of alpha-synuclein caused hypertrophy in these terminals. The terminals were enlarged, filled with structures we normally don't see." [As] alpha-synuclein accumulates in the terminals, it appears to hinder normal degradation and recycling processes in neurons. This would progressively impair the release of neurotransmitters. In time, the neurons might simply stop functioning and die."

AN ACTUARIAL OVERVIEW ON HUMAN LONGEVITY AND MORTALITY
Thursday, February 7, 2013
http://www.fightaging.org/archives/2013/02/an-actuarial-overview-on-human-longevity-and-mortality.php
When you look at the vast sums of money involved, one might argue that the actuarial community has a greater incentive to understand aging than the aging research establishment does - billions of dollars rest on the degree to which predictions of future human longevity match up to reality. Unfortunately for the actuaries (and the rest of us) that future is very uncertain. We stand at a cusp in biomedical research, an era of rapid progress in fundamental biotechnology, and one in which great leaps forward in application may or may not happen at any time. Producing true rejuvenation in laboratory mammals is a matter of a billion dollars and ten years or so at this point in time, and the vagaries of human organization that lead up to sufficient interest and funding to start on that goal are essentially random: perhaps we manage to talk the world around to it five years from now, perhaps fifteen, perhaps longer. Who knows - it's a people and persuasion issue, and those are hard to pin to a timeline. Here is an interesting PDF that tours some of the present thinking on human longevity by the actuarial community: "Longevity is an important issue: the implication of increasing longevity has far-reaching effects for our social programs; and for our financial security as we grow into old age. It is also a trend which actuaries are well suited to analyze: we have unique training and experience that allows us to distill large volumes of data into key elements that can inform predictions of future events. As we partner with other experts, we are helping to shape the discussion on the implications of increasing longevity. First, around the globe people are living longer. While there is evidence that the rate of improvement is different between men and women, and between people of different races, geographies and social statuses, the evidence remains that we are all living longer. Secondly, our understanding of what factors have a material effect on our expected lifetime is growing, but it is not complete. In particular, our understanding of older age mortality is limited, in part because the data at older ages is sparse and of varying quality. There are open questions related both to the rate of improvement and the ultimate age at which it is appropriate to assume a mortality table should end. Thirdly, in many regions, there is no broad consensus on the appropriate base mortality rates and improvement factors that should be used to value life-contingent liabilities, or on the models that should be used to forecast those rates into the future. This creates challenges for practitioners who must develop their own projections; inefficiencies as the use of different data, assumptions and models leads to different mortality forecasts; and inconsistencies across disciplines - for example, between the pension and insurance communities - as each develops its own independent view of future mortality. Having said this, the actuarial community has dealt with issues of this magnitude in the past: We need to begin to hone in on techniques that will allow us to become comfortable with the wide variances that can be produced by our projection models. As evidenced by the material presented in the body of this report, there are techniques - stress testing, scenario testing, risk heat maps, screening systems - that we can use to give us insight into what base mortality rates and improvement factors could be."

A POPULAR SCIENCE ARTICLE ON THE STUDY OF THE AXOLOTL
Thursday, February 7, 2013
http://www.fightaging.org/archives/2013/02/a-popular-science-article-on-the-study-of-the-axolotl.php
From the Australian press, an example of one of a number of research groups that are studing the axolotl with an eye to mapping the mechanisms that drive their exceptional regenerative prowess: "They are masters at regenerating their own limbs, tails, jaws, retina and heart. They can recover from spinal chord and brain injury and can easily tolerate organ transplants. And to top things off, they don't get cancer. Meet the axolotl, otherwise known as the Mexican walking fish. ''This animal guards so many interesting biological secrets. Things that would leave humans in a wheelchair or dead they can just repair in no time at all.'' In Mexican walking fish, limbs can be removed and re-grown without so much as a scar and, amazingly, the heart can regenerate after having a third of it removed. Similarly, it can have sections of its spinal chord ''cut and pasted'' without killing it. Try doing that to a lab rat - let alone any other mammal. Some of the key genes that regulate spinal chord regeneration in axolotls have been established and compared with that of the mouse and rat. Chief among the questions surrounding the axolotl is whether a cure for cancer might lie beneath the translucent skin of the albino axolotl. Essentially, controlling cancer is about controlling cell growth. ''Cancer is like a wound that never heals and how the immune cells deal with this perpetuates cancer and allows rogue cells to proliferate and grow crazy. How axolotls can suppress cancer and activate regeneration is one of the things [we] would like to get to.''"

TELOMERE LENGTH AS BIOMARKER OF SOMATIC REDUNDANCY
Wednesday, February 6, 2013
http://www.fightaging.org/archives/2013/02/telomere-length-as-biomarker-of-somatic-redundancy.php
A paper of relevance to the reliability theory view of aging: "Biomarkers of aging are essential to predict mortality and aging related diseases. Paradoxically, age itself imposes a limitation on the use of known biomarkers of aging, because their associations with mortality generally diminish with age. How this pattern arises is however not understood. With meta-analysis we show that human leucocyte telomere length (TL) predicts mortality, and that this mortality association diminishes with age, as found for other biomarkers of aging. Subsequently, we demonstrate with simulation models that this observation cannot be reconciled with the popular hypothesis that TL is proportional to biological age. Using the reliability theory of aging we instead propose that TL is a biomarker of somatic redundancy, the body's capacity to absorb damage, which fits the observed pattern well. We discuss to what extent diminishing redundancy with age may also explain the observed diminishing mortality modulation with age of other biomarkers of aging. Considering diminishing somatic redundancy as the causal agent of aging may critically advance our understanding of the aging process, and improve predictions of life expectancy and vulnerability to aging-related diseases."

BEING OVERWEIGHT IS HARMFUL AT ALL AGES, IN NO WAY PROTECTIVE
Wednesday, February 6, 2013
http://www.fightaging.org/archives/2013/02/being-overweight-is-harmful-at-all-ages-in-no-way-protective.php
Researchers here argue that flawed data led to some scientists to conclude that being overweight is less harmful to long-term health than it in fact is: "Obesity kills, giving rise to a host of fatal diseases. This much is well known. But when it comes to seniors, a slew of prominent research has reported an "obesity paradox" that says, at age 65 and older, having an elevated BMI won't shorten your lifespan, and may even extend it. A new study takes another look at the numbers, finding the earlier research flawed. The paradox was a mirage: As obese Americans grow older, in fact, their risk of death climbs. The researchers argue that past studies of longevity and obesity were biased due to limitations of the National Health Interview Survey, or NHIS, which provides information on obesity. The survey excludes individuals who are institutionalized, such as in a hospital or nursing home - a group largely made up of seniors. Consequently, the data is overrepresented by older respondents who are healthy, including the relatively healthy obese. What's more, many obese individuals fail to make it to age 65 - and thus do not live long enough to participate in studies of older populations. "Obesity wreaks so much havoc on one's long-term survival capacity that obese adults either don't live long enough to be included in the survey or they are institutionalized and therefore also excluded. In that sense, the survey data doesn't capture the population we're most interested in.""

CHROMATIN AND TRANSPOSONS IN SENESCENT CELLS
Tuesday, February 5, 2013
http://www.fightaging.org/archives/2013/02/chromatin-and-transposons-in-senescent-cells.php
Senescent cells have removed themselves from normal operation and really should be destroyed, either by their own programmed cell death processes or by the immune system. Senescent cells accumulate with age, however, and while in place cause harm to surrounding tissues. Removing these unwanted and damaging senescent cells with targeted cell killing technologies is one of the necessary goals in longevity science; it has already been shown to provide benefits in gene-engineered mice, and several lines of research are presently leading towards the tools needed to build therapies to attain the same results for everyone else. Here is another example of the way in which senescent cells are not in good shape: "Parasitic strands of genetic material called transposable elements - transposons - lurk in our chromosomes, poised to wreak genomic havoc. Cells have evolved ways to defend themselves, but in a new study, [researchers] describe how cells lose this ability as they age, possibly resulting in a decline in their function and health. "The cell really is trying to keep these things quiet and keep these things repressed in its genome. We seem to be barely winning this high-stakes warfare, given that these molecular parasites make up over 40 percent of our genomes." Cells try to clamp down on transposons by winding and packing transposon-rich regions of the genome around little balls of protein called nucleosomes. This confining arrangement is called heterochromatin, and the DNA that is trapped in such a tight heterochromatin prison cannot be transcribed and expressed. What the research revealed, however, is that carefully maintaining a heterochromatin prison system is a younger cell's game. "It's very clear that chromatin changes profoundly with aging." Young and spry cells distinctly maintain open "euchromatin" formations in regions where essential genes are located and closed "heterochromatin" formations around areas with active transposable elements and few desirable genes. The distinction appeared to become worn in aging, or senescent, cells. In the observations, the chromatin that once was open tended to become more closed and the chromatin that was once closed, tended to become more open. Then the scientists compared the DNA that was coming from open or closed chromatin formations in the young and senescent cells. In their study not only did they find that the chromatin lockdown was breaking down, but also that the newly freed transposons were taking full advantage. What's not clear from the study is the relevance of the damage that the cells suffer from the transposable element jailbreak and resulting genetic crime spree. "Is the transposition really bad for the organism or is it something that happens so late that by that point the organism has already accumulated so much age-associated damage? Then maybe this extra insult of transposition is not going to make a lot of difference.""

GENE COPY NUMBER VARIATIONS ASSOCIATED WITH LONGEVITY
Tuesday, February 5, 2013
http://www.fightaging.org/archives/2013/02/gene-copy-number-variations-associated-with-longevity.php
One imagines that genetic copy number variations between individuals will prove to be much like other small differences in DNA, in that there are many tiny contributions to longevity, and it is hard to find consistent results in different study populations. "Copy number variations (CNVs) are rare losses and gains in DNA sequences that have been importantly implicated in the pathogenesis of various neurodevelopmental and psychiatric diseases. As opposed to SNP genotypes which have revealed common variants conferring modest relative risk to the individual with the variant, CNVs are often rare variants not observed or extremely rare in a normal control population and conferring high relative risk. SNP arrays have vastly improved the detection of CNVs across the human genome, [but] it remains to be determined if there are certain gene classes or networks of genes that are pathogenic or disease-causing in general, and if there are other gene networks that may be protective in the same manner. One way of testing this is to compare CNV states and frequencies between pediatric and geriatric subjects and determine if certain CNVs are lost in the older age group (i.e. suggesting pathogenic impact with shortened lifespan), and if other CNVs are enriched and considered protective. To test the hypothesis that rare variants could influence lifespan, we compared the rates of CNVs in healthy children (0-18 years of age) with individuals 67 years or older. CNVs at a significantly higher frequency in the pediatric cohort were considered risk variants impacting lifespan, while those enriched in the geriatric cohort were considered longevity protective variants. We performed a whole-genome CNV analysis on 7,313 children and 2,701 adults of European ancestry. [Positive] findings were evaluated in an independent cohort of 2,079 pediatric and 4,692 geriatric subjects. We detected 8 deletions and 10 duplications that were enriched in the pediatric group, while only one duplication was enriched in the geriatric cohort. Population stratification correction resulted in 5 deletions and 3 duplications remaining significant in the replication cohort. Evaluation of these genes for pathway enrichment demonstrated ~50% are involved in alternative splicing. We conclude that genetic variations disrupting RNA splicing could have long-term biological effects impacting lifespan."

THE PROXIMAL CAUSE OF AGING FROM THE POINT OF VIEW OF THE PROGRAMMED AGING CAMP
Monday, February 4, 2013
http://www.fightaging.org/archives/2013/02/the-proximal-cause-of-aging-from-the-point-of-view-of-the-programmed-aging-camp.php
I noted a review paper a few months back that considered the proximal cause of aging in terms of the evolution of cellular damage versus damage repair mechanisms. That aging is caused by an accumulation of certain forms of molecular and cellular damage is the dominant paradigm at present, though there is always debate over which forms of damage are primary, which secondary, and which important over a human life span. Of those researchers who aim to intervene in aging, most look to merely slow down the pace of damage by manipulating metabolism, while a minority follow the Strategies for Engineered Negligible Senescence (SENS) plan and aim to repair and reverse the damage without changing our metabolism. Meanwhile, off in left field there are those who theorize that aging is an evolved program, and therefore could be halted or reversed by suitable changes to metabolism or the genes governing it. To their eyes damage doesn't cause aging, it is a result of the program. This is something of a dangerous viewpoint, should it gather steam, even worse than the "slow aging by metabolic manipulation" camp for steering researchers away from the most effective course for treating aging - which is the SENS approach of repairing damage. But it is a sign of just how complex aging is as a phenomenon that we can still see such widely divergent interpretations of the existing data. Here is an open access consideration of the proximal cause of aging from one of the more prolific researchers in the programmed aging camp, by way of illustrating the points made above. You should probably read the whole thing, as the argument made is somewhat hard to excerpt and condense: "As discussed in detail previously, aging is of course not a program, but it is a quasi-program, a useless and unintentional continuation (or run on) of developmental programs. Similarly, cellular senescence is a continuation of cellular growth. In brief, over-stimulation leads to increased functions - [harmful hyperfunctions]. But what about the molecular damage? It was assumed that molecular damage contributes to aging because it accumulates with time. Well, over time you may accumulate money in your bank account. However, neither accumulation of molecular damage nor accumulation of money is a cause of your aging. Yes, molecular damage must accumulate. But although molecular damage accumulates, it does not necessarily limit lifespan, particularly if other causes limit life span. By analogy, if everyone died from accidents, starvation and infection early in life, then aging and age-related diseases (such as obesity and atherosclerosis) would not even be known. By the same token, "aging" due to molecular damage will not manifest itself, if aging due to hyperfunction invariably limits life span. For complex organisms like mammals the relationships between hyperfunctions (aging), diseases and damage (decline) are: 1. Hyperfunctions (increased cellular functions) including hypertrophy are primary. This is the essence of aging, which silently causes malfunctions and age-related diseases. 2. Decline of functions, malfunctions and atrophy are secondary. For example, hyper-stimulation of beta-cells by nutrients and mitogens can cause its apoptosis. Here is important to emphasize however that apoptosis can be also a form of hyperfunction, unneeded continuation primary function such as apoptosis during development of the immune system. 3. Damage is caused by aging, not the reverse. 4. Damage is not molecular. It is macro-damage (tissue, system and organ damage), like stroke, infarction, metastases, broken hip fracture and renal failure. Damage may take a form of sudden "catastrophe", even though hyperfunctional aging slowly generates diseases for decades. If a patient survives infarction (due to medical intervention), she can live for many years, reflecting the fact that catastrophe was not due to the burden of molecular damage."

THE FIRST PERSON TO LIVE TO 150 HAS ALREADY BEEN BORN
Monday, February 4, 2013
http://www.fightaging.org/archives/2013/02/the-first-person-to-live-to-150-has-already-been-born.php
Wagering on the proposition that the person who will first reach 150 years of age is already alive is no wager at all, really. It's a very safe bet that at some point in the next century the medical technologies needed for significant human rejuvenation will be developed. The risky bet is on whether it will happen soon enough for those of us in mid-life now - that will take much more advocacy, public enthusiasm, and rapid growth in research funding than has so far emerged. Here is an interview with Aubrey de Grey of the SENS Research Foundation at Forbes: "[Forbes]: Please comment on the myth of aging how how we need not accept it as "just part of getting old". [de Grey]: It's always been a mystery to me why this isn't totally obvious to everyone. Do we let cars fall apart when they get old? - yes in general, but not if we really want them not to - that's why we have 50 year old VW Beetles driving around, and even vintage cars. It's bizarre that people don't see that the exact same thing is true of the machine we call the human body, just that that machine is a lot more complicated so the development of sufficiently comprehensive preventative maintenance is a lot more challenging. [Forbes]: Could you briefly explain the nature of free radicals and the role in aging? [de Grey]: Free radicals come in a lot of flavours, and a number of them are created by the body. Some of them are good for us, but others are harmful, because they react with and damage molecules that we need for survival, such as our DNA. The body has a massive array of defences against these problems, which can be grouped into four categories - tricks to minimise the rate at which these toxic free radicals come into existence in the first place, enzymes and compounds that react harmlessly with them before they can react harmfully with something else, chemical tricks that make the harmful reactions happen less easily, and systems that repair the resulting damage after it's occurred - but those tricks are not completely comprehensive, so some damage still occurs and accumulates throughout life. We'd like to stop that happening, and we could theoretically do it by enhancing to perfection any one (or more) of those four types of defence. My view is that the last one, repairing damage post hoc, is the most practical. Eliminating free radical production would involve completely redesigning aspects of our metabolism, especially the way we use oxygen to extract energy from food. It would also have the problem that even the bad free radicals are also good in some ways, so we actually need them around somewhat; this is also the problem with perfecting the elimination of free radicals via harmless reactions. Ramifying our cells so that the reactions just don't occur is also tantamount to completely redesigning the body, So we're left with perfecting repair. [Forbes]: The digital health and quantified self movement are increasingly gaining steam. Do you see this an a critical step forward in the quest for longevity? [de Grey]: Not really, no. It's valuable, but only temporarily. That's because all personalised medicine is only valuable temporarily, while the treatments for such-and-such a condition are only modestly effective and can thereby be made more effective by being tuned to the specifics of the patient. We don't have personalised polio vaccines, because we don't need them - the same vaccine just works perfectly, on everyone. [Forbes]: Does the wait for "extensive data" and "controlled trials" adversely impact innovation in aging research? [de Grey]: Yes, but it adversely impacts innovation across all medical research. There's a huge need for greater creativity in the regulatory process, and that's coming: "adaptive licensing" is a big theme in that area right now."

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Posted 17 February 2013 - 06:42 PM

FIGHT AGING! NEWSLETTER
February 18th 2013

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

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CONTENT

- Intern at the SENS Research Foundation This Summer
- Much of Modern Aging Research in a Short and Pithy Nutshell
- Deconstructing Deathism, an Essay
- Protein Restriction Slows Alzheimer's Progression in Mice
- Discussion
- Latest Headlines from Fight Aging!
- Nitric Oxide and Longevity in Nematodes
- On Greater Longevity in Colder Environments
- Searching for Commonalities in Cancer
- Dietary Fatty Acids and Autophagy
- Comments on Teaching an Ethical View of Life Extension
- Arguing DNA Damage as a Cause of Aging
- Relative Risk For Causes of Cognitive Decline
- An Upcoming Oxford Debate With Aubrey de Grey and Richard Faragher
- More on mTOR and Gender Longevity Differences
- Blocking Development of Rheumatoid Arthritis in Mice

INTERN AT THE SENS RESEARCH FOUNDATION THIS SUMMER
http://www.fightaging.org/archives/2013/02/are-you-an-ambitious-life-science-student-intern-at-the-sens-research-foundation-this-summer.php

Here is a great opportunity for undergraduate and recently graduated life scientists: a chance to intern this coming summer at the SENS Research Foundation, an ambitious and well-connected organization that funds work on repairing the cellular and molecular damage that causes aging. If this is an area of applied medical biotechnology that interests you - and it should, as today you stand at the ground floor of a field that will expand in decades ahead to dwarf present behemoth research communities like the cancer establishment - then I encourage you to apply. If this isn't your cup of tea, then point it out to any biologist friends you might have.

SENS Research Foundation's summer internships are for undergraduates (students working towards a Bachelor's degree) and students who have just completed their undergraduate work. Interns in this program can expect to do a considerable amount of scientific research using various techniques in the biosciences, which can include PCR, western blotting, DNA purification, gel electrophoresis, and many others. Each intern will be working on a different project, so no two will be doing the exact same thing. Though interns will build their lab skills considerably during their internship period, the strongest applicants will already have laboratory experience.

In 2013, SENS Research Foundation will be placing summer interns at four different locations: SRF's own Research Center in Mountain View, California; the Buck Institute for Research on Aging in Novato, California; the Wake Forest Institute for Regenerative Medicine in Winston-Salem, North Carolina; and SUNY Upstate Medical University in Syracuse, New York. Note that the SRF Research Center and the Buck Institute are in the same metropolitan area: the San Francisco Bay Area.

The application deadline for the summer internship program is March 31, 2013 at 11:00 PM PST. However, there will be an early deadline for applicants who would like to be considered for the SUNY Upstate program: February 24th, 2013 at 11:00 PM PST. Each program will run on its own schedule, with its own stipend and arrangements.

MUCH OF MODERN AGING RESEARCH IN A SHORT AND PITHY NUTSHELL
http://www.fightaging.org/archives/2013/02/much-of-modern-aging-research-in-a-short-and-pithy-nutshell.php

As a nod to the oft-quoted evolutionary theorist George Williams, "It is remarkable that after a seemingly miraculous feat of morphogenesis, a complex metazoan should be unable to perform the much simpler task of merely maintaining what is already formed". How and why we age are mysteries of the ages.

The "how" of this mystery is the purview of experimental biologists who try to understand the basic processes that lead to system maintenance failure - from the level of molecules to that of entire organisms - that we term "aging".

The "why" of this mystery is the purview of evolutionary theorists whose ideas shape the questions that biogerontologists pose, on the basis of the premise put forth by another preeminent geneticist and evolutionary biologist, Theodosius Dobzhansky, that "[n]othing in biology makes sense except in the light of evolution".

These experimental and evolutionary perspectives converge in the modern science of aging, and its curious cousin "longevity", in an attempt to unify extensive findings from diverse areas of biology.

DECONSTRUCTING DEATHISM, AN ESSAY
http://www.fightaging.org/archives/2013/02/deconstructing-deathism-an-essay.php

The essay linked in this Fight Aging! post was originally published back in 2004, but I have no recollection of reading it back then - so I'm going to assume that many of you folk also missed it the first time around. Another item lost to the mists of memory is exactly where and when I first heard the term "deathism," in the sense of an outlook that promotes death as a good thing rather than something to be avoided. You won't find much mention of it prior to 2007 here at Fight Aging!, for example. Deathism is usually put forward in the context of aging as an essentially conservative view: deathists are people who stand against change and for the continuation of the status quo, often without any great consideration, no matter how terrible it might be, and no matter that rampant change is underway in all aspects of human life and society nowadays.

Many similarities can be found when comparing the person who believes that everyone should live the same lives as their parents, aging to death at the same count of years, with the person who doesn't want a new train line built, or decries the latest addition to the downtown skyline, or waxes nostalgic for the foods of yesteryear. But there is an important difference here: people who advocate for the continuation of death and aging are also advocating destruction, pain, and suffering on a grand scale in a way that other conservatives are not. Destruction, pain, and suffering is invariably not their motivation, but it is what they call for nonetheless, and that fact should not be swept politely under the table.

Tens of millions of lives are lost every year, and hundreds of millions more are locked in terrible degenerative suffering and frailty - the human cost of death by aging year upon year is four times that of an eternally ongoing World War II, a horrific toll that our society does its best to ignore. Thus it is socially acceptable to say that aging should continue, and the average person in the street will claim to want to age and die on the same schedule as his or her parents - because that is the socially correct answer, the conforming answer, the one that seems to be taught at a young age by some form of educational osmosis. Sheep and cliffs spring to mind.

PROTEIN RESTRICTION SLOWS ALZHEIMER'S PROGRESSION IN MICE
http://www.fightaging.org/archives/2013/02/protein-restriction-slows-progression-of-mouse-model-of-alzheimers-disease.php

Lower protein levels are one of the triggers for metabolic changes that occur due to a calorie restricted diet. In past years researchers have shown that reducing proteins - especially methionine - in the diet of laboratory animals while keeping calorie levels constant can reproduce a portion of the benefits provided by full calorie restriction.

In this recently published research, mice with many of the pathologies of Alzheimer's Disease showed fewer signs of the disease when given a protein-restricted diet supplemented with specific amino acids every other week for four months. Upcoming studies [will] attempt to determine whether humans respond similarly - while simultaneously examining the effects of dietary restrictions on cancer, diabetes and cardiac disease. Researchers found that a protein-restricted diet reduced levels of IGF-1 circulating through the body by 30 to 70 percent, and caused an eight-fold increase in a protein that blocks IGF-1's effects by binding to it. IGF-1 helps the body grow during youth but is also associated with several diseases later in life in both mice and humans.

This quote is from the principal researcher: "We always try to do things for people who have the problem now. Developing a drug can take 15 years of trials and a billion dollars. Although only clinical trials can determine whether the protein-restricted diet is effective and safe in humans with cognitive impairment, a doctor could read this study today and, if his or her patient did not have any other viable options, could consider introducing the protein restriction cycles in the treatment - understanding that effective interventions in mice may not translate into effective human therapies."

You might take note of those remarks as indicative of one of the ways in which regulation steers researchers towards deliberately aiming to produce marginal benefits rather than revolutionary advances - slowing the pace of progress and shutting down promising avenues of medical science before they even get started.

DISCUSSION

The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!

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LATEST HEADLINES FROM FIGHT AGING!

NITRIC OXIDE AND LONGEVITY IN NEMATODES
Friday, February 15, 2013
http://www.fightaging.org/archives/2013/02/nitric-oxide-and-longevity-in-nematodes.php
Nitric oxide shows up in many places in the the biochemistry of longevity, the processes by which differences in the operation of metabolism influence the pace of aging. In this example, however, it isn't particularly clear that it has any great relevance to human biology: "Although humans and many other organisms have the enzyme needed to produce nitric oxide, C. elegans does not. Instead, [the] worm can "hijack" the compound from the soil-dwelling Bacillus subtilis bacterium that is not only a favored food but also a common colonist within its gut. This resourcefulness [partially] explains why worms fed B. subtilis live roughly 50 percent longer than counterparts fed Escherichia coli, which does not produce the compound. In the new study, the average C. elegans lifespan increased by nearly 15 percent, to about two weeks, when researchers fed the worms nitric oxide-producing B. subtilis bacteria, compared to worms fed mutant B. subtilis with a deleted nitric oxide production gene. The research group also used fluorescent sensors to show that C. elegans does not make its own nitric oxide gas. When the worms were fed normal B. subtilis bacteria, however, the fluorescent signal appeared in their guts. Fluorescent labeling and other tests also demonstrated that B. subtilis-derived nitric oxide penetrated the worms' tissues, where it activated a set of 65 genes. Some had been previously implicated in stress resistance, immune response, and increased lifespan, though others have unknown functions. Importantly, the researchers showed that two well-known regulatory proteins were essential for activating all of the genes. "What we found is that nitric oxide gas produced in bacteria inside the worms diffuses into the worm tissue and activates a very specific set of genes acting through two master regulators, hsf-1 and daf-16, resulting in a high resistance to stress and a longer life. It's striking that a small molecule produced by one organism can dramatically affect the physiology and even lifespan of another organism through direct cell signaling.""

ON GREATER LONGEVITY IN COLDER ENVIRONMENTS
Friday, February 15, 2013
http://www.fightaging.org/archives/2013/02/on-greater-longevity-in-colder-environments.php
Why do cold-blooded species live longer in colder environments? Researchers have a prospective mechanism that is shared by mammals: "Scientists have known for nearly a century that cold-blooded animals, such as worms, flies and fish all live longer in cold environments, but have not known exactly why. Researchers [have] identified a genetic program that promotes longevity of roundworms in cold environments - and this genetic program also exists in warm-blooded animals, including humans. "This raises the intriguing possibility that exposure to cold air - or pharmacological stimulation of the cold-sensitive genetic program - may promote longevity in mammals." Scientists had long assumed that animals live longer in cold environments because of a passive thermodynamic process, reasoning that low temperatures reduce the rate of chemical reactions and thereby slow the rate of aging. "But now, at least in roundworms, the extended lifespan observed at low temperature cannot be simply explained by a reduced rate of chemical reactions. It's, in fact, an active process that is regulated by genes." [Researchers] found that cold air activates a receptor known as the TRPA1 channel, found in nerve and fat cells in nematodes, and TRPA1 then passes calcium into cells. The resulting chain of signaling ultimately reaches DAF-16/FOXO, a gene associated with longevity. Mutant worms that lacked TRPA1 had shorter life spans at lower temperatures. Because the mechanisms [also] exist in a range of other organisms, including humans, the research suggests that a similar effect might be possible. The study also links calcium signaling to longevity for the first time and makes a novel connection between fat tissue and temperature response. Researchers have known that lowering the core body temperature of warm-blooded animals, such as mice, by 0.9 degrees Fahrenheit can extend lifespan by 20 percent, but it hasn't been practical for humans to attempt to lower the core body temperature." It's worth noting that past research has shown that not all methods of lowering core body temperature in mammals will extend life. It matters how it's done, which suggests that it isn't so much temperature as the particular mechanisms that are running that is driving the effect. For example, calorie restriction is associated with a lower core body temperature.

SEARCHING FOR COMMONALITIES IN CANCER
Thursday, February 14, 2013
http://www.fightaging.org/archives/2013/02/searching-for-commonalities-in-cancer.php
The broad variety and rapid change in mechanisms within cancerous cells is one of the reasons that cancer is hard to tackle - every cancer is different and evolving. Circumventing this to find truly effective cancer therapies will require the discovery of some mechanistic commonality that can be targeted, some biological process that all cancers depend on and which distinguishes their cells from non-cancerous cells. The proposed SENS approach, for example, is to go right to the root and remove all ability to lengthen telomeres in the body, as all cancers depend on that. The mainstream research community aims to find markers for cancer stem cells, or low-level mechanisms shared between cancers to some degree and which can be sabotaged to slow down or reverse progression of the disease. Not all shared mechanisms are sufficient to build a true cure, unfortunately. Here is an example of one such lesser mechanism in the early stages of research and development: "Epithelial to mesenchymal transition is important to embryonic development, turning stationary epithelial cells into mobile mesenchymal cells to move them within the embryo. For example, a cell might be converted and then gather with other cells forming, for example, the kidney. Once there, it transitions back to an epithelial cell again and stays put. Research has shown that carcinomas, tumors that form in the epithelium (lining) of organs are able to reactivate EMT. About 85 percent of all solid tumors are carcinomas. "We found that FOXC2 lies at the crossroads of the cellular properties of cancer stem cells and cells that have undergone epithelial to mesenchymal transition (EMT), a process of cellular change associated with generating cancer stem cells. There are multiple molecular pathways that activate EMT. We found many of these pathways also activate FOXC2 expression to launch this transition, making FOXC2 a potentially efficient check point to block EMT from occurring." [Researchers believe] that targeting FOXC2 pathway [will] be an effective therapeutic strategy for inhibiting EMT and consequently reducing EMT/cancer stem cell-associated metastasis, relapse and therapy resistance."

DIETARY FATTY ACIDS AND AUTOPHAGY
Thursday, February 14, 2013
http://www.fightaging.org/archives/2013/02/dietary-fatty-acids-and-autophagy.php
The cellular housekeeping processes of autophagy show up everywhere in considerations of metabolism and aging: better repair of cellular damage and removal of unwanted metabolic byproducts has a noticeable beneficial effect on the longevity of an organism. Many of the genetic manipulations that extend life in laboratory species have been shown to enhance autophagy, just as does the practice of calorie restriction. Here researchers find that the marginal benefits resulting from the inclusion of omega fatty acids in the diet may also result from increased autophagy: "Researchers have discovered that simple mutations in genetic pathways conserved throughout evolution can double or triple the lifespan of C. elegans and that similar mutations in the corresponding mammalian pathways also regulate lifespan. Many of these mutations also make animals resistant to starvation, suggesting that common molecular mechanisms may underlie both response to nutrient deprivation and the regulation of lifespan. To find these mechanisms [scientists] searched genomic databases covering many types of animals for shared genes that respond to fasting by changing their expression. She found that expression of the C. elegans gene lipl-4 increases up to seven times in worms not given access to nutrients. A transgenic strain that constantly expresses elevated levels of lipl-4, even when given full access to food, was found to have increased levels of arachidonic acid (AA), an omega-6, and eicosapentanoic acid (EPA), an omega-3 fatty acid and to resist the effects of starvation. Following the implication that omega fatty acids stimulate a process leading to starvation resistance, the researchers found that feeding AA and another omega-6 fatty acid, but not EPA, activated autophagy in non-transgenic C. elegans with full access to nutrients. Since activation of autophagy has been shown to increase lifespan in several genetic models, the authors tested the effect of omega-6 fatty acids on C. elegans lifespan and found that roundworms consuming a full normal diet supplemented with omega-6 fatty acids lived 20 to 25 percent longer than usual. Since dietary supplementation with both omega-3 and omega-6 fatty acids has been shown to prevent or improve several human health conditions, the researchers tested the response of cultured human cells to omega fatty acid supplementation. As in C. elegans, the human cells responded to supplementation with the omega-6 acids, but not to EPA, by activation of autophagy, measured by levels of marker proteins. That result suggests that omega-6 acids induce autophagy across the full range of multicellular animal species. The researchers then showed that the lifespan-increasing properties of omega-6 fatty acids in C. elegans depend on the presence of genes required for autophagy."

COMMENTS ON TEACHING AN ETHICAL VIEW OF LIFE EXTENSION
Wednesday, February 13, 2013
http://www.fightaging.org/archives/2013/02/comments-on-teaching-an-ethical-view-of-life-extension.php
Some comments from a social studies professor with an interest in engineered human longevity: "This year I devote two whole classes to aging and the ethics of life extension. Last week was our first class on the topic and I asked my students, who are all graduate level students in the humanities and social sciences, how many of them had taken a course where aging was either the focus, or even just a topic covered in, the course. Not a single hand went up! This simply reinforced my conviction that it is absolutely essential to teach the course I am teaching, and to dedicate two weeks to aging and the ethics of life extension. I hope it helps to fill what is an unfortunate gap in the education our students receive. In my opinion, the aging of the world's populations is the most interesting and important development of the 21st century. And yet the education our students (many of whom will go on to be teachers, professors, politicians, work in public policy, law, medicine, etc.) receive is one that is completely blind to this reality. This neglect is itself an oddity worthy of serious reflection. Why do so many scholars in the humanities and social sciences appear to have "aging blinders" on? I think the answer to this question is complex, and many distinct cultural and institutional factors account for this neglect. I will write a longer post about this in a few weeks. I believe that one of the main reasons for this neglect is that scholars ignore the ultimate causation of morbidity, mortality and behaviour. While the proximate causation of mortality (such as poverty and war) is on the radar of many in the humanities and social sciences, they do not adopt as diverse an explanatory toolbox as they ought to. Once you add an evolutionary perspective into the mix, the questions, topics and debates to be discussed and pondered are wondrous and pressing. And doing this has profoundly altered the topics I work on, and the manner in which I approach them, in both ethics and political theory."

ARGUING DNA DAMAGE AS A CAUSE OF AGING
Wednesday, February 13, 2013
http://www.fightaging.org/archives/2013/02/arguing-dna-damage-as-a-cause-of-aging.php
A stochastic accumulation of nuclear DNA damage progresses throughout life. This is definitely a cause of increased cancer risk, one of the reasons why cancer is predominantly a disease of the old, but is it also a contributing cause of degenerative aging in general? This is an arguable proposition, with some researchers suggesting that DNA damage doesn't meaningfully impact aging over the length of a human life span, while others consider it the most important cause of aging. Here is a review paper on the subject. It is always pleasant to see researchers openly discuss increasing life span through biotechnology, even if I don't necessarily agree with the likely effectiveness of the research path they choose. It is still the case that many scientists will not talk openly about the goal of extending human life. "Genome instability has long been implicated as the main causal factor in aging. Somatic cells are continuously exposed to various sources of DNA damage, from reactive oxygen species to UV radiation to environmental mutagens. To cope with the tens of thousands of chemical lesions introduced into the genome of a typical cell each day, a complex network of genome maintenance systems acts to remove damage and restore the correct base pair sequence. Occasionally, however, repair is erroneous, and such errors, as well as the occasional failure to correctly replicate the genome during cell division, are the basis for mutations and epimutations. There is now ample evidence that mutations accumulate in various organs and tissues of higher animals, including humans, mice, and flies. What is not known, however, is whether the frequency of these random changes is sufficient to cause the phenotypic effects generally associated with aging. The exception is cancer, an age-related disease caused by the accumulation of mutations and epimutations. Here, we first review current concepts regarding the relationship between DNA damage, repair, and mutation, as well as the data regarding genome alterations as a function of age. We then describe a model for how randomly induced DNA sequence and epigenomic variants in the somatic genomes of animals can result in functional decline and disease in old age. Finally, we discuss the genetics of genome instability in relation to longevity to address the importance of alterations in the somatic genome as a causal factor in aging and to underscore the opportunities provided by genetic approaches to develop interventions that attenuate genome instability, reduce disease risk, and increase life span."

RELATIVE RISK FOR CAUSES OF COGNITIVE DECLINE
Tuesday, February 12, 2013
http://www.fightaging.org/archives/2013/02/relative-risk-for-causes-of-cognitive-decline.php
Cognitive decline, like most of the consequences of aging, stems from a range of root causes. Here researchers look at which of these causes contribute the most to the harmful end result: "Vascular brain injury from conditions such as high blood pressure and stroke are greater risk factors for cognitive impairment among non-demented older people than is the deposition of the amyloid plaques in the brain that long have been implicated in conditions such as Alzheimer's disease, a study [has] found. The research was conducted in 61 male and female study participants who ranged in age from 65 to 90 years old, with an average age of 78. Thirty of the participants were clinically "normal," 24 were cognitively impaired and seven were diagnosed with dementia, based on cognitive testing. The researchers also sought to determine whether there was a correlation between vascular brain injury and the deposition of beta amyloid (Αβ) plaques, thought to be an early and important marker of Alzheimer's disease. [They] also sought to decipher what effect each has on memory and executive functioning. "We looked at two questions. The first question was whether those two pathologies correlate to each other, and the simple answer is 'no.' Earlier research, conducted in animals, has suggested that having a stroke causes more beta amyloid deposition in the brain. If that were the case, people who had more vascular brain injury should have higher levels of beta amyloid. We found no evidence to support that." "The second was whether higher levels of cerebrovascular disease or amyloid plaques have a greater impact on cognitive function in older, non-demented adults. Half of the study participants had abnormal levels of beta amyloid and half vascular brain injury, or infarcts. It was really very clear that the amyloid had very little effect, but the vascular brain injury had distinctly negative effects. The more vascular brain injury the participants had, the worse their memory and the worse their executive function - their ability to organize and problem solve.""

