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The birth of neoSENS


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#1

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Posted 20 February 2005 - 03:31 AM


All human beings are both gifted and cursed by a singular consequence of our mode of cognition - a unique point of view. At times this can bias the interpretation and processing of information to such a degree that it induces a paradigm shift in human knowledge. At other times the very same distortion can lead to a stifling of human endeavor. Albert Einstein, upon developing the Relativity centric theories of cosmology could not accept and consequently could not extend and unify his theories into the dimensions of quantum physics. One genius can only give humanity so much.

Dr. Aubrey de Grey pioneered the biogerontology research focus for anti-senescence and coined the term Strategies for Engineered Negligible Senescence (SENS), an approach to dealing with aging that is encapsulated by a philosophy of attaining maximum therapeutic results with minimal knowledge on the complexities of the underlying mechanisms. Consequently he is not as concerned about the causes of subtleties such as perturbed gene expression as he is about addressing their physiological effects. Using this approach, and having identified the most prominent consequences of the aging process he proposed seven innovative methods of addressing them.

Essentially de Grey took Descartes' statement of

"A healthy man is like a well functioning clock, and an ill man is like a clock that needs repairing"

and changed it to:

"A young man is like a well functioning clock, and an old man is like a clock that needs repairing"


Whilst he has been spectacularly successful in capturing certain segments of the public imagination and aroused great curiosity in the press as to the proximity of a solution to aging using his proposed methods, the mainstream scientific community has been less than captivated.

In between these extremes are some, who believe in his vision, admire his passion and the skill with which he wields it but remain to be convinced about all aspects of the scientific methodology proposed to achieve what de Grey calls "escape velocity" - implementing the requisite number of interventions to enable biological survival until the next technological paradigm. This is not to take away from the man's enormous mass of knowledge on aging related science and reasoning skill - which is not the issue here - but to promote discourse and encourage exploration on alternative anti-senescence methodologies in the context of biology, medicine and technological implementation.

So we find ourselves standing in the midst of the following facts: theories of aging other than those chosen by de Grey to formulate SENS exist; the interpretation of research literature when it comes to matters of pure conjecture can be subjective without being essentially wrong; the landscape of knowledge is constantly changing. Thus in these forums, alternative views have been presented on the causes of aging and subsequent means of addressing senescence. I term such hypotheses as neoSENS because they are a new and distinct form of the existing SENS proposed methods. NeoSENS is an unwanted child of de Grey's grand vision and unyielding stance on incorporating into the fold of existing SENS new approaches, that are at least as technologically feasible, as hypothetically testable and as anti-senescence potent as the existing seven proposals (ie - SENSworthy versus subSENS).

#2 reason

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Posted 20 February 2005 - 05:34 AM

On the other hand, no-one else has yet managed to unify general relativity with quantum theory - and they've had a great many more man-hours to put into it than Einstein did. I'm not poking at the necessity for criticism, debate or offshoot work from SENS, just the flawed nature of this analogy. My take on debating SENS is here:

http://www.fightagin...ives/000389.php

"My position on these sorts of discussions is that we are still in the stage of needing many more qualified and useful people (e.g. scientists, folks with money to spend on research, advocates with a large audience, etc) to take part. It's never too early to critique and improve ideas - especially when it comes to getting to the end goal more rapidly - but we still need to devote much more effort to raise awareness and bring new faces to the debating table."

In other words, we're still at the stage of needing to sell people on the idea of life extension period, never mind the implementation details. I worry about groups disappearing down the rabbit hole of devoting ever more energy to debate over the science rather than bringing in new folks - if we focus on activism, then debates over science happen as a matter of course if we are successful. Vice versa is simply not the case, however.

Reason
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http://www.longevitymeme.org

#3 bgwowk

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Posted 20 February 2005 - 05:47 AM

Thus in these forums, alternative views have been presented on the causes of aging and subsequent means of addressing senescence. I term such hypotheses as neoSENS because they are a new and distinct form of the existing SENS proposed methods.

Be careful that you don't dilute SENS into meaninglessness. Interventive gerontology is a wide field that is both older and more expansive than just SENS or "neoSENS". As I understand it, Aubrey coined SENS to specifically describe an engineering approach to repairing a short list of aging-related changes at the cellular level. To call alternative approaches to delaying or reversing senescence "neoSENS" is a disservice to both SENS and interventive gerontology.

I submit that only refinements to Aubrey's list should qualify as "neoSENS." Completely different approaches, such as attempts to delay senescence by replicating and extending mechanisms of calorie restriction, should not be confused with SENS. For they are not what Aubrey would call "engineering strategies". Furthermore, many of these approaches pre-date SENS, so could hardly be called "neo". They are best called "alternatives to SENS", or research complements of SENS.

Whatever they are called, it's good for people to know that SENS is not the only propulsion method for movement toward "escape velocity".

---BrianW

#4 kevin

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Posted 20 February 2005 - 06:27 AM

The actual mainstream scientists I know are still in the trance that aging places over the majority of individuals regardless of their professional stripes. The ones I have spoken to about SENS do not appear to need some new 'bright idea' to convince them that curing aging is possible. What they do need is the same smelling salts that the rest of the world needs that aging is even a disease, then they will begin to consider the suggested methods of attacking it.

From my background in business I realize that there is a time when a project needs to be launched "as is" if a deadline is going to be reached.. warts and all.. and this is where I feel we are at. Aubrey's suggestions may be incomplete, and he is the first to admit that, but I would submit that it is complete enough to use as a springboard for discussion and to attract the attention of mainstream researchers. I would also suggest that resources as precious as expertise and time are best spent dealing with the fundamental prejuidices and ignorance which are preventing SENS as it stands from being discussed.

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Posted 20 February 2005 - 12:14 PM

"It has been said (and it is very likely) that no great cultural revolution can be a sudden event. It must necessarily be preceded by a long period of incubation, possibly in unlikely places and by the hands of unimpeachable players."

--Marcello Barbieri, The Organic Codes


We all must do what we feel is appropriate to further the cause of anti-senescence interventions. Most do it by activism, few by capital, and even fewer by science.

Is it not a paradox, then, that the very same who stand defiant against the granite face of scientific establishment themselves become unyielding when presented with new opportunities? Is the threat so great for SENS to evolve from a futuristic science marketing tool into a more serious and realistic approach to anti-senescence with practicable solutions using today's technology? It is understandably difficult for a non-life scientist to appreciate the subtleties in implementing entirely hypothetical propositions with insufficient grounding in experimentally based science. It is disconcerting to encounter, however, such ideological resistance that borders on ignorance. One must question who in fact is in a trance - those who stubbornly deny the inevitability of biological immortality or those who blindly await its coming.

I am not prepared to wait around and see if SENS ever manages to succeed as a marketing tool or as a broad research objective. Marketing is not an area I am professed in, but I was fortunate to have received training as a scientist and consider it my obligation that if I can modulate the message of SENS so that scientists may hear it better I will do so, even if it gets the noses of its most ardent supporters out of joint.

So it is important to note that when I made my stand to uphold the need for the induction of enhanced genomic stability to be more seriously considered as an anti-senescence objective it was after the disturbing realization that Aubrey had no intention of incorporating into the SENS collective, irregardless of how much evidence was provided from published findings. This recalcitrance against a different perspective also manifested when providing evidence on the impracticability of existing SENS imperatives. Thus I concluded that no matter how many friends SENS made with the public, unless a bridge could be formed between today's technology and life science knowledge base and the futuristic premises of SENS, that the scientific community would maintain its aloofness.

It is the mission of neoSENS hypotheses to become such a bridge. Rather than concerning itself with engaging the public, it is the core imperative to establish experimental protocols that are doable within realistic timeframes using available technology. Thus neoSENS seeks to engage the scientific community by realistic challenges that would not fall prey to such criticism as Estep's depiction of SENS as "magic wand" science or Pontin's depiction of SENS as science fiction. NeoSENS is the necessary evolutionary path that SENS must take if it is to fulfill its objective as a bridge to the future.

It does not matter if SENS supporters are not happy. It matters if scientists are.

#6 Da55id

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Posted 20 February 2005 - 03:00 PM

Prometheus: I'm curious about how much money and how many years will it take to research, develop and deliver a therapy based on your centrally held belief of best approach. Also, what in your best guesstimate is the believed outcome of a/the resulting therapy(ies) in terms of additional healthy years achieved?

#7 Da55id

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Posted 20 February 2005 - 03:03 PM

Oh - I forgot. Can you say in 40 words or less (the "elevator pitch") the pathology attacked and method of remediation in layman's terms. I.E. if Rolling Stone magazine were to give you a sidebar, and say - OK, what's wrong, what are you fixing, how are you fixing it and what will it do, what's the "it" you would communicate (40 words - the vast majority of R.S. readers will pass on more than that).

#8 kevin

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Posted 20 February 2005 - 05:50 PM

prometheus

My nose is not out of joint in the least at the suggestion that SENS is incomplete or in need of refinement. This is not the point at all.

