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Scientists reverse aging in human cell lines and give theory of aging a new lease of life

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#1 Florian Xavier

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Posted 26 May 2015 - 04:41 PM


http://www.scienceda...50526085138.htm

 

Can the process of aging be delayed or even reversed? Research has shown that, in human cell lines at least, it can. They also found that the regulation of two genes involved with the production of glycine, the smallest and simplest amino acid, is partly responsible for some of the characteristics of aging.

 

This suggests that glycine treatment can reverse the age-associated respiration defects in the elderly human fibroblasts.

 

They reverse aging... again !

 

And strong laugh to the new candidate : glycine, a readily available cheap pill.


Edited by Florian Xavier, 26 May 2015 - 04:42 PM.


#2 niner

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Posted 26 May 2015 - 05:53 PM

Interesting.  The experiment involving glycine exposure entailed soaking the cells in 140 uM gly for 10 days.  If that were a polyphenol or some other thing with horrible PK, I'd say this wouldn't work in vivo.  Gly is different, though.  I don't know what normal endogenous gly levels are, and how much they could be raised by supplementation.  Is there any history of old people getting a big bang out of gly supplementation?



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#3 Florian Xavier

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Posted 26 May 2015 - 06:04 PM

i would loved to know what an anti-tgb1 + glycine would do



#4 sthira

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Posted 26 May 2015 - 06:31 PM

Gelatin is high in glycine. http://www.greatlake...itionalInfo.php

#5 zorba990

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Posted 26 May 2015 - 06:47 PM

glycine is a gh releaser that readily crosses the bbb. Howecer. more.than 8 grams or so gives me a nasty headache.

gh release by glycine
http://www.ncbi.nlm..../pubmed/7376793

high levels of glycine associated with migraine
http://www.ncbi.nlm..../pubmed/1683816

#6 corb

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Posted 26 May 2015 - 07:13 PM

They reverse aging... again !

 

This is more of an "oh look IPSCs do this as legitimate young cells as well" news rather than "we found a new mechanism" news.

In the end the only question anyone should be asking is when will the hundreds of people in need of ipscs therapies be able to get them and how much will it cost.

 

Of course whenever something like this gets in the news no one talks about future introduction into healthcare even though the technology is true and tested for a decade now.


Edited by corb, 26 May 2015 - 07:13 PM.


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#7 Florian Xavier

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Posted 26 May 2015 - 07:36 PM

I know but the fact that we get headline like this every 2 weeks make it somewhat funny


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#8 corb

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Posted 26 May 2015 - 08:01 PM

They use catchy wording to get a reaction. Typical journo gimmicks.
The whole article feels like it's written by a part timer so with that into consideration it could've been written worse. Or infinitely better.
This is why I prefer pubmed to news sites.


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#9 Avatar of Horus

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Posted 26 May 2015 - 09:13 PM

Florian Xavier  Posted Today, 06:41 PM

 

http://www.scienceda...50526085138.htm

...

 

The wording of the scientific details seems rather good, from the article:

Professor Hayashi and his team made this exciting discovery while in the process of addressing some controversial issues surrounding a popular theory of aging.

 

This theory, the mitochondrial theory of aging, proposes that age-associated mitochondrial defects are controlled by the accumulation of mutations in the mitochondrial DNA. Abnormal mitochondrial function is one of the hallmarks of aging in many species, including humans. This is mostly due to the fact that the mitochondrion is the so-called powerhouse of the cell as it produces energy in a process called cellular respiration. Damage to the mitochondrial DNA results in changes or mutations in the DNA sequence. Accumulation of these changes is associated with a reduced lifespan and early onset of aging-related characteristics such as weight and hair loss, curvature of the spine and osteoporosis.

 

There is, however, a growing body of conflicting evidence that has raised doubts about the validity of this theory. The Tsukuba team in particular has performed some compelling research that has led them to propose that age-associated mitochondrial defects are not controlled by the accumulation of mutations in the mitochondrial DNA but by another form of genetic regulation. The research, published this month in the journal Nature's Scientific Reports, looked at the function of the mitochondria in human fibroblast cell lines derived from young people (ranging in age from a fetus to a 12 year old) and elderly people (ranging in age from 80-97 years old). The researchers compared the mitochondrial respiration and the amount of DNA damage in the mitochondria of the two groups, expecting respiration to be reduced and DNA damage to be increased in the cells from the elderly group. While the elderly group had reduced respiration, in accordance with the current theory, there was, however, no difference in the amount of DNA damage between the elderly and young groups of cells. This led the researchers to propose that another form of genetic regulation, epigenetic regulation, may be responsible for the age-associated effects seen in the mitochondria.