AN UPCOMING OXFORD DEBATE WITH AUBREY DE GREY AND RICHARD FARAGHER
Tuesday, February 12, 2013
http://www.fightaging.org/archives/2013/02/an-upcoming-oxford-debate-with-aubrey-de-grey-and-richard-faragher.php
Via the SENS Research Foundation: "Dr. Aubrey de Grey, SENS Research Foundation's Chief Science Officer, will be debating Dr. Richard Faragher, Chair of the British Society for Research on Ageing and Professor of Biological Gerontology at the University of Brighton, at Oxford's Sheldonian Theatre on February 19. Dr. de Grey will argue that the diseases of aging can be treated comprehensively by SENS therapies, and that these therapies could be developed in the coming decades, given sufficient research and funding. Dr. Faragher will dispute these points. Most importantly, both researchers agree that aging research is critically underfunded, and is the key to a healthier future. SENS Research Foundation is proud to be a sponsor of this event, and looks forward to an insightful debate about the most direct and effective research strategies for addressing age-related disability and disease. We would like to thank the Oxford University Society of Biomedical Sciences for hosting the event."

MORE ON MTOR AND GENDER LONGEVITY DIFFERENCES
Monday, February 11, 2013
http://www.fightaging.org/archives/2013/02/more-on-mtor-and-gender-longevity-differences.php
This paper comes from a group that considers aging to be a programmed process involving later-life overactivity of processes vital to early-life development rather than the result of stochastic accumulation of unrepaired cellular and molecular damage. I think that this view isn't well supported by the balance of evidence, but it does illustrate the complexity of aging that such divergent interpretations of the same data exist. The researchers' views don't diminish the data they produce from animal studies, but do mean that you have to read their interpretations of the data with that bias in mind: "One of the most long-standing mysteries of gerontology is that the females of most species live longer than the males. Not only most mammals but also women of different nations and at most historical periods live longer. Ironically, it may seem that males do not age faster but simply are weaker at any age. In fact, the mortality rate is higher in young males and teenagers too. Importantly, however, old males die from age-related diseases, whereas young males mostly die from risky behavior and physical competition with each other. While risky competition increases chances of mating and offspring, this simultaneously results in high accidental mortality (from fights) and males die young. There is no reason for them to be naturally selected for slower aging. Therefore, animals with a high accidental death rate tend to age faster. It is exceptionally important for such males early in life to be bigger and stronger (even on the cost of accelerated aging). In brief, early in life, TOR drives growth, robustness and reproduction, while causing aging and age-related diseases later in life. This example of antagonistic pleotropy is in line with the evolutionary theory. We speculate that aging as a continuation of growth driven by the same mTOR pathway, leading to aging and diseases of aging culminating in organismal damage and death. In sum, mTOR may drive both growth and aging, associated with hyper-functions coupled with signal-resistance and malfunction, loss of homeostasis, leading to development of deadly diseases of aging such as cardiovascular and metabolic diseases, neurodegeneration, cancer and organ atrophy or failure. We hypothesize that males have a higher levels of mTOR activity, providing advantage (and bigger size) for young males even though accelerated aging and early death might follow."

BLOCKING DEVELOPMENT OF RHEUMATOID ARTHRITIS IN MICE
Monday, February 11, 2013
http://www.fightaging.org/archives/2013/02/blocking-development-of-rheumatoid-arthritis-in-mice.php
Progress towards a different approach to therapies for autoimmune conditions such as rheumatoid arthritis, though still not one that addresses root causes directly: "Scientists have demonstrated a new strategy for treating autoimmune disease that successfully blocked the development of rheumatoid arthritis in a mouse model. They say it holds promise for improved treatment of arthritis and other autoimmune disorders in people. Infusing a highly specific type of cell that regulates immune responses into arthritis-prone mice shut down the cascade of inflammation that damages tissues and joints. The method worked best when the infusions of CD8+ Treg cells were given at the same time that the animals were injected with a protein that triggered the arthritis-causing autoimmune reaction. "We found we could almost completely inhibit the disease in this setting." Even when administered weeks after the disease was initiated, CD8+ Treg infusions combined with low doses of methotrexate - a commonly used drug for rheumatoid arthritis - were able to significantly slow the arthritis process. The new strategy also blocked disease progression when the scientists injected peptide antigens to expand the rodents' own pool of CD8+ Tregs, rather than infusing them from outside. Overall, the results "suggest that [these] strategies represent a promising therapeutic approach to autoimmune disorders.""

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Posted 24 February 2013 - 02:08 PM

FIGHT AGING! NEWSLETTER
February 25th 2013

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

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CONTENT

- The New SENS Research Foundation Site
- Noting the Inaugural Breakthrough Prize Awards
- The Old Have Been Persuaded to See Themselves as Worthless
- Rejuvenation Research for February 2013
- Incremental Advances in Machine-Nerve Interfaces
- Discussion
- Latest Headlines from Fight Aging!
    - Drugs to Slow Aging are a Matter of When, Not If
    - An Example of the Future of Stem Cell Therapies
    - Injectable Scaffold Gel to Spur Heart Regeneration
    - Bioengineering an Ear
    - Only Some Mitochondrial DNA Damage Contributes to Aging
    - Discussing Inflammation and Age-Related Disease
    - An Example of Scaffolds to Encourage Bone Regrowth
    - Aging is Emphatically Not an Inescapable Destiny
    - Adiponectin in Centenarians
    - DNA Damage and Reproductive Aging

THE NEW SENS RESEARCH FOUNDATION SITE

The SENS Research Foundation staff launched a newly redesigned website a few days ago. It presents the Foundation mission to "reimagine aging" by building biotechnologies to repair the cellular and molecular damage that causes frailty, disease, and death. Take a look at the new videos and content by following the link below:

http://www.sens.org

NOTING THE INAUGURAL BREAKTHROUGH PRIZE AWARDS
http://www.fightaging.org/archives/2013/02/noting-the-inaugural-breakthrough-prize-awards.php

The Breakthrough Prize in Life Sciences is a new and narrowly focused Nobel-like initiative launched by a noteworthy Russian entrepreneur in collaboration with some of the high net worth individuals that the California start up community has produced over the past decade. The tagline is much as follows: "Breakthrough Prize in Life Sciences is founded by Art Levinson, Sergey Brin, Anne Wojcicki, Mark Zuckerberg and Priscilla Chan, and Yuri Milner to recognize excellence in research aimed at curing intractable diseases and extending human life. The prize is administered by the Breakthrough Prize in Life Sciences Foundation, a not-for-profit corporation dedicated to advancing breakthrough research, celebrating scientists and generating excitement about the pursuit of science as a career."

Note that "extending human life" in the middle there. It looks like we'll have to wait to see whether the ongoing prize initiative will place any real emphasis on that goal, however. The eleven inaugural awards of $3 million each went to researchers who don't have a great deal to do with longevity research. Cancer and its mechanisms form the dominant theme in this first set of awards. In some cases the scientists' work touches on aging, such as the telomere research of Titia de Lange, but then so do a great many other line items - it's quite possible to run a very successful career as a telomere researcher without contributing towards efforts to extend human life by intervening in the aging process.

That said: this is an entirely sensible and rational effort. In the long view the only thing that really matters is progress in technology - not money, not politics, not the chatter of the masses, but technology. What was built and invented, and how fast it arrived. What use is money if you can't use it to change the world for the better? The best way to do that today is through spurring progress in biotechnology. The greatest gains for all humanity, wealthy and poor alike, over the decades to come will be attained through advances derived from the life sciences: better medicine, longer lives, and ultimately the defeat of degenerative aging.

This Nobel for the 21st century is a step in the right direction and to be applauded. It is encouraging to see that the right ideas about medicine, biotechnology, and the near-term promise of radical, transformative applications are percolating through the community of high net worth individuals - that some are seeing clearly enough how and why they can make a difference. Still, the Breakthrough Prize is a drop in the bucket of what could be accomplished should any similarly-sized group of billionaires decide to devote a few hundred million dollars towards developing rejuvenation biotechnologies of the sort specified in detail in the SENS plan.

THE OLD HAVE BEEN PERSUADED TO SEE THEMSELVES AS WORTHLESS
http://www.fightaging.org/archives/2013/02/the-old-have-been-persuaded-to-see-themselves-as-worthless.php

One of the more depressing consequences of degenerative aging is the pervasive ageism of our societies. It is taken as read that the old are worth less than the young, are less deserving, their wants and desires less meaningful, their rights to the pursuit of life and happiness weak to nonexistent. This is something that even the old themselves are largely sold on, one of those shared cultural myths that isn't so much taught as absorbed and spread invisibly, clinging on to every story and conversation as a cloud of assumptions and implicit judgments of value.

The value of a life diminishes with age, or so goes the belief - and as we are creatures of hierarchy and position, it's a short step from there to trampling on the old in any number of ways. If the young get to it before the old trample themselves, in any case. Ageism is as much a matter of people telling themselves that they are of little value as anything else.

In this post you'll find quoted the rather gloomy viewpoint of a near-70-year-old, informed by the Tithonus Error, the incorrect view that extended life achieved through biotechnology will result in more and increasingly decrepit old age rather than more vigor and youth as is in fact the case. As Aubrey de Grey asked in a recent editorial, why do people completely ignore what the research community says on this topic? Or for that matter, why do they ignore history? The incidental lengthening of human life achieved over the past two centuries through general improvement in medical technologies has been an extension of youth rather than an extension of old age. The public doesn't stick its head in the sand in the same way for heart disease or Parkinson's research. One might well ask why this happens for aging.

The goal of longevity science is to roll out ways to slow, halt, and reverse aging: making people healthy and physiologically younger for longer, not older and increasingly frail for longer. Researchers are all agreed on that goal, and say as much in their publications and to the press. Yet as you can see, there remains something of a disconnect - the message has yet to come through to the public at large.

REJUVENATION RESEARCH FOR FEBRUARY 2013
http://www.fightaging.org/archives/2013/02/rejuvenation-research-for-february-2013.php

The latest issue of Rejuvenation Research is available online for those with a subscription. Here is the opening to the editorial by scientist-advocate Aubrey de Grey:

"One of the foremost sources of frustration and incredulity among biogerontologists, in regard to the view of their work held by others, is the public's widespread inability (or unwillingness) to appreciate how huge would be the benefit to health and to the economy arising from even modest progress in comprehensively postponing the ill health of old age, and thus how parlously inappropriate is the prevailing level of funding for biogerontology in general and for translational biogerontology in particular. For at least the past decade, there has been a positive crescendo of expressions of this point in the general-audience scientific and policy literature authored not only by renegades such as myself but by those whose mainstream credentials are second to none.

"A host of explanations for people's resistance to this message are proffered perennially. Arguably the most convincing is that people are just so certain, in their own minds, that no amount of money thrown at translational biogerontology would ever actually deliver even a modest postponement of age-related ill health that they reason that such money would be wasted, even despite the argument for it. In a nutshell, they feel that any number (the benefits of success), however large, when multiplied by zero (the chance of success), is still zero. The explanation leads, of course, the supplementary question of why people are so much less willing to accept expert opinion on this topic, to wit, that the chance of success is certainly not zero."

INCREMENTAL ADVANCES IN MACHINE-NERVE INTERFACES
http://www.fightaging.org/archives/2013/02/incremental-advances-in-machine-nerve-interfaces.php

Computational hardware, electronics, and biotechnology are three of the most rapidly advancing fields of human endeavor at the present time. The years ahead are going to be most interesting, even though progress always seems far too slow and incremental while living it a day at a time. One field that sits within the broad overlap of machinery, computing, and biology is that of nerve-machine interfaces, which spans the gamut from the creation of machines to take on the job of a biological nerve structure, through simulation of nervous system behavior, through to attaching machinery to nerves in order to form a new gestalt system.

Examples of this work being demonstrated today are very crude in comparison to what will be possible in the future - but the path forward, while slow and incremental, definitely leads towards functional prosthetics that are fully tied into a biological nervous system. This sort of technology is important to the 2045 Initiative view of the future, but is less relevant to the SENS vision for human longevity, which is (rightly I think) focused on the biology we have and how to repair it.

Prosthetic technologies of all sorts are a competitor for regenerative medicine, both having the goal to alleviate serious injuries involving loss of body parts or their function. I'm not sure I see a viable outline for the next five decades in which increasingly sophisticated prosthetics can be used to extend life meaningfully - there are parts of the body that you can't easily replace with machinery, even once arbitrary neural interfaces are a robust and easily constructed concern, and so we must learn how to rejuvenate the brain and its supporting structures at a bare minimum regardless of what else happens. The biotechnologies needed for this goal do not seem likely to emerge until after the research community can already rebuild most of the rest of the body, as the brain is a far more complex structure of diverse cells, mechanisms, and cell types than any other organ.

DISCUSSION

The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!

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LATEST HEADLINES FROM FIGHT AGING!

DRUGS TO SLOW AGING ARE A MATTER OF WHEN, NOT IF
Friday, February 22, 2013
http://www.fightaging.org/archives/2013/02/drugs-to-slow-aging-are-a-matter-of-when-not-if.php
It is pleasing to see this sort of article emerging from a university publicity group - a part of the necessary trend within the scientific community towards making it acceptable and desirable to talk about extending human life through biotechnology. The silence of the research community on this topic across past decades was very harmful to the prospects for progress and funding in the field of aging research and longevity science. That said, it is problematic that the vast majority of resources and researchers presently focus on modestly slowing aging rather than trying to repair and reverse the causes of aging. Based on what we know today, it is probably harder to safely adjust metabolism to slow down aging than it is to repair the root causes of aging to restore a metabolism back to its youthful state. Further, slowing aging is of no use to old people, whereas repair based approaches are useful - and given that people in middle age today will be old by the earliest possible time that therapies might emerge, it won't be all that great if all those therapies can do is slow down the progression of aging. So more work on SENS and similar repair-based strategies, and less fiddling around with calorie restriction mimetics, longevity genes, and the like, is what we need to see if there is to be an effective near-term lengthening of human life. That result has to be based on rejuvenation, not slowing of aging. "Evidence is accumulating that not only is it possible to slow down aging, but that by doing so the onset and progression of multiple age-related diseases can be delayed. "Slowing aging should increase both lifespan and healthspan - the period of life spent in relatively good health, free from chronic disease or disability. A shared feature of most medically relevant diseases is that your risk of dying from them increases dramatically as you get older. Unlike traditional approaches, which tend to focus on a specific disease, targeting the aging process itself has a much greater potential to improve human health." Many experts in the biology of aging believe that pharmacological interventions to slow aging are a matter of 'when' rather than 'if'. A leading target for such interventions is the nutrient response pathway defined by mTOR, a protein that controls cell growth. "Inhibition of this pathway extends lifespan in model organisms and confers protection against a growing list of age-related pathologies. Characterized inhibitors of this pathway are already clinically approved, and others are under development. Although adverse side effects currently preclude use in otherwise healthy individuals, drugs that target the mTOR pathway could one day become widely used to slow aging and reduce age-related pathologies in humans.""

AN EXAMPLE OF THE FUTURE OF STEM CELL THERAPIES
Friday, February 22, 2013
http://www.fightaging.org/archives/2013/02/an-example-of-the-future-of-stem-cell-therapies.php
One major branch of future progress in stem cell therapy will discard transplantation of cells in favor of manipulating the signals that tell local cells what to do - which is generally what the transplanted cells are actually doing anyway. This will become more effective as researchers gain a better understanding of the intricacies of cell signalling relevant to growth and repair, but here is an early example of what can be done with this sort of approach: "In the first human study of its kind, researchers activated heart failure patients' stem cells with gene therapy to improve their symptoms, heart function and quality of life. [Researchers] delivered a gene that encodes a factor called SDF-1 to activate stem cells like a "homing" signal. SDF-1 is a naturally occurring protein, secreted by cells, that guides the movement of other cells. Previous research [has] shown SDF-1 activates and recruits the body's stem cells, allowing them to heal damaged tissue. However, the effect may be short-lived. For example, SDF-1 that's naturally expressed after a heart attack lasts only a week. In the study, researchers attempted to re-establish and extend the time that SDF-1 could stimulate patients' stem cells. Study participants' average age was 66 years. Researchers injected one of three doses of the SDF-1 gene [into] the hearts of 17 patients with symptomatic heart failure and monitored them for up to a year. Four months after treatment, they found: 1) Patients improved their average distance by 40 meters during a six-minute walking test. 2) Patients reported improved quality of life. 3) The heart's pumping ability improved. 4) No apparent side effects occurred with treatment. "We found 50 percent of patients receiving the two highest doses still had positive effects one year after treatment with their heart failure classification improving by at least one level. They still had evidence of damage, but they functioned better and were feeling better." Researchers are now comparing results from heart failure patients receiving SDF-1 with patients who aren't. If the trial goes well, the therapy could be widely available to heart failure patients within four to five years."

INJECTABLE SCAFFOLD GEL TO SPUR HEART REGENERATION
Thursday, February 21, 2013
http://www.fightaging.org/archives/2013/02/injectable-scaffold-gel-to-spur-heart-regeneration.php
Researchers are here working on an injectable gel scaffold material that appears to improve regeneration of heart damage: "[Researchers have] developed a protein-rich gel that appears to help repair cardiac muscle in a pig model of myocardial infarction. The researchers delivered the hydrogel via a catheter directly into the damaged regions of the porcine heart, and showed that the product promoted cellular regeneration and improved cardiac function after a heart attack. Compared to placebo-treated animals, the pigs that received a hydrogel injection displayed a 30% increase in heart volume, a 20% improvement in heart wall movement and a 10% reduction in the amount of scar tissue scar three months out from their heart attacks. [The researchers] developed their hydrogel by stripping muscle cells from pig hearts, leaving behind a network of proteins that naturally self-assembles into a porous and fibrous scaffold upon injection into heart tissue. They previously tested its safety and efficacy in rats, where they found increased cardiac function and no toxicity or cross-species reactivity."

BIOENGINEERING AN EAR
Thursday, February 21, 2013
http://www.fightaging.org/archives/2013/02/bioengineering-an-ear.php
An application of 3-D printing and regenerative medicine: "[Researchers] described how 3-D printing and injectable gels made of living cells can fashion ears that are practically identical to a human ear. Over a three-month period, these flexible ears grew cartilage to replace the collagen that was used to mold them. A bioengineered ear replacement like this [would] help individuals who have lost part or all of their external ear in an accident or from cancer. [Replacement ears] are usually constructed with materials that have a Styrofoam-like consistency, or sometimes, surgeons build ears from a patient's harvested rib. This option is challenging and painful for children, and the ears rarely look completely natural or perform well. To make the ears, [researchers] started with a digitized 3-D image of a human subject's ear, and converted the image into a digitized "solid" ear using a 3-D printer to assemble a mold. [This] high-density gel is similar to the consistency of Jell-o when the mold is removed. The collagen served as a scaffold upon which cartilage could grow. The process is also fast: "it takes half a day to design the mold, a day or so to print it, 30 minutes to inject the gel, and we can remove the ear 15 minutes later. We trim the ear and then let it culture for several days in nourishing cell culture media before it is implanted.""

ONLY SOME MITOCHONDRIAL DNA DAMAGE CONTRIBUTES TO AGING
Wednesday, February 20, 2013
http://www.fightaging.org/archives/2013/02/only-some-mitochondrial-dna-damage-contributes-to-aging.php
This research might be taken to illustrate the point that only some specific mutations in mitochondrial DNA (mtDNA) contribute to aging - those occurring in one of thirteen specific genes, per the SENS outline. So mice with accelerated mutation rates in all mitochondrial DNA exhibit accelerated aging, while mice with specific mitochondrial mutations that do not include those that contribute to aging do not exhibit accelerated aging. "It has been hypothesized that pathogenic mtDNA mutations that induce significant mitochondrial respiration defects cause mitochondrial diseases, and could also be involved in aging and age-associated disorders including tumor development. This hypothesis is partly supported by studies in mtDNA mutator mice: they possess a nuclear-encoded mtDNA polymerase with a defective proofreading function that leads to enhanced accumulation of random mutations in mtDNA with age, and the subsequent phenotypic expression of age-associated respiration defects and premature aging phenotypes, but not tumor development. On the contrary, our previous studies showed that transmitochondrial mito-miceΔ carrying mtDNA with a large-scale deletion mutation (ΔmtDNA) expressed age-associated respiration defects, but not express the premature aging phenotypes. Similar results were obtained in other transmitochondrial mito-miceCOIM, which have an mtDNA point mutation in the COI gene. Recently, we generated new transmitochondrial mito-miceND6M, which have an mtDNA point mutation in the ND6 gene that is derived from Lewis lung carcinomas, and confers respiration defects and overproduction of reactive oxygen species (ROS). Mito-miceND6M did not express premature aging phenotypes, but were prone to B-cell lymphoma development. Thus, it appears to be discrepant that premature aging phenotypes are exclusively observed in mtDNA mutator mice, but not in transmitochondrial mito-mice even though they all express mitochondrial respiration defects caused by mutated mtDNA."

DISCUSSING INFLAMMATION AND AGE-RELATED DISEASE
Wednesday, February 20, 2013
http://www.fightaging.org/archives/2013/02/discussing-inflammation-and-age-related-disease.php
Notes from a recent conference at the Impact Aging journal: "The workshop opened with [an] overview of the literature supporting the emergence a mild pro-inflammatory state that is closely linked to the major degenerative diseases of the elderly. The focus of the workshop was to better understand the origins and consequences of this low level chronic inflammation in order to design appropriate interventional studies aimed at improving healthspan. For many, inflammation is simply understood as a trajectory of biomarkers, for example the appearance of IL-6 or C-reactive protein (CRP), associated with a disease. However, inflammation is a very complex response to an injury, infection, or other stimulus, in which many different cells types and secreted factors orchestrate protective immunity, tissue repair, and resolution of tissue damage. Whereas acute inflammation limits tissue damage and resolves, chronic prolongation of the inflammatory state leads to progressive tissue damage. A central question, then, is how do we describe and begin to understand the mild pro-inflammatory state of aging. Among the causal pathways linked to the major diseases associated with aging, including physical frailty, are changes in body composition, energy imbalance, homeostatic dysregulation, and neurodegeneration. Chronic inflammation is strongly connected with each of these aging phenotypes. The inflammatory mediators IL-6, IL-18, and CRP increase with age in both women and men and are highly correlated with obesity and degenerative disease. Muscle strength, as measured by walking speed, also correlates with circulating IL-6 levels. Individuals with the lowest circulating levels had the highest walking speed. [These] data suggest that inflammation blocks critical metabolic signals that support muscle maintenance. In addition, [systemic] inflammation may predispose the microglia to a pro-inflammatory state that is associated with neurodegeneration. Although it is not clear what causes age-associated chronic inflammation, possible mechanisms include a disregulated NF-kB pathway, impaired mitochondrial function leading to excessive reactive oxygen species (ROS) the accumulation of senescent cells, and a decline in autophagy with age. Whether reducing inflammation will lead to beneficial effects on human health and function is the defining biological and medical challenge of the next decade."

AN EXAMPLE OF SCAFFOLDS TO ENCOURAGE BONE REGROWTH
Tuesday, February 19, 2013
http://www.fightaging.org/archives/2013/02/an-example-of-scaffolds-to-encourage-bone-regrowth.php
The use of nanoscale-featured scaffold materials is common in regenerative medicine research. Here is an example that can be used to improve and guide the regrowth of bone: "Artificial bone, created using stem cells and a new lightweight plastic, could soon be used to heal shattered limbs. Researchers have developed the material with a honeycomb scaffold structure that allows blood to flow through it, enabling stem cells from the patient's bone marrow to attach to the material and grow new bone. Over time, the plastic slowly degrades as the implant is replaced by newly grown bone. Scientists developed the material by blending three types of plastics. They used a pioneering technique to blend and test hundreds of combinations of plastics, to identify a blend that was robust, lightweight, and able to support bone stem cells. Successful results have been shown in the lab and in animal testing with the focus now moving towards human clinical evaluation. "We were able to make and look at a hundreds of candidate materials and rapidly whittle these down to one which is strong enough to replace bone and is also a suitable surface upon which to grow new bone. We are confident that this material could soon be helping to improve the quality of life for patients with severe bone injuries, and will help maintain the health of an ageing population.""

AGING IS EMPHATICALLY NOT AN INESCAPABLE DESTINY
Tuesday, February 19, 2013
http://www.fightaging.org/archives/2013/02/aging-is-emphatically-not-an-inescapable-destiny.php
An interview with Aubrey de Grey of the SENS Research Foundation in Tendencias21, a Spanish publication. The occasion is the publication of a Spanish language edition of Ending Aging: "[Tendencias21]: Do you think that aging and death are not an inescapable destiny of human being? [Aubrey de Grey]: What is this thing "aging and death" in the question? It is very instructive that there is so much fatalism about aging that people consider aging to be synonymous with death. Death - from any cause, including causes that are related to how long ago you were born and also causes that are not - is not what I am working to avert. I am working to avert aging, i.e. the ill-health that is currently an inescapable consequence of being alive for a long time. And yes, I think that aging is emphatically NOT an inescapable thing - I am sure that it will eventually be defeated with medicine. [Tendencias21]: What are the steps or progress made so far by the science that could prolong human life and improve its quality, despite the passage of time? [Aubrey de Grey]: All the therapies that we need for the control of aging are within reach. In some cases, such as stem cell therapies to replace cells that die and are not automatically replaced by cell division, we are very close - clinical trials are already in progress. In other cases we are still working with mice, or even just cells in a dish, but even there we have a clear way forward to the development of medicine for people. [Tendencias21]: Do you believe that, in the not too distant future, we could avoid the ballast of the degenerative diseases associated with aging? [Aubrey de Grey]: Yes I do. I think we have at least a 50% chance of developing truly comprehensive rejuvenation medicine within 25 years, just so long as the early-stage, proof-of-concept research that is going on right now is adequately funded."

ADIPONECTIN IN CENTENARIANS
Monday, February 18, 2013
http://www.fightaging.org/archives/2013/02/adiponectin-in-centenarians.php
Adiponectin shows up here and there in considerations of the relationship between metabolism and natural variations in longevity. Researchers here demonstrate an association for adiponectin in human centenarians: "The physiological mechanisms that promote longevity remain unclear. It has been suggested that insulin sensitivity is preserved in centenarians, whereas typical aging is accompanied by increasing insulin resistance. The oldest-old individuals display raised total adiponectin levels, despite the potential correlation between enhanced adiponectin and all-cause and cardiovascular mortality. A group of 58 Polish centenarians (50 women and 8 men, mean age 101±1.34 years) and 68 elderly persons (55 women and 13 men, mean age 70±5.69 years) as controls [were used] to evaluate the level of adiponectin and its isoforms in sera of centenarians and to assess associations between adiponectin and metabolic parameters. The concentrations of all adiponectin isoforms were significantly higher in the oldest-old participants. In the centenarian group, total adiponectin positively correlated with age and HDL-cholesterol, and HMW-adiponectin was negatively associated with insulin and triglycerides. The long-lived participants had a lower incidence of hypertension, type 2 diabetes, overweight and obesity, with lower concentrations of serum glucose and insulin, and reduced [insulin resistance]. Our findings support the thesis that centenarians possess a different adiponectin isoform pattern and have a favorable metabolic phenotype in comparison with elderly individuals. However, additional work is necessary to understand the relevance of these findings to longevity."

DNA DAMAGE AND REPRODUCTIVE AGING
Monday, February 18, 2013
http://www.fightaging.org/archives/2013/02/dna-damage-and-reproductive-aging.php
Researchers here dig into the mechanisms by which female capacity for reproduction diminishes with age. This produces an interesting data point to add to the debate over the degree to which nuclear DNA damage might be a contributing cause of aging: "A woman's eggs decline in quality and quantity as she ages, at least in part because an important DNA repair pathway becomes impaired. The pathway, which includes proteins encoded by the well-known BRCA genes, is supposed to repair double-strand breaks in DNA. But as women get older, the study found, repair mechanisms lose efficiency and reproductive cells accumulate damaged genes and often commit suicide. While women are born with 1 million oocytes, only about 500 turn into full-fledged eggs over their lifetime. By the time women reach their early 50s, the remaining oocytes have almost completely degraded. Why the oocytes degrade so rapidly in comparison to other body tissues was a mystery. [Researchers] first tested mouse and human oocytes for double-strand breaks and found that the damage increased significantly with age. They also looked at expression of several repair proteins in the cells. Expression of BRCA1 and a handful of other repair genes decreased with age. The results implied that dysfunction in DNA repair may lead to genomic damage seen in aging oocytes. The researchers studied both mice and women with mutations in the BRCA1 [gene]. People with mutations in BRCA1 had lower oocyte reserves in their ovaries than those without the mutations, and mice with BRCA1 mutations had smaller litters of pups than wild type mice. "

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Posted 03 March 2013 - 06:53 PM

FIGHT AGING! NEWSLETTER
March 4th 2013

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

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CONTENT

- Nanoparticles and Viruses Will Blur at the Edges
- Health Extension and Science Funding
- Neurons Can Outlast Their Host, But is That Relevant?
- Discussion
- Latest Headlines from Fight Aging!
    - Calorie Restriction Protective of Specific Brain Mechanisms
    - Another Study on Inheritance of Human Longevity
    - Infusing Large Numbers of Immune Cells as a Therapy
    - One View of the Widespread Unthought Opposition to Engineered Human Longevity
    - Cautious Studies Tend to Disprove Dietary Longevity Claims
    - A Podcast Interview With Aubrey de Grey
    - Parthogenesis in Regenerative Medicine
    - Very Healthy Elder Athletes Don't Actually Tell Us All That Much About Aging
    - SENS Research Foundation Site Redesign
    - Considering DNA Methylation and Aging

NANOPARTICLES AND VIRUSES WILL BLUR AT THE EDGES
http://www.fightaging.org/archives/2013/02/in-targeted-cell-destruction-research-nanoparticles-and-viruses-are-categories-that-will-blur-at-the-edges.php

Targeted cell killing technologies are one of the most important developments to emerge from the cancer research community. Beyond the immediate target of cancer cells there are in fact a whole range of specific types of cell that we'd like to periodically eliminate from the body, safely, and with minimal damage to surrounding tissue. Senescent cells, for example, contribute directly to the aging process as they accumulate with the passing of years. Also, the immune system fails in part because it has a limit on the number of cells it can support, and too many of those cells become uselessly specialized to detect and combat mild herpesviruses like CMV that cannot be cleared from the body by its own natural processes. Getting rid of those cells would free up space that is very much needed.

All of these cell types have their characteristic differences, and given a reliable way to take advantage of those differences then some form of targeted destruction can be unleashed to improve health and reverse this aspect of aging. Two of the more popular approaches to targeted cell destruction in the cancer research community involve nanoparticles such as dendrimers and viruses. The former is a bottom-up approach to building a tool: the construction of comparatively simple, minimalistic assemblies that are designed to link together and deliver a collection of specific designer molecules - perhaps a sensor to match to a type of cell, something to cause the cell to ingest the particle and its payload, and something that will sabotage the cell. Viruses on the other hand are much more complex entities, and their use embodies more of a found tool approach: some are useful because they have a preference for cancer cells over normal cells. Others can be tailored to act that way, but you work with what you can find in the wild or breed in the lab.

As researchers build better nanoparticle-protein assemblies and become more adept at manipulating viruses to exhibit specific desired behaviors, the line between the two will eventually blur. Viruses are about as close as you can get to chemistry while still being something that is generally accepted as being biology. There's a way to go yet - no-one is producing self-replicating nanoparticles for medical use that I'm aware of - but it will happen.

HEALTH EXTENSION AND SCIENCE FUNDING
http://www.fightaging.org/archives/2013/02/health-extension-and-science-funding.php

I mentioned the Health Extension group late last year. It is a Bay Area grassroots initiative associated with the technology startup community, with salons and presentations sponsored by the SENS Research Foundation (SRF) among others. California is home to a fair chunk of the US aging research community and related relevant science labs, and the SRF has their research center there in the Bay Area - so it's good to see that the technology community continues the evolution of its support for longevity science.

As an aside, it is interesting to speculate as why there is - and so far as I am aware, always has been - a strong undercurrent of support for engineered human longevity amongst those who work with software for a living, as well as other forms of engineer. From the viewpoint of someone immersed in the entrepreneurial technology startup community, medicine and the development of real, actual therapies to slow or reverse aging shows the promise of a massive market yet to exist, combined with a lazy, over-regulated incumbent industry that's alternating between making a hash of things or doing nothing to advance the state of the art. So it's an engineering problem, it's the classic industry in need of disruption, it's the brief pause before a massive revolution in medicine and biotech, and so forth. If you dwell in the space where technology and starting companies overlaps, it's not hard to see dollar signs and opportunities when it comes to longevity science. It's also not hard to see that regulation is preventing or destroying so much of what could be happening on this front - but that might be worked around via medical tourism and overseas commercial development. To get the research done first and worry about the rest later is a good motto.

In any case, I see that Health Extension is showing signs of moving in the logical direction of fundraising and assembling projects that might be crowdfunded, or punted in the direction of philanthropists, or otherwise brought into the confluence of money and intent. This no doubt mixes something of the Biocurious circuit, something of the fundraising for research projects carried out by Longecity in past years, the growing interest in longevity science found in the technology community, plus the face-to-face networking of the Bay Area folk, and the tendency for that community to spawn meaningful projects at a fair rate.

We shall see where it all goes, and I'm all for more people trying to get things done in this space. There is a massive opportunity ahead: figure out how to persuade sufficient funding to implement the SENS vision of rejuvenation therapies soon enough to extend our own lives in health and vigor. Or fail to achieve that end, and suffer and die a few short decades from now. Sooner or later a sizable minority of the members of exactly the sort of wealthy and active community that generates technology companies in the Bay Area will start to realize just how much it is in their self-interest to aggressively push on progress in rejuvenation biotechnology. All that takes is money - there are detailed plans waiting for the necessary research and development funding.

NEURONS CAN OUTLAST THEIR HOST, BUT IS THAT RELEVANT?
http://www.fightaging.org/archives/2013/03/neurons-can-outlast-their-host-in-at-least-one-species-but-is-that-at-all-relevant.php

A paper on the life span of neurons in relation to their host organism was published earlier in the year and has been doing the rounds in recent days:

"Neurons in mammals do not undergo replicative aging, and, in absence of pathologic conditions, their lifespan is limited only by the maximum lifespan of the organism. Whether neuronal lifespan is determined by the strain-specific lifetime or can be extended beyond this limit is unknown. Here, we transplanted embryonic mouse cerebellar precursors into the developing brain of the longer-living Wistar rats. The donor cells integrated into the rat cerebellum developing into mature neurons while retaining mouse-specific morphometric traits.

"In their new environment, the grafted mouse neurons did not die at or before the maximum lifespan of their strain of origin but survived as long as 36 mo, doubling the average lifespan of the donor mice. Thus, the lifespan of neurons is not limited by the maximum lifespan of the donor organism, but continues when transplanted in a longer-living host."

This is indeed the barnstorming age of biotechnology. As you might already know, we humans possess many nervous system cells that we were born with and which will last our entire lifetime. This is in contrast to much of the rest of our body where cells are replaced over various timescales, from years for some tissues to days for others. It is even that case that some individual macromolecules within brain cells last unchanged throughout life - not just the cell remaining on station for a lifetime, but some of its fundamental building blocks as well.

The fact that many neurons are never replaced is the source of a range of frailties and age-related conditions that result from increasing damage or buildup of unwanted metabolic byproducts in these long-lived cells. Nonetheless, it seems very reasonable to expect that our neurons are capable of outlasting the present limits of human life span, given the fact that it isn't neurodegeneration that kills supercentenarians - their brain cells are, by and large, still marching along even in the final years. No, death by aging is a systems failure, not a timed simultaneous failure of all the components that make up that system.

Is work on rodent neurons quoted above particularly relevant, or does it change anything? I is interesting, but I think that the answer is "no." We already know that developing the means to repair existing neurons in the brain is necessary. Boosting the rate at which new neurons are created will almost certainly be helpful, but a good portion of the brain stores the data that is the mind - those neurons and their encoded data have to be preserved and maintained, not replaced wholesale. So here it seems to me that knowing that neurons have a longer shelf-life doesn't change anything in the game plan.

Further, there's no guarantee that the longer neuron shelf-life in rodents has any great relevance to human cells. The analogous human study might be to pull long-lived neurons from a supercentenarian and culture them in a 3-D engineered environment that replicates their home tissue as closely as possible. Then you wait - for a fair number of decades. By the time that experiment comes to any interesting result, the whole issue will be moot. Either we will be dead, or SENS-like rejuvenation biotechnologies will be developed, and in either case researchers will already know so much more about cellular biology that they will be long past the point of answering all the questions that the study might help to resolve.

DISCUSSION

The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!

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LATEST HEADLINES FROM FIGHT AGING!