I have shared with you that I have spoken at length with many scientists, both Aubrey's peers in the biogerontology community as well as outside of it, concerning his proposals and have garnered first hand information concerning their objections. If they had formulated opinions at all, I found them to be largely based on prejuidices formed in childhood concerning the inevitability of aging rather than any science. These people/scientists are not waiting for some refinement of SENS to be convinced of the possibility of curing aging... what is needed is a shift from treating age-related disease as manifold ailments to a multi-faceted process for which we have technology to intervene. This is singularly the most important message which needs to be communicated.

It is readily apparent what you feel is important and there is no doubt that your suggestions have merit for discussion. It is also apparent, at least to me, that although it may help to refine SENS, further discussion does not advance this most critical goal of communication. Again, I point to discussions I've had with a mitochondrial scientist here at the University of Alberta who prior to Aubrey's talk, had never really looked at the application of multiple technologies to the individual damage syndromes of aging. After reviewing his website and papers this quite hard nosed scientist was not as impressed with the suggested techniques for combatting aging, but the mindset which would bring them together and place aging up as a serious target of technology. I would suggest again, that we have in hand enough information to begin asking the scientific establishment to challenge their beliefs that nothing can be done about aging. Now you may say that this is just 'blind' boosterism, but I will continue to disagree.. ;)

For the record I have spent many months over the years working as an undergrad in NMR, genetics and X-Ray crystallography labs and so have some knowledge of experimental life-science biology. I am currently debating whether or not to finish my major studying mitochondrial dysfunction in c. elegans or look at chromatin remodelling changes with aging in yeast.

Saying that, I'm curious... you say you have received some training as a scientist? Where was that and what was your most interesting undergrad project? I'm already assuming that you would cite DNA damage as the most fruitful avenue of discovery so maybe you can suggest an interesting (SIMPLE) two term experiment that could be done with c. elegans?

Again, curiousity.. Where are you working at the moment?

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Posted 21 February 2005 - 05:14 AM

My dilemma is that when SENS is scientifically scrutinized in its present incarnation, the problems of implementation begin to outweigh the benefits. By providing solutions to these problems then the argument becomes more convincing and the likelihood that investigators begin to view it as a plan for research far greater.

I would suggest again, that we have in hand enough information to begin asking the scientific establishment to challenge their beliefs that nothing can be done about aging.



This is a fine starting point since it is central to your argument that SENS in its present form is more than adequate to mobilize research around the world. What information, in your view, do you - or the collective that you represent - have that is sufficient to convince the gerontology research community that their lines of investigation should be directed elsewhere? I am not being confrontational - I would really like to know how you see this from your perspective. Please be as specific as you can. If you have difficulty answering this question from a technical perspective then either you do not know enough of the science of SENS or there is not enough science in SENS to begin with. Don't be offended. The problem is with SENS, not you.

Saying that, I'm curious... you say you have received some training as a scientist? Where was that and what was your most interesting undergrad project? I'm already assuming that you would cite DNA damage as the most fruitful avenue of discovery so maybe you can suggest an interesting (SIMPLE) two term experiment that could be done with c. elegans?


It has been some time since I was an undergrad, Kevin. In fact it was at a time when the establishment was convinced the genome would take 50 years to be mapped. My primary interest back then was the protein folding problem but I could not pursue it.

But to answer your question on an experiment with c.elegans, it largely depends on the background of your supervisor and the resources you would be permitted to access for your project. I am fascinated by the unique response of RNAi in C. elegans that makes loss of function so easy to induce. From a genome stability perspective I have been unable to find a study that has induced overexpression of a DNA repair gene even though they have been quick to create loss of function, eg for an XPF homolog which became hypersensitive to UV light.


Again, curiousity.. Where are you working at the moment?


Did you want to drop by for a coffee? ;) As I have stated previously I do not have to earn my living on the lab bench. If this inquiry is to determine my competence to question SENS then I suggest you think more carefully about the concerns of technical implementation rather than how I earn my living. There are real issues with SENS that need to be addressed. The adage that all publicity is good publicity does not work amongst the scientific community. As the SENS profile increases so does the risk of it being perceived as fanciful science fiction and making it even more difficult for scientists to enter the arena.


For the record I have spent many months over the years working as an undergrad in NMR, genetics and X-Ray crystallography labs and so have some knowledge of experimental life-science biology.


Then you would appreciate chasm that exists between SENS theory and practical implementation. You would also appreciate the mindset and value system of workers in the life sciences and what sort of evidence they would be be looking for when considering SENS as a possible research direction.


These people/scientists are not waiting for some refinement of SENS to be convinced of the possibility of curing aging... what is needed is a shift from treating age-related disease as manifold ailments to a multi-faceted process for which we have technology to intervene. This is singularly the most important message which needs to be communicated.


This is fine rhetoric, Kevin. Where is the technology? What multi-faceted process? Once again, my objective is not to be confrontational, but to direct you to look more closely at SENS and at the scientific community that you (and I) want to so desperately convince.

#10 kevin

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Posted 21 February 2005 - 06:40 AM

prometheus..

Thank you for your thoughtful response. To be clear, I do not take offence over internet chat forum dialogues easily and neither are my feelings hurt by the knowledge that I have much to learn. I rather enjoy being aware of my lack for at least then I know what direction to move and it helps me to focus on the broader picture, many with much more training than I are at a loss of which thought to put in front of the other.

I believe I was fairly clear in why I do not think further refinement of SENS at this point is necessary and it has nothing to do with the relative technical merits of each suggested arm of SENS. I am quite aware of the chasm between the theory and implementation but differ quite strongly that those involved in the life sciences are going to require the rigourousness you feel they will demand out of the box. Frankly, I'm not at all concerned with what is likely a large discepancy between suggested SENS arms and implementation and the reason is simple.. to recapitulate something I've said often... SENS and the MPrize are not the means to an end.. they are the means to a beginning.

They are a beginning which has done something remarkable.. they have actually begun. This alone will be enough for scientists to sit up and take note and then let the free-for-all debate fly... I'm sure you will be in there in the middle of the melee.

I may take you up on that coffee someday hopefully many many years from now..

Kevin

#11 jaydfox

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Posted 21 February 2005 - 03:24 PM

As a scientific model and hypothesis, representing the profound scientific insight and genius of a single man—and his distillation of the hundreds of mitochondriologists, geneticists, and biogerontologists who came before him—SENS is a great theoretical construct. It lays out the seven causes of aging, as its author sees them, and it lays out seven specific sets of therapeutic solutions.

This is all and well, for the scientific mind and career of this great man.

But, his SENS has been co-opted by a movement, a larger, more encompassing movement, a movement that looks at calorie restriction, cryonics, brain-computer interfacing, protection against cataclysm (natural and species self-induced), and many other protections against the common enemy of death.

This movement has a responsibility, in co-opting such a comprehensive program as SENS, to make sure that it is as "comprehensive" as is pragmatic, and to ensure that the program remains adaptable to a changing information landscape, as well as to the social, political, and economic landscape. It is hubris to think that we can effect any social, political, or economic landscape necessary to drive our goals; we can modulate, to be sure, but results in the near term, let along the long term, are neither predictable nor insurable.

Most of the seven aspects of SENS are hardly controversial at this time, except those founded on currently politically controversial science such as stem cell therapy.

However, two aspects—and unfortuntely the two most critical in my layman's judgment—of SENS are controversial. They are controversial in both their science and in their practical application. The science is not my strong point, though I am doing my best to get caught up. However, the practical applications are serious and are not the sole domain of PhD's.

It is for this reason that we have been debating the mitochondrial and chromosomal DNA aspects of SENS. While I propose only a weak refinement of the mitochondrial DNA aspect, I have been attempting to propose a much stronger refinement of the chromosomal DNA aspect.

#12 jaydfox

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Posted 21 February 2005 - 07:55 PM

Oh - I forgot. Can you say in 40 words or less (the "elevator pitch") the pathology attacked and method of remediation in layman's terms. I.E. if Rolling Stone magazine were to give you a sidebar, and say - OK, what's wrong, what are you fixing, how are you fixing it and what will it do, what's the "it" you would communicate (40 words - the vast majority of R.S. readers will pass on more than that).


Tricky. You see, you have the seven causes of aging, and you have the set of sets of cures. I say set of sets, because some have multiple potential cures, hence a set. For example, under cell depletion, de Grey points out exercise and hormones to build muscle (e.g. a tissue-specific fix), and stem cell therapy (a somewhat tissue-independent fix).

So we have the problem: chromosomal DNA repair.

We have the broad solutions:
1) Increase DNA integrity
2) Remove cells with low integrity, and replace with cells with higher integrity.
2a) Ablate cells with low integrity
2b) Replace with cells with high integrity
3) When cancer does occur, make it non-life-threatening

WILT:
1 is not currently addressed.
2a is addressed by ablating all cells after reaching the Hayflick limit.
2b is addressed by replacement with cells that have not reached the Hayflick limit (even though they might be precancerous or dysfunctional).
3 is obviously addressed.