 

Epigenetic regulation refers to changes, such as the addition of chemical structures or proteins, which alter the physical structure of the DNA, resulting in genes turning on or off. Unlike mutations, these changes do not affect the DNA sequence itself. If this theory is correct, then genetically reprogramming the cells to an embryonic stem cell-like state would remove any epigenetic changes associated with the mitochondrial DNA. In order to test this theory, the researchers reprogrammed human fibroblast cell lines derived from young and elderly people to an embryonic stem cell-like state. These cells were then turned back into fibroblasts and their mitochondrial respiratory function examined. Incredibly, the age-associated defects had been reversed -- all of the fibroblasts had respiration rates comparable to those of the fetal fibroblast cell line, irrespective of whether they were derived from young or elderly people. This indicates that the aging process in the mitochondrion is controlled by epigenetic regulation, not by mutations.

 

The researchers then looked for genes that might be controlled epigenetically resulting in these age-associated mitochondrial defects. Two genes that regulate glycine production in mitochondria, CGAT and SHMT2, were found. The researchers showed that by changing the regulation of these genes, they could induce defects or restore mitochondrial function in the fibroblast cell lines.

...



#10 corb

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Posted 26 May 2015 - 11:03 PM

I'd say it's a mess.
We could look at the title "Scientists reverse aging in human cell lines and give theory of aging a new lease of life" - what does that tell you?
"Scientist reverse aging" - they didn't.

"and give theory of aging a new lease of life" - this part is just written in a bad way, makes you think they reinforced current theories of aging, and again they didn't.

 

There's a couple of other lines I don't like in the article but the most important mistake that really irks me is the "reverse" aging line and presenting it as a new discovery. Also there's other pieces of information either omitted or more possibly the author didn't know about them so he took what he was being told as a fact.

 

I'm personally putting the whole bottom line of their conclusion and methods under question - when you reprogram a cell into pluripotency and back, it does a lot of maintenance and especially with stem cells we know that they have better quality control of their mitochondria than other cell lines. So looking into fibroblasts isn't especially meaningful.

Basically the author wrote whatever he was being told without double checking and he didn't have the basic knowledge to question it either. Coupled with the catchy vague title, I can't say the article is well written.


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#11 xEva

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Posted 26 May 2015 - 11:50 PM

I say this is an important development, especially for SENS. Why, if contrary to de Grey hypothesis, mitochondrial age-associated respiration defects turn out to be not due to random "damage" sustained as a function of time but the result of epigenetic changes, this would seriously undermines mitoSENS. ..though in light of the ongoing developments, it has been begging for a review/update for many years already.

And by the way, did you note that they did not find an increase in the rate of mitochondrial mutations as a function of age? Yet another nail in the coffin of the accumulating damage theory.

..though of course, "reversing aging" is oversimplification. Don't know about glycine, xcept I'm certain that overdosing anything will lead to nasty consequences and that induction of pluripotency is not something the cells of a developed organism can undergo in vivo.

Interesting though how it points at the fascinating program the germ cells run at the onset of life, no? Somehow, just about everything gets repaired, fixed and restored. The holy grail of antiaging research is to elicit the same from cells of an adult organism.

Edited by xEva, 26 May 2015 - 11:52 PM.

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#12 Avatar of Horus

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Posted 27 May 2015 - 04:06 PM

I say this is an important development, especially for SENS. Why, if contrary to de Grey hypothesis, mitochondrial age-associated respiration defects turn out to be not due to random "damage" sustained as a function of time but the result of epigenetic changes, this would seriously undermines mitoSENS.
...