CALORIE RESTRICTION PROTECTIVE OF SPECIFIC BRAIN MECHANISMS
Friday, March 1, 2013
http://www.fightaging.org/archives/2013/03/calorie-restriction-protective-of-specific-brain-mechanisms.php
Calorie restriction produces a general slowing of the progression of degenerative aging and creates sweeping changes at all levels of metabolism. Thus it should not be a surprise to find protective effects no matter how deep you dive into the biochemistry of calorie restricted laboratory animals. Here's one of the many more detailed examples, looking at the abundances of receptors known to be important in brain function: "The effects of aging and long-term caloric restriction, on the regulation of neuropeptide Y (NPY) Y(1), Y(2) and Y(5) receptors subtypes, was studied in 20-month-old male rats fed ad libitum (AL) or submitted to a 40% caloric restriction for 12 months. In the brain of 3-month-old AL rats, the distribution and densities of Y(1), Y(2) and Y(5) receptors were in agreement with previous reports. In the brain of 20-month-old AL rats, a decrease of NPY receptor subtype densities in regions having important physiological functions such as the cingulate cortex, hippocampus and dentate gyrus, thalamus and hypothalamus was observed. In contrast, caloric restriction had multiple effects. It induced specific decreases of Y(1)-receptor densities in the dentate gyrus, thalamic and hypothalamic nuclei and lateral hypothalamic area and Y(2)-receptor densities in the suprachiasmatic nucleus of hypothalamus. Moreover, it prevented the age-induced increase in Y(1)-receptor densities in the ventromedial hypothalamic nucleus and decrease in the mediodorsal thalamic nucleus, and increased Y(2)-receptor densities in the CA2 subfield of the hippocampus. These results indicate that caloric restriction not only counteracts some of the deleterious effects of aging on NPY receptor subtype densities but exerts specific effects of its own. The overall impact of the regulation of NPY receptor subtypes in the brain of old calorie-restricted rats may protect the neural circuits involved in pain, emotions, feeding and memory functions."

ANOTHER STUDY ON INHERITANCE OF HUMAN LONGEVITY
Friday, March 1, 2013
http://www.fightaging.org/archives/2013/03/another-study-on-inheritance-of-human-longevity.php
Studies suggest that longer life expectancy runs in families to some degree - though it is always the case that what you get in the genetic lottery can be squandered by poor lifestyle choices. Gene variants appear to be more important in determining remaining life expectancy at older ages than at younger ages, which is another way of saying much the same thing. Either way, the end result will be the same until we can build rejuvenation biotechnology. "According to the findings of some recent studies, the centenarians' offspring appear to represent a promising model for research on longevity and healthy aging. This study compares the health status and the functional status of three groups of subjects: 1. individuals with two long-lived parents (one of whom centenarian), 2. individuals with only one long-lived (centenarian) parent, and 3. individuals with no long-lived parents. The goal is to verify whether the centenarians' offspring display any advantage over the offspring of both non-long-lived parents and to evaluate whether the longevity of the non-centenarian parent provides a further advantage. A total of 374 subjects (mean age approximately 70 years) was examined. A threshold for longevity was established for non-centenarian parents through demographic data available for Italy (males surviving to at least 81 years of age and females to 87 years). The participants were assessed for their health and functional status by means of a standardized questionnaire and tests of physical performance. Data were analyzed using multivariate regression models adjusted for socio-demographic characteristics and risk factors for age-related pathologies. The results of the study show that centenarians' offspring have a better functional status, a reduced risk for several age-related pathologies and reduced drug consumption than the offspring of non-long-lived parents. In addition, the health status of centenarians' offspring does not appear to be influenced by the longevity of the second parent. It therefore seems possible to conclude that at ages around 70 years the genetic contribution to health status deriving from having one centenarian parent is not substantially improved if the other parent is also long-lived."

INFUSING LARGE NUMBERS OF IMMUNE CELLS AS A THERAPY
Thursday, February 28, 2013
http://www.fightaging.org/archives/2013/02/infusing-large-numbers-of-immune-cells-as-a-therapy.php
Since it is possible to take a patient's cells and generate a very large number of immune cells, far more than the patient would ever have normally, and since it's possible to make some alterations to immune cells to make them more effective, why not do this? It's probably the case that even generally healthy older people would benefit from a regular infusion of large numbers of their own immune cells, or even donor cells, given the way in which the immune system declines with age, but under present medical regulation you'll only ever see it deployed as a treatment for late stage disease: "[Researchers] have successfully infused large numbers of donor T-cells specific for a key anti-leukemic antigen to prolong survival in high-risk and relapsed leukemia patients after stem cell transplantation. [T-cells were] taken from a donor, programmed in the lab to recognize the Wilm's Tumor Antigen 1 (WT1) and kill leukemia cells, grown in large numbers, and then infused into patients to promote anti-leukemic activity. The WT1 protein is overexpressed in leukemias and is in part responsible for why the cells have become leukemic. All of the patients [received] adoptively transferred infusions of billions of enhanced CD8 cytotoxic T-cell clones. They were considered at high risk of death because they had already relapsed and/or had a poor prognosis due to unfavorable characteristics of their leukemia. Four of the 11 patients in the trial received infusions of T-cells that targeted WT1 and were generated in the presence of IL-21. One had detectable relapsed disease and entered complete remission shortly after the T-cells were infused. All four survived after T-cell therapy without relapse for more than 30 months without suffering graft-vs.-host-disease and required no additional anti-leukemic treatment, according to the study. Among the seven patients who received infused T-cells generated without the presence of IL-21, two showed direct evidence of anti-leukemic activity, including one patient with advanced progressive disease who had a temporary response."

ONE VIEW OF THE WIDESPREAD UNTHOUGHT OPPOSITION TO ENGINEERED HUMAN LONGEVITY
Thursday, February 28, 2013
http://www.fightaging.org/archives/2013/02/one-view-of-the-widespread-unthought-opposition-to-engineered-human-longevity.php
The average fellow in the street thinks that helping people to live longer is a bad idea, and usually expresses some combination of the Tithonus Error (the misapprehension that life extension technologies would make you live in increasing frailty, rather than extending youth) and the modern mixed package of environmentalist / classist / Malthusian / conservative beliefs on wealth and privilege: that equality should come by tearing down those at the top and halting progress, that there are too many people in the world, that any sort of increased consumption is evil, that changing anything to do with aging is bad. This is the major challenge for the future development of means to extend human life - that most people reject it, even at their own cost, even when their beliefs about the way the world works are easily shown to be false: there is no overpopulation, only waste and corruption; stopping progress and trying to impose equality inevitably leads to something like the economic ruins of the old Soviet Union; Malthus was wrong in his time and still wrong now; and so forth. Here is an educator's point of view, from one more embedded in the culture that rejects progress than most: " Our minds are perhaps hardwired to interpret the world in terms of simplistic patterns (like "haves" and "have nots"), but that does not mean it is an accurate representation of reality. Education should challenge our preconceived ideas of the world and dogma. When I teach the weeks of my course on aging and life extension these points become most salient. I am always struck by the fact that (a) very few students understand that chronic diseases are the leading cause of death in the world, and (b) that chronic disease is a problem for both rich and poor countries, and © that people in poorer regions of the world actually age, and that this can cause them to experience suffering, disease, a decline in income, etc. I could go on. Here are actual comments (I am paraphrasing from memory) I have heard students and others express when discussing population aging, global health and a Darwinian approach to medicine: "Old people should die sooner of disease so younger people can get a job". "A cure for cancer already exists, but Big Pharma makes more money off of cancer than curing it". "Wouldn't it be boring being alive longer and thus being married to the same person for longer?" "We shouldn't modify the rate of aging as it is unnatural". "Why don't we just spend all health research money on saving children and forget about helping those who are lucky enough to have lived a long life?" "Slowing human aging will destroy the planet". Such sentiments are common, and part of my research involves trying to understand why people have such attitudes, and how one can help people come to critically examine such attitudes. The students that I encounter who have strong convictions that the world is overpopulated, and that the future of the planet is a bleak one because of population growth, typically have little knowledge of demography."

CAUTIOUS STUDIES TEND TO DISPROVE DIETARY LONGEVITY CLAIMS
Wednesday, February 27, 2013
http://www.fightaging.org/archives/2013/02/cautious-studies-tend-to-disprove-dietary-longevity-claims.php
A research group is presently working through a grand tour of replicating longevity claims in mice, using careful and cautious study designs that eliminate calorie restriction effects as much as is possible. This sort of approach shows that many past claims of dietary additions that modestly extend life in mice were probably the result of inadvertent calorie restriction - which is why you have to look carefully at every study to make sure that researchers controlled for this issue. Calorie restriction has a comparatively large effect on life span in smaller animals, such that even mild restriction can swamp all other contributions to life span that occur in a study: "Phytonutrients reportedly extend the lifespan of C. elegans, Drosophila, and mice. We tested extracts of blueberry, pomegranate, green and black tea, cinnamon, sesame, and French maritime pine bark (Pycnogenol and taxifolin), as well as curcumin, morin, and quercetin for their effects on the lifespan of mice. While many of these phytonutrients reportedly extend the lifespan of model organisms, we found no significant effect on the lifespan of male, F1 hybrid mice, even though the dosages used reportedly produce defined therapeutic endpoints in mice. The compounds were fed beginning at 12 months of age. The control and treatment groups were isocaloric with respect to one another. A 40% calorically restricted and other groups not reported here did experience lifespan extension. Body weights were unchanged relative to controls for all but two supplemented groups, indicating most supplements did not change energy absorption or utilization. Published reports of murine lifespan extension using curcumin or tea components may have resulted from induced caloric restriction. Together, our results do not support the idea that phytonutrient-antioxidants and anti-inflammatories are potential longevity therapeutics, even though consumption of whole fruits and vegetables is associated with enhanced health- and lifespan."

A PODCAST INTERVIEW WITH AUBREY DE GREY
Wednesday, February 27, 2013
http://www.fightaging.org/archives/2013/02/a-podcast-interview-with-aubrey-de-grey-1.php
An audio interview with Aubrey de Grey of the SENS Research Foundation: "Like it or not, aging is a byproduct of the daily activity of life. But Aubrey de Grey believes that the molecular and cellular damage that defines aging and creates disability and disease can be targeted for medical interventions that restore health and radically extend life. We spoke to de Grey, chief scientific officer and founder of the SENS Research Foundation, about the need to think differently about aging, how a new era of regenerative medicine might slow or reverse its effects, and why it is necessary to focus on medical interventions rather than prevention to have a significant impact. In this interview, Dr. de Grey discusses SRF's approach to treating the diseases of aging, and how it differs from most of the research being done today in gerontology. He also talks about his own background, and how he came to the field."

PARTHOGENESIS IN REGENERATIVE MEDICINE
Tuesday, February 26, 2013
http://www.fightaging.org/archives/2013/02/parthogenesis-in-regenerative-medicine.php
This popular science piece looks at parthogenesis as an alternative to both embryonic stem cells and induced pluripotency reprogramming as a source of stem cells: "Parthenogenesis is a form of asexual reproduction that occurs naturally in plants, insects, fish, amphibians and reptiles. During this process, unfertilized eggs begin to develop as if they've been fertilized. In 2007, researchers induced human egg cells with chemicals mimicking fertilization so they would undergo the process. The result were parthenogenetic cells that share the same properties as embryos, except that they can't grow further. The cells are akin to pluripotent stem cells derived from embryos, which means they have the ability to develop into different types of cells - including heart cells. [Researchers] used this knowledge to turn body cells of mice into parthenogenetic stem cells, which were then grown into mature, functional cardiomyocytes. Researchers used these cells to engineer myocardium - heart muscle - with the same structure and function of normal myocardium. The muscle was then grafted onto the hearts of the mice that had contributed the original eggs for parthenogenesis, where it worked the same way as existing muscle."

VERY HEALTHY ELDER ATHLETES DON'T ACTUALLY TELL US ALL THAT MUCH ABOUT AGING
Tuesday, February 26, 2013
http://www.fightaging.org/archives/2013/02/very-healthy-elder-athletes-dont-actually-tell-us-all-that-much-about-aging.php
A number of studies have shown that it is possible to be both old and very healthy in comparison to your peers, and surveying older athletes is a good way to find some of those old, very healthy people. The big question is one of causation: are they healthy because they are athletes, or did they become healthy athletes because they are more physically robust, thanks to genetic or other differences? This is a part of the uncertainty over whether more exercise is always better and the degree to which genetics versus lifestyle versus chance contributes to the course of aging. "People who exercise on a regular basis up to the age of 80 have the same aerobic capacity as someone half their age, says a new study. "These athletes are not who we think of when we consider 80-year-olds because they are in fantastic shape. They are simply incredible, happy people who enjoy life and are living it to the fullest. They are still actively engaged in competitive events." Researchers examined nine endurance athletes from northern Sweden and compared them to a group of healthy men from Indiana in the same age group who only performed the activities of daily living with no history of structured exercise. The endurance athletes were cross-country skiers, including a former Olympic champion and several national/regional champions with a history of aerobic exercise and participation in endurance events throughout their lives. The athletes exercised four to six times a week, averaging 3,700 more steps per day than the non-exercisers. Members of the two study groups rode exercise bikes as researchers measured oxygen uptake. When the participants reached total exhaustion, they had reached maximum oxygen uptake (also known as VO2 max). Skeletal muscle biopsies were then taken to measure the capacity of their mitochondria, the aerobic base of their muscle and other cells. The study also found the endurance athletes established new upper limits for aerobic power in men 80-91 years old, including a maximum oxygen uptake that was nearly twice that of untrained men their age. "To our knowledge, the VO2 max of the lifelong endurance athletes was the highest recorded in humans in this age group, and comparable to nonendurance-trained men 40 years younger. We also analyzed the aerobic capacity of their muscles by examining biopsies taken from thigh muscles, and found it was about double that of typical men. In fact, the oldest gentleman was 91 years old, but his aerobic capacity resembles that of a man 50 years younger. It was absolutely astounding.""

SENS RESEARCH FOUNDATION SITE REDESIGN
Monday, February 25, 2013
http://www.fightaging.org/archives/2013/02/sens-research-foundation-site-redesign.php
The SENS Research Foundation works on the foundational biotechnologies that will be needed to create therapies capable of reversing aging: ways to make mitochondrial DNA damage irrelevant, removing harmful aggregates that build up with age within and between cells, and so forth. The Foundation staff kicked off the first phase of a major site redesign earlier this year, and rolled out the second stage this past weekend. So head over and take a look: "If this is your first time visiting our site, welcome. If you've been here before, you're no doubt noticing plenty that is new: an updated site design, a variety of new content, a new logo, and a new organizational name: "SENS Research Foundation". It all centers around a new tagline: reimagine aging. For a public charity, a tagline can be an enormously powerful thing. Our vision and mission statements remain the primary guides to our planning, but the tag is everywhere, on every business card and letter and web page. More than any other document or phrase, it naturally becomes the daily reminder of who we are and what we are about. Of course we are still "advancing rejuvenation biotechnologies" just as vigorously as when we carried that tagline over the last couple years. We still aim to introduce a new premise for the pharma and biotech industries. And now, our successes in our research, our collaborations, our conferences, and our educational programs have made us increasingly aware of the need to refocus our messaging to people being exposed to us for the first time."

CONSIDERING DNA METHYLATION AND AGING
Monday, February 25, 2013
http://www.fightaging.org/archives/2013/02/considering-dna-methylation-and-aging.php
An article on DNA methylation, which researchers have demonstrated to have the basis for a biomarker of aging; some of the patterns that tend to occur in the way in which these epigenetic decorations to DNA occur correlate well with biological age. This author is optimistic that manipulating DNA methylation can slow aging, which is something of a programmed aging point of view - that epigenetic changes are a root cause of aging and give rise to the damage of aging we can observe, rather than vice versa. It doesn't seem to me that the evidence rises to support that view and course of action over trying to repair the underlying damage of aging. If damage is the root cause, then when it is reverted the DNA methylation changes should also be restored to youthful levels. "How does the body know how old it is? Our metabolisms change as we get older, even though our DNA doesn't change. Different genes are activated at different times of life, and the timing of gene expression is what controls growth, development, sexual maturity, and perhaps aging as well. The body keeps accurate track of how old it is, though there has been no scientific agreement about where the clocks are, or how they work. Recently, some biologists have suggested that one such biological clock might reside in the epigenetic state of the DNA. If this is true, epigenetics will become an attractive, though challenging, target for anti-aging research. If we knew where the body kept its "clock", then perhaps we could target the clock itself with biochemical interventions. We would not just be able to slow the progress of aging, but reset the clock to an earlier age. DNA is decorated with methyl groups, small molecular add-ons that act like "Do Not Disturb" signs for the underlying gene. A gene that is decorated with methyl groups is passed over, and not expressed. Patterns of methylation are programmed into the genome at birth, and they are known to change over a lifetime. The new idea is that these changes can constitute a reference, like a clock face that informs the cell about the body's stage of life, so that it can appropriately adjust its gene expression, and thence its entire metabolism. If we're really lucky, it will turn out that humans, like flies, respond well to a dumb, across-the-board increase in methylation. [The] methyl transferase system in humans is more complicated, but it will still be far easier to engineer a general increase in methylation than to copy youthful methylation patterns in detail. This question could be posed in research project that we know how to do now."

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Posted 10 March 2013 - 06:26 PM

FIGHT AGING! NEWSLETTER
March 11th 2013

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

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CONTENT

- SENS Research Foundation Forges Ahead
- A Mechanism By Which Fat Causes Chronic Inflammation
- The Transhumanist Reader
- Interviews and Commentary from the Transhumanist Community
- Discussion
- Latest Headlines from Fight Aging!
    - SENS Research Foundation's AGE-Breaker Research Programs
    - Investigating the Mechanisms of Liver Regrowth
    - Suggesting that Calorie Restriction Primarily Operates on Mitochondrial Function
    - A Switch to Increase Plasticity in the Adult Brain
    - Sexual Activity and Neurogenesis Rates in Mice
    - More Visceral Fat Means a Greater Risk of Intestinal Cancer
    - A "Calcium Hypothesis" of Declining Vision With Age
    - On Methionine Restriction
    - A Review of Known Links Between Growth Hormone and Aging
    - Casting Doubt on Latent Regenerative Mechanisms in Mammals

SENS RESEARCH FOUNDATION FORGES AHEAD
http://www.fightaging.org/archives/2013/03/the-sens-research-foundation-is-forging-ahead.php

The SENS Research Foundation (SRF) funds research programs aimed at the development of rejuvenation biotechnology - i.e. the basis for medical therapies that can reverse degenerative aging and thus extend healthy, vigorous human life spans. These programs are based on the Strategies for Engineered Negligible Senescence (SENS) first outlined by Aubrey de Grey some years ago. I'm very much in favor of this: the work has to be done, the sooner the better, and the SRF is one of the few places in the world where you can make a donation and know that it's going directly towards high-impact, relevant medical research into human rejuvenation.

Getting the job done doesn't mean doing it all yourself, however. Completing a demonstration of SENS in mice is sketched in at a decade and a billion dollars if fully funded, but that's the opening scene in a longer play devoted to translating animal studies into human clinical medicine. The point of the SENS Research Foundation is to "completely redefine the way the world researches and treats aging and age-related diseases." Some directly funded research is necessary to this goal, such as when fields are neglected and the research community needs a mix of a kick in the pants and an influx of philanthropic funding - as is the case for work on clearing out advanced glycation end-products from our tissues. But the larger aim is persuasion: persuade a large enough fraction of the research community to agree with with SENS vision of aging, and they will form their own labs and research initiatives to help.

In this sense, SENS is a peaceful revolution of the sort that roll through the world's research communities with some regularity. In a way, SENS has already won its place as the forthcoming dominant paradigm, despite its minority status and tiny budget, and the process of getting to that dominance is all just details. You can tell that this is the case by the way that leaders in the research community are willing to become scientific advisers or host collaborative SENS research programs in their laboratories. Note the signing statement on the SENS Research Foundation advisory board page - it is in essence a refutation of much of what has been dominant in aging research for the past twenty years or so, and important figures in the research community now stand by that view:

"Unfortunately, the regenerative medicine approach to combating aging is not yet being adequately pursued by major funding bodies: only a small number of laboratories worldwide are funded (either publicly or privately) to develop therapies that could rejuvenate aged but otherwise undamaged tissues. SRF has risen to the challenge of filling this void in the biomedical research funding arena.

"As and when it is developed, this panel of therapies may provide many years, even decades, of additional youthful life to countless millions of people. Those extra years will be free of all age-related diseases, as well as the frailty and susceptibility to infections and falls that the elderly also experience. The alleviation of suffering that will result, and the resulting economic benefits of maintained productivity of the population, are almost incalculable. In our capacity as the overseers of SRF's research strategy, we urge you to do all you can to help SENS Research Foundation carry out this mission with maximum speed."

Once a critical mass of the movers and shakers in a field agree with you, then the rest is history. It might be a lot of work, but it will happen. The latest figure to join the SRF scientific board is a very well known name in the life science community:

"We are honored to welcome Dr. George Church as the newest member of SENS Research Foundation's Research Advisory Board. Dr. Church brings relevant expertise in a number of fields, genetics in particular. He is Professor of Genetics at Harvard Medical School and Director of PersonalGenomes.org, in addition to being the author of the book, Regenesis: How Synthetic Biology Will Reinvent Nature and Ourselves. His innovations in "next generation" genome sequencing and synthesis & cell/tissue engineering resulted in 12 companies spanning fields including medical genomics and synthetic biology as well as new privacy, biosafety & biosecurity policies. He is director of the NIH Center for Excellence in Genomic Science, and his honors include election to NAS & NAE and Franklin Bower Laureate for Achievement in Science."

So on the whole, things are going well, conforming to a progression that will lead to the SENS approach to aging - i.e. build the means of rejuvenation, and do it soon - becoming a large and important force in the medical research community of tomorrow. That is something of a necessary platform to build up the odds of receiving large-scale funding through the usual channels, rather than requiring visionary philanthropists and the crowdfunding efforts of interested communities to open the way.

It is still the case that one small, wealthy group could accelerate that progression by twenty years at this point by funding SENS to the tune of a few hundred million dollars. The odds of the necessary networking happening to create that event will continue to rise with progress in persuading the research community and existing constellation of funding institutions. Life is worth more than money, so the motivation to back rejuvenation research is strong, but people with access to large amounts of money tend to be very conservative in how they deploy it; only the most mainstream of initiatives can hope to be on the inside track for philanthropy. People like Peter Thiel or Dmitry Itskov are not commonplace, sadly.

A MECHANISM BY WHICH FAT CAUSES CHRONIC INFLAMMATION
http://www.fightaging.org/archives/2013/03/a-mechanism-by-which-fat-causes-chronic-inflammation.php

A large weight of evidence shows that excess body fat - and specifically excess visceral fat - is bad for you in the long term. Put on weight and your life expectancy drops, even as your lifetime medical costs rise. You will most likely be less healthy for the rest of your life than your leaner peers, and they will outlive you. (Unless of course medical technology advances rapidly enough to save you from the consequences of your diet and lifestyle choices. But that's no certainty; why gamble when you don't have to?)

Some fraction of the consequences of being overweight are actually the consequences of a lack of regular exercise. Another fraction of the consequences of being overweight stem from the low-level reactions of your metabolism to the overnutrition required to create that excess body fat - the reverse of dietary restriction, but something that is not as well researched at the level of cells and genes, despite the vast real-life population study in overfeeding taking place in much of the world these days.

The real monster when it comes to fat tissue and long term health appears to be inflammation, however. Temporary inflammation is a necessary portion of the response to damage and disease by the immune system, but chronic, unremitting inflammation accelerates progress towards frailty and ill-health. Indeed, it shows up as a contributing factor in degenerative aging later in life as the immune system becomes increasingly damaged and erratic. Distinct from the aging of the immune system, fat tissue itself spurs chronic inflammation. This has been known for some time, and here researchers present a fairly detailed account of how they think fat cells are causing this issue:

"High calorie diets cause [fat] cells to make major histocompatibility complex II, a group of proteins usually expressed to help the immune system fight off viruses and bacteria. In overweight mice and humans the fat cells, or adipocytes, are issuing false distress signals - they are not under attack by pathogens. But this still sends local immune cells into a tizzy, and that causes inflammation.

"We did not know fat cells could instigate the inflammatory response. That's because for a very long time we thought these cells did little else besides store and release energy. But what we have learned is that adipocytes don't just rely on local resident immune cells for protection - they play a very active role in their own defense. And that's not always a good thing.

"Could the inflammation caused by a high fat diet serve any purpose, or is it a senseless response to an unnaturally caloric diet? The expression of MHCII in adipocytes does not seem to be helpful to the body. It is not at all clear what the advantage would be, given all the negative long-term consequences of fat tissue inflammation in people who are obese, including insulin resistance and, eventually, full diabetes. This just appears to be a runaway immune response to a modern high calorie diet. The bottom line is, you're feeding and feeding these fat cells and they're turning around and biting you back. They're doing the thing they're supposed to do - storing energy - but reacting negatively to too much of it."

THE TRANSHUMANIST READER
http://www.fightaging.org/archives/2013/03/the-transhumanist-reader.php

The Transhumanist Reader: Classical and Contemporary Essays on the Science, Technology, and Philosophy of the Human Future, edited by Max More and Natasha Vita-More, will be published April 29, 2013. It is the "first authoritative and comprehensive survey of the origins and current state of transhumanist thinking", according to the editors, and the anthology includes a roster of leaders in transhumanist thought. "The rapid pace of emerging technologies is playing an increasingly important role in overcoming fundamental human limitations," say the editors.

Transhumanism is an important movement, even while now somewhat diffused into popular culture in comparison to the online salons of the late 1990s. Why is transhumanism important? Primarily, from my perspective, because a range of the most important present ventures in biotechnology and medicine are informed, supported by, and connected to figures in the transhumanist community. There is cryonics, to pick the most obvious example - and one might argue that modern transhumanism was a offshoot of the cryonics communities and related futurists of the 1960s and 1970s. To pick another example, a great deal of the early funding and enthusiasm for SENS research into the repair of aging, back when it was conducted under the umbrella of the Methuselah Foundation, came from transhumanist circles.

From where I stand, transhumanism is nothing more than common sense about technology and the human condition. We can improve things, so why not improve things? We live in far greater comfort and for more years in good health in comparison to our ancestors precisely because those ancestors created new technologies that change the human condition - lengthening healthy life, removing causes of pain and suffering. As technologies become more sophisticated we have the opportunity to move from such things as defeating smallpox to such things as reliably repairing the cellular and molecular damage that causes aging. These are only matters of degree.

Yet many people, even in this age of constant change, are very much up in arms and threatened by such prospects. It's an odd world we live in, in which folk partake in a wealth of new choices and improvements to their standard of living - things that their parents didn't have - while at the same time decrying efforts to build further improvements for their own children. Rationality is in short supply.

INTERVIEWS AND COMMENTARY FROM THE TRANSHUMANIST COMMUNITY
http://www.fightaging.org/archives/2013/03/interviews-and-commentary-from-the-transhumanist-community.php

With the publicity for a new book on transhumanist thought, I noticed a couple of interviews and articles emerge from the community in recent days. Follow the link above for pointers and quotes.

Building medical technologies to repair and reverse degenerative aging is one part of a much broader set of transhumanist ideals: aging is only one of many current limits on the human condition that we can work to transcend through applied technology. It is a very important one, far and away the most important one in my opinion, but still one among many. Transhumanism exists as a named brand of thought and vision that some see as being separate from simple common sense about technology (i.e. use it to make things better) because we are moving, quite rapidly, from an age in which we could only crudely change ourselves into an age where the sky is the limit in terms of changing our biology and our minds. To some eyes there is a line in the sand somewhere past our present medical technology and somewhere before being able to regrow limbs, reverse aging, or build artificial intelligences.

Yet I think we've all seen that line shift ever forward as medicine and other technologies advance. Yesterday's uproar over any specific biotechnology is today's acceptance (take stem cell research as a recent line item, for example). It is a grand flaw in the human condition that people fight so much against all that is new, even while taking full advantage of the benefits provided by everything their parents fought against. It's dumb behavior. It slows things down - and in the case of finding ways to treat and ultimately cure degenerative aging, that has a staggering cost in lives and suffering.

DISCUSSION

The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!

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LATEST HEADLINES FROM FIGHT AGING!

SENS RESEARCH FOUNDATION'S AGE-BREAKER RESEARCH PROGRAMS
Friday, March 8, 2013
http://www.fightaging.org/archives/2013/03/sens-research-foundations-age-breaker-research-programs.php
One of the root causes of aging is the formation of advanced glycation end-products (AGEs), something that happens much faster in a diabetic metabolism, but which nonetheless happens to all of us and causes progressively greater harm as the years pass. AGEs gum together and disable vital protein machinery, and also hammer on cell receptors in ways that cause chronic inflammation and other ills. Past work on ways to break down AGEs - AGE-breaker drugs - largely occurred prior to the present rapid pace of development in biotechnology, and was both laborious and ultimately of little use in people despite promising animal studies. It turned out that the most important types of AGE in long-lived humans are not the same as in short-lived rodents, and thus drugs that help rats do little for people. However, one single form of human AGE - glucosepane - does make up the vast, overwhelming majority of AGEs in tissues such as skin. So it is a very viable, narrow target now that the research community knows enough to identify it as the primary target. A safe way to remove glucosepane is needed in order to largely eliminate this contribution to degenerative aging. Sadly, as for much of the foundations of future rejuvenation therapies, little work and funding is directed to this end. This is thus one of the areas in which the SENS Research Foundation hopes to step in and spur greater interest and progress. Here are some notes on the current research programs funded by the Foundation to this end: "Chemical "crosslinking" of the structural proteins of our arteries slowly stiffens them with age, leading to more rigid blood vessels, rising "systolic" blood pressure (the first or top number in a blood pressure reading), and eventually to the loss of the ability of the kidneys to filter toxins from our blood, and a rising risk of stroke with age. Rejuvenation biotechnology can prevent these scourges at their source. New medicines that break apart these molecular "handcuffs" would allow the proteins of the arteries could move freely again, restoring the supple flexibility and cushioning capacity of aging arteries to youthful health and functionality. As a result, damage to the kidneys would be prevented, and strokes averted. With a generous donation from software entrepreneur Jason Hope, SENS Research Foundation and the Cambridge University Institute of Biotechnology have established a new SENS Research Foundation Laboratory at Cambridge. With no one else taking on this challenging, critical research, the scientists in the Cambridge SENS lab will initiate work on biomedical solutions to glucosepane crosslinks starting from the ground up - with research to develop reagents that can rapidly and specifically detect proteins that have been crosslinked by glucosepane. The development of such reagents is an indispensible enabling technology for the development and testing of candidate glucosepane-breaking drugs. In parallel, SENS Research Foundation is also providing funding to Dr. David Spiegel's group at Yale University, which has special expertise in making glycation crosslinks and which has recently been studying the mechanisms and chemical vulnerabilities of precursors of glucosepane. Dr. Spiegel's group has also recently published a report clarifying how the first generation crosslink-breaking drug worked. Once the Cambridge SRF lab has successfully established methods for identifying proteins that have been handcuffed together by glucosepane, Dr. Spiegel's group will use them to begin developing potential glucosepane-cleaving agents. Completing the cycle, candidate agents can then be tested at the Cambridge center - initially in tissue culture, and eventually in vivo. Once developed, any glucosepane-labeling reagents that emerge from the first phase of this work will made available as openly as possible, to accelerate research into the role of crosslinks in disease and aging, and into ways to combat them."

INVESTIGATING THE MECHANISMS OF LIVER REGROWTH
Friday, March 8, 2013
http://www.fightaging.org/archives/2013/03/investigating-the-mechanisms-of-liver-regrowth.php
The liver is one of the few organs capable of significant regeneration in humans - but even this is more a case of compensatory growth than true regeneration of the sort seen in lower animals. Still, there is probably value in finding out how and why this happens in the liver and not in other organs: "[Researchers have] identified a protein complex that acts as a molecular switch turning on a self-regeneration program in the liver. The protein complex furthermore fine tunes liver metabolism, allowing this to run efficiently in parallel with the tissue damage repair. The new knowledge challenges the current focus on stem cells and may point towards future simplification of treatments used for repairing tissue damage. "Our new data challenge the predominant 'stem cell-mania' as the results reveal important molecular mechanisms that enable ordinary liver cells to divide and repair tissue damage. This may point to ways of using ordinary liver cells for therapeutic purposes, as these cells may be easier to use than stem cells." Tissue renewal [is] a job for the stem cells present in our body. One exception is the specialised cells of the liver called hepatocytes. They are responsible for the metabolic functions of the liver, but can at the same time produce new liver cells. "Our results show how a protein complex is changed upon damage to the liver, making it function as a 'switch' turning on a self-renewal program in the hepatocytes. The protein complex literally turns on selected genes that enable division of the hepatocytes, while maintaining their metabolic functions." The extraordinary ability of the liver cells to divide almost indefinitely resembles the ability of stem cells to self-renew and this finding challenges the current focus on stem cells and stem cell therapy. The new results [are] consistent with new studies of self-renewal in the group of white blood cells called macrophages. "We see a clear overlap in the molecular mechanisms controlling self-renewal in hepatocytes and macrophages and that could indicate the existence of a more general self-renewal program used by specialised cell types. If this is the case, it can really change the current perception that only stem cells are responsible for renewal of our tissues.""

SUGGESTING THAT CALORIE RESTRICTION PRIMARILY OPERATES ON MITOCHONDRIAL FUNCTION
Thursday, March 7, 2013
http://www.fightaging.org/archives/2013/03/suggesting-that-calorie-restriction-primarily-operates-on-mitochondrial-function.php
Mitochondrial damage is important in aging, and a range of evidence suggests it to be perhaps the most important contribution to aging. You might look at the membrane pacemaker theory of aging for example, which points to differences in susceptibility to mitochondrial damage between similar species with divergent life spans, where greater damage resistance correlates to longer life spans. Mitochondria damage themselves quite readily in the course of the normal operations. They generate the fuel used by other cellular processes, and in the course of doing so also create a flurry of oxidizing compounds - free radicals - that can react with and harm protein machinery. There are natural antioxidant compounds localized to the mitochondria that slow this process down by getting to the free radicals first. Researchers have shown that life span in mice can be extended by boosting the presence of some of these compounds. It works the other way too; removing or mutating SOD1, one of these antioxidants, shortens mouse life span. Here is an interesting demonstration showing that calorie restriction reverses this effect. That suggests that, while researchers have shown that the benefits of calorie restriction depend on the cellular recycling process of autophagy in some species, the primary mode of operation might be to alter mitochondrial function. Perhaps this occurs through an enhanced autophagic recycling of damaged mitochondria, but other mechanisms are possible: "Dietary restriction is a powerful aging intervention that extends the life span of diverse biological species ranging from yeast to invertebrates to mammals, and it has been argued that the anti-aging action of dietary restriction occurs through reduced oxidative stress/damage. Using Sod1-/- mice, which have previously been shown to have increased levels of oxidative stress associated with a shorter life span and a high incidence of neoplasia, we were able to test directly the ability of dietary restriction to reverse an aging phenotype due to increased oxidative stress/damage. We found that dietary restriction increased the life span of Sod1-/- mice 30%, returning it to that of wild type, control mice fed ad libitum. Oxidative damage in Sod1-/- mice was markedly reduced by dietary restriction. Analysis of end of life pathology showed that dietary restriction significantly reduced the overall incidence of pathological lesions in the Sod1-/- mice fed the dietary restricted-diet compared to Sod1-/- mice fed ad libitum, including the incidence of lymphoma (27 vs 5%) and overall liver pathology. In addition to reduced incidence of overall and liver specific pathology, the burden and severity of both neoplastic and non-neoplastic lesions was also significantly reduced in the Sod1-/- mice fed the dietary restricted-diet. These data demonstrate that dietary restriction can significantly attenuate the accelerated aging phenotype observed in Sod1-/- mice that arises from increased oxidative stress/damage."

A SWITCH TO INCREASE PLASTICITY IN THE ADULT BRAIN
Thursday, March 7, 2013
http://www.fightaging.org/archives/2013/03/a-switch-to-increase-plasticity-in-the-adult-brain.php
Given an easy switch to increase the plasticity of the adult brain, boosting the pace at which new neurons and new neural connections are formed, researchers will gather much more data in the years ahead as to how effective this might be as a stop-gap therapy to slow or compensate for some of the effects of aging: "Scientists have long known that the young and old brains are very different. Adolescent brains are more malleable or plastic, which allows them to learn languages more quickly than adults and speeds recovery from brain injuries. The comparative rigidity of the adult brain results in part from the function of a single gene that slows the rapid change in synaptic connections between neurons. By monitoring the synapses in living mice over weeks and months, [researchers] have identified the key genetic switch for brain maturation. [The] Nogo Receptor 1 gene is required to suppress high levels of plasticity in the adolescent brain and create the relatively quiescent levels of plasticity in adulthood. In mice without this gene, juvenile levels of brain plasticity persist throughout adulthood. When researchers blocked the function of this gene in old mice, they reset the old brain to adolescent levels of plasticity. "These are the molecules the brain needs for the transition from adolescence to adulthood. It suggests we can turn back the clock in the adult brain and recover from trauma the way kids recover." Rehabilitation after brain injuries like strokes requires that patients re-learn tasks such as moving a hand. Researchers found that adult mice lacking Nogo Receptor recovered from injury as quickly as adolescent mice and mastered new, complex motor tasks more quickly than adults with the receptor."