Hence, the WILT design doesn't truly ablate cells with low integrity, but only those cells with the highest statistical probability of being low integrity. They are replaced by any cells that fall short of that arbitrary limit (e.g. they can be replaced by cells that are five divisions away from the Hayflick limit themselves, and hence not likely to have much more integrity (or utility, for that matter)).

So, WILT does a marginal job of preventing DNA damage and cancer.

However, ss a secondary benefit, WILT will presumably prevent any cancers that do form from becoming life-threatening. I have my doubts that this will be nearly 100% effective, but I will present them when I have completed my background research.


Thus, our 40-word description shouldn't put it in the same terms de Grey has, but in the terms above. From there, we can propose two more specific applications of the above logic: WILT, and DNA integrity. Each can then be described in its own 40-word summary.

Another problem with 40-word summaries is that they can miss the subtleties and nuances, nuances which are complicated but critically important.

So, I have tried a compromise. 40-word description of the problem, 40-word description of the basic blueprint for fixing the problem. Two 40-word descriptions to elaborate. 40-word description of WILT, and 40-word summaries of benefits and drawbacks. Same for DNA integrity. Then the same for the dual-approach.

In all, that's 13 40-word summaries, not including the titles of each summary: not quite the 40 words you asked for. But given my propensity for verbosity, I'm proud of my 520-word summary. (Actually, excluding titles, it would be just under 500 words [thumb] )





Why is chromosomal DNA damage important? (40 words)
Genetic damage accumulates in all our cells, and this accumulation accelerates with age. Some cells accumulate damage faster than others, and a variety of health problems can result. Cancer may pose the most short-term problems in the next couple decades.

Solution in Brief (26 words)
We must prevent the accumulation of DNA damage in the first place, and when this fails, we must address the problems it causes (such as cancer).

Two-part solution (36 words and 40 words)
We must prevent the accumulation of DNA damage in the first place:
- Prevent or slow the accumulation of DNA damage in individual cells
- Eliminate cells with the most DNA damage, and replace them with healthier cells.
When damage builds up enough to cause health problems (for example, cancer), then we must deal with those problems:
- Try to rejuvenate cells that aren't working properly
- Try to destroy or drastically limit the growth of cancer or toxic cells

What is WILT? (38 words)
WILT would involve removing the ability of every cell in our body to divide beyond a certain limit (roughly 50 times). When cells exhaust this limit, they will shut down or die, and be replaced by "younger" cells.

Benefits of WILT (39 words)
WILT would prevent the accumulation of DNA damage by eliminating the cells that have been around the longest. These cells would be replaced by younger cells. Cancer would become non-life-threatening in most cases because of a hard-wired growth limit.

Drawbacks of WILT (38 words)
DNA damage (leading to a variety of health problems including cancer) would not be effectively prevented. Worse, WILT is programmed death. Without regular transfusions of fresh cells, we would die after a couple decades, regardless of our age.

What is the DNA Integrity solution? (38 words)
The DNA integrity solution would increase our cells' natural ability to prevent and repair DNA damage. Additionally, the cells with the most DNA damage would be eliminated, and be replaced by cells that have relatively higher DNA integrity.

Benefits of DNA Integriy (38 words)
DNA damage, which is directly linked to cancer (among other diseases), would become a manageable problem. When the rare cancer does come along, technology available in the next decade or two will make this problem manageable or curable.

Drawbacks of DNA Integrity (37 words)
Cancers would happen rarely, but when they do happen, they would not have hard-wired growth limits. Also, infrequent transfusions of fresh cells might be necessary to increase this solution's effectiveness (but there would be no programmed death).

A dual approach? (39 words)
We can even consider the case of combining the approaches. DNA repair and maintenance can be increased, and cells with the most DNA damage can be eliminated. However, as a backup plan, we place a limit on tumor growth.

Benefits of the dual approach (40 words)
The main benefit of adding DNA integrity to WILT is that DNA damage and cancer would become rarer problems. The main benefit of adding WILT to the DNA integrity solution is that what rare cancers do happen will be non-life-threatening.

Drawbacks of the dual approach (40 words)
The main drawback of adding DNA integrity to WILT is cost: more money for research, and more resources to provide the initial treatment to the public. The main drawback of adding WILT to the DNA integrity solution is programmed death.

#13 jaydfox

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Posted 21 February 2005 - 07:55 PM

The dual approach deserves more words. I mentioned that the resource cost to provide the initial treatment would be higher, and it would. However, the necessary frequency of treatments might be lower, making the costs lower for subsequent treatments.

Whether WILT could be made less frequent with the addition of DNA integrity is a tricky issue. Presumably, cell ablation through tumor suppressors has been upregulated, so stem cells will be under greater pressure to divide, meaning reseedings would actually have to be more often. On the other hand, with increased DNA integrity in the first place, cell ablation could be tenuated, leading to no net increase on stem cell division, and perhaps even a net reduction. Finally, with better integrity, cancers would be rarer and would require more cell divisions to develop from fresh stem cell lines, so telomeres could engineered longer in the first place, meaning that reseedings can be made less frequent in the dual approach model. So on the balance, I believe there is still a very strong case that reseedings can be made less frequent under the dual approach, with a consequent savings which balances and probably outweighs the extra cost of the initial treatment.

#14 jaydfox

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Posted 21 February 2005 - 08:11 PM

Aubrey might not like my 40-word characterizations of SENS, but this was mainly to serve as a conceptual template. Reducing something so sophisticated to 40 words is a feat worthy of poetic geniuses. While I might possess some level of "genius", "poet" I definitely am not.

#15 jaydfox

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Posted 22 February 2005 - 02:23 AM

A 44-word distillation of SENS. I know it's more than 40, but who could stop in the middle of that last sentence? And yes, it's shamelessly ripped from de Grey's SENS website. Next, we need 40-word distillations of each component of SENS. And finally, a 40-word summary. In all, less than 360 words, 9x40.

I don't like the chromosomal DNA damage one. I really think that chromosomal DNA damage and cancer should be treated separately. WILT is not a cure for DNA damage, it's a cure for cancer. I will thus provide the alternative view, which means we'd need 8 things, if we're sticking to 40 word synopses. One for DNA damage, one for cancer. They are inextricably linked at the scientific level, but at the therapeutic level, there's a strong distinction, and hence a need for the separate category. This became most obvious as I tried to write the 40-word synopsis of the chromosomal DNA damage problem. However, it also became clear that, in the interest of expediency, we present them as an either/or, with doing both as even better. Thus, we still only need to fix 7 things, but we have 8 things which lead to aging/death. Six must be fixed, and then either of the remaining two must be fixed. It's just not something that can be explained in 40 words.

(44 words)
There are only seven things we need to fix to cure aging! Why only seven? Because as fast as biotechnology is improving, we haven't found a new thing in last 23 years. And all seven things can be cured in the next 25 years.

(40 words)
Problem: Too few cells. Organs such as the heart, brain, and muscle fill up with scar tissue, or just shrink.
Solution: Replace cells.
Specific proposal: Use hormone therapy to grow muscle cells.
Specific proposal: Use stem cells to rejuvenate organs.

(39 words)
Problem: Too many cells. Fat cells, "old" and often toxic cells called "senescent" cells, and immune cells.
Solution: Get rid of the cells, preferably without surgery.
Specific proposal: Use chemicals and gene therapy to make these cells "commit suicide".

(40 words)
Problem: Chromosomal DNA damage. Leads to cancer and "senescent" cells, among other problems.
Solution: Prevent DNA damage and eliminate cells that get too damaged. As a last resort, make cancer relatively harmless.
Specific proposal: WILT, a possible cure for cancer.

(36 words)
Problem: Mitochondrial DNA damage. Damage that can take over entire cells, making them toxic.
Solution: Protect the mitonchodrial DNA.
Specific proposal: Using genetic engineering, move the mitochondrial DNA to the cell nucleus, where it's much safer.

(36 words)
Problem: Junk inside cells that builds up and becomes toxic.
Solution: Make the cell capable of breaking down the junk.
Specific proposal: Use genetic engineering to give the cell the ability to digest the toxic junk.

(38 words)
Problem: Junk outside the cells that builds up and becomes toxic.
Solution: Break down the junk with chemicals, or make cells that can digest the junk.
Specific proposal: Use "vaccines" to make the immune system attack the junk.

(40 words)
Problem: "Extracellular Protein Crosslinks". Proteins outside our cells get damaged and tangled together.
Solution: Target and break down the crosslinks.
Specific solution: The drug ALT-711, already in clinical trials.
Specific solution: If necessary, design custom enzymes to do the job.

(37 words)
And that's it. Just seven things. It's been over 23 years since another thing has been found, and it's not for lack of trying by the biotech industry. So let's get to work on those seven things!

#16 jaydfox

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Posted 22 February 2005 - 02:25 AM

The list with 8 items. Need to address that two of the items are complementary, but not both required (both would be better, of course). Total words, less than 400.

(44 words)
There are only eight things we need to fix to cure aging! Why only eight? Because as fast as biotechnology is improving, we haven't found a new thing in last 23 years. And all eight things can be cured in the next 25 years.