 
Aubrey made a comment in reason's coverage in fightaging.org of the study:
Another Example of Induced Pluripotency Reversing Mitochondrial Damage in Aging
http://www.longecity...amage-in-aging/
https://www.fightagi...ge-in-aging.php
 
in Comments:

It has long been very obvious that mito dysfunction in the elderly is hardly at all caused by mutations (since they are too rare) and rather, by elimination, almost entirely by “deliberate” (i.e. regulated) nuclear gene expression changes, occurring as an adaptation to other things that are going wrong. That’s not to say that mito mutations are harmless though, not at all - but that their harm is via other means, such as my “reductive hotspot hypothesis” from 1998.

There is one interesting result in the paper, namely that glycine supplementation partly rejuvenates mito function - but I don’t think the authors believe that the result is robust, because they have relegated it to one sentence at the end of the results and one supplementary figure.
Posted by: Aubrey de Grey at May 27, 2015 6:31 AM

 
the other comment is interesting too:

Yeah, it's rather puzzling that they seem to downplay the possible therapeutic potential of glycine, especially considering other research on lifespan benefits from glycine supplementation. For instance:
http://www.fasebj.or...Abstracts/528.2
Posted by: gheme at May 27, 2015 9:15 AM

The cited fasebj.org abstract:

Dietary glycine supplementation mimics lifespan extension by dietary methionine restriction in Fisher 344 rats
Joel Brind1,2, Virginia Malloy2, Ines Augie2, Nicholas Caliendo2, Joseph H Vogelman2, Jay A. Zimmerman2,3 and Norman Orentreich2

1 Natural Sciences, Baruch College, City University of New York, New York, NY
2 Orentreich Foundation for the Advancement of Science, Inc., Cold Spring-on-Hudson, NY
3 Biology, St. John’s University, Queens, NY

Dietary methionine (Met) restriction (MR) extends lifespan in rodents by 30–40% and inhibits growth. Since glycine is the vehicle for hepatic clearance of excess Met via glycine N-methyltransferase (GNMT), we hypothesized that dietary glycine supplementation (GS) might produce biochemical and endocrine changes similar to MR and also extend lifespan. Seven-week-old male Fisher 344 rats were fed diets containing 0.43% Met/2.3% glycine (control fed; CF) or 0.43% Met/4%, 8% or 12% glycine until natural death. In 8% or 12% GS rats, median lifespan increased from 88 weeks (w) to 113 w, and maximum lifespan increased from 91 w to 119 w v CF. Body growth reduction was less dramatic, and not even significant in the 8% GS group. Dose-dependent reductions in several serum markers were also observed. Long-term (50 w) 12% GS resulted in reductions in mean (±SD) fasting glucose (158 ± 13 v 179 ± 46 mg/dL), insulin (0.7 ± 0.4 v 0.8 ± 0.3 ng/mL), IGF-1 (1082 ± 128 v 1407 ± 142 ng/mL) and triglyceride (113 ± 31 v 221 ± 56 mg/dL) levels compared to CF. Adiponectin, which increases with MR, did not change in GS after 12 w on diet. We propose that more efficient Met clearance via GNMT with GS could be reducing chronic Met toxicity due to rogue methylations from chronic excess methylation capacity or oxidative stress from generation of toxic by-products such as formaldehyde. This project received no outside funding.

 

Apart from these, I'd wait with definitive verdicts regarding the mtDNA damage, because in the damage theories there is a distinction between post-mitotic, terminally differentiated and dividing cells. On the other hand when dealing with mtDNA I think there are other things that also need to be taken into consideration, namely the internal biological mechanisms, the mitochondrial quaility control - in connection with lysosomes - , and the intracellular DNA exchange between mitochondria in cells, and the mitochondria - and lysosome - exchange between the cells. Imho only after these things have been clarified can one say more definite anwers to the programming vs. damage question of aging.


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#13 Kalliste

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Posted 27 May 2015 - 05:28 PM

I say this is an important development, especially for SENS. Why, if contrary to de Grey hypothesis, mitochondrial age-associated respiration defects turn out to be not due to random "damage" sustained as a function of time but the result of epigenetic changes, this would seriously undermines mitoSENS. ..though in light of the ongoing developments, it has been begging for a review/update for many years already.

And by the way, did you note that they did not find an increase in the rate of mitochondrial mutations as a function of age? Yet another nail in the coffin of the accumulating damage theory.

..though of course, "reversing aging" is oversimplification. Don't know about glycine, xcept I'm certain that overdosing anything will lead to nasty consequences and that induction of pluripotency is not something the cells of a developed organism can undergo in vivo.