SEXUAL ACTIVITY AND NEUROGENESIS RATES IN MICE
Wednesday, March 6, 2013
http://www.fightaging.org/archives/2013/03/sexual-activity-and-neurogenesis-rates-in-mice.php
With hindsight, it seems that this should be a fairly obvious development. Given that evolution leads to organisms that adjust the operation of their metabolism in response to the prospects for food availability (see calorie restriction and related mechanisms), since that impacts reproductive success and thus evolutionary fitness, then it shouldn't be surprising to find that these organisms also do so based on the prospects for actual reproductive activity. "Aging is associated with compromised hippocampal function and reduced adult neurogenesis in the dentate gyrus. As new neurons have been linked to hippocampal functions, such as cognition, age-related decline in new neuron formation may contribute to impaired hippocampal function. We investigated whether a rewarding experience known to stimulate neurogenesis in young adult rats, namely sexual experience, would restore new neuron production and hippocampal function in middle-aged rats. Sexual experience enhanced the number of newly generated neurons in the dentate gyrus with both single and repeated exposures in middle-aged rats. Following continuous long-term exposure to sexual experience, cognitive function was improved. However, when a prolonged withdrawal period was introduced between the final mating experience and behavioral testing, the improvements in cognitive function were lost despite the presence of more new neurons. Taken together, these results suggest that repeated sexual experience can stimulate adult neurogenesis and restore cognitive function in the middle-aged rat as long as the experience persists throughout the testing period. The extent to which changes in adult neurogenesis underlie those in cognition remain unknown." That said, it is worth noting that almost any environmental enrichment produces the same effect for rats as noted by these researchers, which might say more about the insufficiency of the standard laboratory rat environment than about potential ways to boost neurogenesis in the rest of us.

MORE VISCERAL FAT MEANS A GREATER RISK OF INTESTINAL CANCER
Wednesday, March 6, 2013
http://www.fightaging.org/archives/2013/03/more-visceral-fat-means-a-greater-risk-of-intestinal-cancer.php
We know that removing visceral fat extends life in mice - even a drastic measure such as surgery to remove the fat increases mouse life span. Given that mice are little cancer factories, it shouldn't be surprising to see that at least part of this effect on life expectancy stems from reduced incidence of cancer: "There has been some skepticism as to whether obesity per se is a bona fide cancer risk factor, rather than the habits that fuel it, including a poor diet and a sedentary lifestyle. Although those other lifestyle choices play a role, this study unequivocally demonstrates that visceral adiposity is causally linked to intestinal cancer. Prior research has shown that obesity markedly increases the likelihood of being diagnosed with and dying from many cancers. [Researchers] sought to determine if removing visceral fat in mice genetically prone to developing colon cancer might prevent or lessen the development of these tumors. They randomly assigned the mice to one of three groups. Mice in the first group underwent a sham surgery and were allowed to eat an unrestricted "buffet style" diet, for the entirety of the study, which resulted in these mice becoming obese. Those in the second group were also provided an unrestricted diet and became obese, but they had their visceral fat surgically removed at the outset of the study. Mice in the third group also underwent a sham surgery, but were provided only 60 percent of the calories consumed by the other mice in order to reduce their visceral fat by dieting. "Our sham-operated obese mice had the most visceral fat, developed the greatest number of intestinal tumors, and had the worst overall survival. However, mice that had less visceral fat, either by surgical removal or a calorie-restricted diet, had a reduction in the number of intestinal tumors. This was particularly remarkable in the case of our group where visceral fat was surgically removed, because these mice were still obese, they just had very little abdominal fat.""

A "CALCIUM HYPOTHESIS" OF DECLINING VISION WITH AGE
Tuesday, March 5, 2013
http://www.fightaging.org/archives/2013/03/a-calcium-hypothesis-of-declining-vision-with-age.php
Researchers here propose that a mechanism associated with age-related cognitive decline is also involved in the poorly understood general declines in vision that occur with age. From the perspective of SENS and aging as damage, this is exactly the sort of thing we'd expect to be a secondary consequence of one of the fundamental changes that drive aging, such as a build up of aggregates or damage to cell mitochondria. Given the complexities of metabolism and cellular operation, the fastest and most efficient way to prove or disprove that - and many similar propositions - is to implement SENS and fix the underlying damage. "Extensive research in the CA1 region of the rat hippocampus has revealed an age-related increase in neuronal Ca2+ influx though L-type voltage-gated calcium channels (L-VGCCs) that is strongly linked with impaired synaptic plasticity and reduced cognitive function. Diminished visual performance is another important behaviorally-evident functional decline that occurs with aging, beginning in young adulthood, but whose underlying mechanisms are poorly understood. Concurrent declines in neuroretinal function, when measured by electroretinogram (ERG), have also been noted: rod sensitivity and the maximum amplitude of rod responses to light both decrease with age. However, [such] physiological changes were too modest to account for the age-related vision declines. Here, we test an alternative hypothesis: that changes in retinal ion influx via L-VGCCs occur with age, and are linked to visual performance declines. In Long-Evans rats we find a significant age-related increase in ion flux through retinal L-VGCCs in vivo [that] are longitudinally linked with progressive vision declines. Importantly, the degree of retinal Mn2+ uptake early in adulthood significantly predicted later visual contrast sensitivity declines. Furthermore, as in the aging hippocampus, retinal expression of a drug-insensitive L-VGCC isoform (α1D) increased - a pattern confirmed in vivo by an age-related decline in sensitivity to L-VGCC blockade. These data highlight mechanistic similarities between retinal and hippocampal aging, and raise the possibility of new treatment targets for minimizing vision loss during healthy aging."

ON METHIONINE RESTRICTION
Tuesday, March 5, 2013
http://www.fightaging.org/archives/2013/03/on-methionine-restriction.php
Methionine is an essential amino acid, one that we do not manufacture ourselves but must obtain from what we eat. It seems that a large fraction of the benefits of calorie restriction derive from alterations in metabolism that are based on sensing levels of methionine. Here is a review: "Comparative studies indicate that long-lived mammals have low rates of mitochondrial reactive oxygen species production (mtROSp) and oxidative damage in their mitochondrial DNA (mtDNA). Dietary restriction (DR), around 40%, extends the mean and maximum life span of a wide range of species and lowers mtROSp and oxidative damage to mtDNA, which supports the mitochondrial free radical theory of aging (MFRTA). Regarding the dietary factor responsible for the life extension effect of DR, neither carbohydrate nor lipid restriction seem to modify maximum longevity. However protein restriction (PR) and methionine restriction (at least 80% MetR) increase maximum lifespan in rats and mice. Interestingly, only 7 weeks of 40% PR (at least in liver) or 40% MetR (in all the studied organs, heart, brain, liver or kidney) are enough to decrease mtROSp and oxidative damage to mtDNA in rats, whereas neither carbohydrate nor lipid restriction change these parameters. In addition, old rats also conserve the capacity to respond to 7 weeks of 40% MetR with these beneficial changes. Most importantly, 40% MetR, differing from what happens during both 40% DR and 80% MetR, does not decrease growth rate and body size of rats. All the available studies suggest that the decrease in methionine ingestion that occurs during DR is responsible for part of the aging-delaying effect of this intervention likely through the decrease of mtROSp and ensuing DNA damage that it exerts. We conclude that lowering mtROS generation is a conserved mechanism, shared by long-lived species and dietary, protein, and methionine restricted animals, that decreases damage to macromolecules situated near the complex I mtROS generator, especially mtDNA. This would decrease the accumulation rate of somatic mutations in mtDNA and maybe finally also in nuclear DNA."

A REVIEW OF KNOWN LINKS BETWEEN GROWTH HORMONE AND AGING
Monday, March 4, 2013
http://www.fightaging.org/archives/2013/03/a-review-of-known-links-between-growth-hormone-and-aging.php
The longest-lived genetically engineered mice are those in which growth hormone or growth hormone receptors have been diminished or removed entirely. This review looks at some of what is know about the mechanisms involved in this extended life: "Studies in mutant, gene knock-out and transgenic mice have demonstrated that growth hormone (GH) signalling has a major impact on ageing and longevity. Growth hormone-resistant and GH-deficient animals live much longer than their normal siblings, while transgenic mice overexpressing GH are short lived. Actions of GH in juvenile animals appear to be particularly important for life extension and responsible for various phenotypic characteristics of long-lived hypopituitary mutants. Available evidence indicates that reduced GH signalling is linked to extended longevity by multiple interacting mechanisms including increased stress resistance, reduced growth, altered profiles of cytokines produced by the adipose tissue, and various metabolic adjustments such as enhanced insulin sensitivity, increased oxygen consumption (VO2/g) and reduced respiratory quotient. The effects of removing visceral fat indicate that increased levels of adiponectin and reduced levels of pro-inflammatory cytokines in GH-resistant mice are responsible for their increased insulin sensitivity. Increased VO2 apparently represents increased energy expenditure for thermogenesis, because VO2 of mutant and normal mice does not differ at thermoneutral temperature. Recent studies identified GH- and IGF-1-dependent maintenance of bone marrow populations of very small embryonic-like stem cells (VSELs) as another likely mechanism of delayed ageing and increased longevity of GH-deficient and GH-resistant animals. Many of the physiological characteristics of long-lived, GH-related mouse mutants are shared by exceptionally long-lived people and by individuals genetically predisposed to longevity."

CASTING DOUBT ON LATENT REGENERATIVE MECHANISMS IN MAMMALS
Monday, March 4, 2013
http://www.fightaging.org/archives/2013/03/casting-doubt-on-latent-regenerative-mechanisms-in-mammals.php
Demonstrations such as the unusual regenerative capacity of MRL mice have bolstered the idea that we mammals retain the vestiges of an ability to regenerate shared with lower animals such as salamanders - but suppressed or buried in some way. Hence work on deciphering the mechanisms of limb and organ regeneration in a variety of species could lead to the ability to turn on similar regeneration in humans. This work casts doubt on that view, however, suggesting that exceptional regeneration is not an ancient process shared across many species: "Tiny and delicate it may be, but the red spotted newt (Notophthalmus viridescens) has tissue-engineering skills that far surpass the most advanced biotechnology labs. The newt can regenerate lost tissue, including heart muscle, components of its central nervous system and even the lens of its eye. Doctors hope that this skill relies on a basic genetic program that is common - albeit often in latent form - to all animals, including mammals, so that they can harness it in regenerative medicine. Attempts to analyse the genetics of newts in the same way as for humans, mice and flies have so far been hampered by the enormous size of the newt genome, which is ten times larger than our own. [Researchers] therefore looked at the RNA produced when genes are expressed - known as the transcriptome - and used three analytical techniques to compile their data. The team compiled the first catalogue of all the RNA transcripts expressed in N. viridescens, looking at both primary and regenerated tissue in the heart, limbs and eyes of both embryos and larvae. The researchers found more than 120,000 RNA transcripts, of which they estimate 15,000 code for proteins. Of those, 826 were unique to the newt. What is more, several of those sequences were expressed at different levels in regenerated tissue than in primary tissue. [The] findings add to existing evidence that the ability evolved recently, [such as] evidence that regenerating tissue in salamanders express proteins that are not found in other vertebrates. "I no longer believe that there is an ancestral program that is waiting to be reawakened. However, I absolutely do believe it's possible to coax mammal tissues into regenerating to a greater degree with the lessons we learn from newts.""

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Posted 17 March 2013 - 07:26 PM

FIGHT AGING! NEWSLETTER
March 18th 2013

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

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CONTENT

- Scientific Approaches and the Creation of Human Longevity
- Considering the Sirtuin Approach
- Considering the mTOR Approach
- Video: Aubrey de Grey on Defeating Aging
- Discussion
- Latest Headlines from Fight Aging!
    - On Mortality Rates and Life Expectancy
    - Testing Neurons Created From Skin Cells in Primates
    - Malate and Nematode Lifespan
    - Global Futures 2045 Conference in June
    - Calorie Restriction Reduces Levels of Astrogliosis
    - More on Lipid Metabolism and Inherited Longevity
    - On Rapamycin's Detrimental Effects
    - Correlations Between Status and Longevity are Due to Other Factors
    - Being Overweight Harms the Heart Over the Long Term
    - A Different Approach To Biological Replacements for Teeth

SCIENTIFIC APPROACHES AND THE CREATION OF HUMAN LONGEVITY
http://www.fightaging.org/archives/2013/03/a-few-recent-papers-on-human-longevity.php

A great many researchers are presently engaged in amassing data on human longevity. There are the longitudinal studies running for decades, familial studies searching for measures of inheritance in long-term health, the vast statistical epidemiological studies, and behind them all the growing databases of various biological measurements, taken in ever greater detail as the costs of doing so fall rapidly. This is all very interesting, and will ultimately lead to a complete (and very, very complex) vision of how human metabolism runs and alters throughout aging, from the uppermost and more familiar processes all the way down to cellular mechanisms and accrued damage.

But strangely, very little of this is strictly necessary in order to engineer far longer lives. We don't need to know much more than we do already about human biology in order to have a good shot at building functional rejuvenation biotechnologies. The differences between old tissues and young tissues are pretty well enumerated at this time: the remaining lack of knowledge relates to the (many, many) details of the intricate dance of molecular and epigenetic mechanisms involved in moving from young to old. That dance is what the majority of the aging research community - and the majority of funding - is involved in deciphering. But anyone with a bunch of money could short-cut all of that and stomp right down the path to rejuvenation therapies today, if they cared to do it. All that needs to happen is that the known differences between old tissue and young tissue be repaired - it doesn't matter how it happens, so long as you can repair it.

Think of it this way: a man could spend a very long time building the mathematical models needed to show exactly how paint cracks and flakes on a wall. In doing that he might learn a lot about how to create paint that lasts a little longer, or which materials make for longer-lasting painted surfaces. That's a life's labor right there. Or he could just take a day every now and then to sand off the wall and paint it over. This is essentially the same comparison between the relative amounts of labor involved in aging and longevity science - with the note that in this analogy the man needs to create the paint from scratch and chase down a horse and a tree to make the brush.

So longevity science is as much a matter of persuasion as getting the work done. We need to see more funding going to repainting and less to the general theory of decay in painted surfaces. It's very clear what needs to happen, but gathering the necessary large-scale funding for work on SENS-like rejuvenation biotechnology is a work in progress.

CONSIDERING THE SIRTUIN APPROACH
http://www.fightaging.org/archives/2013/03/a-collection-of-sirtuin-research-results.php

Sirtuin research is probably the most overhyped area of present day research into the mechanistic interactions between metabolism, health, and aging - certainly more so than for the calorie restriction studies that it branched from. This is the somewhat inevitable result of more than a billion dollars of capital going into research and development, as funding at that level always generates a bright public relations aura, plus the shills of the "anti-aging" marketplace latching on to something they can use to push new products to the gullible. The bottom line for research into sirtuins is this: (a) it's relevant if you want to learn more about the detailed operation of metabolism, and (b) it's near completely irrelevant if your goal is to live longer in good health.

The press has reacted in their normal clueless way to a recent piece of news from the researchers that first popularized SIRT1; it is essentially a defense of earlier work against the proposition that there were significant artifacts in the data caused by some of the experimental protocol details. There's nothing in this new release to change the overall story, however - that despite a decade and a billion dollars, there's nothing much to see here other than increased understanding of a narrow slice of metabolism. Little in the way of meaningful extension of life in normal rodents, no therapies to even slightly slow aging in humans, considerable dispute over the basic science, etc, etc. Give that much money to SENS research and it'd be a very different story.

This is plain old metabolic science - interesting stuff if you're in that line of work, but not the road to greatly enhanced human longevity. Calorie restriction has a far greater effect on human metabolism, and it's generally accepted by the research community that it only grants a marginal improvement to human life span, even while producing tremendous benefits to health. If it did more we'd certainly know about it; there are plenty of human communities that undertake calorie restriction to various degrees.

The only way that large enhancements to human longevity will happen in our lifetimes is through biotechnologies designed and targeted to repair specific forms of cellular and molecular damage that cause aging. Conveniently, this is a path that is considerably better known and less costly than even marginal attempts to change a very narrow set of mechanisms in the operation of metabolism. Consider that for the money and time spent so far on sirtuins - with no signs of coming to any sort of meaningful result any time soon - most or all of the SENS program to build rejuvenation therapies could be implemented in laboratory mice.

From where I stand, metabolic manipulation of the sort exemplified by sirtuin research is a gargantuan false path for medicine and the biotechnologies of human health. Its chief output is to steer resources away from where they might produce meaningful results in a short enough time frame to matter to those of us reading this now. Even if fabulously successful beyond the wildest dreams of the researchers involved, sirtuin research would do no more than recapitulate some of the effects of calorie restriction - that wouldn't help the old, as slowing aging doesn't help those already harmed by aging, it wouldn't reverse or repair the effects of aging, it wouldn't even be as effective as actual calorie restriction. In no way would any of this add decades of healthy years to life; there is simply no path to that end goal via the likes of Sirtris and similar groups working on sirtuins or other calorie restriction mimetic mechanisms.

CONSIDERING THE MTOR APPROACH
http://www.fightaging.org/archives/2013/03/mtor-is-something-of-a-hot-topic-in-longevity-science.php

The study of mTOR, mechanistic target of rapamycin, in the context of aging and longevity in mammals has been gathering pace and funding in recent years. I expect that there will be a brace of well-funded biotech startups running through the standard, expensive, old-school path to building and commercializing drugs over the next ten years, much akin to what has been happening for suirtuin research - and with just about as little to show for it in the end, I'd imagine, although mTOR is a much better and more proven target for modestly slowing aging than are the sirtuins.

Drugs to slow aging by poking around with metabolism are not the future of longevity science; even if successful, they'll take decades to produce end results, and those end results will be largely useless for people already old. The only future with any future in it for us is SENS research and similar targeted approaches to repairing the damage of aging: ways to produce actual rejuvenation of the old. All the rest is just a distraction, and possibly a lethal one if it keeps on dominating the mainstream of research funding.

There are some quite prolific authors writing papers on the subject of mTOR, many of whom fall into the programmed aging camp. They theorize aging to be an evolved genetic and metabolic program of changes that are beneficial in youth but then run amok to cause damage and dysfunction in old age. This is as opposed to the presently more mainstream view of aging as being caused at root by a stochastic accumulation of cellular and molecular damage that then in turn leads to epigenetic and metabolic changes as our biology tries (and ultimately fails) to cope. Cart, horse, horse, cart: it is a measure of the sheer complexity of the data that the current research community can (more or less) support two completely opposite interpretations of what is actually taking place.

I favor the damage based theories (and hence SENS as a course of research and development). I think it's hard to reconcile programmed aging with the reliability theory view of aging, and the success of reliability theory in general, not to mention the large body of evidence that points toward damage repair strategies like SENS as the best step forward.

VIDEO: AUBREY DE GREY ON DEFEATING AGING
http://www.fightaging.org/archives/2013/03/aubrey-de-grey-defeating-aging.php

Staff at the British Institute of Arts and Ideas have been putting presentation and interview videos up on YouTube of late, presumably to help drum up traffic for their forthcoming festival of philosophy and music. (It is billed as the "world's largest philosophy and music festival", which seems a low bar to be aiming for, for all that it looks to be well assembled as an event and populated by noted speakers). A couple of videos of biogerontologist and longevity science advocate Aubrey de Grey can be found amongst those uploaded recently - such as the one you'll find by following the link above.

DISCUSSION

The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!

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LATEST HEADLINES FROM FIGHT AGING!

ON MORTALITY RATES AND LIFE EXPECTANCY
Friday, March 15, 2013
http://www.fightaging.org/archives/2013/03/on-mortality-rates-and-life-expectancy.php
Here is a piece to act as fuel for people who like to argue policy and don't look much beyond the now. I think this is chiefly interesting for the potential support it gives to lifestyle differences between the genders as a noteworthy contributing cause to the fact that women live longer. Otherwise, it reinforces the point that differences in life expectancy at birth between regions or over time is not all that relevant to the intersection of medicine and aging - more attention should be given to statistics for life expectancy at 50 or 60. "Higher mortality rates among Americans younger than 50 are responsible for much of why life expectancy is lower in the United States than most of the world's most developed nations. The research [found] that excess mortality among Americans younger than 50 accounted for two-thirds of the gap in life expectancy at birth between American males and their counterparts and two-fifths between females and their counterparts in the comparison countries. Most of the excess mortality of those younger than 50 was caused by noncommunicable diseases, including perinatal conditions, such as pregnancy complications and birth trauma, and homicide and unintentional injuries including drug overdose, a fact that she said constitutes a striking finding of the study. "These deaths have flown under the radar until recently. This study shows that they are an important factor in our life expectancy shortfall relative to other countries."" You get further in life by comparing what you have to what is possible, not with what other people have. But relativism of status, circumstances, and possessions is deeply set into the human mind. It's ever a struggle to get people to look beyond what is to see what might be.

TESTING NEURONS CREATED FROM SKIN CELLS IN PRIMATES
Friday, March 15, 2013
http://www.fightaging.org/archives/2013/03/testing-neurons-created-from-skin-cells-in-primates.php
An example of an application of induced pluripotent stem cells moving closer to use in humans. The transplant of new brain cells is a potential treatment for a range of neurodegenerative conditions: "Scientists have transplanted neural cells derived from a monkey's skin into its brain and watched the cells develop into several types of mature brain cells. [After] six months, the cells looked entirely normal, and were only detectable because they initially were tagged with a fluorescent protein. Because the cells were derived from adult cells in each monkey's skin, the experiment is a proof-of-principle for the concept of personalized medicine, where treatments are designed for each individual. And since the skin cells were not "foreign" tissue, there were no signs of immune rejection - potentially a major problem with cell transplants. "When you look at the brain, you cannot tell that it is a graft. Structurally the host brain looks like a normal brain; the graft can only be seen under the fluorescent microscope." The transplanted cells came from induced pluripotent stem cells (iPS cells), which can, like embryonic stem cells, develop into virtually any cell in the body. iPS cells, however, derive from adult cells rather than embryos. In the lab, the iPS cells were converted into neural progenitor cells. These intermediate-stage cells can further specialize into the neurons that carry nerve signals, and the glial cells that perform many support and nutritional functions. This final stage of maturation occurred inside the monkey."

MALATE AND NEMATODE LIFESPAN
Thursday, March 14, 2013
http://www.fightaging.org/archives/2013/03/malate-and-nematode-lifespan.php
The smaller and shorter lived the animal, the easier it is to extend its life in the laboratory. This is in part because more experiments can run at lower cost, but also because it seems that many of the evolved, shared mechanisms for adjusting the pace of aging or degree of tissue maintenance in response to environmental circumstances (e.g. calorie restriction) have a larger effect in shorter-lived species. Any given mechanism for lengthening life span can be triggered or partially triggered or gently influenced in numerous ways. A lot of present research is focused on enumerating these many methods, and then matching them up to the few known underlying mechanisms for lengthening life. So we see research publications like this one: "Although mitochondrial-derived oxygen radicals have been questioned as the main driving force for the aging process, changes in mitochondrial metabolism almost certainly play a role. Dietary restriction (DR), which extends lifespan, also delays the aging-induced electron transport chain dysfunction in rodents. DR increases the NAD/NADH ratio in many tissues, which stimulates mitochondrial tricarboxylic acid (TCA) cycle dehydrogenases that utilize NAD as a cofactor. The increased TCA cycle function likely necessitates increased anaplerosis, important for longevity. Alteration of mitochondrial TCA cycle function influences lifespan in C. elegans. Malate, the tricarboxylic acid (TCA) cycle metabolite, increased lifespan and thermotolerance in the nematode C. elegans. The increased longevity provided by malate addition did not occur in fumarase (fum-1), glyoxylate shunt (gei-7), succinate dehydrogenase flavoprotein (sdha-2), or soluble fumarate reductase F48E8.3 RNAi knockdown worms. Therefore, to increase lifespan, malate must be first converted to fumarate, then fumarate must be reduced to succinate by soluble fumarate reductase and the mitochondrial electron transport chain complex II. Lifespan extension induced by malate depended upon the longevity regulators DAF-16 and SIR-2.1. Malate supplementation did not extend the lifespan of long-lived eat-2 mutant worms, a model of dietary restriction. Malate and fumarate addition increased oxygen consumption, but decreased ATP levels and mitochondrial membrane potential suggesting a mild uncoupling of oxidative phosphorylation. Malate also increased NADPH, NAD, and the NAD/NADH ratio. Fumarate reduction, glyoxylate shunt activity, and mild mitochondrial uncoupling likely contribute to the lifespan extension induced by malate and fumarate by increasing the amount of oxidized NAD and FAD cofactors."

GLOBAL FUTURES 2045 CONFERENCE IN JUNE
Thursday, March 14, 2013
http://www.fightaging.org/archives/2013/03/global-futures-2045-conference-in-june.php
The next conference put on by the 2045 Initiative will be held in mid-June in New York. The initiative is backed by a wealthy Russian businessman and aims to move from biological bodies and minds to machine bodies and minds as rapidly as possible. This is not my favored path to greatly enhanced longevity - largely for reasons of efficiency and speed, as I've outlined in the past - but it is at least promising that the world's high net worth individuals are starting to see that they can do a great deal to change the state of human longevity. The costs of doing so have fallen to the point at which one billionaire could push the research and development community in the right direction by following the standard playbook for encouraging the foundation and growth of a research and development community. Every movement has its quirks, and it remains to be seen where the focus on engineering of human culture and building bridges to religious communities, wrapped into the work on artificial bodies, will take the 2045 initiative. I'd certainly be more comfortable with more of a focus on technology and less on societal engineering involving religion. The latter has a lot of failure modes, amply demonstrated throughout history in many large and small groups: "The second international Global Future 2045 congress will take place on 15-16 June 2013 at the Lincoln Center in New York, and will be focused on discussion of a new evolutionary strategy for humanity aimed at overcoming the 21st century's civilization challenges. The strategy is based on carrying out two revolutions: spiritual and sci-tech. We believe this is the only way to overcome existing crises. At the congress, a vision will be presented for the spiritual transformation of humanity, and new technologies will be demonstrated which are likely to form the basis of the sci-tech revolution. The congress will also showcase our Avatar science mega-project, aimed at accelerating the creation of technologies enabling a gradual transition from our biological bodies to an increasingly advanced artificial carrier of the human self. The first GF2045 congress took place in Moscow in February 2012. Its main goal was a discussion of global threats and opportunities arising from the development of new technologies, and the formulation of recommendations for the realization of the optimal scenario for the future with regard to the expected usage of these technologies. In the world of international science, this was the first time at this level and in this form, that not only the key directions of innovations in the coming decades were examined, but also their ethical and philosophical aspects. The main goals of the 2045 Initiative: the creation and realization of a new strategy for the development of humanity which meets global civilization challenges; the creation of optimale conditions promoting the spiritual enlightenment of humanity; and the realization of a new futuristic reality based on 5 principles: high spirituality, high culture, high ethics, high science and high technologies.

The main science mega-project of the 2045 Initiative aims to create technologies enabling the transfer of a individual's personality to a more advanced non-biological carrier, and extending life, including to the point of immortality. We devote particular attention to enabling the fullest possible dialogue between the world's major spiritual traditions, science and society."

CALORIE RESTRICTION REDUCES LEVELS OF ASTROGLIOSIS
Wednesday, March 13, 2013
http://www.fightaging.org/archives/2013/03/calorie-restriction-reduces-levels-of-astrogliosis.php
Another specific benefit of calorie restriction is enumerated in this primate study, one that suggests a generally lower level of damage to the brain is taking place in calorie restricted individuals. The lack of impact on β-amyloid is interesting, however, given that calorie restriction has been shown to slow near every other measurable aspect of aging: "While moderate calorie restriction (CR) in the absence of malnutrition has been consistently shown to have a systemic, beneficial effect against aging in several animals models, its effect on the brain microstructure in a non-human primate model remains to be studied using post-mortem histopathologic techniques. In the present study, we investigated differences in expression levels of glial fibrillary acid protein (GFAP) and β-amyloid plaque load in the hippocampus and the adjacent cortical areas of 7 Control (ad libitum)-fed and 6 CR male rhesus macaques using immunostaining methods. CR monkeys expressed significantly lower levels (~30% on average) of GFAP than Controls in the CA region of the hippocampus and entorhinal cortex, suggesting a protective effect of CR in limiting astrogliosis. These results recapitulate the neuroprotective effects of CR seen in shorter-lived animal models. There was a significant positive association between age and average amyloid plaque pathology in these animals, but there was no significant difference in amyloid plaque distribution between the two groups. Two of the seven Control animals (28.6%) and one of the six CR animal (16.7%) did not express any amyloid plaques, five of seven Controls (71.4%) and four of six CR animals (66.7%) expressed minimal to moderate amyloid pathology, and one of six CR animals (16.7%) expressed severe amyloid pathology. That CR affects levels of GFAP expression but not amyloid plaque load provides some insight into the means by which CR is beneficial at the microstructural level, potentially by offsetting the increased load of oxidatively damaged proteins, in this non-human primate model of aging."

MORE ON LIPID METABOLISM AND INHERITED LONGEVITY
Wednesday, March 13, 2013
http://www.fightaging.org/archives/2013/03/more-on-lipid-metabolism-and-inherited-longevity.php
Some characteristic differences in lipid metabolism are associated with greater human longevity; this is one of the few markers of an inherited predisposition to longevity that clearly shows up in multiple population studies. Here is more detail on this topic: "Middle aged offspring of nonagenarians, as compared to their spouses (controls) show a favorable lipid metabolism marked by larger LDL particle size in men and lower total triglyceride levels in women. To investigate which specific lipids associate with familial longevity, we explore the plasma lipidome by measuring 128 lipid species [in] 1526 offspring of nonagenarians (59 years ± 6.6) and 675 (59 years ± 7.4) controls from the Leiden Longevity Study. In men, no significant differences were observed between offspring and controls. In women however, nineteen lipid species associated with familial longevity. Female offspring showed higher levels of ether phosphocholine (PC) and sphingomyelin (SM) species (3.5-8.7%) and lower levels of phosphoethanolamine PE (38:6) and long-chain triglycerides (TG) (9.4-12.4%). The association with familial longevity of two ether PC and four SM species was independent of total triglyceride levels. In addition, the longevity-associated lipid profile was characterized by a higher ratio of monounsaturated (MUFA) over polyunsaturated (PUFA) lipid species suggesting that female offspring have a plasma lipidome less prone to oxidative stress. Ether PC and SM species were identified as novel longevity markers in females, independent of total triglycerides levels. Several longevity-associated lipids correlated with a lower risk of hypertension and diabetes in the Leiden Longevity Study cohort. This sex-specific lipid signature marks familial longevity and may suggest a plasma lipidome with a better antioxidant capacity, lower lipid peroxidation and inflammatory precursors, and an efficient beta-oxidation function."

ON RAPAMYCIN'S DETRIMENTAL EFFECTS
Tuesday, March 12, 2013
http://www.fightaging.org/archives/2013/03/on-rapamycins-detrimental-effects.php
Rapamycin extends life in mice via mechanisms that seem at least somewhat complementary to those of calorie restriction, but it isn't the sort of thing you'd want to take haphazardly given the other effects it has. Its primary use in medical practice is as an immunosuppressant, for example. Research teams have made inroads in splitting out the bad from the good, but there's a way to go there yet. "The evolutionarily conserved target of rapamycin (TOR) signaling controls growth, metabolism, and aging. In the first robust demonstration of pharmacologically-induced life extension in mammals, longevity was extended in mice treated with rapamycin, an inhibitor of mechanistic TOR (mTOR). However, detrimental metabolic effects of rapamycin treatment were also reported, presenting a paradox of improved survival despite metabolic impairment. How rapamycin extended lifespan in mice with such paradoxical effects was unclear. Here we show that detrimental effects of rapamycin treatment were only observed during the early stages of treatment. These effects were reversed or diminished in mice treated for 20 weeks, with better metabolic profiles, increased oxygen consumption and ketogenesis, and markedly enhanced insulin sensitivity. Thus, prolonged rapamycin treatment lead to beneficial metabolic alterations, consistent with life extension previously observed. Our findings provide a likely explanation of the "rapamycin paradox" and support the potential causal importance of these metabolic alterations in longevity."

CORRELATIONS BETWEEN STATUS AND LONGEVITY ARE DUE TO OTHER FACTORS
Tuesday, March 12, 2013
http://www.fightaging.org/archives/2013/03/correlations-between-status-and-longevity-are-due-to-other-factors.php
We humans are complex creatures, and variations in our longevity in any given generation can be shown to correlate with all sorts of societal line items: status, wealth, intelligence, education, happiness, and so forth. But what are the mechanisms that create these correlations? Here is a small piece of research to suggest that status, at least, doesn't seem to have a significant and consistent effect in and of itself - that correlation must be based on other related items, such as wealth or intelligence: "Research has long linked high socioeconomic status with better health and lower mortality. But what's remained unclear is whether this association has more to do with access to resources (education, wealth, career opportunity, etc.) or the glow of high social status relative to others. Scholars call the latter "relative deprivation." To tease apart these factors, a team of investigators [studied] Baseball Hall of Fame inductees, Emmy Award winners, and former Presidents and Vice Presidents, comparing each to nominated losers in the same competition or election. The result: There were no consistent advantages for winners. The association between winning and longevity is sometimes positive, sometimes negative, and sometimes nonexistent, though the specifics are revealing. Overall, the results suggest that access to resources and opportunity is more important than relative status. "The relative deprivation theory would predict that losers would consistently be at a disadvantage for health and longevity compared to winners, but this is not what we see." A more likely explanation [is] that the advantages and disadvantages of winning depend on the mix of opportunities and stresses that they bring. "Our findings provide an important correction to an overemphasis on relative deprivation as an explanation of health inequalities. Relative deprivation likely plays some role in health inequalities, but it is not as important as the life circumstances and opportunities that result from one's socioeconomic position.""

BEING OVERWEIGHT HARMS THE HEART OVER THE LONG TERM
Monday, March 11, 2013
http://www.fightaging.org/archives/2013/03/being-overweight-harms-the-heart-over-the-long-term.php
Carrying excess fat tissue for years in youth and mid-life is associated with a greater risk of age-related disease and a shorter life expectancy down the line. An increased level of chronic inflammation is one of the reasons why this is the case, but here is a closer look at another of the mechanisms involved: "Results of this longitudinal study found that people who carry excess weight over their lifetime are much more likely to have increases in left ventricular mass and relative wall thickness - both strong and independent predictors of cardiovascular morbidity and mortality. In this instance, timing is indeed everything; the earlier someone becomes overweight, the greater the increase in the heart's mass later in life. "Being overweight in your 20s can have detrimental effects on the heart 40 years in the future, especially if you keep the weight on over the years. It's probably the wrong attitude to think 'I know I'm overweight now, but I'll lose the weight later' because the longer you spend overweight, the greater the weight of your heart muscle. And we know from other studies that even if we take away or account for high blood pressure, diabetes or other risk factors for heart disease, somebody with a bigger heart muscle is more likely to have a heart attack, die or have other problems, such as stroke." Researchers tracked the body mass index (BMI) of 1,653 men and women at different points in their lives to examine the effects of being overweight on the structure of the heart. BMI is a simple measure of the body's fat using a calculation of weight to height. People who were considered overweight, with a BMI of 25 to 29.9, or obese, with a BMI of 30 or above, had the heaviest hearts. [Few], if any, studies have been able to look at this question over such a long duration. He and his team drew from 44 years of data. Strikingly, the heart was 7 percent heavier for those who were overweight beginning in their 20s compared to those who only became overweight in their 60s."

A DIFFERENT APPROACH TO BIOLOGICAL REPLACEMENTS FOR TEETH
Monday, March 11, 2013
http://www.fightaging.org/archives/2013/03/a-different-approach-to-biological-replacements-for-teeth.php
Tissue engineering of teeth has so far focused on growing new teeth and then implanting them - but you don't necessarily have to produce an exact replacement if you can produce something that works: "Research towards achieving the aim of producing bioengineered teeth - bioteeth - has largely focussed on the generation of immature teeth (teeth primordia) that mimic those in the embryo that can be transplanted as small cell 'pellets' into the adult jaw to develop into functional teeth. Remarkably, despite the very different environments, embryonic teeth primordia can develop normally in the adult mouth and thus if suitable cells can be identified that can be combined in such a way to produce an immature tooth, there is a realistic prospect bioteeth can become a clinical reality. In this new work, the researchers isolated adult human gum tissue from [patients], grew more of it in the lab, and then combined it with the cells of mice that form teeth. By transplanting this combination of cells into mice the researchers were able to grow hybrid human/mouse teeth containing dentine and enamel, as well as viable roots. "Epithelial cells derived from adult human gum tissue are capable of responding to tooth inducing signals from embryonic tooth mesenchyme in an appropriate way to contribute to tooth crown and root formation and give rise to relevant differentiated cell types, following in vitro culture. These easily accessible epithelial cells are thus a realistic source for consideration in human biotooth formation. The next major challenge is to identify a way to culture adult human mesenchymal cells to be tooth-inducing, as at the moment we can only make embryonic mesenchymal cells do this.""

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Posted 24 March 2013 - 07:37 PM

FIGHT AGING! NEWSLETTER
March 25th 2013

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

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CONTENT

- The Fable of the Dragon-Tyrant, Animated
- We Already Live in a Gerontocracy
- In Search of a Useful Scientific Definition of Aging
- Evidence Against the Role of Nuclear DNA Damage in Aging
- Discussion
- Latest Headlines from Fight Aging!
    - A Look at the Aging Liver
    - Comments on Recent Research Relevant to Combating Aging
    - Considering Longevity, Aging, and Medical Science
    - An Update on Trialing Engineered T Cells Against Leukemia
    - Further Investigation of Deer Antlers
    - A Possibly Important Finding in Alzheimer's Research
    - Publicity for the 2045 Initiative
    - An Interview With David Ettinger
    - A Look at Halting or Reversing Thymic Involution
    - A Review on the Topic of Microglia in Aging

THE FABLE OF THE DRAGON-TYRANT, ANIMATED
http://www.fightaging.org/archives/2013/03/an-animated-fable-of-the-dragon-tyrant.php

Nick Bostrom's Fable of the Dragon-Tyrant is a noted modern morality tale, written to highlight our acceptance of death by aging, and more importantly our grand, widespread failure to work towards building therapies to treat aging. Even though the research community now knows enough to achieve that goal, and even though biotechnology is in the midst of an unprecedented revolution in capacity and capabilities, research aimed at producing human rejuvenation is hardly funded at all in comparison to other more prosaic fields.