(40 words)
Problem: Too few cells. Organs such as the heart, brain, and muscle fill up with scar tissue, or just shrink.
Solution: Replace cells.
Specific proposal: Use hormone therapy to grow muscle cells.
Specific proposal: Use stem cells to rejuvenate organs.

(39 words)
Problem: Too many cells. Fat cells, "old" and often toxic cells called "senescent" cells, and immune cells.
Solution: Get rid of the cells, preferably without surgery.
Specific proposal: Use chemicals and gene therapy to make these cells "commit suicide".

(40 words)
Problem: Chromosomal DNA damage. Leads to cancer and "senescent" cells, among other problems.
Solution: Prevent DNA damage and eliminate cells that get too damaged.
Specific proposal: Using genetic engineering, make cells better at repairing their DNA and killing damaged cells.

(35 words)
Problem: Cancer. Cancer is caused by chromosomal DNA damage.
Solution: Preventing DNA damage makes cancer more rare. However, we still need a cure for those rare cases.
Specific proposal: WILT, a possible cure for cancer.

(36 words)
Problem: Mitochondrial DNA damage. Damage that can take over entire cells, making them toxic.
Solution: Protect the mitonchodrial DNA.
Specific proposal: Using genetic engineering, move the mitochondrial DNA to the cell nucleus, where it's much safer.

(36 words)
Problem: Junk inside cells that builds up and becomes toxic.
Solution: Make the cell capable of breaking down the junk.
Specific proposal: Use genetic engineering to give the cell the ability to digest the toxic junk.

(38 words)
Problem: Junk outside the cells that builds up and becomes toxic.
Solution: Break down the junk with chemicals, or make cells that can digest the junk.
Specific proposal: Use "vaccines" to make the immune system attack the junk.

(40 words)
Problem: "Extracellular Protein Crosslinks". Proteins outside our cells get damaged and tangled together.
Solution: Target and break down the crosslinks.
Specific solution: The drug ALT-711, already in clinical trials.
Specific solution: If necessary, design custom enzymes to do the job.

(37 words)
And that's it. Just eight things. It's been over 23 years since another thing has been found, and it's not for lack of trying by the biotech industry. So let's get to work on those eight things!

#17 jaydfox

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Posted 22 February 2005 - 02:37 AM

Seven things just has a better ring. Like the seven deadly sins.

#18 John Schloendorn

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Posted 22 February 2005 - 03:04 AM

Brief criticism of point8 (chromosomal mutations):

1) You don't merely want to replace cells with DNA damage, but also those with mutations. Now how do you recognize the number of mutations in a cell if not by their statistical probability over time?
2) Is there any positive data demonstrating a putative mechanism to "make cells better at repairing their DNA". E.g. I'm not aware of any studies that would have reversed any of the symptoms cited in point 8 by overexpressing DNA repair proteins, in the absence of specific genotoxic stressors (is there?; not saying there would have to be in order to validate your point.). So how would you go about to do that?
3)

Cancer may pose the most short-term problems in the next couple decades.

If that is so, this would diminish the urgency of your idea enroute to escape velocity, if a reliable cure for cancer were found.

I think the utility of this idea will depend mostly on the response to 2)

And:

Drawbacks of WILT (38 words) DNA damage (leading to a variety of health problems including cancer) would not be effectively prevented.

I don't understand that. When a cell is replaced by a fresh cell from ex vivo, the fresh cell would obviously not have the old cell's mutations. (Nor its DNA damage, for that matter) If you do that every 10 years, cells would not get the opportunity to accumulate more mutations that the averarge 10 year old has, which is pretty good in terms of cancer incidence. (It's not that any one mutation in the wrong place can cause cancer. Quite a number of such mutations have to accumulate in any one cell, before it can do everything it needs to do to become cancer. Otherwise cancer incidence with age should be more linear than exponential)

When the rare cancer does come along, technology available in the next decade or two will make this problem manageable or curable.

Hmm, does not sound precisely like a mechanistic solution to me... but OK it's rare after all. For RMR we don't need the perfection we need for ourselves.

#19 John Schloendorn

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Posted 22 February 2005 - 03:07 AM

Seven things just has a better ring. Like the seven deadly sins.

I suspect this was one of the reasons why crosslinks and extracellular junk were seperated. Why don't you merge them ;-)

#20 jaydfox

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Posted 22 February 2005 - 01:49 PM

Drawbacks of WILT (38 words) DNA damage (leading to a variety of health problems including cancer) would not be effectively prevented.

I don't understand that. When a cell is replaced by a fresh cell from ex vivo, the fresh cell would obviously not have the old cell's mutations. (Nor its DNA damage, for that matter) If you do that every 10 years, cells would not get the opportunity to accumulate more mutations that the averarge 10 year old has, which is pretty good in terms of cancer incidence.


You fell into the trap that Prometheus pointed out. WILT is not replacing cells with fresh cells every ten years. That's just the bandaid that prevents WILT from killing you. WILT is the removal from all cells of the capacity to divide beyond the Hayflick limit. The consequence of this is programmed death, so stem cell reseeding is the bandaid.

Stem cell reseeding does not require WILT to be effective. WILT requires stem cell reseeding to be effective. Do you see the difference?

This is precisely the reason that Prometheus suggested separating the two components. There are multiple ways to accomplish ablation (e.g. WILT or tumor suppressors, etc.), and multiple ways to accomplish cell replacement (e.g. reversing methylation changes in stem cells, or outright stem cell replacement (the latter ensures genomic stability of the fresh cells)).

Reseeding stem cells accomplishes the cell replacement portion of the ablation-replacement formula for ensuring systemic DNA integrity (and, coincidentally, accomplishes nothing for ensuring cellular-level DNA integrity of existing cells, except perhaps to reduce the systemic oxidative load that partially drives the DNA damage).

WILT is putatively the ablation portion, but relies on statistics. Cancer is the result of outliers in those statistics, so clearly statistics are not the best strategy. Tumor suppressors are selective, and can be tuned to respond to as little as one mutation (of course, that level of tuning can't be applied systemically because turnover would be too frantic, but it can be applied to the most important cells, i.e. stem cells, and tuned as appropriate system-wide). Of course, tumor suppressors are not infallible themselves, so WILT might still be useful as a failsafe. But that gives the tradeoff of a potentially little used failsafe in exchange for programmed death.

So, we should keep WILT on the back burner, that ace up our sleeves, in case after 25 years of biotech research we can't ensure long-term genomic stability through DNA repair/maintenance and selective ablation. Tumor suppressors for systemic DNA integrity, and kDRM factors for cellular DNA integrity (which is the statistical driver of the decline in systemic DNA integrity).

Keeping it on the back burner necessarily means continuing research on it, but that research need not be the primary focus nor the "selling point" of SENS.

#21 jaydfox

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Posted 22 February 2005 - 01:52 PM

2) Is there any positive data demonstrating a putative mechanism to "make cells better at repairing their DNA". E.g. I'm not aware of any studies that would have reversed any of the symptoms cited in point 8 by overexpressing DNA repair proteins, in the absence of specific genotoxic stressors (is there?; not saying there would have to be in order to validate your point.). So how would you go about to do that?

Prometheus should be able to provide more than adequate coverage of this subject. It is well-studied (even if the effects on lifespan are still controversial to some, the effects on DNA repair are not. But, MLSP is a multifactorial thing, with multiple limiting factors of various degrees).

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Posted 23 February 2005 - 07:50 AM

A case for nuclear DNA damage in aging - Part I: Causes

It was Kirkwood (1) who first proposed that the drive to increase biological process efficiency places a limit on the resources that could be allocated to the maintenance of information in cells. Consequently it would not be efficient to maintain 100% repair in cells. DNA is expected, and has been observed to accumulate damage.

Whilst there is a broad agreement that DNA damage contributes to aging, there has been great resistance by some to accept that nuclear DNA damage, as distinct from mitochondrial DNA damage, contributes to much more than the cancer phenotype. It is the position of SENS advocates, particularly in view of the SENS theoretical intervention known as WILT, that nDNA mutations threaten the organism only in respect to cancer incidence and that when mutations are sufficient to cause cellular dysfunction that it is so rare an event that it should be considered negligible. The neoSENS group agrees that mtDNA damage is a substantive contributor to the aging phenotype but also emphasizes the role of nDNA damage an important aging and disease contributor outside of cancer.


Comparing nDNA damage to mtDNA damage

The relative amount of DNA damage in mitochondria as compared to the nucleus (some studies report as much as 100 fold) is often cited as evidence to support the limited impact that nuclear DNA damage would presumably have on cell dysfunction other than cancer. This information must be placed in the proper context: whilst a cell has only one copy of nuclear DNA there can be thousands of copies of mitochondrial DNA. Furthermore, whilst mitochondria encode for only 13 polypeptides the nucleus encodes for tens of thousands of proteins. Due to the limited number of genes that can be affected in mitochondria, deficiencies are so much easier to quantify. Furthermore, the mitochondrial genome, unlike nDNA has no non-coding regions and is not afforded the protection of histones. Thus random nDNA damage would manifest in a slower and more complex fashion than mtDNA damage. Finally, mitochondrial biogenesis and turnover occurs independently of the rest of the cell. One may speculate that the greater the mitochondrial turnover, the less the possible rate of mtDNA damage that could occur (prospective neoSENS?). It is intriguing to consider the potentially immortal female germline mitochondria in this case. Finally one must bring into question the validity of 8-oxoG as an indicator of mitochondrial damage since the results of a recent investigation suggest that such lesions have no effect on mitochondrial respiratory dysfunction (12). Clearly the comparison of mtDNA damage to nDNA damage in terms of cause and effect is much more complex than the SENS people would have us believe.


Direct Evidence: nDNA damage increases with aging.

8-oxoG is only one of about 20 known damage products in the DNA molecule but is used as a broad representative of DNA damage for experimental expedience. Experiments have shown that 8-oxoG levels in hepatocyte and brain nDNA of 24 month old mice are three fold higher than 4 month old mice (2,3). 7-methylguanine levels in brain, liver and kidney nDNA were found to be two fold higher in 28 month mice than 11 month old mice (4). These comparisons were made in post-mitotic, living cells presenting a possible interpretation that the reason greater levels were not observed was because they were not survivable.


Indirect Evidence: Some consequences of DNA damage

It is known that DNA damage can interfere with the mechanism of transcription including but not limited to binding of polymerase, binding of transcription factors, acetylation and methylation events, and the reading of the coding region. Such interference can reduce or entirely prevent the expression of a gene. Aside from possible perturbations in regulatory networks resulting from altered inducer/repressor expression, it would be expected that an overall reduction in protein synthesis would occur with age. Various studies have reported ranges between 90% - 45% reduction in transcription and protein synthesis in various mammals in the brain, muscle, liver and kidney (5). One obvious effect of reduction in proteins synthesis, aside from function impairment is the reduction of organ size and the number of cells per organ as is confirmed in aging mammals (5). The bystander effect can further exacerbate tissue damage (6).


Indirect Evidence: The premature aging syndromes and mutants

Numerous DNA repair genes and pathways have been now identified that contribute to the maintenance of genomic stability. Human premature aging conditions have been characterized on the basis of loss of function mutation in such genes including xeroderma pigmentosum, Werners syndrome, Cockayne syndrome, Trichothiodystrophy, Blooms syndrome and others. Modeling of such conditions in mice mutants has reproduced similar accelerated aging physiology. What is common amongst these conditions is their association with nDNA and that the corresponding genetic deficiency is associated with a DNA repair system that acts specifically in the nucleus. Since faulty nDNA repair induces premature aging syndromes, and according to Kirkwood's hypothesis of resource efficiency it can be postulated that nDNA repair efficiency is as variable in the population as any other trait. Human centenarians indeed demonstrate a significantly lower incidence and higher onset age of cancer (7) suggesting a low rate of chromosomal aberrations and increased DNA repair activity.


Some ways that nDNA damage can drive aging

Nuclear DNA encodes 99.999% of the genes in the mammalian cell. Damage can interfere with transcription related processes which in turn can result in genes important to cell and tissue function being switched off and in genes that normally are silenced to be switched on (ie oncogene activation). We know that providing double strand breaks do not occur a cell can survive a great deal of damage to its DNA (8). Even if such damage is not properly corrected (9) resulting in possible transcription errors and alteration to binding sites. With the enormous diversity of genes existent in the nucleus it is possible that compensatory mechanisms could be activated when one gene whose function could be to produce a ligand, transcription factor or other network component becomes silenced. Such transformation would result in more subtle and ambiguous phenotypic effects. Ultimately, however, the accumulation of such events would result in increasing inefficiencies. In parralel, one must consider the role that nDNA damage may have on mtDNA function and inevitably damage considering that the vast majority of mitochondrial genes are encoded in the nucleus. As an example nuclear encoded mitochondrial antioxidant protein SOD is significantly lowered in aged rats which would in turn destabilize mitochondria due to increased ROS (13). If lowered SOD levels are due to global reduction in protein synthesis due to DNA damage then mtDNA damage becomes a function of nDNA damage. SOD is of course one of many enzymes involved in mitochondria that could be down-regulated due to nDNA damage.


Conclusion

This is a very brief survey of evidence and some fairly constrained speculation on the link between nDNA damage and aging. It is certainly not intended to be authoritative. On the contrary, it is designed to encourage further discussion, exploration and of course, criticism. I am concerned with some recent developments (12) and the implications they hold on our interpretation on experimental evidence and await to hear from interested parties..

If you have difficulty obtaining any articles cited let me know.





(1) Nature 270:5635, 301-4 (1977)
Evolution of ageing.
Kirkwood, TB

(2) Mech Ageing Dev 125:10-11, 755-65 (2004)
Age-dependent modulation of DNA repair enzymes by covalent modification and subcellular distribution.
Szczesny, B, Bhakat, KK, Mitra, S and Boldogh, I

(3) Mut Res 446 (1999) 215-223
Age-related increases of 8-hydroxy-2'-deoxyguanosine and DNA–protein crosslinks in mouse organs
Alberto Izzotti, Cristina Cartiglia, Maurizio Taningher, Silvio De Flora, Roumen Balansky

(4) Mut Res 237 (1990) 229-238
Steady-state levels of 7-methylguanine increase in nuclear DNA of postmitotic mouse tissues during aging 
Boen H. Tan, F. Aladar Bencsath and James W. Gaubatz

(5) Academic Press
Aging, Sex & DNA Repair (1991)
Bernstein, C. and Benstein, H.

(6) Radiat Res. 2004 Dec;162(6):677-86.
Induction of replication protein a in bystander cells.
Balajee AS, Ponnaiya B, Baskar R, Geard CR

(7) Mech Ageing Dev. 2005 Feb;126(2):263-7.
Cancer in the oldest old.
Andersen SL, Terry DF, Wilcox MA, Babineau T, Malek K, Perls TT

(8) Int J Radiat Biol. 2000 Jan;76(1):67-75.
Comparison of biological effects of DNA damage induced by ionizing radiation and hydrogen peroxide in CHO cells.
Dahm-Daphi J, Sass C, Alberti W.

(9) Carcinog Compr Surv. 1985;10:481-93.
In vitro models of mutagenesis.
Strauss BS, Larson K, Sagher D, Rabkin S, Shenkar R, Sahm J.

(10) DNA Repair (Amst). 2003 Jun 11;2(6):673-93.
Decline of nuclear and mitochondrial oxidative base excision repair activity in late passage human diploid fibroblasts.
Shen GP, Galick H, Inoue M, Wallace SS.

(11) J Radiat Res (Tokyo). 2003 Mar;44(1):31-5.
Age-associated decrease of oxidative repair enzymes, human 8-oxoguanine DNA glycosylases (hOgg1), in human aging.
Chen SK, Hsieh WA, Tsai MH, Chen CC, Hong AI, Wei YH, Chang WP.

(12) Free Radic Biol Med. 2005 Mar 15;38(6):737-745.
No evidence of mitochondrial respiratory dysfunction in OGG1-null mice deficient in removal of 8-oxodeoxyguanine from mitochondrial DNA.
Stuart JA, Bourque BM, de Souza-Pinto NC, Bohr VA.

(13) J Ster Biochem Mol Bio 88: 1 Jan 2004 61-67
Aging alters the functional expression of enzymatic and non-enzymatic anti-oxidant defense systems in testicular rat Leydig cells
Cao L , Leers-Sucheta S, Azhar S

#23 John Schloendorn

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Posted 23 February 2005 - 09:47 AM

Thanks Prometheus, that was nice and clear. I think your hypothesis would benefit from further differentiation between its putative key players namely nDNA damage, nDNA damage-induced senescence, nDNA mutations and mtDNA mutations. To my knowlege, all four of them increase with age and are elevated in the premature aging syndromes. So we're not ready to say which is(are) the primary cause(s). How would you experimentally decide?

#24

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Posted 23 February 2005 - 03:18 PM

"Experimentally" is the pivotal point here.

Some techniques for testing DNA damage/mutation include lacZ plasmid based transgenics, PCR amplification & sequencing, liquid chromatography-tandem mass spectrometry, comet assay, immunofluorescent detection of 8-oxo-dG, urine 8-oH-dG concentration, etc. However these techniques are normally applied to cell populations.

I would like to see a study that was able to demonstrate transcription alteration, say a reduction in transcription due to DNA damage in a directly related gene. This is of course rather difficult to achieve when working with large numbers of cells due to the stochastic nature of damage incidence. Presumably one could set up cell cultures in such a way where single cells could be tracked but the problem one encounters is that unless the product of transcription is being secreted it cannot be detected without the destruction of the cell.

A study (1) was able to provide quantitative gene expression of 20 genes in a single cell using RT-PCR to allow precise measurement of the number of mRNA molecules per cell. By extending the scope of the technique to include say, the expression of 500 characterized genes that are highly transcribed, and in parallel sequencing the corresponding regions of DNA, the effect of nDNA damage on transcription could be observed over a period of time in cells of different ages.