Further, if asked, most people gladly declare that they have no interest in living longer or treating aging as a disease to be cured - despite the fact that they would no doubt be among the masses taking advantage of rejuvenation therapies were those treatments available, just as they now take advantage of modern medicine unavailable to their ancestors. So we march towards death and suffering, doing next to nothing about this avoidable fate. It is this sort of everyday madness that inspires the writing of fables.

You might recall that a couple of years back there was some talk of animating the Fable of the Dragon-Tyrant. This was generally agreed to be a good idea. I'm pleased to note that someone actually went ahead and did it. Follow the link above to watch the animation.

WE ALREADY LIVE IN A GERONTOCRACY
http://www.fightaging.org/archives/2013/03/we-already-live-in-a-gerontocracy.php

Gerontocracy: government by a council of elders, or government by old people. There are many knee-jerk reactions to the prospect of greatly increased healthy human life spans, most based on mistaken beliefs regarding the technologies needed, or mistaken beliefs regarding the way the world actually works - economics, human action, incentives. Some people believe that longer lives will result in stagnation, which is actually one of the more ridiculous and improbably outcomes once you start to pick it apart in any detail. Human society is restless and changeable on timescales far shorter than current lifespans, and the reasons why are rooted in day to day human nature. Our ambitions operate on a horizon of a few years, and that wouldn't change all that much were we to live for centuries. We are driven to influence the world today, now, regardless of the years that lie ahead of us. So the fashions of this year are gone by the next. The idols of popular culture rise and fall with rapidity. The political and business leaders of this decade are gone in the next, displaced by peers. Even corruption and revolution on a grand scale are usually only a matter of a few decades, not lifetimes.

Nonetheless, rationality rarely prevails in knee-jerk reactions - so folk think of stagnation, even in the midst of this boundlessly energetic society we live in, packed wall to wall with constant, ongoing change. A subset of these beliefs on human longevity and stagnation involve the nebulous fear of a future gerontocracy, the rise of a self-perpetuating ruling elite of ageless individuals. Funnily, this is often voiced by people who are, unlike myself, perfectly comfortable with today's Western governments. I say funnily because I have to ask: are not our present societies already gerontocracies? Isn't any civilized society a gerontocracy? Who has had the most time to gather connections, a network, and make good use of them? The old. Who has had the most time to gather resources and invest them? The old. Who has had to most time to become truly talented and sought after? The old. Who has had the most time to work their way through a social hierarchy to challenge its existing leaders? The old. Where then will the elite and the leaders tend to arise? From the old.

Take a look at who just runs and influences companies, governments, knitting circles, successful non-profit initiatives, extended families, and so on and so forth for every human endeavor. Young leaders exist, but they are a minority among the ranks of the old. This is the natural state of affairs for any society that possesses enough technology to make thought and craft more important than strength and vigor.

All that is terrible in our present societies lies in the growing centralization of power, not the chronological age of those eagerly engaged in furthering the road to serfdom and empire. Even as power is centralized, there is still a year by year turnover of figures - even in the most defensible and corruptly secure positions of power and influence. They are largely kicked out by some combination of their peers and the mob in the sort of political anarchy that exists at the top, above the laws made for the little people. It is the rare individual who can stick it out long enough to be removed by the infirmities of age, even now, in this age of human lives that are all too brief in comparison to what is to come.

But back to the point. We live in a gerontocracy, and so did most of our ancestors. Yet change still happens just as rapidly as in past centuries when fewer people lived into later life in the sort of good shape they can manage today. Fear of some sort of comic-book gerontocracy emerging in the future seems, frankly, somewhat silly. The historical record shows that people at the top are not all that good at staying at the top for extended periods of time. There are always outliers, but they are rare in comparison to the vast majority of leaders and the famous who are just part of the churn, coming and going, displaced and quickly forgotten once their few years are done. The top of a pyramid is a challenging place to stand.

IN SEARCH OF A USEFUL SCIENTIFIC DEFINITION OF AGING
>http://www.fightaging.org/archives/2013/03/in-search-of-a-useful-scientific-definition-for-aging.php

Commentary from Aubrey de Grey on the many definitions of aging and their consequences: "Surely everyone who studies the biology of aging fundamentally agrees on what it is they are studying, even if they may prefer somewhat different terminology to define it? I'm afraid you'd be wrong. Disagreement within the field about what aging really is and is not is very far from purely semantic, and the substance of those disagreements leads to profound differences of opinions concerning both what research gerontologists should prioritise and how they should communicate their work to others.

"First: is aging a disease? Some gerontologists will just tell you "No, it is separate from age-related diseases". Some will say "No, but it is a risk factor for age-related diseases". Some will say "No, it is the set of precursors of the age-related diseases". Some will say "Yes, it is the set of precursors of the age-related diseases"! Self-evidently, whether X is a Y depends not only on the definition of X but also on the definition of Y, so one might excuse this chaos on the basis of a failure to agree on what is and is not a disease - and there is indeed no such agreement. But it gets worse.

"Is aging a thing that is amenable, in principle, to medical intervention? Not if you believe the protestations of such eminent gerontologists as Bruce Carnes and Jay Olshansky, who in a recent paper critiquing (I employ classic British understatement in my choice of words here) various colleagues' work made, in spite of reviewers' efforts to educate them, the assertion that "What Wilmoth fails to acknowledge is that in order to reduce death rates at advanced ages to zero or close to it, our biology would need to be modified" (my emphasis). This sort of language, without stating explicitly that medicine can never maintain the body in a state of health so youthful that death rates will be vastly lower than today, unequivocally seeks to convey that view. So, do other gerontologists agree? Indeed they do not: if any evidence were needed, I may merely cite the fact that almost every mainstream conference on the biology of aging these days has a subtitle referring to delaying or even reversing aging.

"Finally, is aging even a bad thing? At least here we find broad consensus among biogerontologists - those who study the biology of aging (though there are a few exceptions). But the same does not apply to all gerontologists: those whose field is more on the clinical, or the sociological, side tend to be among the most viciously and vocally opposed to any talk (let alone action) concerning actually doing anything about aging. As an example, a very senior (and, I am afraid to say, highly influential) clinical gerontologist from Canada recently wrote to me as follows: "I do not wish in any way shape or form to have my name associated with anti-aging medicine, regenerative or restorative medicine or some such". No kidding. I will be interested to discover, at some point, whether she is willing to defend that view publicly.

"It should by now be apparent that there is a bit of a problem. Let me emphasise, however, just how much of a problem. At present, translational biogerontology (alternatively, biomedical gerontology) commands an absolutely minuscule proportion of the medical research budget of any industrialised nation. Why? Simply because the idea that postponing aging is a feasible and valuable goal, both socially and economically, has failed - despite the best efforts of many biogerontologists over many decades - to gain any significant traction among funding bodies. I contend that gerontologists' muddled thinking outlined above concerning what aging really is is actually the number one reason for this failure."

EVIDENCE AGAINST THE ROLE OF NUCLEAR DNA DAMAGE IN AGING
http://www.fightaging.org/archives/2013/03/evidence-against-the-role-of-nuclear-dna-damage-in-aging.php

n some circles within the aging research community it is taken as read that accumulating damage to nuclear DNA - the DNA that resides in the nucleus of your cells - contributes to degenerative aging, most likely by causing cellular maintenance and other programs to run awry to an ever increasing degree. The nucleus of the cell is well protected, and equipped with extremely efficient DNA repair mechanisms, but nonetheless damage accumulates across the years. Being alive necessarily involves the generation of reactive chemical compounds, and sooner or later some of them run into the structure of DNA within a cell and react with it. The processes of DNA repair, while ever watchful, slip up once in a while and fail to fix the resulting breakage. Every cell bears its load of unrepaired mutations.

This sort of ongoing stochastic damage is certainly a contributing cause of cancer: the more mutations you suffer, the greater the chance that one or more of them manage to alter cellular programming in just the right way to create a cancerous cell, readily to act as the seed of a malignant neoplasm. That's just a numbers game - you can be unlucky and suffer cancer young, but you are far more likely to suffer cancer later in life.

But is nuclear DNA damage a cause of general degenerative aging? Is it actually a contributing cause of frailty, failing tissue maintenance, failing organs, and so forth? The point can be argued; Aubrey de Grey puts forward the position that the levels of nuclear DNA damage experienced don't rise to producing any significant effect outside of cancer risk over a human lifetime. If we live far longer than our ancestors, as we hope we might, this damage will probably become something that has to be dealt with at some point - perhaps via swarms of adaptive medical nanorobots akin to the chromallocytes envisaged by Robert Freitas.

Recent research adds weight to the suggestion that nuclear DNA damage is not a cause of aging: "Here, we quantified DNA damage in liver and brain of both normal and prematurely aging, DNA repair defective mice. The results indicate a marginal, but statistically significant, increase of spontaneous DNA damage with age in normal mouse liver but not in brain. Increased levels of DNA damage were not observed in the DNA repair defective mice. We also show that oxidative lesions do not increase with age. These results indicate that neither normal nor premature aging is accompanied by a dramatic increase in DNA damage. This suggests that factors other than DNA damage per se, e.g., cellular responses to DNA damage, are responsible for the aging phenotype in mice."

DISCUSSION

The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!

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LATEST HEADLINES FROM FIGHT AGING!

A LOOK AT THE AGING LIVER
Friday, March 22, 2013
http://www.fightaging.org/archives/2013/03/a-look-at-the-aging-liver.php
This paper examines some aspects of aging in the liver, giving a general review in the course of getting to a discussion on immune system changes that occur in aging and their influence on the liver. Note the importance of a buildup of unwanted protein byproducts inside liver cells, something that occurs due to the progressive failure of cellular housekeeping components known as lysosomes. You might recall that researchers reversed aspects of liver aging in mice a few years back by boosting lysosomal activity, so as to counteract some of the usual decline. "Although the human liver is not unscathed by the process of aging, the changes it undergoes are minor compared with other organ systems. It has been ascertained that there are no liver diseases specific to advanced age. However, the clinical course and management of liver diseases in the elderly may differ in several aspects from those of younger adults. Human and experimental studies suggest that, in comparison with other organs, the liver ages fairly well. Aging is however associated with a variety of morphological changes in the liver, but their underlying mechanisms are still unclear. The liver progressively shrinks by 20-40% during the course of a human life, and there is a concomitant age-related decrease in liver volume. The classic gross appearance of the liver in the elderly is known as "brown atrophy", and the brown is due to an accumulation of highly oxidized insoluble proteins, known as lipofuscin, stored into hepatocytes. These accumulations of highly cross-linked protein are thought to relate to chronic oxidative stress and a failure to degrade damaged and denatured proteins. Increasing evidence suggests that lipofuscin interferes with complex cellular pathways. One of the most important age-related changes in liver function observed in animal models is a significant decrease in regenerative capacity of the liver, but not in the capacity to restore the organ to its original volume. [It] has also been shown that aging is associated with multiple changes in. Elderly humans secrete less bile acid, have increased biliary cholesterol levels, and show an increased oxidative stress that is mainly attributable to a reduced capacity to eliminate metabolically generated superoxide radicals as efficiently as before. The reduction in hepatic blood flow during aging reduces the metabolism of rapidly cleared drugs. Aging of the liver is also associated with impaired metabolism of drugs, adverse drug interactions, and susceptibility to toxins."

COMMENTS ON RECENT RESEARCH RELEVANT TO COMBATING AGING
Friday, March 22, 2013
http://www.fightaging.org/archives/2013/03/comments-on-recent-research-relevant-to-combating-aging.php
Commentary on various recently published research relevant to the SENS view of biotechnology to repair and reverse aging appears as an occasional feature at the journal Rejuvenation Research. The latest is open access, so take a look at the PDF format paper, containing commentaries such as this one on a method of wrapping enzymes in polymer nanocapsules to ensure their delivery to specific locations within cells or the body: "The accumulation of recalcitrant waste substances in cells' lysosomes is implicated in a wide spectrum of aging-related diseases, including atherosclerosis, age-related macular degeneration (AMD), and many others. Being one of the clearest examples of the build-up of "junk" in aging bodies, it is expected that means to degrade lysosomal waste will be among the first rejuvenation biotechnologies to reach clinical application. Indeed, the required development time before an effective therapy can be deployed is expected to be so brief that SENS Research Foundation devotes a substantial portion of its budget to identifying and refining enzymes for just this purpose. However, this tight schedule poses a specific problem; it is quite probable that hydrolases effective, for example, against 7-ketocholesterol (the dominant "junk" molecule in atherosclerotic plaque) or A2E18 (predominant in AMD) will be ready for clinical use before safe and effective somatic gene therapy becomes available. It will therefore be necessary to introduce these garbage-clearing enzymes into patients directly, rather than by genetically engineering the recipient's cells to produce them - an approach termed enzyme replacement therapy, currently in widespread clinical use to treat congenital lysosomal disorders. Of course, enzymes introduced into the body by such methods cannot be replaced once degraded (a particularly rapid fate in the harsh conditions of the lysosome), necessitating regular infusions to maintain their function. The polymer-coating method described in this study enhances the hardiness of the enzymes thus treated, and might be reasonably expected to thus appreciably reduce the required frequency of reintroduction, and/or minimise the dosages required (and hence any side-effects)."

CONSIDERING LONGEVITY, AGING, AND MEDICAL SCIENCE
Thursday, March 21, 2013
http://www.fightaging.org/archives/2013/03/considering-longevity-aging-and-medical-science.php
An open access review on the topic of aging and longevity, largely focused on mainstream work aimed at producing ways to gently slow aging by metabolic manipulation: "Aging drives disease. Nearly every major killer in developed countries shares a common feature: your risk of getting the disease increases dramatically as you get older. For example, the likelihood of being diagnosed with Alzheimer's disease doubles every five years after the age of 65. A similar kind of relationship can be seen for most types of cancer, heart disease, diabetes, kidney disease, and many others. What is it about getting older that simultaneously increases risk for all of these disorders? Are there common molecular changes that cause an organism to switch from youthful and healthy to aged and infirm? Can we intervene in this process to do something about it? These are some of the big questions that scientists who study the biology of aging are interested in answering. The perspective that most age-related disorders share a common underlying biology is a departure from traditional biomedical science, one that potentially offers a more powerful approach towards improving human health. Rather than focus on curing the individual disease, interventions that target the molecular processes of aging can simultaneously delay the onset and progression of most age-related disorders. Such an intervention is predicted to have a much larger effect on life expectancy than can be attained by treating individual diseases. This is because even if one disease is cured, the relationship between age and all the other disorders of aging still holds. For example, it has been estimated that curing cancer will lead to only a 3-5 year increase in survival for an average 50 year-old woman, while slowing aging to an extent that is routine in laboratory organisms has about a 5-10-fold greater impact on life expectancy. Importantly, these added years from slowing aging are spent largely free from chronic disease and disability, while the relatively small gains in survival by curing cancer (or any other individual disease of aging) are still associated with the inevitable age-related declines in function of every other bodily system. This concept of extending the period of life spent free from chronic disability and disease, referred to as healthspan, is a critically important idea in the field of aging-related research."

AN UPDATE ON TRIALING ENGINEERED T CELLS AGAINST LEUKEMIA
Thursday, March 21, 2013
http://www.fightaging.org/archives/2013/03/an-update-on-trialing-engineered-t-cells-against-leukemia.php
Following on from research noted last year: "Genetically engineered immune cells can drive an aggressive type of leukaemia into retreat, a small clinical trial suggests. The results of the trial - done in five patients with acute lymphoblastic leukaemia - [represent] the latest success for a 'fringe' therapy in which a type of immune cell called T cells are extracted from a patient, genetically modified, and then reinfused back. In this case, the T cells were engineered to express a receptor for a protein on other immune cells, known as B cells, found in both healthy and cancerous tissue. "All of our patients very rapidly cleared the tumour. The treatment worked much faster than we thought." The next step [is] to move the technique out of the 'boutique' academic cancer centres that developed it and into multicentre clinical trials. "What needs to be done is to convince oncologists and cancer biologists that this new kind of immunotherapy can work." [A researcher] remembers the day that he had to tell one of the patients in the trial that the weeks of high-dose chemotherapy the 58-year-old man had endured had not worked after all. "It was painful to have that conversation. He tells me now it was the worst news he has ever heard in his life." Another month in the hospital on intensive chemotherapy drugs did nothing to help. By the time the man started the trial, 70% of his bone marrow was tumour. [Researchers] then extracted T cells from the patient and engineered them to express a 'chimeric antigen receptor', or CAR, that would target cells expressing a protein called CD19. Because CD19 is found on both healthy and cancerous B cells, the engineered T cells were unable to discriminate between the two. However, patients can live without B cells. By two weeks after the procedure, the patient was showing signs of improvement. The treatment had driven his cancer into remission - as it did for the other four patients in the trial - so he became eligible for a bone-marrow transplant. A hundred days later, he is doing well. Four of the five patients were well enough to receive transplants; the remaining patient relapsed and was ineligible."

FURTHER INVESTIGATION OF DEER ANTLERS
Wednesday, March 20, 2013
http://www.fightaging.org/archives/2013/03/further-investigation-of-deer-antlers.php
One lesser branch of regenerative medicine is involved in searching the animal kingdom for examples of potent regeneration and seeking to understand the mechanisms involved. For example, there is the quest to discover whether the potential for salamander-like organ and limb regeneration, observed in many lower species, lies dormant in mammals by virtue of being an ancient process, evolved long ago and shared across most species. The jury is still out on that question - more work is needed. Searching for exceptional regeneration in mammals is also a viable strategy - there are fewer instances, but the thinking is that whatever mechanisms are involved would be easier to introduce to humans. Deer antlers are one of the better known examples, and here researchers dig into some the cellular biochemistry involved. This is a small start; there are actually very few researchers looking at deer in this way, probably fewer than are, say, working with regeneration in salamanders or zebrafish: "A team of researchers [have] reported finding evidence that deer antlers - unique in that they regenerate annually - contain multipotent stem cells that could be useful for tissue regeneration in veterinary medicine. "We successfully isolated and characterized antler tissue-derived multipotent stem cells and confirmed that the isolated cells are self-renewing and can differentiate into multiple lineages. Using optimized culture conditions, deer antler displayed vigorous cell proliferation." Deer antler is of interest, said the researchers, "because antlers are very peculiar organs in that they are lost and re-grown annually....a rare example of a completely regenerating organ in mammals." According to the researchers, they subjected deer antler to differentiation assays for osteogenic (bone), adipogenic (fat) and chondrogenic (cartilage) lineages under culture conditions specific for each lineage to confirm the multi-lineage differentiation ability of antler multipotent stem cells. They concluded that deer antler tissue might be a "valuable source of stem cells" that could "be a potentially useful source of regenerative therapeutics in veterinary science." The researchers noted that the development of deer-specific antibodies "is essential to confirm the identification of antler multipotent stem cells". They specifically noted that injury to wild animals, including deer, might be treated using deer antler derived cells. They also pointed out that studies involving the use of horse stem cells have found clinical application of equine-derived stem cells."

A POSSIBLY IMPORTANT FINDING IN ALZHEIMER'S RESEARCH
Wednesday, March 20, 2013
http://www.fightaging.org/archives/2013/03/a-possibly-important-finding-in-alzheimers-research.php
This has the look of something that might lead to an intermediary therapy for Alzheimer's disease, one that allows patients to better function despite beta amyloid build up - but it will be compensatory only, and won't solve the underlying damage and dysfunction of aging that causes beta amyloid to accumulate in the first place. "The scientific community so far has widely accepted that Alzheimer's disease is caused by the accumulation of a peptide called Amyloid beta. When Amyloid beta is applied to neurons, neuronal morphology becomes abnormal and synaptic function is impaired. However, how Amyloid beta causes dysfunction is unknown. [New] research indicates that the presence of Amyloid beta triggers increased levels of a signaling protein, called centaurin alpha 1 (CentA1), that appears to cause neuronal dysfunction - a potentially groundbreaking discovery that uncovers an important intermediary step in the progression of the disease. As part of the research, the scientists were able to identify CentA1 and measure its negative effects on neurons. Utilizing an RNA silencing technique, they turned down the cellular production of CentA1, and showed that affected neurons, exposed to Amyloid beta and exhibiting Alzheimer's related symptoms, returned to normal morphology and synaptic function, even with the continued presence of Amyloid beta. They further found that increased CentA1 activates a series of proteins, and these proteins form a signaling pathway from CentA1 to neuronal dysfunction. Thus, inhibiting other proteins in the pathway also "cured" affected neurons. The initial tests reported were conducted on rat brain slices. [Researchers have] already started to expand their studies to mouse models of Alzheimer's disease and preliminary experiments show promising results."

PUBLICITY FOR THE 2045 INITIATIVE
Tuesday, March 19, 2013
http://www.fightaging.org/archives/2013/03/publicity-for-the-2045-initiative.php
Some press for the 2045 Initiative: " Russian multi-millionaire is targeting the business community to raise money to fund a project that aims to make immortality a reality by 2045. It may sound like something straight out of a science fiction novel, but Dmitry Itskov, a 35-year-old media mogul, is seeking investors to fund research for technology that will make eternal life possible by transferring human consciousness in an artificial form to avatars (robotic bodies). Itskov is the founder of Initiative 2045, a non-profit organization focused on creating an international research center where scientists will research and develop the technologies to make eternal life possible. Last year, Itskov wrote a public letter to individuals on Forbes billionaires list asking them to invest in his project. While Itskov did not receive any public responses, he did accomplish his goal of getting word out about the project and he is continually in talks with wealthy individuals about his project, he said. "The goal was to get the public's attention," Itskov said. "I do communicate with some of the richest people in the world, but I can't share who they are." This summer, Itskov will make a pitch to not only to the world's most wealthy individuals, but the entire business community, to invest in his project as well as research and development in areas that help further his cause. In June, Itskov's organization will be hosting the second annual Global Future 2045 World Congress, an event where leading scientists, technologists and entrepreneurs will gather to discuss and demonstrate new technologies that are paving the way for life expansion."

AN INTERVIEW WITH DAVID ETTINGER
Tuesday, March 19, 2013
http://www.fightaging.org/archives/2013/03/an-interview-with-david-ettinger.php
An interview on the topic of cryonics, the low-temperature preservation of the body and brain following death. This aims to preserve the brain's fine structure - where the data of the mind is stored - so as to enable a chance at the development of future technologies to restore that individual to life: "Cryonics is based on a bet about the future, that technology will advance. A bet that we think is very sound, but is it evidence-based, it's not. Some people say, well do you have faith in cryonics? No, I just look at history and think this is a good bet. It's not certain by any means, but it's the best alternative. And that's how [Robert Ettinger] approached things. I mean, he wrote some articles about probability theory and what he called the probability of rescue. So cryonics was always from the first, scientifically based, and though there were people at the time who said this isn't going to happen, my father always challenged them and said, what's your evidence? Is the damage [caused by freezing] so limited that you can freeze and revive a person today? It is not. I mean, there is too much damage that we cannot reverse currently for that, but that's part of why you need more time, but people frozen have the time. [Robert Ettinger] said that what some people want, will not be satisfied. Some people will not be satisfied until someone is frozen, and revived, and lives forever. Well, we can't wait for them. The quicker you do it, the less damage will occur. And the process begins with cooling of the body, and especially the head, sometimes while continuing to pump the blood so that oxygenated blood flows to the brain and that limits the damage in the meantime. The next step is, and the cooling goes through several steps, starting with ice, then the body is perfused with cryoprotective agents to protect against damage in the freezing. You know, the next stage is dry ice and then liquid nitrogen vapors and ultimately liquid nitrogen, and the entire process takes a couple of days, takes a few days, really, to be finished."

A LOOK AT HALTING OR REVERSING THYMIC INVOLUTION
Monday, March 18, 2013
http://www.fightaging.org/archives/2013/03/a-look-at-halting-or-reversing-thymic-involution.php
Left to its own devices, your immune system supports a fairly fixed upper limit of T-cells, and the fraction of those cells that can respond effectively to new threats, or patrol the body to destroy senescent or precancerous cells, declines with age. On the one side ever more T-cells become specialized in futile attempts to deal with persistent but otherwise not terribly threatening viruses such as CMV, and thus become useless for other activities. On the other side, the new supply of T-cells dwindles to nothing as the thymus atrophies - a process called thymic involution, something that happens comparatively early in life. So a range of possible approaches could be taken to restore a sufficient number of aggressive T-cells to the body. Using stem cell technologies to create large numbers of a patient's own T-cells and then infuse them periodically, for example - that's possible today, but only being tried in trials for specific named diseases, as is usually the case for things that might be beneficial to all old people. Hopefully overseas clinics and medical tourism will pick up the slack. Other approaches involve destroying the unneeded specialized cells to free up immune system capacity, or trying to increase the supply of new immune cells by at least partially regenerating and restoring the thymus. "The thymus is a thumb-sized organ just above the sternum where our immune cells are trained to recognize self from other. It is fully developed by the time we are 10 years old, but after that it begins gradually to shrink. By age 25, it has already lost 30% of its mass, and by age 60 it is less than half its peak size. There is evidence that this is related to the immune decline that contributes so much to growing mortality risk with age, and that reversing that decline might lead to longer, healthier lives. Research on reversal of thymic [degeneration] is a backwater of medical science. If this is an opportunity for major gains in life expectancy, then it is a neglected opportunity that has attracted little interest or funding. Based on evolutionary arguments, the general attitude seems to be that if the thymus shrinks over a lifetime, then it must not be much needed; or, conversely, that a Law of Nature assures us that any therapy to maintain its function must necessarily have dangerous side-effects that outweigh the benefits. [But] this is ideology, a misplaced faith in general theory over explicit experimental results. Reality in the lab appears to be that: "Thymic involution [seems] to provide no obvious benefits in humans that would outweigh the benefits of [its] elimination once the hazards associated with such issues as insulin-like signaling can be set aside.""

A REVIEW ON THE TOPIC OF MICROGLIA IN AGING
Monday, March 18, 2013
http://www.fightaging.org/archives/2013/03/a-review-on-the-topic-of-microglia-in-aging.php
Microglia are immune cells of the central nervous system (CNS). As is the case for the rest of the immune system, they are involved in the rising levels of chronic inflammation that accompany aging, inflammation that contributes to the development of neurodegenerative disease. Here is an open access review on this topic and the prospects for intervention: "Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and age-related macular degeneration (AMD), share two characteristics in common: (1) a disease prevalence that increases markedly with advancing age, and (2) neuroinflammatory changes in which microglia, the primary resident immune cell of the CNS, feature prominently. These characteristics have led to the hypothesis that pathogenic mechanisms underlying age-related neurodegenerative disease involve aging changes in microglia. If correct, targeting features of microglial senescence may constitute a feasible therapeutic strategy. This review explores this hypothesis and its implications by considering the current knowledge on how microglia undergo change during aging and how the emergence of these aging phenotypes relate to significant alterations in microglial function. Evidence and theories on cellular mechanisms implicated in driving senescence in microglia are reviewed, as are "rejuvenative" measures and strategies that aim to reverse or ameliorate the aging microglial phenotype. Understanding and controlling microglial aging may represent an opportunity for elucidating disease mechanisms and for formulating novel therapies."

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Posted 31 March 2013 - 06:30 PM

FIGHT AGING! NEWSLETTER
April 1st 2013

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

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CONTENT

- Why Prioritize SENS Research for Human Longevity?
- Induced Pluripotency Removes Some Markers of Cell Age
- A Late Tissue Engineering Year in Review for 2012
- A Surprising Lack of Age-Related Degeneration in Muscles
- Discussion
- Latest Headlines from Fight Aging!
- Metformin May Act to Reduce Chronic Inflammation
- More on CD47 as a Potentially Broad Cancer Therapy Target
- On Nanoscale-Featured Scaffolds in Regenerative Medicine
- An Investigation into Rates of Aging and Heart Disease Risk
- Amniotic Fluid Stem Cells Spur Repair of Gut Damage
- Building Functional Ovarian Tissue
- On Autophagy in Stem Cells
- An Analysis of Mitochondrial Dysfunction in Aging and Disease
- A Popular Science Article on Organ Engineering
- SENS6 Conference Registration Open

WHY PRIORITIZE SENS RESEARCH FOR HUMAN LONGEVITY?
http://www.fightaging.org/archives/2013/03/why-prioritize-sens-research-for-human-longevity.php

Why do I vocally support rejuvenation research based on the Strategies for Engineered Negligible Senescence (SENS) over other forms of longevity science? Why do I hold the view that SENS and SENS-like research should be prioritized and massively funded? The short answer to this question is that SENS-derived medical biotechnology has a much greater expected utility - it will most likely produce far better outcomes, and at a lower cost - than other presently ongoing lines of research into creating greater human longevity.

But firstly, what is SENS? It is more an umbrella collection of categories than a specific program, though it is the case that narrowly focused SENS research initiatives run under the auspices of the SENS Research Foundation. On the science side of the house, SENS is a synthesis of existing knowledge from the broad mainstream position regarding aging and the diseases of aging: that aging is caused by a stochastic accumulation of damage at the level of cells and protein machinery in and around these cells. SENS is a proposal, based on recent decades of research, as to which of the identified forms of damage and change in old tissues are fundamental - i.e. which are direct byproducts of metabolic operation rather than cascading effects of other fundamental damage. On the development side of the house, SENS pulls together work from many subfields of medical research to show that there are clear and well-defined ways to produce therapies that can repair, reverse, or make irrelevant these fundamental forms of biological damage associated with aging.

(You can read about the various forms of low-level damage that cause aging at the SENS Research Foundation website and elsewhere. This list includes: mitochondrial DNA mutations; buildup of resilient waste products inside and around cells; growing numbers of senescent and other malfunctioning cells; loss of stem cells; and a few others).

Present arguments within the mainstream of aging research are largely over the relative importance of damage type A versus damage type B, and how exactly the extremely complex interaction of damage with metabolism progresses - but not what that damage actually is. A large fraction of modern funding for aging research goes towards building a greater understanding this progression; certainly more than goes towards actually doing anything about it. Here is the thing, however: while understanding the dynamics of damage in aging is very much a work in progress, the damage itself is well known. The research community can accurately enumerate the differences between old tissue and young tissue, or an old cell and a young cell - and it has been a good number of years since anything new was added to that list.

If you can repair the cellular damage that causes aging, it doesn't matter how it happens or how it affects the organism when it's there. This is the important realization for SENS - that much of the ongoing work of the aging research community is largely irrelevant if the goal is to get to human rejuvenation as rapidly as possible. Enough is already known of the likely causes of aging to have a reasonable expectation of being able to produce laboratory demonstrations of rejuvenation in animal models within a decade or two, given large-scale funding.

Expected value drives human endeavor. What path ahead do we expect to produce the greatest gain? In longevity science the investment is concretely measured in money and time, and we might think of the expected value in terms of years of healthy life added by the resulting therapies. The cost of these therapies really isn't much of a factor - all major medical procedures and other therapies tend to converge to similar costs over time, based on their category: consider a surgery versus an infusion versus a course of pills, for example, where it's fairly obvious that the pricing derives from how much skilled labor is involved and how much care the patient requires as a direct result of the process.

On the input side, there are estimates for the cost in time and money to implement SENS therapies for laboratory mice. For the sake of keeping things simple, I'll note that these oscillate around the figures of a billion dollars and ten years for the crash program of fully-funded research. A billion dollars is about the yearly budget of the NIA these days, give or take, which might be a third of all research funding directed towards aging - by some estimates, anyway, though this is a very hard figure to verify in any way. It's by no means certain the that the general one third/two thirds split between government and private research funding extends to aging research.

On the output side, early SENS implementations would be expected to take an old mouse and double its remaining life expectancy - e.g. produce actual rejuvenation, actual repair and reversal of the low-level damage that causes aging, with repeated applications at intervals producing diminishing but still measurable further gains. This is the thing about a rejuvenation therapy that works; you can keep on applying it to sweep up newly accruing damage.

So what other longevity science do we have to compare against? The only large running programs are those that have grown out of the search for calorie restriction mimetic drugs. So there is the past decade or so of research into surtuins, and there is growing interest in mTOR and rapamycin analogs that looks to be more of the same, but slightly better (though that is a low bar to clear).

In the case of sirtuins, money has certainly flowed. Sirtris itself sold for ~$700 million, and it's probably not unreasonable to suggest that a billion dollars has gone into broader sirtuin-related research and development over the past decade. What does the research community have to show for that? Basically nothing other than an increased understanding of some aspects of metabolism relating to calorie restriction and other adaptations that alter life span in response to environmental circumstances. Certainly no mice living longer in widely replicated studies as is the case for mTOR and rapamycin - the sirtuin results and underlying science are still much debated, much in dispute.

The historical ratio of dollars to results for any sort of way to manipulate our metabolism to slow aging is exceedingly poor. The thing is, this ratio shouldn't be expected to get all that much better. Even if marvelously successful, the best possible realistic end result of a drug that slows aging based on what is known today - say something that extracts the best side of mTOR manipulation with none of the side-effects of rapamycin - is a very modest gain in human longevity. It can't greatly repair or reverse existing damage, it can't much help those who are already old become less damaged, it will likely not even be as effective as actual, old-fashioned calorie restriction. The current consensus is that calorie restriction itself is not going to add more than a few years to a human life - though it certainly has impressive health benefits.

(A sidebar: we can hope that one thing that ultimately emerges from all this research is an explanation as to how humans can enjoy such large health benefits from calorie restriction, commensurate with those seen in animals such as mice, without also gaining longer lives to match. But if just eating fewer calories while obtaining good nutrition could make humans reliably live 40% longer, I think that would have been noted at some point in the last few thousand years, or at least certainly in the last few hundred).

From this perspective, traditional drug research turned into longevity science looks like a long, slow slog to nowhere. It keeps people working, but to what end? Not producing significant results in extending human longevity, that's for sure.

The cost of demonstrating that SENS is the right path or the wrong path - i.e. that aging is simply an accumulation of damage, and the many disparate research results making up the SENS vision are largely correct about which forms of change in aged tissue are the fundamental forms of damage that cause aging - is tiny compared to the cost of trying to safely eke out modest reductions in the pace of aging by manipulating metabolism via sirtuins or mTOR.

The end result of implementing SENS is true rejuvenation if aging is caused by damage: actual repair, actual reversal of aging. The end result of spending the same money and time on trying to manipulate metabolism to slow aging can already be observed in sirtuin research, and can reasonably be expected to be much the same the next time around the block with mTOR - it produces new knowledge and little else of concrete use, and even when it does eventually produce a drug candidate, it will likely be the case that you could do better yourself by simply practicing calorie restriction.

The expectation value of SENS is much greater than that of trying to slow aging via the traditional drug discovery and development industry. Ergo the research and development community should be implementing SENS. It conforms to the consensus position on what causes aging, it costs far less than all other proposed interventions into the aging process, and the potential payoff is much greater.

INDUCED PLURIPOTENCY REMOVES SOME MARKERS OF CELL AGE
http://www.fightaging.org/archives/2013/03/creating-induced-pluripotent-cells-from-old-cells-removes-at-least-some-of-the-markers-of-age.php

A cell is basically a (very complicated) self-modifying program, encoded in proteins. The same basic outline of human cellular machinery can encompasses everything from germline cells - that seem to be essentially immortal - through to the embryonic stem cells that give rise to all other lineages in the body during early development, through to the hundreds of types of specialized, differentiated cell that run the day to day operations of a living organism.

At some point in the process of creating a new individual, old cells with comparatively heavy damage loads work together to create young cells with comparatively light damage loads (the developing embryo). So there is rejuvenation hidden in there somewhere - possibly occurring in very early embryonic development, prior to the point at which a lot of tissue structure exists to be disrupted by what has to happen.

As the research community is learning to reprogram cells to look and act more like embryonic stem cells or germline cells, producing what are known as induced pluripotent stem cells (or iPS cells), we might not be terribly surprised to see what looks like rejuvenation. Some markers of age in reprogrammed cells and their offspring are removed or diminished in comparison to the cells prior to this reprogramming - though scientists are far from any sort of complete measure of all of the effects, and there are numerous different ways in which cells can be reprogrammed to become more like stem cells. Back in 2010, one group of researchers demonstrated the removal of accumulated mitochondrial damage: take skin cells, obtain induced pluripotent cells from them, then differentiate those iPS cells back into skin cells, and find that the new skin cells lack the mitochondrial damage of the old ones.

This sort of research is encouraging when it comes to the prospects for cell therapies that depend on taking cells from the patient, growing large numbers of them, and then infusing them back into the body. The returning cells are likely going to be of a better quality than those removed.

In this post is a more recent example of some specific markers of age being removed from a cell lineage via the use of induced pluripotency. The researchers focused on blood-generating stem cells, reprogramming them into iPs cells, and then deriving a new lineage of these stem cells that was placed into laboratory animals to assess their function. The find that young blood-generating stem cells and old cells that go through this process are fairly similar, which suggests that it is epigenetic changes that cause observed differences between old and young blood in the wild, and that those changes are somehow smoothed out by the reprogramming process.

A LATE TISSUE ENGINEERING YEAR IN REVIEW FOR 2012
http://www.fightaging.org/archives/2013/03/a-late-tissue-engineering-year-in-review-for-2012.php

The merging of tissue engineering and regenerative medicine (TERM) forms an enormously broad, energetic, and important field of medical research. Here is an excerpt from a review paper published earlier this year and only recently made open access:

The pace of growth is now so fast that it impossible for most of us to keep up with the field as a whole, or even a small subset of it. For example, a TERM search specific to "cartilage" returns more than 450 articles published in 2011 alone, meaning that one would need to read more than one article per day just to stay abreast of this small portion of the TERM terrain.