(1) Genome Res. 2004 Oct;14(10A):1938-47.
Quantification of multiple gene expression in individual cells.
Peixoto A, Monteiro M, Rocha B, Veiga-Fernandes H.

#25 Michael

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Posted 24 February 2005 - 11:36 PM

All:

I'd first like to make the parenthetical meta-point that "neoSENS" is an unfortunate choice of terminology for the kind of approaches apparently being suggested under the rubric. The central feature of SENS per se as an approach to biomedical gerontology is to directly attack the accumulating damage that causes dysfunction, rather than attempting to prevent it (as eg by augmenting, interfering with, or neutralizing the toxic results of normal metabolism and short-lived molecules -- the "gerontologist's approach) or to attempt to prevent this damage from leading to pathology and death (the "geriatrician's approach") (21, 22).

Attempts to increase DNA repair/maintenance, whatever one may think of their likelihood of success as anti-aging interventions, are instances of the preventive/"Gerontologist" school, not the SENS "engineer's" approach (tho' of course implementing them would doubtless entail some molecular or biotechnological "engineering"), so "neoSENS" as a term for such approaches introduces confusion in the debate.

In short (and the following is intended as a mildly amusing mnemonic pun based on this terminological self-contradiction, not an argument about the merits of the approach), "neoSENS" is actually nonSENS.

[quote]
A case for nuclear DNA damage in aging ...

Comparing nDNA damage to mtDNA damage
The relative amount of DNA damage in mitochondria as compared to the nucleus (some studies report as much as 100 fold) is often cited as evidence to support the limited impact that nuclear DNA damage would presumably have on cell dysfunction other than cancer.[/quote]

As I've pointed out a couple of times now in response to this misunderstanding of the argument:

[quote]
To observe the fact that some kind of damage increases, and even accumulates, with age is distinct from showing that the rate at which this happens it is related to the rate of aging. To show the latter, we need evidence either from intervention (interventions that reduce a particular kind of damage with age increase max LS, and interventions that do not do the former do not do the latter) or from interspecies comparisons (more longevous spp suffer less of this damage with age than more short-lived ones). [CR demonstrates the former;] Barja and others have shown [the latter to be] true of oxidative mtDNA and not of nuDNA [damage].[/quote]

Again,

[quote]
[quote]
Let's go back to the evidence you are presenting:

- 8-oxodG amount is higher in mtDNA than in nDNA

If this is all then it is hardly evidence to support your hypothesis.[/quote]
I agree. I already emphasized that the simple fact of higher mtDNA than nuDNA damage was not the issue. The contention that mt, but not nuclear, DNA damage is causally related to aging lies, as I indicated, in the interspecies and CR data relating the former, but not the latter, to species maximum lifespan [etc -- see original post].[/quote]

[quote]
Direct Evidence: nDNA damage increases with aging.[/quote]

Not disputed, but also not evidential, as indicated above.

[quote]
Indirect Evidence: Some consequences of DNA damage...[/quote]

Sure. As I said previously,
[quote]
[quote]
On this front, it should be noted that while individual cells and their progeny certainly can be expected to become dysfunctional when their nuDNA aquire mutations, the low rate of cell division in vivo in most tissues -- and the virtual nonexistance of same in postmitotic tissues like heart and brain -- means that individual cell's mutations get little chance to "take over" the tissue and render the whole dysfunctional. As I suggested in reply to Estep, age-related changes in nuclear gene expression appear to be most clearly secondary to other, primary lesions: [etc][/quote]
[quote]
You're saying that it is possible for cell nDNA to acquire mutations that result in dysfunction but that it is so rare an event and unlikely have any effect on the overall tissue physiology because of the low mitotic potential of the cell with damage?[/quote]
Yes.[/quote]

See previously-cited comments by de Grey in the same thread on Jan Vijg's data on nuclear mutation accumulation with aging.

[quote]
Some ways that nDNA damage can drive aging
... We know that providing double strand breaks do not occur a cell can survive a great deal of damage to its DNA (8)... Ultimately, however, the accumulation of such events would result in increasing inefficiencies. ...[/quote]

See above; also, in this already linked post,

[quote]
[quote]
It seems obvious to me (and I expect that Aubrey agrees) that it is likely that nuDNA mutations would eventually become pathological if not repaired over the course of a greatly extended LS, as eventually all cells would have accumulated a great many true mutations; however, evidence to hand indicates that they are not accumulating at high enough levels over the course of a "normal" lifespan to significantly contribute to aging per se.[/quote]
[quote]
So finally the point of contention is when and not if nDNA damage is going to lead to altered cell function.[/quote]
Not quite: the point of contention is when and not if non-cancer nDNA mutations are going to lead to meaningful increases in pathology and to contributing to aging per se (as opposed to cancer) in a way that is not obviable by the existing SENS interventions. Aubrey has never claimed that the "Seven Deadlies" include all of the lesions that would ever become pathological in a greatly-extended lifespan -- just that they include all of the lesions that contribute to pathology in a current, "normal" lifetime. After we correct these defects, other, more subtle forms of damage which are irrelevant to pathology within a current, normal lifetime will emerge, and require increasingly refined therapies to correct in order to further push back aging. Fortunately, as time goes on we will have increasingly powerful tools with which to identify and then obviate these newly-hazardous forms of damage or de-link them from pathology. See his "actuarial escape velocity" paper [ref], and also his chapter in the Immortality Institute's book [ref][cited material and Imminst forums quotes from de Grey -- see linked post][/quote]

[quote]
Indirect Evidence: The premature aging syndromes and mutants[/quote]

Even to refer to these disorders as "premature aging" is a petitio principii. Almost anything that messes up normal gene function but takes a while to kill one will look like "premature aging;" the question is what if any relationship they bear to normal aging.

[quote]
"Until you show me that you can postpone aging, I don't know that you've done anything," sniffs Michael R. Rose, geneticist at the University of California. "A lot of people can kill things off sooner, by screwing around with various mechanisms, but to me that's like killing mice with hammers -- it doesn't show that hammers are related to aging."[/quote]

((15); see (16-20) for examples).


-Michael

(1) Nature 270:5635, 301-4 (1977)
Evolution of ageing.
Kirkwood, TB

(2) Mech Ageing Dev 125:10-11, 755-65 (2004)
Age-dependent modulation of DNA repair enzymes by covalent modification and subcellular distribution.
Szczesny, B, Bhakat, KK, Mitra, S and Boldogh, I

(3) Mut Res 446 (1999) 215-223
Age-related increases of 8-hydroxy-2'-deoxyguanosine and DNA–protein crosslinks in mouse organs
Alberto Izzotti, Cristina Cartiglia, Maurizio Taningher, Silvio De Flora, Roumen Balansky

(4) Mut Res 237 (1990) 229-238
Steady-state levels of 7-methylguanine increase in nuclear DNA of postmitotic mouse tissues during aging
Boen H. Tan, F. Aladar Bencsath and James W. Gaubatz

(5) Academic Press
Aging, Sex & DNA Repair (1991)
Bernstein, C. and Benstein, H.

(6) Radiat Res. 2004 Dec;162(6):677-86.
Induction of replication protein a in bystander cells.
Balajee AS, Ponnaiya B, Baskar R, Geard CR

(7) Mech Ageing Dev. 2005 Feb;126(2):263-7.
Cancer in the oldest old.
Andersen SL, Terry DF, Wilcox MA, Babineau T, Malek K, Perls TT

(8) Int J Radiat Biol. 2000 Jan;76(1):67-75.
Comparison of biological effects of DNA damage induced by ionizing radiation and hydrogen peroxide in CHO cells.
Dahm-Daphi J, Sass C, Alberti W.

(9) Carcinog Compr Surv. 1985;10:481-93.
In vitro models of mutagenesis.
Strauss BS, Larson K, Sagher D, Rabkin S, Shenkar R, Sahm J.

(10) DNA Repair (Amst). 2003 Jun 11;2(6):673-93.
Decline of nuclear and mitochondrial oxidative base excision repair activity in late passage human diploid fibroblasts.
Shen GP, Galick H, Inoue M, Wallace SS.

(11) J Radiat Res (Tokyo). 2003 Mar;44(1):31-5.
Age-associated decrease of oxidative repair enzymes, human 8-oxoguanine DNA glycosylases (hOgg1), in human aging.
Chen SK, Hsieh WA, Tsai MH, Chen CC, Hong AI, Wei YH, Chang WP.

(12) Free Radic Biol Med. 2005 Mar 15;38(6):737-745.
No evidence of mitochondrial respiratory dysfunction in OGG1-null mice deficient in removal of 8-oxodeoxyguanine from mitochondrial DNA.
Stuart JA, Bourque BM, de Souza-Pinto NC, Bohr VA.

(13) J Ster Biochem Mol Bio 88: 1 Jan 2004 61-67
Aging alters the functional expression of enzymatic and non-enzymatic anti-oxidant defense systems in testicular rat Leydig cells
Cao L , Leers-Sucheta S, Azhar S

15. http://exn.ca/Storie...98/05/13/66.asp

16: Trifunovic A, Wredenberg A, Falkenberg M, et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature. 2004 May 27;429(6990):417-23. PMID: 15164064 [PubMed - indexed for MEDLINE]

17. Nature 1997 Nov 6;390(6655):45-51
Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Kuro-o M, Matsumura Y, Aizawa H, et al.
PMID: 9363890 [PubMed - indexed for MEDLINE]

18. Mol Cell Biol 2000 Jun;20(11):3772-80
Analysis of ku80-mutant mice and cells with deficient levels of p53.
Lim DS, Vogel H, Willerford DM, Sands AT, Platt KA, Hasty P.
PMID: 10805721

19. Takeda T.
[Senescence-accelerated mouse (SAM): with special reference to age-associated pathologies and their modulation]
Nippon Eiseigaku Zasshi. 1996 Jul;51(2):569-78. Review. Japanese.
PMID: 8783874 [PubMed - indexed for MEDLINE]

20: Baker DJ, Jeganathan KB, Cameron JD, et al.
BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice.
Nat Genet. 2004 Jul;36(7):744-9. Epub 2004 Jun 20.
PMID: 15208629 [PubMed - indexed for MEDLINE]

21. de Grey AD. An engineer's approach to the development of real anti-aging medicine. Sci Aging Knowledge Environ. 2003 Jan 8;2003(1):VP1. Review. PMID: 12844502 [PubMed - indexed for MEDLINE]
http://www.gen.cam.a...sens/manu16.pdf

22. de Grey AD. An engineer's approach to the development of real anti-aging medicine. Sci Aging Knowledge Environ. 2003 Jan 8;2003(1):VP1. Review. PMID: 12844502 [PubMed - indexed for MEDLINE]
http://www.gen.cam.a...sens/manu16.pdf

#26

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Posted 25 February 2005 - 04:59 AM

I'd first like to make the parenthetical meta-point that "neoSENS" is an unfortunate choice of terminology for the kind of approaches apparently being suggested under the rubric. The central feature of SENS per se as an approach to biomedical gerontology is to directly attack the accumulating damage that causes dysfunction, rather than attempting to prevent it (as eg by augmenting, interfering with, or neutralizing the toxic results of normal metabolism and short-lived molecules -- the "gerontologist's approach) or to attempt to prevent this damage from leading to pathology and death (the "geriatrician's approach") (21, 22).

Attempts to increase DNA repair/maintenance, whatever one may think of their likelihood of success as anti-aging interventions, are instances of the preventive/"Gerontologist" school, not the SENS "engineer's" approach (tho' of course implementing them would doubtless entail some molecular or biotechnological "engineering"), so "neoSENS" as a term for such approaches introduces confusion in the debate.

In short (and the following is intended as a mildly amusing mnemonic pun based on this terminological self-contradiction, not an argument about the merits of the approach), "neoSENS" is actually nonSENS.

(see references from original post)

NonSENS - bravo! What a riposte! I can just see the Jason Pontins of this world drooling over such a caption - is SENS really nonSENSe?

On a more serious note I think we need some firmer footing on the definitions of: neoSENS vs SENS, direct or engineering approaches vs prevention or gerontological approaches

Firstly SENS is no more than a number of hypothetical interventions to address aging. NeoSENS is an approach of formulating hypothetical interventions to address aging that are designed to meet the criteria for consideration by scientists rather than impressing the public. This may sound harsh but is ultimately true - SENS does not care what the scientific community thinks and it positions itself above it. NeoSENS seeks to build a bridge between hypothesis and the existing knowledge and technology base. The prime consideration of neoSENS is to satisfy the scientific community that the hypothesis proposed are congruent with and follow along the lines of present research directions.

This is better illustrated by comparing the SENS and neoSENS approaches to mitochondrial DNA damage:

SENS: allotopic expression of mitochondrial genome
Supporting research: NEGATIVE


Title: Limitations of Allotopic Expression of Mitochondrial Genes in Mammalian Cells
Abstract: The possibility of expressing mitochondrial DNA-coded genes in the nuclear-cytoplasmic compartment provides an attractive systemfor genetic treatment of mitochondrial disorders associated with mitochondrial DNA mutations. In theory, by recoding mitochondrial genes to adapt them to the universal genetic code and by adding a DNA sequence coding for a mitochondrial-targeting sequence, one could achieve correct localization of the gene product. Such transfer has occurred in nature, and certain species of algae and plants express a number of polypeptides that are commonly coded by mtDNA in the nuclear-cytoplasmic compartment. In the present study, allotopic expression of three different mtDNA-coded polypeptides (ATPase8, apocytochrome b, and ND4) into COS-7 and HeLa cells was analyzed. Among these, only ATPase8 was correctly expressed and localized to mitochondria. The full-length, as well as truncated forms, of apocytochrome b and ND4 decorated the periphery of mitochondria, but also aggregated in fiber-like structures containing tubulin and in some cases also vimentin. The addition of a hydrophilic tail (EGFP) to the C terminus of these polypeptides did not change their localization. Overexpression of molecular chaperones also did not have a significant effect in preventing aggregations. Allotopic expression of apocytochrome b and ND4 induced a loss of mitochondrial membrane potential in transfected cells, which can lead to cell death. Our observations suggest that only a subset of mitochondrial genes can be replaced allotopically. Analyses of the hydrophobic patterns of different polypeptides suggest that hydrophobicity of the N-terminal segment is the main determinant for the importability of peptides into mammalian mitochondria.
(1)


neoSENS: increase mitochondrial DNA repair by directing the overexpression of DNA repair enzymes in mitochondria
Supporting research: POSITIVE


Title: Conditional Targeting of the DNA Repair Enzyme hOGG1 into Mitochondria
Abstract: Oxidative damage to mitochondrial DNA (mtDNA) has been suggested to be a key factor in the etiologies of many diseases and in the normal process of aging. Although the presence of a repair system to remove this damage has been demonstrated, the mechanisms involved in this repair have not been well defined. In an effort to better understand the physiological role of recombinant 8-oxoguanine DNA glycosylase/apurinic lyase (OGG1) in mtDNA repair, we constructed an expression vector containing the gene for OGG1 downstream of the mitochondrial localization sequence from manganese-superoxide dismutase. This gene construct was placed under the control of a tetracycline-regulated promoter. Transfected cells that conditionally expressed OGG1 in the absence of the tetracycline analogue doxycycline and targeted this recombinant protein to mitochondria were generated. Western blots of mitochondrial extracts from vector- and OGG1-transfected clones with and without doxycycline revealed that removal of doxycycline for 4 days caused an approximate 8-fold increase in the amount of OGG1 protein in mitochondria. Enzyme activity assays and DNA repair studies showed that the doxycycline-dependent recombinant OGG1 is functional. Functional studies revealed that cells containing recombinant OGG1 were more proficient at repairing oxidative damage in their mtDNA, and this increased repair led to increased cellular survival following oxidative stress. (2)


Secondly, SENS claims to provide a superior methodology to addressing the aging problem since it distinguishes itself from other approaches (termed indirect or gerontological) by so-called "directly attacking accumulating damage". The problem with this statement is the implied increase in efficacy of the "direct" method over the other. One simply cannot compare and contrast on this basis since both methods are in the realm of the hypothetical and require evidence of relative efficacy, let alone proof of concept.

NeoSENS is not a public relations exercise. NeoSENS is about quantifiable problems and implementable solutions.


(1) Genetics 165: 707–720 (October 2003)

(2) Journal of Biological Chemistry 277: (47) 44932–44937 (November 2002)

#27

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Posted 25 February 2005 - 07:12 AM

In reference to the evidence provided by premature aging disorders:

Even to refer to these disorders as "premature aging" is a petitio principii. Almost anything that messes up normal gene function but takes a while to kill one will look like "premature aging;" the question is what if any relationship they bear to normal aging.


For those that do not know what petitio principii means, it refers to a circular argument.

Michael, I would suggest you field the label of petitio principii to the authors of papers, who have in their published results drawn the conclusion that genes associated with premature aging disorders are associated with modulating the aging process. I would be interested to hear their comments at your suggestion that they have committed petitio principii. ;)

May I also suggest, in the interest of a constructive debate, that you place less emphasis on clever verbalisms and more emphasis on evidence based reasoning within a scientific framework.

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#28

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Posted 25 February 2005 - 08:27 AM

A case for nuclear DNA damage in aging - Part II: Intervention Theory Background

The first suggestion that I could find in the literature of how it could be possible that increased lifespan was able to evolve by increased repair and protection of the genome was by Cutler in 1973. From his theory, the higher the repair capacity the greater the lifespan achievable.

Despite numerous studies that have focused on a positive correlation between lifespan and DNA repair capacity by observing DNA repair rates in different species, acceleration of aging by DNA-damaging agents, the premature aging syndromes in humans and mutant animal models, the most eagerly anticipated results are those where an increase in DNA repair and maintenance systems is induced. Unfortunately, such studies, promising as they may be, are limited and only just beginning to emerge. A recently published study (2) reported on the use of liposomes as topical delivery vehicles for the DNA repair enzyme T4 endonuclease V to human skin increased repair by 18% and decreased the incidence of keratosis by 68%.