We found considerable innovation in a number of traditional TERM fields, but also new ideas that are beginning to take hold in emerging focal areas. For instance, in the realm of tissue replacement, we are now seeing not just scaffolds of ever-increasing complexity derived from standard engineering methods, but also complex scaffolds predicated on natural designs (and native tissues themselves, once decellularized). In the broader field of regenerative medicine, we are seeing developmental biology begin to address not just the formation of tissues, but the specific role that endogenous stem cells play in both generative and regenerative processes. Integrating these basic science findings with novel materials that specifically recruit endogenous populations may provide a next wave in smart biomaterials for tissue repair. Likewise, new cell sources, most prominently iPSCs, have come to the fore, making autologous cell-based therapies for any tissue a real possibility.

Finally, our objective screen showed that ours is truly a translational field, and that TERM advances are being reduced to clinical practice at an ever-increasing rate. [Both] the quantitative nature of these outcome measures and levels of evidence in support of these applications are advancing as well. Together, these advances are now beginning to change the lives of small subsets of the population, and in the future, these novel approaches will be able to address a host of diseases and instances of tissue degeneration that were heretofore untreatable.

A SURPRISING LACK OF AGE-RELATED DEGENERATION IN MUSCLES
http://www.fightaging.org/archives/2013/03/a-surprising-lack-of-age-related-degeneration-in-muscles.php

How much of age-related degeneration stems from lifestyle (secondary aging) versus inherent processes derived from the operation of metabolism (primary aging)? If you become sedentary with age, or pile on the visceral fat, then both of those are going to harm you in ways that overlap with the inherent mechanisms of aging - accelerating the accumulation of damage and dysfunction in and between the cells of your tissues.

The balance of primary versus secondary aging is likely to be different in different tissues. I noticed a few recent papers that look at narrow aspects of muscle aging and find a surprising lack of primary aging, for example. This suggests that many of the observed changes that occur in muscle early in the aging process are driven as much by a lack of exercise - and related matters of lifestyle that have a negative impact on health - as by the known forms of biological damage down at the level of cells and tissues.

You can't exercise your way out of aging to death, but you can certainly make life harder for yourself (and shorter, and more expensive) by failing to remain trim and fit. On the flip side of the coin, however, another set of recent research suggests that the intrinsic primary aging of muscle isn't something that you can do much about through exercise, even while exercise is enormously beneficial for other reasons. That damage of aging will march onward in your muscle tissues, exercised or not.

DISCUSSION

The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!

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LATEST HEADLINES FROM FIGHT AGING!

METFORMIN MAY ACT TO REDUCE CHRONIC INFLAMMATION
Friday, March 29, 2013
http://www.fightaging.org/archives/2013/03/metformin-may-act-to-reduce-chronic-inflammation.php
Metformin, used as a treatment for diabetes, is a weak candidate for a calorie restriction mimetic drug, one that causes some of the same metabolic changes (and thus hopefully health and longevity benefits) as calorie restriction. The evidence for health and longevity benefits actually resulting from this usage is mixed and debatable, however; certainly nowhere near as clear as for, say, rapamycin. Here researchers propose that metfomin's method of action stems in part from suppressing chronic inflammation, which is known to contribute to the progression of age-related frailty and disease: "[Researchers] found that the antidiabetic drug metformin reduces the production of inflammatory cytokines that normally activate the immune system, but if overproduced can lead to pathological inflammation, a condition that both damages tissues in aging and favors tumor growth. Cells normally secrete these inflammatory cytokines when they need to mount an immune response to infection, but chronic production of these same cytokines can also cause cells to age. Such chronic inflammation can be induced, for example by smoking, and old cells are particular proficient at making and releasing cytokines. "We were surprised by our finding that metformin could prevent the production of inflammatory cytokines by old cells. The genes that code for cytokines are normal, but a protein that normally triggers their activation called NF-kB can't reach them in the cell nucleus in metformin treated cells. We also found that metformin does not exert its effects through a pathway commonly thought to mediate its antidiabetic effects. We have suspected that metformin acts in different ways on different pathways to cause effects on aging and cancer. Our studies now point to one mechanism.""

MORE ON CD47 AS A POTENTIALLY BROAD CANCER THERAPY TARGET
Friday, March 29, 2013
http://www.fightaging.org/archives/2013/03/more-on-cd47-as-a-potentially-broad-cancer-therapy-target.php
All commonalities in cancer are interesting, as part of the high cost of dealing with cancer is based on the many, many different varieties and the great variability of its biochemistry even between individual tumors. Anything that is common between many types of cancer and between tumors offers a possibility of a lower-cost and broader therapy. The cell surface marker CD47 has shown up of late as a possible commonality, and work continues to see whether a therapy can be built on this: "A decade ago, [researchers] discovered that leukemia cells produce higher levels of a protein called CD47 than do healthy cells. CD47 [is] also displayed on healthy blood cells; it's a marker that blocks the immune system from destroying them as they circulate. Cancers take advantage of this flag to trick the immune system into ignoring them. In the past few years, [researchers] showed that blocking CD47 with an antibody cured some cases of lymphomas and leukemias in mice by stimulating the immune system to recognize the cancer cells as invaders. Now, [researchers] have shown that the CD47-blocking antibody may have a far wider impact than just blood cancers. "What we've shown is that CD47 isn't just important on leukemias and lymphomas. It's on every single human primary tumor that we tested." Moreover, [the scientists] found that cancer cells always had higher levels of CD47 than did healthy cells. How much CD47 a tumor made could predict the survival odds of a patient. To determine whether blocking CD47 was beneficial, the scientists exposed tumor cells to macrophages, a type of immune cell, and anti-CD47 molecules in petri dishes. Without the drug, the macrophages ignored the cancerous cells. But when the CD47 was [blocked], the macrophages engulfed and destroyed cancer cells from all tumor types. Next, the team transplanted human tumors into the feet of mice, where tumors can be easily monitored. When they treated the rodents with anti-CD47, the tumors shrank and did not spread to the rest of the body. In mice given human bladder cancer tumors, for example, 10 of 10 untreated mice had cancer that spread to their lymph nodes. Only one of 10 mice treated with anti-CD47 had a lymph node with signs of cancer. Moreover, the implanted tumor often got smaller after treatment - colon cancers transplanted into the mice shrank to less than one-third of their original size, on average."

ON NANOSCALE-FEATURED SCAFFOLDS IN REGENERATIVE MEDICINE
Thursday, March 28, 2013
http://www.fightaging.org/archives/2013/03/on-nanoscale-featured-scaffolds-in-regenerative-medicine.php
An interesting piece on the use of scaffold materials to guide regrowth in regenerative medicine: "A research group [is] weaving nanoscale nerve-guide scaffolds from a mixture of natural chitosan and an industrial polyester polymer, using a process called electrospinning. The raw materials are dissolved in solvents and placed into a syringe, the needle of which is attached to a high-voltage supply. Charged liquid is then expelled from the needle towards an earthed collector plate. Like a spark between a cloud and a lightning conductor, the liquid stretches out to the collector, and the molecules within it form into a solid but incredibly thin thread. The resulting minuscule fibres accrete into a dense mesh whose texture is similar to that of the body's own connective tissue. In laboratory tests, prototype nerve guides built from this nanomaterial sustained the growth of new neural cells, produced no immune reactions and were much stronger and more flexible than commercial collagen tubes. By adjusting the electrospinning process, the orientation of the nanofibres can be controlled to build scaffolds suitable for cultivating cells that need precise alignment, such as elongated muscle fibres and heart tissue."

AN INVESTIGATION INTO RATES OF AGING AND HEART DISEASE RISK
Thursday, March 28, 2013
http://www.fightaging.org/archives/2013/03/an-investigation-into-rates-of-aging-and-heart-disease-risk.php
People age at different paces: accumulating damage, dysfunction, and age-related disease comes earlier and faster for some. The current consensus is that some of that is genetic, some epigenetic, but (absent serious genetic abnormalities) most of the difference is due to commonplace lifestyle choices such as smoking, exercise, and calorie intake. "[Researchers have] found new evidence that links faster 'biological' ageing to the risk of developing several age-related diseases - including heart disease, multiple sclerosis and various cancers. "Although heart disease and cancers are more common as one gets older, not everyone gets them - and some people get them at an earlier age. It has been suspected that the occurrence of these diseases may in part be related to some people 'biologically' ageing more quickly than others." The research team measured telomere lengths in over 48,000 individuals and looked at their DNA and identified seven genetic variants that were associated with telomere length. They then asked the question whether these genetic variants also affected risk of various diseases. As DNA cannot be changed by lifestyle or environmental factors, an association of these genetic variants which affect telomere length with a disease also would suggest a causal link between telomere length and that disease. "These are really exciting findings. We had previous evidence that shorter telomere lengths are associated with increased risk of coronary artery disease but were not sure whether this association was causal or not. This research strongly suggests that biological ageing plays an important role in causing coronary artery disease, the commonest cause of death in the world. This provides a novel way of looking at the disease and at least partly explains why some patients develop it early and others don't develop it at all even if they carry other risk factors.""

AMNIOTIC FLUID STEM CELLS SPUR REPAIR OF GUT DAMAGE
Wednesday, March 27, 2013
http://www.fightaging.org/archives/2013/03/amniotic-fluid-stem-cells-spur-repair-of-gut-damage.php
This sort of regenerative medicine research will in the long term help to decipher the signaling produced by different sorts of stem cells in different tissues. Researchers will ultimately remove the need for cell transplants to boost regenerative capabilities and rebuild damaged organs, and produce these effects by controlling existing cell populations: "Amniotic fluid stem (AFS) cells were harvested from rodent amniotic fluid and given to rats with necrotizing enterocolitis (NEC). Other rats with the same condition were given bone marrow stem cells taken from their femurs, or fed as normal with no treatment, to compare the clinical outcomes of different treatments. NEC-affected rats injected with AFS cells showed significantly higher survival rates a week after being treated, compared to the other two groups. Inspection of their intestines, including with micro magnetic resonance imaging (MRI), showed the inflammation to be significantly reduced, with fewer dead cells, greater self-renewal of the gut tissue and better overall intestinal function. While bone marrow stem cells have been known to help reverse colonic damage in irritable bowel disease by regenerating tissue, the beneficial effects from stem cell therapy in NEC appear to work via a different mechanism. Following their injection into the gut, the AFS cells moved into the intestinal villi - the small, finger-like projections that protrude from the lining of the intestinal wall and pass nutrients from the intestine into the blood. However, rather than directly repairing the damaged tissue, the AFS cells appear to have released specific growth factors that acted on progenitor cells in the gut which in turn, reduced the inflammation and triggered the formation of new villi and other tissues. "Stem cells are well known to have anti-inflammatory effects, but this is the first time we have shown that amniotic fluid stem cells can repair damage in the intestines. [Although] amniotic fluid stem cells have a more limited capacity to develop into different cell types than those from the embryo, they nevertheless show promise for many parts of the body including the liver, muscle and nervous system.""

BUILDING FUNCTIONAL OVARIAN TISSUE
Wednesday, March 27, 2013
http://www.fightaging.org/archives/2013/03/building-functional-ovarian-tissue.php
A modest step forward on the path towards tissue engineered ovaries: "A proof-of-concept study suggests the possibility of engineering artificial ovaries in the lab to provide a more natural option for hormone replacement therapy for women. [Researchers] report that in the laboratory setting, engineered ovaries showed sustained release of the sex hormones estrogen and progesterone. The project to engineer a bioartificial ovary involves encapsulating ovarian cells inside a thin membrane that allows oxygen and nutrients to enter the capsule, but would prevent the patient from rejecting the cells. With this scenario, functional ovarian tissue from donors could be used to engineer bioartificial ovaries for women with non-functioning ovaries. [Researchers] isolated the two types of endocrine cells found in ovaries (theca and granulosa) from 21-day-old rats. The cells were encapsulated inside materials that are compatible with the body. The scientists evaluated three different ways of arranging the cells inside the capsules. The function of the capsules was then evaluated in the lab by exposing them to follicle-stimulating hormone and luteinizing hormone, two hormones that stimulate ovaries to produce sex hormones. The arrangement of cells that most closely mimicked the natural ovary (layers of cells in a 3-D shape) secreted levels of estrogen that were 10 times higher than other cell arrangements. The capsules also secreted progesterone as well as inhibin and activin, two hormones that interact with the pituitary and hypothalamus and are important to the body's natural system to regulate the production of female sex hormones. "Cells in the multilayer capsules were observed to function in similar fashion to the native ovaries. The secretion of inhibin and activin secretion suggests that these structures could potentially function as an artificial ovary by synchronizing with the body's innate control system.""

ON AUTOPHAGY IN STEM CELLS
Tuesday, March 26, 2013
http://www.fightaging.org/archives/2013/03/on-autophagy-in-stem-cells.php
Autophagy is the collection of housekeeping processes that aim to keep a cell in good shape - free from damaged components and unwanted metabolic byproducts. More autophagy is a good thing, and boosted levels of autophagy seem to be involved in many of the methods found to extend life in laboratory animals. By way of following up on a post from yesterday on apparent damage repair and reversal of some markers of aging in induced pluripotent stem cells (iPSCs), I thought I'd direct your attention to a recent open access paper on the involvement of autophagy in stem cell biology. Perhaps much of the seeming cellular rejuvenation brought about through passing old cell lineages through an induced pluripotent stage has to do with greatly enhanced autophagy: "The implication of autophagy in the maintenance of stemness adds a new layer of control on stem cell activity. Firstly, autophagy may serve as a critical mechanism for the regulation of self-renewal and differentiation. Indeed, stem cells require especially efficient protein turnover to eliminate unwanted proteins, which may otherwise accumulate and impair identity and function. Both autophagy and the ubiquitin-proteasome system (UPS) are important for protein quality control and the maintenance of cellular homeostasis, and they cooperate to regulate cellular aging. Dysfunction or decrease of the stem cell pools is typical of physiological and pathological aging; it would be therefore interesting to determine how these two protein degradation pathways are coordinated in the regulation of stem cell homeostasis, and how the dysregulation of autophagy in stem cells is linked to aging and degenerative diseases. Additionally, the involvement of autophagy in somatic reprogramming suggests a new methodological basis for developing strategies to efficiently generate iPSCs. Finally, increased autophagy may enable cells to overcome the cellular senescence barrier by remodelling the cell cycle machinery or by promoting the turnover of the 'senescent' subcellular architecture. In summary, the study of the interplay between autophagy and cell stemness will not only increase our understanding of the mechanisms and pathways through which autophagy contributes to stem cell maintenance and differentiation, but also enhance our knowledge of the roles of autophagy in human development, aging, and various degenerative diseases. Stem cell rejuvenation and function and large-scale production of high quality transplantable materials through active manipulation of autophagic pathways using small molecules and/or targeted genome-editing technology may be more than a dream."

AN ANALYSIS OF MITOCHONDRIAL DYSFUNCTION IN AGING AND DISEASE
Tuesday, March 26, 2013
http://www.fightaging.org/archives/2013/03/an-analysis-of-mitochondrial-dysfunction-in-aging-and-disease.php
Every cell has its herd of bacteria-like mitochondria, generating fuel for cellular metabolism but also emitting damaging reactive compounds - largely damaging themselves, in fact. Differences in mitochondrial damage resistance are thought to be an important determinant of differences in species life span. Similarly, accumulated mitochondrial damage is most likely an in important contribution to degenerative aging in individuals - making therapies capable of repair a high priority. Here researchers dig in to the degree to which mitochondrial dysfunction appears in aging and various diseases: "Besides their cardinal role in ATP metabolism mitochondria are the main producers of endogenous oxidative radicals. These highly volatile species react with lipids, proteins and nucleic acids in their vicinity. The mitochondrial theory of aging states that an accumulation of damage to these macromolecules throughout the lifetime of an organism leads to cellular decay, loss of tissue homeostasis, and finally to death. Multiple lines of evidence have corroborated this theory and suggested that mitochondrial maintenance may be important in promoting longevity and healthy aging. Indeed, mitochondria have been implicated in most age related diseases such as neurodegeneration, cardiovascular disease and diabetes. If mitochondrial dysfunction is causative in aging, we would expect the accelerated aging disorders to exhibit features of mitochondrial disease. To investigate this, we compiled a database of the clinical parameters seen in mitochondrial diseases, www.mitodb.com. Based on this database we developed extensive bioinformatics tools to dissect whether a disease could be characterized as mitochondrial or not. [Using] these tools we identified a number of diseases as mitochondrially associated that had not previously been considered as mitochondrial. Recently a number of [accelerated aging conditions] have been suggested to have mitochondrial dysfunction and these disorders were also identified by our tools. With the validation of the tools we went on to investigate the mitochondrial involvement in a number of monogenic diseases. Interestingly, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis all showed a substantial mitochondrial involvement. Further, when adding the accelerated aging disorders to the database two groups of progeria appeared; one group associated with chromosomal instability and another group clustered with mitochondrial diseases. Normal aging seemed to associate closer with the mitochondrial group in the clustering algorithm but showed mixed mitochondrial and non-mitochondrial [attributes]. Taken together these findings indicate at least two separate causes of aging, one of them possibly being mitochondrial."

A POPULAR SCIENCE ARTICLE ON ORGAN ENGINEERING
Monday, March 25, 2013
http://www.fightaging.org/archives/2013/03/a-popular-science-article-on-organ-engineering.php
The engineering of replacement organs is progressing. There are ongoing successes with less functional tissue masses such as the bladder wall and trachea, but sights are set on building complex organs such as the heart: "Since a laboratory in North Carolina made a bladder in 1996, scientists have built increasingly more complex organs. There have been five windpipe replacements so far. A London researcher, Alex Seifalian, has transplanted lab-grown tear ducts and an artery into patients. He has made an artificial nose he expects to transplant later this year in a man who lost his nose to skin cancer. Now, with the quest to build a heart, researchers are tackling the most complex organ yet. The payoff could be huge, both medically and financially, because so many people around the world are afflicted with heart disease. Researchers see a multi-billion-dollar market developing for heart parts that could repair diseased hearts and clogged arteries. In additional to the artificial nose, Dr. Seifalian is making cardiovascular body parts. He sees a time when scientists would grow the structures needed for artery bypass procedures instead of taking a vein from another part the body. As part of a clinical trial, Dr. Seifalian plans to transplant a bioengineered coronary artery into a person later this year. Dr. Aviles trained as a cardiologist but became frustrated with the difficulty of treating patients with advanced heart disease. [He] was approached in 2009 by a U.S. scientist, Doris Taylor, who had already grown a beating rat heart in the [lab]. Instead of using a man-made scaffold, Dr. Taylor had used the scaffolding from an actual rat heart as the starting point. Growing a heart is much harder than, say, growing a windpipe, because the heart is so big and has several types of cells, including those that beat, those that form blood vessels, and those that help conduct electrical signals. For a long time, scientists didn't know how to make all the cells grow in the right place and in the right order. Dr. Aviles said he hopes to have a working, lab-made version ready in five or six years, but the regulatory and safety hurdles for putting such an organ in a patient will be high. The most realistic scenario, he said, is that "in about 10 years" his lab will be transplanting heart parts. He and his team already have grown early-stage valves and patches that could be used some day to repair tissue damaged by heart attack."

SENS6 CONFERENCE REGISTRATION OPEN
Monday, March 25, 2013
http://www.fightaging.org/archives/2013/03/sens6-conference-registration-open.php
Registration for the forthcoming SENS6 conference is now open. To get a sense of how this conference series runs and the noteworthy folk who attend, you might take a look at the recorded presentations or list of abstracts from SENS5, held in 2011: "You are cordially invited to participate in the sixth Strategies for Engineered Negligible Senescence (SENS) Conference, which will be held from 3rd - 7th September, 2013 at Queens' College, Cambridge. The purpose of the SENS conference series, like all the SENS initiatives (such as the journal Rejuvenation Research), is to expedite the development of truly effective therapies to postpone and treat human aging by tackling it as an engineering problem: not seeking elusive and probably illusory magic bullets, but instead enumerating the accumulating molecular and cellular changes that eventually kill us and identifying ways to repair - to reverse - those changes, rather than merely to slow down their further accumulation. This broadly defined regenerative medicine - which includes the repair of living cells and extracellular material in situ - applied to damage of aging, is what we refer to as rejuvenation biotechnologies. The meeting will comprise invited talks, short oral presentations of submitted abstracts, and poster sessions. There will be no concurrent sessions. Talks will take place in the Fitzpatrick Lecture Hall. Poster sessions will take place each evening in the conservatory adjacent to the bar. The conference will also feature the traditional punting on the Cam: an hour on the Backs for the faint-hearted, and an afternoon or evening trip to Grantchester for the rest of us."

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Posted 07 April 2013 - 03:51 PM

FIGHT AGING! NEWSLETTER
April 8th 2013

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

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CONTENT

- Video: Why Isn't Longevity Science the World's Greatest Concern?
- Deploying the Argument from Authority for SENS Research
- On Costs and Opportunity Costs of Aging
- Technological Progress, Hope, and Human Longevity
- Discussion
- Latest Headlines from Fight Aging!
- Another Step Towards Early Artificial Cells
- Longer Life or Unlimited Life?
- Within a Species, Larger Size Tends to Mean a Shorter Life
- An Example of Mitohormesis
- On Hunger Without Calorie Restriction
- A Trial of Very Small Embryonic-Like Stem Cells for Bone Regrowth
- Pharmacology Lags Behind Genetic Engineering and Environmental Causes of Longevity
- Old Blood Versus Young Blood From a Programmed Aging Perspective
- The Importance of Autophagy for Mitochondria
- Height Loss Correlates Well With Other Aspects of Aging

VIDEO: WHY ISN'T LONGEVITY SCIENCE THE WORLD'S GREATEST CONCERN?
http://www.fightaging.org/archives/2013/04/why-isnt-longevity-science-the-worlds-greatest-concern.php

Without the biotechnologies of human rejuvenation that could be created over the next twenty years given a fully funded crash program of development, we and our descendants will all die due to the effects of aging, exactly as did our ancestors. Aging to death has never been a choice - but now it is, and every needless day of delay comes at a cost of 100,000 lives. Everyone presently alive will suffer greatly due to aging and age-related conditions unless new medical technologies of the sort envisaged by the SENS Research Foundation are developed to repair and reverse the low-level biological damage that causes of aging. So why isn't this front and center on everyone's list of concerns? Why does longevity science and the elimination of age-related suffering barely even register in the public eye?

Follow the link above to view a talk on this subject given at the Stanford Advancing Humanity Symposium last month by Maria Konovalenko of the Russian Science For Life Extension Foundation, an advocacy initiative.

DEPLOYING THE ARGUMENT FROM AUTHORITY FOR SENS RESEARCH
http://www.fightaging.org/archives/2013/04/deploying-the-argument-from-authority-for-sens-research.php

Arguments from authority are frowned upon in most forms of formal debate, since the purpose of said debate is to argue and build upon facts firsthand - as opposed to merely repeating other people's consideration of those facts. But for the purposes of advocacy and informal discussion, invoking authority is tremendously useful for getting past knee-jerk rejection of new ideas. Most people are quick to bypass anything that they are unfamiliar with; in this information-dense age some sort of filter is needed to keep a focus on important matters, but folk in every era have been reluctant to engage with the new and the unusual.

Thus one of the necessary activities for any growing concern in any field of human endeavor is to convince influential, knowledgeable people to publicly provide their blessing. On the one hand this is all part and parcel of networking: if you're working on a disruptive new approach to aging research, say, then at some point you have to convince a sizable fraction of the existing research community leadership that you are right, and that your approach is indeed better than the established dogma. You need to build a network, and bootstrap your support.

In most cases, great new ideas can be easily discerned in hindsight, but in the early days it's a matter of a hundred rejections for every cautious expression of interest. You have to kick down a lot of doors. No good idea is accepted without a fight - and that is the human condition for you.

The disruptive and vastly better new approaches to aging research and extending human longevity that I favor are (as I'm sure you all know by now) collectively known as SENS: the Strategies for Engineered Negligible Senescence. SENS is is an assembly of tremendously good ideas expressed in the form of detailed research plans for medical biotechnology, and is (to my eyes) enormously better than the sort of work presently undertaken by the mainstream of longevity science. I say this meaning that it will most likely produce better outcomes at far lower cost in time and money. The present mainstream seeks only to slightly slow aging, and is moving glacially and at great expense. SENS aims to achieve rejuvenation of the old, and can be proven to work or not for a fraction of the amount it would take for the mainstream to develop a single drug to safely and modestly slow down aging through metabolic reprogramming.

Needless to say, with SENS being such a great idea and better plan of action, it's been a struggle this past decade to get it to its present level of respect and adoption. No good plan goes unchallenged in this madhouse world of ours. Congratulations should go to the Methuselah Foundation and SENS Research Foundation teams over the years, most of whom have worked tirelessly behind the scenes and for little recognition. The public at large, however, lagging behind some years in following the scientific conversation, remain suspicious of anything that presents itself as SENS does - new ideas, involving only a small portion of the scientific community at first, talking about human longevity, the existence of public scientific debates over validity in past years, and so forth. It's easy for the fellow in the street to knee-jerk and reject, just as he does for any new idea that has yet to take over the mainstream.

This is where the argument from authority is useful and indeed often necessary in the real world give and take of advocacy for a cause. It launches you past the first hurdle of immediate rejection, to a point at which people might actually start to consider factual arguments - i.e. start to give any sort of fair consideration to your position at all. For SENS, the resource of first recourse for the argument from authority is the SENS Research Foundation scientific advisory board. Again, this is not primarily why the advisory board exists: an initiative grows by networking. But it is enormously helpful when in casual discussion or debate for someone like such like myself to be able to point to that advisory board and say "look at these leading scientists in the fields of aging research, genetics, regenerative medicine, cancer research, and others: they have evaluated the scientific merits and goals of SENS and support it."

ON COSTS AND OPPORTUNITY COSTS OF AGING
http://www.fightaging.org/archives/2013/04/on-costs-and-opportunity-costs-of-aging.php

ew people seem terribly interested in noting the opportunity costs of aging, for all that a great deal of work goes into trying to build models for the direct costs. Insurers, government program administrators, and so forth, are all eager to put numbers to their potential future outlays - but they have fewer incentives to work on better numbers for the lost ability to earn that comes with advancing age. Here are some figures from a recent paper on dementia in the US, for example:

"The estimated prevalence of dementia among persons older than 70 years of age in the United States in 2010 was 14.7%. The yearly monetary cost per person that was attributable to dementia was either $56,290 (95% confidence interval [CI], $42,746 to $69,834) or $41,689 (95% CI, $31,017 to $52,362), depending on the method used to value informal care. These individual costs suggest that the total monetary cost of dementia in 2010 was between $157 billion and $215 billion. Dementia represents a substantial financial burden on society, one that is similar to the financial burden of heart disease and cancer."

If you go digging around in US census data on income, or the quick summaries thereof, you'll see that median income sits somewhere a little under $40,000/year in the prime earning years of life. It tapers off to a little more than half of that for surviving members of the 75 and older demographic. So while one of seven completely median older people incurs costs of roughly $40,000/year for dementia, all seven completely median older people suffer an opportunity cost of roughly $20,000/year as a result of becoming old. A range of income that might have been earned if still healthy and vigorous is no longer within reach.

These are very rough and ready comparisons, but you can see that even piling in a bunch of other direct medical costs for the rest of the population - cancer, diabetes, cardiovascular disease, and the other common foes - the opportunity costs of being old still look sizable in comparison. In another study that gives average medical costs over time for people in Japan aged between 40 and 80 followed over 13 years, the average yearly expenditure was in the ~$3,500 range, rising to more like ~$25,000 in the last year prior to death. The error bars for casual use of any of the numbers mentioned in this post is large - probably a factor of two, given all of the oddities and politics that goes into medical expenditures and recording of income, and especially when comparing data between different regions on the world. But you can still draw very rough conclusions about relative sizes.

Lastly, I should note that all of the above only considers the living. Once you get to the age 75 demographic in the US, half of the original population is dead, give or take. The dead accrue even higher opportunity costs than those mentioned above, as they have (for the most part) lost all ability to earn or contribute to building new things.

So aging causes a largely unseen cost to go along with what is seen, the cost of what might have been but for disability and death. As is often the case, the cost of research and development to build the means of rejuvenation is small in comparison to what is lost to aging - and also in comparison to what is spent in coping with the aftermath of loss rather than trying to prevent it.

TECHNOLOGICAL PROGRESS, HOPE, AND HUMAN LONGEVITY
http://www.fightaging.org/archives/2013/04/technological-progress-hope-and-human-longevity.php

Forecasting is really hard, especially when it involves the future - or so they say. One of Ray Kurzweil's more noteworthy achievements has been, I think, to help popularize the idea that technological progress can be predicted fairly well at the level of general capabilities (as opposed to specific implementations). This is not a new idea, but despite - or because of - the sweeping, glittering changes transforming our society, at a pace that is only getting faster, it hasn't achieved any great adoption in the public eye, at least beyond some few narrow and often misquoted instances such as Moore's law for computing power.

If the outcome of technological progress only meant smaller widgets and brighter lights, then I probably wouldn't be as interested in it as I am. In the grand scheme of things, does it much matter that you can be modestly confident in predicting whether widgets will be half the size and a tenth of the cost in twenty years versus forty years? If you're in the widget business for the long haul, it matters. If not ... well, everyone has their own specialty to attend to.

There is one branch of technology which is now of great importance to everyone, however, and that is medicine. We stand on the verge of being able to extend human life by reversing the underlying biological damage that causes aging. "On the verge" means that either you die just a little later than your parents, or you live for centuries or longer, depending on whether or not you live long enough to benefit from the first therapies capable of actual rejuvenation. The early rejuvenation therapies will be poor in comparison to what comes afterwards, but they will give you time to wait for better treatments: you just have to be young enough at the outset to stay ahead of the curve of improvement.

This is vastly more important than widgets: being able to more or less predict the course of electronics, computing, or space flight gives you an idea of what you might see before you die. Predicting the course of capacities in medicine even at a very high level may show you whether you will have to age to death at all, should things progress as expected. On this topic, here is an open access paper that delves into historical technologies to suggest that progress is predictable:

"Using a new database on the cost and production of 62 different technologies, which is the most expansive of its kind, we test the ability of six different postulated laws to predict future costs. We discover a previously unobserved regularity that production tends to increase exponentially. Our results show that technological progress is forecastable, with the square root of the logarithmic error growing linearly with the forecasting horizon at a typical rate of 2.5% per year."

I point you to the research quoted above as a form of reassurance: progress will continue in medicine, and via efforts such as the Methuselah Foundation and SENS Research Foundation the medical research community is presently being brought around to the idea of extending human life via rejuvenation biotechnology. The uncertainty in timelines at present all lies in how long it will take for SENS-style rejuvenation research to gather a firm, mainstream, well-funded position: once that happens then progress is inevitable and tends to unfold as outlined above. Prior to that point there is much uncertainty, with things progressing in fits and starts - the standard tyranny of progress under minimal funding and participation.

Thus the present goal for advocates is to persuade enough people and funds to make progress inevitable from that point on. The sooner that happens, the higher the fraction of those presently alive who will live to see and benefit from human rejuvenation. If you're in mid-life like I am, you only have forty years or so of grace - and less if you're not taking care of your health, or are just plain unlucky in the cancer lottery. Four decades is probably only enough time if things go very well over the next ten to twenty years, and SENS or SENS-like programs colonize a large enough chunk of the life science research community in a short enough space of time.

So: hope or help. One of the two, but the letter is generally a better plan.

DISCUSSION

The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!

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LATEST HEADLINES FROM FIGHT AGING!

ANOTHER STEP TOWARDS EARLY ARTIFICIAL CELLS
Friday, April 5, 2013
http://www.fightaging.org/archives/2013/04/another-step-towards-early-artificial-cells.php
It is worth keeping an eye on progress towards the creation of artificial cells and cell-like structures, as they are potentially useful in a very broad range of biotechnologies relevant to longevity science, regenerative medicine, and so forth. The first swarms of medical microrobots will quite likely be modified cells or artificial cells, packed with specific forms of molecular machinery to achieve some sort of effect in the body - such as manufacturing signaling compounds in response to local conditions, so as to steer the activities of surrounding cells. "A custom-built programmable 3D printer can create materials with several of the properties of living tissues. The new type of material consists of thousands of connected water droplets, encapsulated within lipid films. Because droplet networks are entirely synthetic, have no genome and do not replicate, they avoid some of the problems associated with other approaches to creating artificial tissues - such as those that use stem cells. Each droplet is an aqueous compartment about 50 microns in diameter. Although this is around five times larger than living cells the researchers believe there is no reason why they could not be made smaller. The networks remain stable for weeks. "We aren't trying to make materials that faithfully resemble tissues but rather structures that can carry out the functions of tissues. We've shown that it is possible to create networks of tens of thousands of connected droplets. The droplets can be printed with protein pores to form pathways through the network that mimic nerves and are able to transmit electrical signals from one side of a network to the other.""

LONGER LIFE OR UNLIMITED LIFE?
Friday, April 5, 2013
http://www.fightaging.org/archives/2013/04/longer-life-or-unlimited-life.php
This article looks past the immediate challenges of aging and early medical biotechnologies aimed at extending human longevity, and into the future of merged molecular manufacturing and biotechnology, when it will become possible to replace our biology with far more robust and long-lasting machinery: "If we're talking far-future, non-biological approaches to life-extension will win out over biological approaches, due mainly to their comparative advantages (e.g. ease of repair and modification). [I] think that the distinction between non-biological and biological systems (especially if Drexlerian nanotech - that is, using mechanosynthesis - is implemented with any ubiquity) will increasingly dissolve. If a system exhibits the structural, functional and operational modalities of a biological cell, tissue, organ or organism, yet consists of wholly inorganic materials, is it not closer to a biological system than to what we would typically consider a non-biological system? Either the distinction between the two will eventually dissolve, or we will use the term "biological" to designate systems exhibiting the structural, functional, and/or operational modalities of biological systems. I make a distinction between life-extension therapies and indefinite-longevity therapies, and I'd like to elaborate more on this distinction here. Life-extension therapies extend longevity, but for various reasons fail to make it necessarily indefinite or unlimited. Often this is because such therapies aren't comprehensive - a given therapy solves one contributing factor of aging, but not all of them. Others, like SENS (which I'm in no way discounting), fix the major causes of damage, but use a different methodology for each respective source of damage or aging; the drawback of this approach is that if previously overshadowed causes of aging now begin to make a non-negligible impact on aging, in the absence of the more predominant causes, then we have no methodology to combat it. Because each strategy is tied intimately to the cause it seeks to ameliorate, the techniques often cannot be applied to the new source of molecular damage. Indefinite or unlimited longevity therapies, on the other hand, use one comprehensive approach to mitigate all sources of aging. One example is Drexlerian nanotech (and to a shared but somewhat lesser extent Robert Freitas's nanomedicine - only because it has specifically-tailored strategies not dependent on the feasibility of Drexlerian molecular assembly or "mechanosynthesis", in addition to the more comprehensive ones). This approach fixes not the source of the damage but the damage itself, iteratively, and can thus be used to combat any source of molecular damage using the same tools, technologies and techniques. With such therapies we wouldn't need to come up with a second wave of strategies to combat those sources of aging that might crop up in the future, and which remained unnoticed until such a time only because their impact couldn't be seen (or allowed to take effect) while the first wave of sources was still predominant." I'm not totally convinced that this last point is the case; I think it's more that a designed replacement for tissue can be made to have far fewer and more comprehensibly understood forms of aging (which can be repaired on an ongoing basis). But there will still be the unknowns, pushed into an ever-smaller corner, and ever less important. Yet by the time it is possible to build artificial tissue and cell replacements in this way, will we not have come to understand biology so well that the unknowns in biological aging are already equally small?

WITHIN A SPECIES, LARGER SIZE TENDS TO MEAN A SHORTER LIFE
Thursday, April 4, 2013
http://www.fightaging.org/archives/2013/04/within-a-species-larger-size-tends-to-mean-a-shorter-life.php
You might look at this research on size and longevity in the context of what is known of growth hormone and aging. The presently longest lived mice, for example, are those in which growth hormone is removed or blocked, and they are small in comparison to their peers. Also worth considering are analogous rare human lineages with non-functional growth hormone receptors, such as those exhibiting Laron-type dwarfism. "Large body size is one of the best predictors of long life span across species of mammals. In marked contrast, there is considerable evidence that, within species, larger individuals are actually shorter lived. This apparent cost of larger size is especially evident in the domestic dog, where artificial selection has led to breeds that vary in body size by almost two orders of magnitude and in average life expectancy by a factor of two. Survival costs of large size might be paid at different stages of the life cycle: a higher early mortality, an early onset of senescence, an elevated baseline mortality, or an increased rate of aging. After fitting different mortality hazard models to death data from 74 breeds of dogs, we describe the relationship between size and several mortality components. We did not find a clear correlation between body size and the onset of senescence. The baseline hazard is slightly higher in large dogs, but the driving force behind the trade-off between size and life span is apparently a strong positive relationship between size and aging rate. We conclude that large dogs die young mainly because they age quickly."