The complexity of DNA repair systems

DNA repair mechanisms involve discrete protein complexes that address specific types of damage. In total about 130 DNA repair genes have been identified in humans (3, 4). As an example, the nucleotide excision repair (NER) pathway involves some 30 proteins and proceeds in a multistep reaction involving damage recognition, excision, repair synthesis and ligation. Furthermore, chromatin remodeling, which requires additional factors to associate with histone deacetylases, is required to allow the formation of the pre-initiation complex. Overall this is a complex process involving a number of steps and a number of enzymes to act in a coordinated fashion. For example the xeroderma pigmentosum diseases are associated with mutations in the following genes: XPA, XPC - damage recognition factors, XPG - an endonuclease, XPB, XPD - helicases to assist with strand unwinding and separation. The complexity of such systems provides numerous opportunities for failure and dysfunction despite some functional overlaps between different components.


Choosing the DNA repair system to be upregulated

Not all DNA repair genes products are created equal. In some we see functional redundancy (5,6), others are more error-prone in their activity (7,8) and others such as the double strand breakage detector, ATM, appear to be essential (9) or non-redundant (12). We do not yet have, however, a clear map of which are the most critical DNA repair genes, even though some evidence is beginning to suggest that DNA damage recognition is the rate limiting step (11). Such research promises to be reasonably easy, particularly with the advent of RNAi technology that can rapidly silence selected DNA repair genes alone or in combination. The results of such studies are eagerly anticipated. Transcriptional studies are also required to determine the changes if any in the type and concentration of DNA repair genes throughout lifespan.


How much life extension?

The basis for any speculation on how much lifespan can be increased by, is directly related to the assumption of how much nDNA (and mtDNA) damage contributes to the aging process. In my view DNA damage is the pre-eminent basis of aging. Even if it is intermeshed with a downward extension of the developmental program, ie a degeneration program, then such a program works by permitting increased damage to occur. From an evolutionary perspective some DNA damage must be permitted in order to keep the genome adaptable. From a conservation of energy perspective only so many resources can be allocated towards DNA repair. I would expect to see a cell whose DNA is free of defect and damage-induced transcriptional changes to propagate indefinitely given a suitable nutritional and signaling substrate. How would such cells behave in situ, however? There are many identified and some unidentified ligands that influence cell behavior irrespective of its DNA health. For example a cell can be instructed to apoptose or differentiate into a senescent state. Similarly a senescent cell's nucleus can be reprogrammed to revert to its embryonic totipotential origin. Such instructions are transmitted from the environment suggesting that no matter how much work we do in improving genomic stability that we must be wary of and find a solution for senescence influencing ligands. A solution that presents itself is the ablation of such senescence receptors, once they are discovered.

In any case, I would decline to offer any specific number or percentage without any supporting evidence. What is being proposed in this neoSENS is a fundamental change in the rate - a braking - of what appears to be a stochastically driven process of transcriptional alteration and a radical departure from methods that seek to indirectly modulate transcriptional events.




(1) Mech Ageing Dev. 1973 Dec-1974 Feb;2(6):381-408.
Redundancy of information content in the genome of mammalian species as a protective mechanism determining aging rate.
Cutler RG.

(2) Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
After sun reversal of DNA damage: enhancing skin repair , In Press, Corrected Proof, Available online 26 January 2005,
Daniel B. Yarosh, Matthew T. Canning, Danielle Teicher and David A. Brown

(3) Toxicology. 2003 Nov 15;193(1-2):3-34.
Mechanisms of human DNA repair: an update.
Christmann M, Tomicic MT, Roos WP, Kaina B.

(4) http://www.cgal.icne...pair_Genes.html

(5) Genes Dev 15:20, 2730-40 (2001)
Functional overlap between Sgs1-Top3 and the Mms4-Mus81 endonuclease.
Kaliraman, V, Mullen, JR, Fricke, WM, Bastin-Shanower, SA and Brill, SJ

(6) Mol Microbiol 19:4, 871-80 (1996)
Overlapping functions for recF and priA in cell viability and UV-inducible SOS expression are distinguished by dnaC809 in Escherichia coli K-12.
Sandler, SJ

(7) Ann N Y Acad Sci 1028, 247-57 (2004)
A unifying mechanism in the initiation of cancer and other diseases by catechol quinones.
Cavalieri, EL and Rogan, EG

(8)FEBS Lett 566:1-3, 147-50 (2004)
Evidence of finely tuned expression of DNA polymerase beta in vivo using transgenic mice.
Bergoglio, V, Fréchet, M, Philippe, M, Bieth, A, Mercier, P, Morello, D, Lacroix-Tricki, M, Delsol, G, Hoffmann, JS and Cazaux, C

(9) Cancer Res 65:3, 933-8 (2005)
Combined haploinsufficiency for ATM and RAD9 as a factor in cell transformation, apoptosis, and DNA lesion repair dynamics.
Smilenov, LB, Lieberman, HB, Mitchell, SA, Baker, RA, Hopkins, KM and Hall, EJ

(10) Cell Mol Life Sci 61:17, 2168-72 (2004)
Gene silencing in DNA damage repair.
Soejima, H, Joh, K and Mukai, T

(11) Mol Carcinog. 2003 Sep;38(1):1-13.
Critical DNA damage recognition functions of XPC-hHR23B and XPA-RPA in nucleotide excision repair.
Thoma BS, Vasquez KM.

(12) Cancer Lett. 2005 Mar 10;219(2):125-35.
The RAD51 gene family, genetic instability and cancer.
Thacker J.

#29 John Schloendorn

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Posted 27 February 2005 - 07:32 AM

Prometheus,
Please take this as constructive criticism:
As cool as your ideas are, I'm afraid what they most suffer from is your determination to prove something, or convince us of something. This sometimes reflects in a depiction of the results that is so biased as to limit its usefullness (at least for me). To illustrate what I mean, take this example:

A recently published study (2) reported on the use of liposomes as topical delivery vehicles for the DNA repair enzyme T4 endonuclease V to human skin increased repair by 18% and decreased the incidence of keratosis by 68%.

Only a look at the title of the study revealed that this is in response to an exogenous stress known to increase DNA damage (Sunlight). If you want to tackle aging, on the other hand, you will want to decrease base levels of mutagenic damage, rather than stress levels, which can also be managed by avoiding the stress, e.g. applying some TiO2 smear.
(The same kind of ommission is currently being made by the antioxidant industry to increase the market value of their products that also show a clear benefit only under stress conditions.)

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Posted 27 February 2005 - 09:15 AM

Prometheus,
Please take this as constructive criticism:
As cool as your ideas are, I'm afraid what they most suffer from is your determination to prove something, or convince us of something. This sometimes reflects in a depiction of the results that is so biased as to limit its usefullness (at least for me). To illustrate what I mean, take this example:


Only a look at the title of the study revealed that this is in response to an exogenous stress known to increase DNA damage (Sunlight). If you want to tackle aging, on the other hand, you will want to decrease base levels of mutagenic damage, rather than stress levels, which can also be managed by avoiding the stress, e.g. applying some TiO2 smear.
(The same kind of ommission is currently being made by the antioxidant industry to increase the market value of their products that also show a clear benefit only under stress conditions.)


Thank you for taking the time to read the references and provide comment. Firstly, John, my motive is to share my observations on SENS with all that have an interest in its development. Secondly, if you place the above comment in context:

Despite numerous studies that have focused on a positive correlation between lifespan and DNA repair capacity by observing DNA repair rates in different species, acceleration of aging by DNA-damaging agents, the premature aging syndromes in humans and mutant animal models, the most eagerly anticipated results are those where an increase in DNA repair and maintenance systems is induced. Unfortunately, such studies, promising as they may be, are limited and only just beginning to emerge. A recently published study (2) reported on the use of liposomes as topical delivery vehicles for the DNA repair enzyme T4 endonuclease V to human skin increased repair by 18% and decreased the incidence of keratosis by 68%.




You will observe that the context is on the scarcity of such studies rather than their efficacy Unfortunately, such studies, promising as they may be, are limited and only just beginning to emerge. The study is mentioned as an example of progress in the field. Furthermore the second point of the particular reference used is to demonstrate that DNA repair:
a) has been investigated as a bona fide treatment
b) is efficacious when delivered in one of the simplest forms of gene therapy (liposomes)
c) provided a quantifiable improvement in the study framework

Perhaps I was mistaken to consider that the above points and were self evident, but I hope that now that I have explained them that they are much clearer to you and to anyone else that may have drawn the inappropriate conclusion. In light of the above would you mind explaining your reasoning in comparing an emerging DNA repair application with the use of sunscreen? At the very least you should understand that whilst sunscreen reduces the amount of UV light transmitted to the skin, this example of DNA repair enhancement ensures that any damage caused can be repaired. ;)

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