AN EXAMPLE OF MITOHORMESIS
Thursday, April 4, 2013
http://www.fightaging.org/archives/2013/04/an-example-of-mitohormesis.php
Mitohormesis is a process by which a low dose of some toxic substance or environmental effect causes mitochondria in cells to emit a little more in the way of damaging reactive oxygen species, which in turn causes cellular maintenance mechanisms to ramp up their efforts. The end result is a net gain in health and longevity: "Arsenite is one of the most toxic chemical substances known and is assumed to exert detrimental effects on viability even at lowest concentrations. By contrast and unlike higher concentrations, we here find that exposure to low-dose arsenite promotes growth of cultured mammalian cells. In the nematode C. elegans, low-dose arsenite promotes resistance against thermal and chemical stressors, and extends lifespan of this metazoan, whereas higher concentrations reduce longevity. While arsenite causes a transient increase in reactive oxygen species (ROS) levels in C. elegans, co-exposure to ROS scavengers prevents the lifespan-extending capabilities of arsenite, indicating that transiently increased ROS levels act as transducers of arsenite effects on lifespan, a process known as mitohormesis. This requires two transcription factors, namely DAF-16 and SKN-1, which employ the metallothionein MTL-2 as well as the mitochondrial transporter TIN-9.1 to extend life span. Taken together, low-dose arsenite extends lifespan, providing evidence for non-linear dose-response characteristics of toxin-mediated stress resistance and longevity in a multicellular organism." SKN-1 and DAF-16 are already well known as longevity-related genes in nematodes - more data for the importance of mitochondria in aging.

ON HUNGER WITHOUT CALORIE RESTRICTION
Wednesday, April 3, 2013
http://www.fightaging.org/archives/2013/04/on-hunger-without-calorie-restriction.php
It is suspected that some fraction of the benefits of calorie restriction for health and longevity are keyed to the hunger response in some way - i.e. that being hungry more often is necessary to gain the full effects. There's not all that much work on this so far as I'm aware, however. You might look at one study suggesting increased levels of ghrelin, the hunger hormone, are linked to an improved immune system response, for example. Studies investigating the contribution of hunger to the benefits of calorie restriction would have to run by manipulating the hunger response separately from calorie intake to try to isolate its effects. Here is one recently published example of such a study. It is unfortunately focused only on aspects of Alzheimer's disease rather than on longevity, but it is still intriguing. The reduced inflammation is a sign that the researchers might be on the right track: "It has been shown that caloric restriction (CR) delays aging and possibly delays the development of Alzheimer's disease (AD). We conjecture that the mechanism may involve interoceptive cues, rather than reduced energy intake per se. We determined that hunger alone, induced by a ghrelin agonist, reduces AD pathology and improves cognition in [a] mouse model of AD. Long-term treatment with a ghrelin agonist was sufficient to improve the performance in the water maze. The treatment also reduced levels of amyloid beta (Aβ) and inflammation (microglial activation) at 6 months of age compared to the control group, similar to the effect of CR. Thus, a hunger-inducing drug attenuates AD pathology, in the absence of CR, and the neuroendocrine aspects of hunger also prevent age-related cognitive decline."

A TRIAL OF VERY SMALL EMBRYONIC-LIKE STEM CELLS FOR BONE REGROWTH
Wednesday, April 3, 2013
http://www.fightaging.org/archives/2013/04/a-trial-of-very-small-embryonic-like-stem-cells-for-bone-regrowth.php
"Very small embryonic-like stem cells" (VSELs) is one name given to populations of stem cells in the adult body that appear to share some characteristics with embryonic stem cells - such as the ability to differentiate into multiple cell types. If this pans out, these cells will be useful in therapy - and here is news of an upcoming trial: "Preparations are underway for the first known human trial to use embryonic-like stem cells collected from adult cells to grow bone. [The] research partners hypothesize that the VSEL stem cells, which mimic properties of embryonic stem cells, can provide a minimally invasive way to speed painful bone regeneration for dental patients and others with bone trauma. Within a year, researchers hope to begin recruiting roughly 50 patients who need a tooth extraction and a dental implant. Before extracting the tooth, [researchers] harvest the patient's cells, and then NeoStem's VSEL technology is used to purify and isolate those VSEL stem cells from the patient's other cells. This allows [researchers] to implant pure populations of the VSEL stem cells back into test patients. Control patients receive their own cells, not the VSELs. After the new bone grows, researchers remove a small portion of it to analyze, and replace it with an implant. "We're taking advantage of the time between extraction and implant to see if these cells will expedite healing time and produce better quality bone. They are natural cells that are already in your body, but NeoStem's technology concentrates them so that we can place a higher quantity of them onto the wound site.""

PHARMACOLOGY LAGS BEHIND GENETIC ENGINEERING AND ENVIRONMENTAL CAUSES OF LONGEVITY
Tuesday, April 2, 2013
http://www.fightaging.org/archives/2013/04/pharmacology-lags-behind-genetic-engineering-and-environmental-causes-of-longevity.php
This is a somewhat obvious point, but seems worth making once or twice. The primary methods of extending life in laboratory animals involve genetic engineering and environmental line items such as calorie restriction - these are how new metabolic states that lead to increased longevity are discovered in the research mainstream. The process of then developing drugs to try to recapture some of these effects inevitably lags behind in effectiveness: it's a complex process with many dead ends and only partial successes, whereas testing new genetic alterations in lower animals proceeds fairly rapidly these days. This recent paper illustrates the point: "The regulation of animal longevity shows remarkable plasticity, in that a variety of genetic lesions are able to extend lifespan by as much as 10-fold. Such studies have implicated several key signaling pathways that must normally limit longevity, since their disruption prolongs life. Little is known, however, about the proximal effectors of aging on which these pathways are presumed to converge, and to date, no pharmacologic agents even approach the life-extending effects of genetic mutation. In the present study, we have sought to define the downstream consequences of age-1 nonsense mutations, which confer 10-fold life extension to the nematode Caenorhabditis elegans - the largest effect documented for any single mutation. Such mutations insert a premature stop codon upstream of the catalytic domain of the AGE-1/p110α subunit of class-I PI3K. As expected, we do not detect class-I PI3K, [nor] do we find any PI3K activity as judged by immunodetection of phosphorylated AKT, which strongly requires PIP3 for activation by upstream kinases, or immunodetection of its product, PIP3. We tested a variety of commercially available PI3K inhibitors, as well as three phosphatidylinositol analogs (PIAs) that are most active in inhibiting AKT activation, for effects on longevity and survival of oxidative stress. Of these, GDC-0941, PIA6, and PIA24 [extended] lifespan by 7-14%, while PIAs 6, 12, and 24 (at 1 or 10 μM) increased survival time [under oxidative stress] by 12-52%. These effects may have been conferred by insulinlike signaling."

OLD BLOOD VERSUS YOUNG BLOOD FROM A PROGRAMMED AGING PERSPECTIVE
Tuesday, April 2, 2013
http://www.fightaging.org/archives/2013/04/old-blood-versus-young-blood-from-a-programmed-aging-perspective.php
The programmed aging camp points to experiments such as this as supportive of their view that aging is a genetic program that gives rise to damage and change, rather than resulting from damage that causes epigenetic changes to arise in reaction. The data could be interpreted either way, however, and there are other reasons to believe that aging is caused by damage: "In a 2005 experiment, one old mouse and one young mouse became artificial Siamese twins. For control, [researchers] also paired two old mice and two young mice. After the surgery, they injured one mouse from each pair, and monitored the healing process at a cellular level. As expected, the young mice recovered from injury much more efficiently than old mice. The surprise was that old mice that were paired with young mice healed as if they were young. "Importantly, the enhanced regeneration of aged muscle was due almost exclusively to the activation of resident, aged progenitor cells, not to the engraftment of circulating progenitor cells from the young partner." In other words, it was not young cells that implanted themselves in the old mice; it was signal proteins in the blood that told the old mouse tissue to go ahead and heal as if it were young. [A recent paper] culminates in a proposal for whole-body rejuvenation that might be practical in the near term. Fortuitously, its safety in humans has already been established, so people might be willing to try it if a course of animal experiments shows promise. The idea is simply to transfuse older subjects with blood plasma from a young donor, repeated often enough to sustain levels of signaling proteins that control gene expression." The mainstream view on why stem cells and tissue maintenance decline with age is that it is an evolved response to rising levels of damage that reduces cancer risk. Flooding an old system with young signaling overrides that response, but would probably be accompanied by an increased risk of cancer - though in the case of a short-term signal change as a therapy to promote regeneration of a specific injury, that may be an acceptable risk. In the long term, however, the underlying damage has to be repaired, rather than just forcing our biochemistry to continue as though it didn't exist.

THE IMPORTANCE OF AUTOPHAGY FOR MITOCHONDRIA
Monday, April 1, 2013
http://www.fightaging.org/archives/2013/04/the-importance-of-autophagy-for-mitochondria.php
Mitochondria are the powerplants of the cell, bacteria-like entities that produce chemical stores of energy to power cellular processes. The accumulation of damaged mitochondria is thought to cause a fair portion of degenerative aging, and differences in the ability of mitochondria to resist damage appear to play an important role in determining variation in life span between similar species. Autophagy is one of the processes by which damaged mitochondria are removed from consideration, in this case by destroying them and freeing up the materials for recycling. Autophagy also removes other damaged cell components and unwanted metabolic byproducts. Mitochondria-specific autophagy is often called mitophagy or macromitophagy, and a large pile of evidence suggests that it is this aspect of autophagy that is most responsible for the association between increased levels of autophagy and increased longevity in a range of laboratory species and different methods of life extension. At some point in the near future, development will be underway in earnest on drugs to boost autophagy. Here researchers add more evidence to considerations of autophagy and longevity while examining mitophagy in yeast under calorie restriction (CR), a well-known method of life extension: "In this study, we provide the first evidence that selective macroautophagic mitochondrial removal plays a pivotal role in longevity extension by a CR diet in chronologically aging yeast; such a diet was implemented by culturing yeast cells in a nutrient-rich medium initially containing low (0.2%) concentration of glucose, a fermentable carbon source. It should be emphasized that under these longevity-extending CR conditions yeast cells are not starving but undergo an extensive remodeling of their metabolism in order to match the level of ATP produced under longevity-shortening non-CR conditions. Moreover, our study also reveals that in chronologically aging yeast limited in calorie supply macromitophagy is essential for longevity extension by LCA. This bile acid is a potent anti-aging intervention previously shown to act in synergy with CR to enable a significant further extension of yeast lifespan under CR conditions by modulating so-called "housekeeping" longevity pathways. In sum, these findings imply that macromitophagy is a longevity assurance process that in chronologically aging yeast underlies the synergistic beneficial effects of anti-aging dietary and pharmacological interventions (i.e., CR and LCA) on lifespan. Our data suggest that macromitophagy can maintain survival of chronologically aging yeast limited in calorie supply by controlling a compendium of vital cellular processes known for their essential roles in defining longevity. [It] is conceivable that in chronologically aging yeast limited in calorie supply macromitophagy selectively eliminates dysfunctional mitochondria impaired in vital mitochondrial functions that define longevity."

HEIGHT LOSS CORRELATES WELL WITH OTHER ASPECTS OF AGING
Monday, April 1, 2013
http://www.fightaging.org/archives/2013/04/height-loss-correlates-well-with-other-aspects-of-aging.php
Aging is a global phenomenon throughout the body, and thus we should expect the pace of progression of any one aspect to correlate well with the others. So it is for height loss - meaning that you have the same modest level of control via lifestyle choices such as exercise and calorie restriction as is the case for aging in general: "Using unique data from a new massive longitudinal survey of 17,708 adults beginning at age 45, the researchers show for the first time that lifestyle choices we make in adulthood - and not just the hand we're dealt as children - influence how tall we stand as we age. While prior work has looked for the connection between height and health - both in childhood and adulthood - the researchers are the first to examine height loss as we age. They show that regardless of your maximum height, the loss of height over time is also an important indicator for other health issues as we age. For example, the research reveals an especially strong relationship between height loss and cognitive health. Those who had lost more height were also much more likely to perform poorly on standard tests of cognitive health such as short-term memory, ability to perform basic arithmetic and awareness of the date. All humans go through physical changes with age, including an increase in body fat and decrease in bone mass. But a decrease in height can be further exacerbated by certain kinds of arthritis, inflammation of spine joints or osteoporosis, which other studies have shown are associated with such lifestyle choices as diet, exercise and smoking."

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Posted 14 April 2013 - 05:37 PM

FIGHT AGING! NEWSLETTER
April 15th 2013

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

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CONTENT

- Perverse Incentives in Age and Funding Longevity Research
- Robust Cancer Therapies Will Mean More Aggressive Stem Cell Therapies
- On Genetic Association Studies of Human Longevity
- Exercise in Mice and Men
- Neural Plasticity and the Brain's Stem Cells
- Discussion
- Latest Headlines from Fight Aging!
- Limited Evidence for the Universality of Heat Shock Hormesis as a Way to Induce Longevity
- Examining the Biochemistry of Arctica Islandica Longevity
- On Intermittent Fasting
- Engineered Stem Cells Show Promise in Heart Therapy Trial
- Building Better Blood Vessels
- Support for Radical Life Extension in Canadian Public Survey
- Kidney Disease Risk is Another Reason Not to Be Overweight
- An Example of the Evolution of Life Span
- Considering Transposons and Neurodegeneration in Aging Flies
- More Chimeric Antigen Receptor Based Cancer Targeting

PERVERSE INCENTIVES IN AGE AND FUNDING LONGEVITY RESEARCH
http://www.fightaging.org/archives/2013/04/perverse-incentives-in-age-and-funding-longevity-research.php

Here is a thing to consider: as folk grow older they generally grow wealthier at the same time. There's nothing magical about this, of course. The longer you have to save and invest, the more you will have saved and invested. I'd imagine that the freedom and security that comes with not living hand to mouth or as a dependent is one of the more important reasons why older people are generally happier than younger people.

Older people also have the greatest need for the fruits of longevity science: better ways to treat age-related disease, but more importantly ways to reverse the course of aging by repairing its root causes, the various forms of low-level biochemical damage that accumulate over the years. So you might think that there is a fortunate confluence of circumstances here, in the the people who most need rejuvenation biotechnologies are also the people who have more in the way of resources that might help fund its development.

But there are perverse incentives at work here. The older you are, the less time you have to wait for the results of research and development to arrive. If you don't have decades to wait, then you are unlikely to benefit personally - unless you can write a check for a few hundred million dollars to the SENS Research Foundation and later buy yourself a couple of labs and clinics in less regulated Asia-Pacific countries to move directly to clinical application without going through the FDA or other equally hostile regulatory bodies. But most people can't do that, and there are few bold billionaires in this sense; most embody their own businesses and look little beyond them. The Elon Musk or Richard Branson of applied longevity science has yet to emerge.

So for the rest of the elder population, and from the raw self-interest point of view, there is no incentive to give meaningful sums to longevity science when the first rejuvenation therapies are, under the very best scenarios, at least twenty years away. Few people even see that possibility, offered by SENS if large-scale funding arrives soon, as most researchers in the longevity science mainstream tell the world that results are both far further out in time and will not achieve actual rejuvenation when they do arrive. So the old have diminished incentives to do anything to meaningful advance the state of research even as their bodies are constantly reminding them of their ongoing degeneration.

The young, of course, are extremely talented at ignoring the future. Humans, I should say, are extremely talented at ignoring the future - but the young don't yet have the constant nagging pain and lost-function reminders of a failing body, they are usually not on first name terms with the local medical community, and nor do they have as much in the way of money to donate to research into applied longevity science.

So the incentives founder at both ends of the human life span. You need vision if you're likely to benefit personally and selflessness if you are not, and neither of those things are as common as we'd all like them to be.

ROBUST CANCER THERAPIES WILL MEAN MORE AGGRESSIVE STEM CELL THERAPIES
http://www.fightaging.org/archives/2013/04/robust-cancer-therapies-will-mean-a-greater-use-of-aggressive-stem-cell-therapies.php

When it comes to medical procedures, everyone has their own definition of acceptable risk. Sadly we're then overruled by faceless bureaucrats at the US Food and Drug Administration (FDA) and similar government bodies - people who have only their own interests in mind, and suffer no consequences from making useful medical technologies illegal or too expensive for commercial use. Fortunately, the FDA doesn't rule the world: there are regions in which medical regulations are less onerous and therapies less costly, and these locations are only a plane flight away.

People who undertake medical tourism for stem cell therapies are demonstrating their own risk preferences: balancing the plausible expected benefits based on what is presently known of the science and the outcomes (in the absence of rigorous trials) against the cost and estimated risk. For stem cell treatments perhaps the largest inherent risk for early stage therapies is that of cancer resulting from the activities of transplanted cells. Work in the laboratory suggests that this risk is generally lower than first thought, but it still exists.

The world of cancer treatments is, meanwhile, changing profoundly, gearing up for a new generation of therapies that will displace chemotherapy and radiotherapy. Reprogramming immune cells or introducing targeted viruses and nanoparticles to seek out and kill cancer cells with few side-effects will be the standard operating procedure twenty years from now - and probably available outside the US in a decade. In early trials and the laboratory, these technologies are already showing impressive results.

Improvements in cancer treatment - leading to the introduction of robust therapies that can clear most common forms of cancer quickly and without accompanying illness - will, I think, go hand in hand with a far greater demand for and use of very aggressive stem cell treatments. Things like periodic infusions of massive numbers of immune cells cloned from a patient's own cells, done not just for people with medical conditions, but for the healthy as a beneficial preventative measure. Similarly, why boost regeneration and tissue maintenance via stem cell therapies only in the sick and the wounded? That makes sense if there is a significant risk associated with treatment, but in a world in which cancer is merely troublesome, why not make stem cell therapies a part of general health maintenance?

These are the sort of shifts in the cost-benefit picture of regenerative medicine that will emerge over the next couple of decades, driven by a growing ability to control the undesirable aspects of cellular biology, such as cancer.

ON GENETIC ASSOCIATION STUDIES OF HUMAN LONGEVITY
http://www.fightaging.org/archives/2013/04/examples-of-genetic-association-studies-of-human-longevity.php

A fair number of research groups worldwide are gathering and processing data in search of associations between minor genetic variations and human longevity. As for all studies of long-term human health, this a challenging process: statistics become involved, it is costly to gather data of even moderate quality, and the underlying biology is exceedingly complex. This is illustrated by the fact that comparatively few genetic associations can be validated across different study populations: if you find a genetic polymorphism with a statistically significant association with longevity in Italian lineages, the odds are very good that it won't show up in Asian populations, or even in other Italian study populations, for that matter. The range of minor variation in the human genome is very large, and it seems to be the case that there are many, many tiny genetic contributions to the way in which metabolism interacts with environment to determine natural longevity, most of which differ widely in different populations.

So while the funding lasts, this is a deep well for researchers to work on - just not one likely to produce more than knowledge for the foreseeable future. If you want actual results in terms of therapies to reverse the course of aging, then look to the programs described in the SENS research outline. The research community already knows what needs to be repaired in aged tissue, as the low-level differences between old and young tissue are well enumerated - it is the intricate, enormously complex metabolic dance of progressing from undamaged to damaged that remains an open field of work. The difference between SENS and the mainstream efforts to fully understand aging is the difference between on the one hand making the effort to rust-proof a metal surface and on the other producing a complete and detailed model of how rust progresses and interacts with metal structures at every level, from chemistry through to the physics of forces acting on structures and material strengths. The latter isn't necessary to achieve the goal of prevention once you know what rust is, and indeed will probably prove to cost far more than just preventing the rust.

EXERCISE IN MICE AND MEN
http://www.fightaging.org/archives/2013/04/exercise-in-mice-and-men.php

The weight of scientific evidence tells use that regular moderate exercise is very beneficial; aside from calorie restriction, it is the best thing that basically healthy people can do for themselves. No presently available medical technology surpasses the benefits of exercise and calorie restriction for long term health for the vast majority of the population - which is a strange thing to be saying in the midst of modern medicine and biotechnology. Strange but nonetheless true. This is a state of affairs we'd all like to see change for the better, via the introduction of new biotechnologies of rejuvenation, therapies that can be envisaged in some detail today, and which (if research and development is well funded) lie only a few decades ahead of us.

Near enough to matter, but still out of reach. So at this point exercise and calorie restriction are all that most of us have to work with to increase the odds of you still being alive to benefit from future rejuvenation therapies. It has to be said that the odds are not going to be moved to anywhere near the degree they would if a very large amount of funding arrived at the SENS Research Foundation, thus speeding up progress towards clinical reversal of age-related degeneration, but most of us are not in a position to make that happen.

The benefits of exercise are very broad, much like those offered by calorie restriction. It impacts mechanisms and the speed of change throughout the body and the aging process. On this topic, I recently noticed a couple of papers that note two small aspects of the interaction of exercise and aging, one in mice, and one in we humans. In mouse studies, it's quite possible to show that exercise causes numerous health benefits: mice are short-lived and thus researchers can follow them all the way through their lives.

n the case of humans a research group must instead work with shorter snapshots of time, drawing data from existing populations with their quirks and histories. Given that, it is much harder to prove the degree to which exercise causes good health and slower aging versus only being associated with these line items. Causation is hard to demonstrate - but the general presumption is that the causation shown in animal studies is also operating in human ones when it comes to things like exercise and cardiovascular health in aging. Proving and then putting numbers to that presumption are the challenges.

NEURAL PLASTICITY AND THE BRAIN'S STEM CELLS
http://www.fightaging.org/archives/2013/04/neural-plasticity-and-the-legions-of-stem-cells-in-the-brain.php

Neural plasticity - the ability of the brain to generate new neurons and make good use of them in its circuitry - is a topic of growing interest in the research community. That adult brains continue to create and assimilate new neurons was a comparatively recent discovery, first made in the 1960s, but lacking conclusive proof until the 1990s. Unfortunately, the pace at which this happens declines with age. Neurogenesis, the creation of neurons, requires an active neural stem cell population, and as appears to be the case for all stem cell populations, those in the brain decline in their activities with age. At the high level this is generally thought to be an evolutionary adaptation related to cancer, a part of the evolved balance between maintaining tissues and suppressing those maintenance activities when cellular damage (which grows with age) raises the odds of spawning a cancer.

It is thought that there are benefits to be gained by boosting the pace at which new neurons are created in old individuals. Aims include restoring the general loss of cognitive function that occurs with aging, developing new types of treatment for the named neurodegenerative diseases, and so forth. This ties into much of the present ongoing work on stem cells and aging: why do they stop performing their tasks; do they decline in number or just stop working; what exactly are the biochemical cues involved? The answers are emerging piece by piece, probably broadly similar but different in detail for every different stem cell population. The best outcome we can hope for is that all stem cell declines are a reaction to growing levels of damage and disarray in cells and cellular machinery - and thus the development of therapies to repair that damage will lead stem cell populations to revert to youthful behaviors without the need for further intervention.

DISCUSSION

The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!

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LATEST HEADLINES FROM FIGHT AGING!

LIMITED EVIDENCE FOR THE UNIVERSALITY OF HEAT SHOCK HORMESIS AS A WAY TO INDUCE LONGEVITY
Friday, April 12, 2013
http://www.fightaging.org/archives/2013/04/limited-evidence-for-the-universality-of-heat-shock-hormesis-as-a-way-to-induce-longevity.php
Researchers here examine the published literature on hormesis via heat shock, one of the ways shown to induce modest gains in longevity in laboratory animals, and find less support for positive outcomes than was thought. This may or may not be significant - the goal for researchers, as for calorie restriction and other means of extending longevity, is to find the underlying mechanism of action and build a therapy that triggers it with minimal side-effects. So long as heat shock can be demonstrated to improve long term health and longevity under at least some conditions, then there is a mechanism to be found and exploited. "Hormesis is the response of organisms to a mild stressor resulting in improved health and longevity. Mild heat shocks have been thought to induce hormetic response because they promote increased activity of heat shock proteins (HSPs), which may extend lifespan. Using data from 27 studies on 12 animal species, we performed a comparative meta-analysis to quantify the effect of heat shock exposure on longevity. Contrary to our expectations, heat shock did not measurably increase longevity in the overall meta-analysis, although we observed much heterogeneity among studies. Thus, we explored the relative contributions of different experimental variables (i.e. moderators). Higher temperatures, longer durations of heat shock exposure, increased shock repeat and less time between repeat shocks, all decreased the likelihood of a life-extending effect, as would be expected when a hormetic response crosses the threshold to being a damaging exposure. We conclude that there is limited evidence that mild heat stress is a universal way of promoting longevity at the whole-organism level. Life extension via heat-induced hormesis is likely to be constrained to a narrow parameter window of experimental conditions."

EXAMINING THE BIOCHEMISTRY OF ARCTICA ISLANDICA LONGEVITY
Friday, April 12, 2013
http://www.fightaging.org/archives/2013/04/examining-the-biochemistry-of-arctica-islandica-longevity.php
The clam species Arctica islandica is very long-lived, reaching at least four centuries in the wild. Researchers are comparing its biochemistry with similar but shorter-lived species to see if they can pinpoint the mechanisms that lead to its exceptional longevity. Here is recent research on this topic: "The observation of an inverse relationship between lifespan and mitochondrial H2 O2 production rate would represent strong evidence for the disputed oxidative stress theory of aging. Studies on this subject using invertebrates are surprisingly lacking, despite their significance in both taxonomic richness and biomass. Bivalve molluscs represent an interesting taxonomic group to challenge this relationship. They are exposed to environmental constraints such as microbial H2 S, anoxia/reoxygenation, and temperature variations known to elicit oxidative stress. Their mitochondrial electron transport system is also connected to an alternative oxidase that might improve their ability to modulate [the reactive oxygen species (ROS) generated by mitochondria and which produce oxidative stress]. Here we compared H2 O2 production rates in isolated mantle mitochondria between the longest living metazoan - the bivalve Arctica islandica - and two taxonomically related species of comparable size. In an attempt to test mechanisms previously proposed to account for a reduction of ROS production in long-lived species, we compared oxygen consumption of isolated mitochondria and enzymatic activity of different complexes of the electron transport system in the two species with the greatest difference in longevity. We found that A. islandica mitochondria produced significantly less [of the reactive oxygen species] H2 O2 than those of the two short-lived species in nearly all conditions of mitochondrial respiration tested, including forward, reverse, and convergent electron flow. Alternative oxidase activity does not seem to explain these differences. However, our data suggest that reduced complex I and III activity can contribute to the lower ROS production of A. islandica mitochondria, in accordance with previous studies." Reduced activity within mitochondria in this sense shows up in some longevity-inducing mutations in laboratory animals. Mitochondrial activity and composition (how much damage they cause per unit time, and how resistant they are to damage) appears to be very important as a determinant of longevity differences between species. This should increase our interest in ways to repair mitochondrial damage in humans as a potential rejuvenation therapy.

ON INTERMITTENT FASTING
Thursday, April 11, 2013
http://www.fightaging.org/archives/2013/04/on-intermittent-fasting-2.php
Here is a popular science article on intermittent fasting, something that extends life in mice, but which is not as well researched as calorie restriction, the gold standard for science on healthy life extension. There appears to be considerable overlap in the mechanisms involved in calorie restriction and intermittent fasting, but it's not all exactly the same when gene expression patterns are examined, to pick one example. "Many diet and exercise trends have origins in legitimate science, though the facts tend to get distorted by the time they achieve mainstream popularity. Benefits are exaggerated. Risks are downplayed. Science takes a backseat to marketing. One needn't look any further than the emerging trend of intermittent fasting for a prime example. There is indeed a large body of research to support the health benefits of fasting, though most of it has been conducted on animals, not humans. Still, the results have been promising. Fasting has been shown to improve biomarkers of disease, reduce oxidative stress and preserve learning and memory functioning. [There] are several theories about why fasting provides physiological benefits. "The one that we've studied a lot, and designed experiments to test, is the hypothesis that during the fasting period, cells are under a mild stress. And they respond to the stress adaptively by enhancing their ability to cope with stress and, maybe, to resist disease." But perhaps it isn't so much the fasting that produces health benefits, per se, as the resulting overall reduction in calorie intake (if, that is, you don't overeat on nonfasting days, which could create a caloric surplus instead of a deficit). That appears, at least, to be the case in slowing diseases such as cancer in mice. "Caloric restriction, undernutrition without malnutrition, is the only experimental approach consistently shown to prolong survival in animal models," In [a] study, mice fasted twice a week for 24 hours, but were otherwise permitted to eat at liberty. During nonfasting days, the mice overate. Overall, they did not lose weight, counteracting whatever benefits they might have seen from fasting. Intermittent fasting with compensatory overeating "did not improve mouse survival nor did it delay prostrate tumor growth," the study concluded." Equally, there are studies showing that intermittent fasting without calorie restriction does extend life in nematode worms. A lot more research is needed to bring intermittent fasting up to the level of confidence that we can have in calorie restriction.

ENGINEERED STEM CELLS SHOW PROMISE IN HEART THERAPY TRIAL
Thursday, April 11, 2013
http://www.fightaging.org/archives/2013/04/engineered-stem-cells-show-promise-in-heart-therapy-trial.php
Modest progress is demonstrated in a recent stem cell therapy trial for heart failure, putting some ballpark numbers to the level of benefits obtained by patients in reputable overseas clinics for some years now. It is to be expected that this sort of published result will lend further support for medical tourism while these therapies remain restricted and largely unavailable in countries like the US, thanks to the heavy hand of the FDA and similar regulatory bodies. This trial also shows the scope of remaining progress yet to be achieved if the goal is complete organ repair, something that will likely prove impossible without an accompanying repair of at least some of the low-level biochemical damage of aging. Heart failure doesn't just randomly happen in the vast majority of cases - it emerges as a consequence of the accumulated damage of aging in heart tissue and other organs. "The multi-center, randomized Cardiopoietic stem cell therapy in heart failure (C-CURE) trial involved heart failure patients from Belgium, Switzerland and Serbia. Patients in the control group received standard care for heart failure in accordance with established guidelines. Patients in the cell therapy arm received, in addition to standard care, cardiopoietic stem cells - a first-in-class biotherapeutic. In this process, bone marrow was harvested from the top of the patient's hip, and isolated stem cells were treated with a protein cocktail to replicate natural cues of heart development. Derived cardiopoietic stem cells were then injected into the patient's heart. Every patient in the stem cell treatment group improved. Heart pumping function improved in each patient within six months following cardiopoietic stem cell treatment. In addition, patients experienced improved fitness and were able to walk longer distances than before stem cell therapy. "Six months after treatment, the cell therapy group had a 7 percent absolute improvement in EF (ejection fraction) over baseline, versus a non-significant change in the control group. This improvement in EF is dramatic, particularly given the duration between the ischemic injury and cell therapy. It compares favorably with our most potent therapies in heart failure.""

BUILDING BETTER BLOOD VESSELS
Wednesday, April 10, 2013
http://www.fightaging.org/archives/2013/04/building-better-blood-vessels.php
One of the major hurdles in tissue engineering is populating tissue with blood vessels sufficient to support it. This is absolutely essential to enable the growth of anything more than a tiny amount of tissue. Decellularization has proven to be a useful way to work around present limits, but that requires donor tissue in order to obtain the guiding extracellular matrix structure. When it comes to building tissue from scratch, researchers are still working on techniques to create the necessary blood vessel networks. "One of the major obstacles to growing new organs - replacement hearts, lungs and kidneys - is the difficulty researchers face in building blood vessels that keep the tissues alive. "It's not just enough to make a piece of tissue that functions like your desired target. If you don't nourish it with blood by vascularizing it, it's only going to be as big as the head of a pen." Today, biomedical researchers are taking two main approaches to growing new capillaries, the smallest blood vessels and those responsible for exchanging oxygen, carbon dioxide and nutrients between blood and muscles or organs. One group of researchers is developing drug compounds that would signal existing vessels to branch into new tributaries. These compounds - generally protein growth factors - mimic how cancerous tumor cells recruit blood vessels. The other group [is] using a cell-based method. This technique involves injecting cells within a scaffolding carrier near the spot where you want new capillaries to materialize. [Researchers] deliver endothelial cells, which make up the vessel lining and supporting cells. Their scaffolding carrier is fibrin, a protein in the human body that helps blood clot. "The cells know what to do. You can take these things and mix them and put them in an animal. Literally, it's as easy as a simple injection and over a few days, they spontaneously form new vessels and the animals' own vasculature connects to them. The adult stem cells from fat and bone marrow both work equally well. If we want to use this clinically in five to 10 years, I think it's crucial for the field to focus on a support cell that actually has some stem cell characteristics.""

SUPPORT FOR RADICAL LIFE EXTENSION IN CANADIAN PUBLIC SURVEY
Wednesday, April 10, 2013
http://www.fightaging.org/archives/2013/04/support-for-radical-life-extension-in-canadian-public-survey.php
An interesting result here, given that most surveys of the public conducted in recent years show mixed interest or a lack of interest in greatly extending healthy human life via medical biotechnology. Perhaps measurable progress in changing minds and educating the public is occurring now - and certainly such progress should speed up at some point after a slow start - but we need to see more such encouraging surveys before drawing that conclusion: "This paper explores Canadian public perceptions of a hypothetical scenario in which a radical increase in life expectancy results from advances in regenerative medicine. A national sample of 1231 adults completed an online questionnaire on stem cell research and regenerative medicine, including three items relating to the possibility of Canadians' average life expectancy increasing to 120 years by 2050. Overall, Canadians are strongly supportive of the prospect of extended lifespans, with 59% of the sample indicating a desire to live to 120 if scientific advances made it possible, and 47% of respondents agreeing that such increases in life expectancy are possible by 2050. The strongest predictors of support for radical life extension are individuals' general orientation towards science and technology and their evaluation of its plausibility. These results contrast with previous research, which has suggested public ambivalence for biomedical life extension, and point to the need for more research in this area. They suggest, moreover, that efforts to increase public awareness about anti-aging research are likely to increase support for the life-extending consequences of that research program."

KIDNEY DISEASE RISK IS ANOTHER REASON NOT TO BE OVERWEIGHT
Tuesday, April 9, 2013
http://www.fightaging.org/archives/2013/04/kidney-disease-risk-is-another-reason-not-to-be-overweight.php
Being overweight appears to behave much as though you are accumulating damage to your biology. The more time you spend being overweight and the more excess visceral fat tissue you carry, the greater your risk of suffering age-related conditions later in life, the greater your lifetime medical expenditures, and the shorter your life expectancy. The mechanisms that cause these effects may be largely linked to levels of chronic inflammation, which are increased by visceral fat tissue, though there are undoubtedly other things going on under the hood. "Being overweight starting in young adulthood may significantly increase individuals' risks of developing kidney disease by the time they become seniors, according to [a new study]. The findings emphasize the importance of excess weight as a risk factor for chronic kidney disease (CKD). The researchers analyzed information from the Medical Research Council National Survey of Health and Development, a sample of children born in one week in March 1946 in England, Scotland, and Wales. A total of 4,584 participants had available data, including body mass index at ages 20, 26, 36, 43, 53, and 60 to 64 years. Participants who were overweight beginning early in adulthood (ages 26 or 36 years) were twice as likely to have CKD at age 60 to 64 years compared with those who first became overweight at age 60 to 64 years or never became overweight. The link between overweight and CKD was only in part explained by taking diabetes and hypertension into account. Larger waist-to-hip ratios ("apple-shaped" bodies) at ages 43 and 53 years were also linked with CKD at age 60 to 64 years. "We estimated that 36% of CKD cases at age 60 to 64 in the current US population could be avoided if nobody became overweight until at least that age, assuming the same associations as in the analysis sample.""

AN EXAMPLE OF THE EVOLUTION OF LIFE SPAN
Tuesday, April 9, 2013
http://www.fightaging.org/archives/2013/04/an-example-of-the-evolution-of-life-span.php
Life span in a species is an evolved trait: if longer lives provide a competitive advantage over shorter-lived peers, then a species will tend to become longer lived over time. We humans are long-lived for our size in comparison to other mammals, and the current thinking on that is that it may have to do with our intelligence and social nature - there is a selection effect based on advantages to survival provided by the presence of post-reproductive elders in a collaborative environment. Salmon provide another example of the impact of evolution on aging, with their unusual aging process driven by levels of predation. The environment in which a species lives has a strong effect on life span. Here is an open access paper that considers another collection of fish species in which life spans evolved to adapt to differing mortality rates caused by environmental factors: "Early evolutionary theories of aging predict that populations which experience low extrinsic mortality evolve a retarded onset of senescence. [Here], we study annual fish of the genus Nothobranchius whose maximum lifespan is dictated by the duration of the water bodies they inhabit. Different populations of annual fish do not experience different strengths of extrinsic mortality throughout their life span, but are subject to differential timing (and predictability) of a sudden habitat cessation. In this respect, our study allows testing how aging evolves in natural environments when populations vary in the prospect of survival, but condition-dependent survival has a limited effect. We use 10 Nothobranchius populations from seasonal pools that differ in their duration to test how this parameter affects longevity and aging in two independent clades of these annual fishes. We found that replicated populations from a dry region showed markedly shorter captive lifespan than populations from a humid region. Shorter lifespan correlated with accelerated accumulation of lipofuscin (an established age marker) in both clades. Analysis of wild individuals confirmed that fish from drier habitats accumulate lipofuscin faster also under natural conditions. This indicates faster physiological deterioration in shorter-lived populations. [The] characterization of pairs of closely related species with different longevities should provide a powerful paradigm for the identification of genetic variations responsible for evolution of senescence in natural populations."

CONSIDERING TRANSPOSONS AND NEURODEGENERATION IN AGING FLIES
Monday, April 8, 2013
http://www.fightaging.org/archives/2013/04/considering-transposons-and-neurodegeneration-in-aging-flies.php
You might recall a recent article on transposons as a form of more aggressive genetic damage and disarray in the later stages of aging. It is unclear as to whether this is a secondary effect or whether it does in fact contribute to age-related decline at that stage; the arguments would be much the same as those made for other forms of stochastic DNA damage in aging. Here is another example of recently published research on transposons and aging: "[Researchers] showed that when the activity of a protein called Ago2 (Argonaute 2) was perturbed, so was long-term memory [in fruit flies] - which was tested using a trained Pavolvian response to smell. Since Ago2 is known to be involved in protecting against transposon activity in fruit flies, [the scientists] were compelled to look for transposons. Though transposons have been shown to be active during normal brain development, they are silenced soon afterward. The implication is that they have some functional role in development. When [the team] looked for transposons they found that there is a marked increase in transposon levels in the brain cells, or neurons, by 21 days of age in normal fruit flies. The levels were observed to increase steadily with age. These transposons, including one in particular called gypsy, were highly active, jumping from place to place in the genome. When they blocked Ago2 from being expressed in fruit flies, transposons accumulated at a much younger age. Accompanying this transposon accumulation were defects in long-term memory that mirrored those usually seen in much older flies, as well as a much-reduced lifespan. "Essentially the Ago2 knock out flies have no long-term memory by the time they are 20 days old, while normal flies have a normal long-term memory at the same age." [The researchers propose] that a "transposon storm" may be responsible for age-related neurodegeneration as well as the pathology seen in some neurodegenerative disorders. However, [the] studies so far don't address whether transposons are the cause or an effect of aging-related brain defects. "The next step will be to activate transposons by genetically manipulating fruit flies and ask whether they are a direct cause of neurodegeneration."" The challenge with this sort of research is that it's easy to exhibit reduced life span by pulling out necessary parts of an animal's biochemistry, but very hard to show that this is actually relevant to aging versus just another form of causing damage. The real test in this case would be to find a way to suppress transposons with minimal other changes to biochemistry and show extended life - or at least preserved cognitive function - as a result. That would be compelling.

MORE CHIMERIC ANTIGEN RECEPTOR BASED CANCER TARGETING
Monday, April 8, 2013
http://www.fightaging.org/archives/2013/04/more-chimeric-antigen-receptor-based-cancer-targeting.php
Immune cells can be engineered to selectively target cancer cells for destruction via use of chimeric antigen receptors that match up with proteins that are more common on the exterior of a cancer cell. This strategy has been in the news of late with impressive successes against leukemia. Here researchers show that better results can be obtained by chaining together two marginal targets, each of which is only slightly discriminating for cancer cells if used on its own. "T cells made to express a protein called CAR, for chimeric antigen receptor, are engineered by grafting a portion of a tumor-specific antibody onto an immune cell, allowing them to recognize antigens on the cell surface. Early first-generation CARs had one signaling domain for T-cell activation. Second-generation CARs are more commonly used and have two signaling domains within the immune cell, one for T-cell activation and another for T- cell costimulation to boost the T cell's function. Importantly, CARs allow patients' T cells to recognize tumor antigens and kill certain tumor cells. A large number of tumor-specific, cancer-fighting CAR T cells can be generated in a specialized lab using patients' own T cells, which are then infused back into them for therapy. Despite promising clinical results, it is now recognized that some CAR-based therapies may involve toxicity against normal tissues that express low amounts of the targeted tumor-associated antigen. To address this issue [researchers] developed an innovative dual CAR approach in which the activation signal for T cells is physically dissociated from a second costimulatory signal for immune cells. The two CARs carry different antigen specificity - mesothelin and a-folate receptor. Mesothelin is primarily associated with mesothelioma and ovarian cancer, and a-folate receptor with ovarian cancer. [Dual] CAR T cells are more selective for tumor cells since their full activity requires interaction with both antigens, which are only co-expressed on tumor cells, not normal tissue."

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Posted 21 April 2013 - 06:25 PM

FIGHT AGING! NEWSLETTER
April 22nd 2013

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

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CONTENT

- Converting this Newsletter to HTML Formatting
- Aubrey de Grey on "the Undoing of Aging"
- A Short Interview With Researcher João Pedro de Magalhães
- Longevity, Technological Progress, and Economic Growth
- At the Intersection of Aging, Cancer, and Cellular Senescence
- Audience Data for Fight Aging!
- Discussion
- Latest Headlines from Fight Aging!
- Mitochondrial Functional Mutations and Worm Longevity
- Indy Mutations and Fly Longevity
- Sterilized Dogs Live Longer
- Exploring Genetic Regulation of Heart Regeneration
- The Other Side of CD47: a Way to Spawn Induced Pluripotent Stem Cells
- A Popular Science Article on the Genetics of Human Longevity
- Cell-Nanoparticle Hybrids, an Illustration of What is to Come
- An Update on Protofection
- A Look at Some of Ray Kurzweil's Predictions on Longevity
- Decellularization Produces Partially Functional Kidneys in Rats

CONVERTING THIS NEWSLETTER TO HTML FORMATTING

I would like to begin sending out the Fight Aging! Newsletter in HTML format rather than the present plain text. This would allow for the same general visual layout as the Fight Aging! website, which in theory will make the newsletter more attractive and easier to read - it will certainly improve separation between comments and quotes, for example. The last time I brought this up as a possibility, some years ago, it was greeted by a modest chorus of grumbles from the old school of mail readers, but I think that the state of email software has since advanced to the point at which everyone should be able to receive an HTML email and still read it as text without the formatting if they so choose.

If you have strong opinions either way on this topic, do let me know.

AUBREY DE GREY ON "THE UNDOING OF AGING"
http://www.fightaging.org/archives/2013/04/aubrey-de-grey-on-the-undoing-of-aging.php

A recent short article from Aubrey de Grey of the SENS Research Foundation:

The desire to defeat aging is surely even more long-standing than the quest to reach the stars. Unfortunately, the idea that we will crumble and die is so crippling that most people evidently need to convince themselves, by whatever means, that it is not such a bad thing after all. Whether it's the existence of a joyous afterlife, or the presumption that a post-aging world would be unsustainably overpopulated, or the fear of immortal dictators, a conversation with nearly anyone about the idea of developing medicine to prevent age-related ill-health is almost certain to be derailed into arguments about whether such medicine would be a good thing at all.

A key pillar of many people's thinking about this topic is the misconception that "aging itself" is somehow a different sort of thing than the diseases of old age. There is actually no such distinction. Age-related diseases spare young adults simply because they take a long time to develop, and they affect everyone who lives long enough because they are side-effects of the body's normal operation rather than being caused by external factors such as infections. In other words, aging is simply the collection of early stages of the diseases and disabilities of old age, and treatment of aging is simply preventative medicine for those conditions - preventative geriatrics. It is thus logically incoherent to support medicine for the elderly but not medicine for aging.

I claim no originality for the above: it has long been the virtually universal view of those who study the biology of aging. I believe it is resisted by the wider world, despite those experts' energetic efforts, overwhelmingly because people don't believe there is much chance of significant progress in their or even their children's lifetimes and they don't want to get their hopes up. But in recent years, the justification for such pessimism has evaporated.

It has done so above all because of progress in regenerative medicine, which colloquially (but see below) consists of stem cells and tissue engineering. Regenerative medicine can be defined as the restoration of bodily function by restoration of structure. We may replace entire organs (tissue engineering), or we may repair organs by replacing their constituent cells (stem cell therapy). In a sense, regenerative medicine is maintenance for the human body. as such, it should in principle be capable of constituting preventative maintenance for the chronic, slowly progressive, initially harmless but eventually fatal processes that jointly make up aging and the diseases of old age. Regenerative medicine has only recently, however, become recognized as a promising avenue for postponing age-related ill-health. This is for two reasons. firstly, it was originally conceived and pursued for its potential to treat acute injury, such as spinal cord trauma, rather than chronic damage: thus, regenerative medicine pioneers and biologists of aging simply didn't talk to each other very much, with the result that those studying aging were insufficiently informed about progress in regenerative medicine to appreciate its potential. The second reason was equally important: in order to be plausibly applicable to aging, regenerative medicine must be broadened into a host of other areas, over and above stem cells and tissue engineering, and those areas are mostly at considerably earlier stages of development.

But not fancifully early. In the decade since I first laid out a putatively comprehensive classification of the various types of molecular and cellular "damage" that must be periodically repaired in order to stave off the decline of old age, and the specifics of how we might do it, progress has been gratifyingly rapid (though I estimate it could be at least three times faster if the potential of this approach were more widely understood and funding for it correspondingly elevated). Furthermore, that plan has abundantly stood the test of time, undergoing only minor adjustments.

In this short, general-audience piece I can only hint at the advances over the past year or two achieved by researchers worldwide in this space. SENS Research Foundation was created for this purpose, and alongside numerous other institutes and organizations, both commercial and nonprofit, we have achieved not only the retardation of aging but its actual repair, restoring youthful health to animals that were suffering widespread age-related decline. Much remains to be done to extend these results, before they can realistically be applied in the clinic. However, the removal of toxic metabolic by-products shows clear promise of completely eliminating cardiovascular disease, the Western world's foremost killer, and also macular degeneration, the leading cause of blindness in the elderly. Similarly, removing cells that have become dysregulated and toxic to the body was recently shown, in multiple models, to restore function to sick animals. Advances like these, in combination with traditional regenerative medicine, may in the next few decades deliver a truly comprehensive and dramatic postponement of age-related ill-health.

A SHORT INTERVIEW WITH RESEARCHER JOÃO PEDRO DE MAGALHÃES
http://www.fightaging.org/archives/2013/04/a-short-interview-with-researcher-joao-pedro-de-magalhaes.php

João Pedro de Magalhães is the researcher behind the excellent senescence.info site, the Animal Aging and Longevity Database, the Aging Gene Database, and sundry other projects. He presently heads the Integrative Genomics of Ageing Group at the University of Liverpool, and is one of the modern generation of life scientists unafraid to declare in public that the goal of the field should be nothing less than to cure aging. Many more people of this vision and drive are needed in the field of aging research if we are to see more rapid progress towards rejuvenation biotechnology. I noticed a short iinterview with de Magalhães in the Argentinian Spanish language press today that gives an executive summary of some of his views. Follow the link above for a translated version.

LONGEVITY, TECHNOLOGICAL PROGRESS, AND ECONOMIC GROWTH
http://www.fightaging.org/archives/2013/04/longevity-technological-progress-and-economic-growth.php

Longevity and wealth go hand in hand. This association is very evident in many periods of history, such as the century leading up to the industrial revolution in England, or the more recent and very rapid transformation of South Korean society from rural poverty to industrialized wealth, accompanied by an equally rapid rise in life expectancy.

Thus economics should be a topic of at least passing interest for everyone who follows longevity science, or looks forward to a future of extended healthy life provided by new medical biotechnologies. Frankly, economics in the broadest sense of human action and its explanations should be of at least passing interest to everyone: societies rise and fall based upon the public understanding or lack of understanding regarding the origins of wealth and economic growth. There seem to be cycles in which those who understand dominate and thus build prosperity, only for their descendants to give it all back to waste and destruction because they fail to grasp why it is that their society is prosperous. Comparative wealth is very good at sheltering people from the realities of how the world works, sadly. These days the US seems to be on the downward slope of that cycle: there is a lot more of eating of seed corn and corruption than even as recently as twenty years ago.

On the grand scale this will slow down progress in technology across the board in comparison to what might have been. Corruption manifests itself most evidently as centralization of power and resulting regulation, which in turn attracts those who live to propagate control for the sake of control. Medicine and biotechnology are being choked beneath a mountain of red tape. One can hope that other regions of the world will take up the slack as the grand medical research community of the US is slowly crushed into an inability to produce and commercialize anything truly new and innovative.

But I hadn't intend this to be a gloomy post, and the very readable paper I want to bring to your attention today is, ultimately, an optimistic take on human progress - both in longevity and in wealth. And indeed, I am optimistic for the long term; empires rise and fall, the US only different in detail from those that came before, and humanity nonetheless marches onward, building new technologies at what seems to be an every-increasing pace, despite the politics, politicians, and parasites. What gloom there is stems from that fact that you and I don't have forever to wait for the just-around-the-corner biotechnologies that will enhance human longevity - there is plenty of room for ugly economic or political collapse to delay matters long enough to produce a poor outcome for us, while still winding up as just another fiddling detail of early 21st century history to the ageless folk of the 2100s and later.

AT THE INTERSECTION OF AGING, CANCER, AND CELLULAR SENESCENCE
http://www.fightaging.org/archives/2013/04/further-research-on-bubr1-cellular-senescence-and-aging.php

The gene BubR1 is of interest to cancer researchers involved in the study of various forms of nuclear DNA damage, the intricate but usually very reliable DNA repair mechanisms that strive to revert that damage, dysfunction in those repair mechanisms, and how these items relate to cancer and aging. Cancer is quite clearly a condition spawned by damage to the DNA in the cell nucleus; the more of that damage you suffer, the more likely it is that one of your cells will undergo the right combination of mutations to turn it into an unfettered, self-replicating cancer seed - something that looks and acts a lot like a stem cell, spawning copies of itself and a legion of descendants prone to further mutation and causing havoc.

For those of us who follow longevity science, the gene BubR1 is of interest because altering its gene expression level is one of the few simple mechanisms than can both shorten and extend life in mice. Less BubR1 produces an accelerated aging condition, while more of it appears to slow aging, reducing the incidence of various common age-related conditions in the mice that have this gene therapy applied to them.

It is important to note that accelerated aging conditions are generally classed as DNA repair dysfunctions. The worse the dysfunction, the faster that the individual suffers what looks a lot like accelerated aging - but there is some debate in the research community as to whether what is happened should be described as accelerated aging. From the perspective of those of us interested in ways to extend healthy life, research results involving laboratory animals suffering from artificially induced forms of accelerated aging have to be viewed carefully, because they are rarely straightforwardly applicable to normal aging. When you alter genes in a way that causes accelerating aging, such as by reducing the efficiency of some crucial part of DNA repair, this is analogous to breaking a part of a machine - you shouldn't be surprised to find that it fails sooner and more readily than its unbroken peers. That doesn't necessarily say anything about how you might extend the working life of that type of machinery, however.

So you really have to look at each research result on a case by case basis; the ones that are interesting and do have something to say about normal aging are almost always those in which the mechanism causing accelerating aging can be turned around to extend life, as is the case for BubR1 levels.

As it so happens, this all ties in to cellular senescence, another topic of interest to those of us who follow developments in longevity science. Senescent cells are those that have left the cell cycle due to age or damage - such as damage to their nuclear DNA - and really should be destroyed, either by their own programmed cell death processes or by the immune system. Cellular senescence might be thought of as a part of the evolved balance between cancer risk and the need for cells to work and maintain tissues; the more damage there is in the cellular environment, the more cells become senescent, an adaptation that lowers the risk of cancer by preventing damaged cells from undertaking their normal range of activities.

Unfortunately senescent cells are still harmful in and of themselves, as they secrete all sorts of unwanted signals and remodel their local environment. The more of them there are, the more their presence damages the surrounding tissue. The growth in senescent cells with age is one of the root causes of degenerative aging, and getting rid of them on a regular basis is one of the proposed rejuvenation therapies in the SENS vision for reversing the course of aging.

A demonstration of improved health measures in mice through destruction of senescent cells was carried out two years ago. The study used BubR1 mutants suffering from accelerated aging - and thus a faster accumulation of DNA damage and senescent cells. Researchers often use accelerated aging as a way to enable studies to conclude more rapidly, and thus be conducted at an affordable cost; there is an enormous difference in cost between a study that runs a few months and one that runs a few years. Here, however, it is the case that the researchers involved are as much interested in cancer and DNA damage as they are in aging, and the BubR1 mice are their main object of study for many reasons. That they are producing results of interest to longevity science on the matter of cellular senescence is a side-effect of the main thrust of their research, and a consequence of the overlapping mechanisms involved: DNA damage, DNA repair, cancer, aging, accelerated aging, and cellular senescence.

AUDIENCE DATA FOR FIGHT AGING!
http://www.fightaging.org/archives/2013/04/revisiting-audience-data-for-fight-aging-long-tails-and-bear-consumption.php

I thought it time to one again say something about the Fight Aging! audience data; for all the numbers, follow the link above. I am occasionally asked about this, so I'm given to think that some of the other folk who run similar sites may benefit from this very infrequent series of posts. Other regular readers may take the information below as a data point to add to what is known about the size and scope of the longevity science community: researchers, advocates, and supporters. As is always the case, I should note that Fight Aging! is a niche concern: any hard science site is already a low traffic venture, and this is even more the case for specialist hard science sites that focus on small fields. Much as I would like to say otherwise, longevity science is a small subfield of aging research, which in turn is a small field within the medical life sciences, tiny in comparison to many of its peers. Neither human longevity nor aging research in general have the funding or attention they merit, given the possibilities for rejuvenation biotechnology that lie ahead and the level of harm caused by aging. We'd all like to see this change - and it needs to change if we are going to anything other than age to death like our ancestors did.

DISCUSSION

The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!

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LATEST HEADLINES FROM FIGHT AGING!

MITOCHONDRIAL FUNCTIONAL MUTATIONS AND WORM LONGEVITY
Friday, April 19, 2013
http://www.fightaging.org/archives/2013/04/mitochondrial-functional-mutations-and-worm-longevity.php
Many longevity mutations discovered in lower animals such as nematodes involve alterations to mitochondrial function - which only reinforces the apparent importance of mitochondria in determining life span. Mitochondria swarm within cells, working to produce the chemical energy stores used to power cellular operations. In doing so they emit reactive oxygen species, however, that can cause all sorts of harm to the molecular machinery of a cell if not neutralized by a cell's native antioxidants. It is damage to mitochondrial DNA, however, that seems to be one of the root causes of degenerative aging, via a Rube Goldberg sequence of consequences that causes cells to become dysfunctional mass exporters of reactive, harmful molecules. From a practical therapy standpoint, the research community should be working on ways to repair, replace, or back up mitochondrial DNA in our cells if we want this contribution to aging to go away. That work is very poorly funded, however, in comparison to the benefits it might deliver. Meanwhile, examination of longevity mutations in lower animals continues to reinforce the fact that this is an important direction for therapies to treat and reverse aging. Some mitochondrial longevity mutations work via hormesis; they cause a slight increase in the level of emitted reactive oxygen species, which in turn causes the cell to react with increased housekeeping and repair activities, resulting in a net gain - less damage over the long term translates into slower aging. Other mutations lower the level of emitted reactive oxygen species, which again means less damage over the long term. Yet more mitochondrial mutations extend life in less obvious ways, or cause mitochondrial dysfunction that appears at the high level to be broadly similar to that of longevity mutants, yet reduces life span. Once you start digging in to the mechanisms of the mitochondrial interior - the electron transport chain with it's multiple complexes - it's all far from simple Here is an example of research into the mechanisms of mitochondrial longevity mutations in nematode worms: "Many Caenorhabditis elegans mutants with dysfunctional mitochondrial electron transport chain are surprisingly long lived. Both short-lived (gas-1(fc21)) and long-lived (nuo-6(qm200)) mutants of mitochondrial complex I have been identified. However, it is not clear what are the pathways determining the difference in longevity. We show that even in a short-lived gas-1(fc21) mutant, many longevity assurance pathways, shown to be important for lifespan prolongation in long-lived mutants, are active. Beside similar dependence on alternative metabolic pathways, short-lived gas-1(fc21) mutants and long-lived nuo-6(qm200) mutants also activate hypoxia-inducible factor-1α (HIF-1α) stress pathway and mitochondrial unfolded protein response (UPRmt). The major difference that we detected between mutants of different longevity is in the massive loss of complex I accompanied by upregulation of complex II levels, only in short-lived, gas-1(fc21) mutant. We show that high levels of complex II negatively regulate longevity in gas-1(fc21) mutant by decreasing the stability of complex I. Furthermore, our results demonstrate that increase in complex I stability, improves mitochondrial function and decreases mitochondrial stress, putting it inside a "window" of mitochondrial dysfunction that allows lifespan prolongation."

INDY MUTATIONS AND FLY LONGEVITY
Friday, April 19, 2013
http://www.fightaging.org/archives/2013/04/indy-mutations-and-fly-longevity.php
The indy gene - named for "I'm not dead yet" - was one of the earliest longevity mutations to be uncovered in flies, and consequently is somewhat better studied than the many that have followed since then. Here is an open access paper on the subject: "Decreased expression of the fly and worm Indy genes extends longevity. The fly Indy gene and its mammalian homolog are transporters of Krebs cycle intermediates, with the highest rate of uptake for citrate. Cytosolic citrate has a role in energy regulation by affecting fatty acid synthesis and glycolysis. Fly, worm, and mice Indy gene homologs are predominantly expressed in places important for intermediary metabolism. Consequently, decreased expression of Indy in fly and worm, and the removal of mIndy in mice exhibit changes associated with calorie restriction, such as decreased levels of lipids, changes in carbohydrate metabolism and increased mitochondrial biogenesis. Here we report that several Indy alleles in a diverse array of genetic backgrounds confer increased longevity." The paper is a good example of the way in which calorie restriction muddies the water of longevity studies; the effects of calorie restriction on life span are very strong in lower animals like flies and worms, and many past studies failed to fully account for differing dietary calorie intakes between populations of these animals. The authors of this paper point out a number of past papers with results that may tainted due to differing calorie intake, and note that their own work tries to control for this.

STERILIZED DOGS LIVE LONGER
Thursday, April 18, 2013
http://www.fightaging.org/archives/2013/04/sterilized-dogs-live-longer.php
A range of research in laboratory animals associates alterations to the reproductive system with alterations in longevity. Nematode worms live longer if you remove their germ cells, for example. Transplanting younger ovaries into older mice extends life as well. There is some thought that these varied approaches work through common longevity mechanisms such as insulin-like signaling pathways, but that's by no means certain. Here is another set of data to add to the existing research on this topic: "Reproduction is a risky affair; a lifespan cost of maintaining reproductive capability, and of reproduction itself, has been demonstrated in a wide range of animal species. However, little is understood about the mechanisms underlying this relationship. Most cost-of-reproduction studies simply ask how reproduction influences age at death, but are blind to the subjects' actual causes of death. Lifespan is a composite variable of myriad causes of death and it has not been clear whether the consequences of reproduction or of reproductive capability influence all causes of death equally. To address this gap in understanding, we compared causes of death among over 40,000 sterilized and reproductively intact domestic dogs, Canis lupus familiaris. We found that sterilization was strongly associated with an increase in lifespan, and while it decreased risk of death from some causes, such as infectious disease, it actually increased risk of death from others, such as cancer. Although a retrospective, epidemiological study such as this cannot prove causality, our results suggest that close scrutiny of specific causes of death, rather than lifespan alone, will greatly improve our understanding of the cumulative impact of reproductive capability on mortality. Our results strongly demonstrate the need to determine the physiologic consequences of sterilization that influence causes of death and lifespan. Shifting the focus from when death occurs to why death occurs could also help to explain contradictory findings from human studies."

EXPLORING GENETIC REGULATION OF HEART REGENERATION
Thursday, April 18, 2013
http://www.fightaging.org/archives/2013/04/exploring-genetic-regulation-of-heart-regeneration.php
Will it be possible in years ahead to temporarily adjust the programming of existing cell populations in the body to cause them to regenerate from damage and injuries more effectively than is presently the case? Most likely so, though it is a fair distance from present early explorations to a safe and effective therapy. Here is an example of work presently underway in the laboratory: ""We found that the activity of the Meis1 gene increases significantly in heart cells soon after birth, right around the time heart muscle cells stop dividing. Based on this observation we asked a simple question: If the Meis1 gene is deleted from the heart, will heart cells continue to divide through adulthood? The answer is 'yes.'" The research team demonstrated that deletion of Meis1 extended the proliferation period in the hearts of newborn mice, and also re-activated the regenerative process in the adult mouse heart without harmful effect on cardiac functions. This new finding demonstrates that Meis1 is a key factor in the regeneration process, and the understanding of the gene's function may lead to new therapeutic options for adult heart regeneration. The findings also provide a possible alternative to current adult heart regeneration research, which focuses on the use of stem cells to replace damaged heart cells. "Meis1 is a transcription factor, which acts like a software program that has the ability to control the function of other genes. In this case, we found that Meis1 controls several genes that normally act as brakes on cell division. As such, Meis1 could possibly be used as an on/off switch for making adult heart cells divide. If done successfully, this ability could introduce a new era in treatment for heart failure.""

THE OTHER SIDE OF CD47: A WAY TO SPAWN INDUCED PLURIPOTENT STEM CELLS
Wednesday, April 17, 2013
http://www.fightaging.org/archives/2013/04/the-other-side-of-cd47-a-way-to-spawn-induced-pluripotent-stem-cells.php
CD47 is a cell surface marker that tells immune cells to leave a cell alone. Researchers are presently using CD47 as a target for next-generation cancer therapies - and quite effectively. The marker seems to be present to a greater level that usual in all cancers examined to date, and blocking it frees the immune system to attack the cancer cells. I noticed another research item today in which a group found that removing CD47 triggers the set of genes known to cause normal adult cells to become induced pluripotent stem (iPS) cells. This is a very interesting result given the cancer connection, and given that this manipulation doesn't seem to make cells prone to generating cancer: "In 2008 [researchers] were using agents that block a membrane protein called CD47 to explore their effects on blood vessels. When cells from the lining of the lungs, called endothelium, had been treated with a CD47 blocker, they stayed healthy and maintained their growth and function for months. [The] team continued to experiment with CD47 blockade, focusing on defining the underlying molecular mechanisms that control cell growth. They found that endothelial cells obtained from mice lacking CD47 multiplied readily and thrived in a culture dish, unlike those from control mice. [The researchers] discovered that this resulted from increased expression of four genes that are regarded to be essential for formation of iPS cells. When placed into a defined growth medium, cells lacking CD47 spontaneously formed clusters characteristic of iPS cells. By then introducing various growth factors into the culture medium, these cells could be directed to become cells of other tissue types. Despite their vigorous growth, they didn't form tumors when injected into mice, a major disadvantage when using existing iPS cells. "Stem cells prepared by this new procedure should be much safer to use in patients. Also, the technique opens up opportunities to treat various illnesses by injecting a drug that stimulates patients to make more of their own stem cells. These experiments indicate that we can take a primary human or other mammalian cell, even a mature adult cell, and by targeting CD47 turn on its pluripotent capability. We can get brain cells, liver cells, muscle cells and more. In the short term, they could be a boon for a variety of research questions in the lab.""

A POPULAR SCIENCE ARTICLE ON THE GENETICS OF HUMAN LONGEVITY
Wednesday, April 17, 2013
http://www.fightaging.org/archives/2013/04/a-popular-science-article-on-the-genetics-of-human-longevity.php
A great deal of work in the aging research community focuses on trying to untangle the relationship between genes, epigenetic patterns of gene expression, metabolism, and natural variations in human longevity. It's an enormously complex task, far harder than just trying to repair the known biochemical damage of aging - analogous to producing a general theory and full mathematical model of paint peeling rather than just repainting a wall. "In the dimly lit, chilly hallway outside Passarino's university office stand several freezers full of tubes containing centenarian blood. The DNA from this blood and other tissue samples has revealed additional information about the [study population]. For example, people who live into their 90s and beyond tend to possess a particular version, or allele, of a gene important to taste and digestion. This allele not only gives people a taste for bitter foods like broccoli and field greens, which are typically rich in compounds known as polyphenols that promote cellular health, but also allows cells in the intestine to extract nutrients more efficiently from food as it's being digested. Passarino has also found in his centenarians a revved-up version of a gene for what is called an uncoupling protein. The protein plays a central role in metabolism - the way a person consumes energy and regulates body heat - which in turn affects the rate of aging. "We have dissected five or six pathways that most influence longevity," says Passarino. "Most of them involve the response to stress, the metabolism of nutrients, or metabolism in general - the storage and use of energy." His group is currently examining how environmental influences - everything from childhood diet to how long a person attends school - might modify the activity of genes in a way that either promotes or curtails longevity. If nothing else, the plethora of new studies indicates that longevity researchers are pushing the scientific conversation to a new level. [But] genes alone are unlikely to explain all the secrets of longevity. Passarino made the point while driving back to his laboratory after visiting the centenarians in Molochio. "It's not that there are good genes and bad genes," he said. "It's certain genes at certain times. And in the end, genes probably account for only 25 percent of longevity. It's the environment too, but that doesn't explain all of it either. And don't forget chance.""

CELL-NANOPARTICLE HYBRIDS, AN ILLUSTRATION OF WHAT IS TO COME
Tuesday, April 16, 2013
http://www.fightaging.org/archives/2013/04/cell-nanoparticle-hybrids-an-illustration-of-what-is-to-come.php
Work on nanoparticles and artificial cell structures for use in medicine is becoming more sophisticated. There is an emerging generation of simple but effective medical micro- and nanomachines, devices that will be manufactured in their millions and infused into the body to perform useful tasks, such as killing specific cells, or delivering specific signals to cells to cause them to regenerate more effectively, or clearing out unwanted metabolic byproducts that contribute to aging. A lot of interesting projects are presently underway, and this article is a good illustration of one branch of this work and its utility: "Nanoparticles could be used to neutralize toxins produced by many bacteria, including some that are antibiotic-resistant, and could counteract the toxicity of venom from a snake or scorpion attack. [The] "nanosponges" work by targeting so-called pore-forming toxins, which kill cells by poking holes in them. There are a range of existing therapies designed to target the molecular structure of pore-forming toxins and disable their cell-killing functions. But they must be customized for different diseases and conditions, and there are over 80 families of these harmful proteins, each with a different structure. Using the new nanosponge therapy [researchers] can neutralize every single one, regardless of their molecular structure. [Researchers] wrapped real red blood cell membranes around biocompatible polymeric nanoparticles. A single red blood cell supplies enough membrane material to produce over 3,000 nanosponges, each around 85 nanometers (a nanometer is a billionth of a meter) in diameter. Since red blood cells are a primary target of pore-forming toxins, the nanosponges act as decoys once in the bloodstream, absorbing the damaging proteins and neutralizing their toxicity. And because they are so small, the nanosponges will vastly outnumber the real red blood cells in the system. This means they have a much higher chance of interacting with and absorbing toxins, and thus can divert the toxins away from their natural targets. In animal tests, the researchers showed that the new therapy greatly increased the survival rate of mice given a lethal dose of one of the most potent pore-forming toxins. Liver biopsies several days following the injection revealed no damage, indicating that the nanosponges, along with the sequestered toxins, were safely digested after accumulating in the liver."

AN UPDATE ON PROTOFECTION
Tuesday, April 16, 2013
http://www.fightaging.org/archives/2013/04/an-update-on-protofection.php
Here at Fight Aging! the most recent update on protofection, a possible basis for a way to replace damaged mitochondrial DNA (mtDNA) and remove its contribution to degenerative aging, was late last year. Since the first publication on protofection back in 2005 a number of other potential mechanisms for mitochondrial DNA repair or replacement have emerged, but none of these, protofection included, are moving as rapidly as would be liked. One problem is the regulatory environment in the biggest markets: you are only allowed to develop commercial therapies for named diseases, not for aging, and comparatively few people suffer from named diseases that involve specific, characteristic forms of mitochondrial mutation - as opposed to the general stochastic damage of aging. So there is little funding, and it's actually effectively illegal to try to treat aging this way, despite the great possibilities of this research. One of the potential target diseases is Leber's hereditary optic neuropathy (LHON), and if you have a good memory you might recall that one of the researchers involved in work on the SENS approach to mitochondrial DNA damage - move the vulnerable genes into the cell nucleus to create a secondary source of the necessary proteins - is primarily concerned with LHON rather than aging. Here is an open access paper on the use of protofection (among other options) as a LHON therapy, which is also of general interest to anyone looking at this sort of approach to mitochondrial gene therapy for aging or other conditions: "An optimal cure [for LHON] would be gene therapy, which involves introducing the missing gene(s) into the mitochondria to complement the defect. Our recent research results indicate the feasibility of an innovative protein-transduction ("protofection") technology, consisting of a recombinant mitochondrial transcription factor A (TFAM) that avidly binds mtDNA and permits efficient targeting into mitochondria in situ and in vivo. Thus, the development of gene therapy for treating mitochondrial disease offers promise, because it may circumvent the clinical abnormalities and the current inability to treat individual disorders in affected individuals. We successfully demonstrated introduction of labeled rhTFAM and healthy mtDNA complexed with rhTFAM into homoplasmic LHON cybrid cells containing the G11778A mutation. [Further] results in LHON cybrid cells, demonstrated an increase in mitochondrial genome replication, transcription, translation, and respiration initiated within a week when the complex was introduced into the mitochondria. We also observed the activation of the mitochondrial biogenesis (creation of new mitochondria) program in these human LHON cybrid cells. [It] is expected that this mitochondrial genome manipulation approach based on introduction of exogenous normal or pathogenic mtDNA provides hope for LHON patients afflicted with other mutations in the mitochondrial genome. The current studies indicate that the mitochondrial genome can be manipulated and lead to improvement in mitochondrial function in in vitro and in vivo models. Future coordinated efforts between scientists and clinicians are necessary to translate these findings towards development of therapies for LHON patients." This is far from a niche study, despite being related to a niche disease; mitochondrial DNA damage arguably causes a fairly large fraction of degenerative aging. It is incredible to think that regulators actively work to prevent greater funding and more work on this and other items that could help to reverse the effects of aging in the old.

A LOOK AT SOME OF RAY KURZWEIL'S PREDICTIONS ON LONGEVITY
Monday, April 15, 2013
http://www.fightaging.org/archives/2013/04/a-look-at-some-of-ray-kurzweils-predictions-on-longevity.php
Like many, I think that Ray Kurzweil is overly optimistic on the timeline for progress in technology. I don't think he's wrong in terms of his high level view on where our technology is going, just a few decades on the early side - which is unfortunate for those of us who will age to death before the advent of rejuvenation biotechnology. It is certainly the case that the first draft of technologies to repair the underlying biological damage that causes aging could arrive fairly soon, within two decades - but it's not just a matter of building them, even though there are detailed research and development plans for doing so. The issues are persuasion and fundraising; when it comes to aging, the mainstream of the research community is set on goals that either have nothing to do with human longevity, or will do very little to extend life even after being realized at great cost. So the comparatively tiny and underfunded shard of the scientific community whose members are interested in realizing effective means of rejuvenating the old will likely spend the next twenty years on laying the groundwork, prototyping the biotechnologies, proving their case ever more completely, growing funding, and persuading ever more researchers to do the same. If there were hundreds of millions of dollars devoted to this cause today, we could leap ahead twenty years in this timeline - but there are not. The money and large supportive community still has to be bootstrapped, building on the present early phase in the growth of modern rejuvenation research, underway successfully but slowly for the past decade or so, giving rise to organizations like the Methuselah Foundation and SENS Research Foundation. Here is Kurzweil's take on timelines, which are derived from his analysis of trends in technological capabilities: "To listen to Mr. Kurzweil or read his several books is to be flummoxed by a series of forecasts that hardly seem realizable in the next 40 years. But this is merely a flaw in my brain, he assures me. Humans are wired to expect "linear" change from their world. They have a hard time grasping the "accelerating, exponential" change that is the nature of information technology. "A kid in Africa with a smartphone is walking around with a trillion dollars of computation circa 1970," he says. Project that rate forward, and everything will change dramatically in the next few decades. "I'm right on the cusp," he adds. "I think some of us will make it through" - he means baby boomers, who can hope to experience practical immortality if they hang on for another 15 years. By then, Mr. Kurzweil expects medical technology to be adding a year of life expectancy every year. We will start to outrun our own deaths. And then the wonders really begin. Mr. Kurzweil's ideas on death and immortality, not his impressive record as an entrepreneur, are what bring TV newsmagazines and print reporters to his door these days. I suggest to him he's discovered the power of the prophetic voice and is borne forward by the rewarding feelings that come from giving people hope in the face of their profoundest fears. My insight does not impress him. He says he just gets satisfaction from seeing his ideas, like his inventions, wield a positive force in the world. People blame technology for humanity's problems, he says. They are much too pessimistic about its power to solve poverty, disease and pollution in our lifetimes."

DECELLULARIZATION PRODUCES PARTIALLY FUNCTIONAL KIDNEYS IN RATS
Monday, April 15, 2013
http://www.fightaging.org/archives/2013/04/decellularization-produces-partially-functional-kidneys-in-rats.php
Decellularization is the process of taking donor tissue, such as a complete organ, stripping out its cells to leave the extracellular matrix structure, and then repopulating that structure with another individual's cells to reform a functional organ. This produces donor tissue that will not be rejected by a transplant recipient, and has been successfully used in a few human transplants of less complicated tissue structures such as the trachea. This technology is an important stepping stone on the way towards organs created from scratch; it works around the present inability to build a sufficiently detailed and functional framework for complex tissue. The extracellular matrix from existing tissue provides chemical cues and other necessary items that allow cells to correctly form the many intricate structures, such as blood vessel networks, needed for a fully functional organ. In the laboratory, a number of complete animal organs have been successfully decellularized and transplanted - and kidneys are now included in that list, albeit only partially functional kidneys, a starting point for better results in years ahead: "[Researchers have] engineered functional rat kidneys by stripping donor kidneys of their cells and then repopulating the remaining collagen substructures with new cells. The bioengineered kidneys produced urine in laboratory dishes and when implanted in living animals. The advance could be good news for the 100,000 Americans waiting for donor kidneys for transplant, because it suggests that someday scientists might be able to grow custom-made kidneys for people, using a patient's own cells to seed tissues. The process at the center of his team's approach is called "decellularization." In a carefully calibrated process, researchers removed a kidney from a cadaver and then introduced a series of washing agents into its vascular system to remove the organ's cells. [Then] they introduced immature cells that could form kidney tissues and blood vessels into the acellular scaffold. After a short time, the new kidneys could produce urine. They didn't work as well as normal, healthy kidneys would - in the laboratory dish, they cleared creatinine (a blood component filtered by the kidneys) 23% as well as a native kidney; once implanted in animals, about 5% to 10% as well. But "the bottom line is, we saw urine production.""

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