Interesting though how it points at the fascinating program the germ cells run at the onset of life, no? Somehow, just about everything gets repaired, fixed and restored. The holy grail of antiaging research is to elicit the same from cells of an adult organism.

 

All kinds of things are probably wrong with SENS, the easiest and cheapest way to find out is to try some repair treatments and see what happens. Personally I would not mind to repair my MitoDNA even if that was not a cure all. I'm curious, what do you think would happen if you checked all the things on the SENS list of in a human subject? Would they grow even older?



#14 xEva

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Posted 30 May 2015 - 12:18 AM

... the easiest and cheapest way to find out is to try some repair treatments and see what happens. Personally I would not mind to repair my MitoDNA even if that was not a cure all. I'm curious, what do you think would happen if you checked all the things on the SENS list of in a human subject? Would they grow even older?


You're talking about "repair treatments" as if such exist. ..or will exist in the foreseeable future. ..and the ease with which you commit to repairing your "MitoDNA even if that was not a cure all" speaks of blessed unawareness of complexities involved. Have you given some thought to the side effects of such treatments? It's worth remembering that the things on the SENS list were authored by a guy with a BS in computer science -- though married to a PhD in biology! :)

#15 niner

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Posted 30 May 2015 - 02:35 AM

 It's worth remembering that the things on the SENS list were authored by a guy with a BS in computer science -- though married to a PhD in biology! :)

 

Aubrey knows a hell of a lot of biology for a guy that you're implying is unqualified.  He didn't author any of the forms of damage that are on the list.  He cataloged them and proposed solutions that may or may not work.   Some of them most likely will fail, some might succeed.  Senescent cell clearance will probably be the first to the clinic, and then we will be able to evaluate its efficacy in humans.  This is something that is going to happen in the quite foreseeable future.  It's worth pointing out that SRF isn't trying to implement all their solutions on their own.  They are investing in academic and industrial partners, in some case to develop the fundamental tool and platform technologies that will be needed to solve these problems.   SENS has said "here are the problems that need to be solved".  They have suggested some solutions, but I don't think that they care all that much if it's their original suggestion that is implemented or something better.  Their goal is to see aging brought under control, not to insist that it happen in a certain way.


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#16 Kalliste

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Posted 30 May 2015 - 05:29 AM

 

... the easiest and cheapest way to find out is to try some repair treatments and see what happens. Personally I would not mind to repair my MitoDNA even if that was not a cure all. I'm curious, what do you think would happen if you checked all the things on the SENS list of in a human subject? Would they grow even older?


You're talking about "repair treatments" as if such exist. ..or will exist in the foreseeable future. ..and the ease with which you commit to repairing your "MitoDNA even if that was not a cure all" speaks of blessed unawareness of complexities involved. Have you given some thought to the side effects of such treatments? It's worth remembering that the things on the SENS list were authored by a guy with a BS in computer science -- though married to a PhD in biology! :)

 

 

They do exist, they cleared senescent cells out of mice with Dasatinib+Quercetin quite recently.

 

So do tell me, if a magic spirit appeared in your room and asked you if you wanted to get all those treatments at once via magic, what would be the biological result for you? Would you die? Would you become younger but loose your brain or something?

 

And I believe it would be the cheapest way to find out to develop some repair treatments, Glucosepane, and try them. If they don't work we will be able to pursue more complex goals like whole organism NDNA/MitoDNA/epigenetic/microRNA whatever reprogramming.



#17 corb

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Posted 30 May 2015 - 10:28 AM

Whether the damage (or whatever you decide to call it) is genetic or epigenetic it doesn't really matter, in the end the technology used to repair it is the same - CRISPR for instance can edit both genes and methylation.

 

xEva repair treatments exist. Surgeons have been doing grafts for decades, transplantations as well - it's a primitive type of repair but it is repair, I'm sure a medical professional can point out many other examples.

As for when a more advanced technique will become widely available, it's probably going to be stem cells in about ten to fifteen years in the more forward looking countries like Japan and China.


Edited by corb, 30 May 2015 - 10:44 AM.

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#18 Michael

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Posted 30 May 2015 - 11:43 PM

All:
 

You will not be surprised to learn that we've several inquiries put to Dr. de Grey and/or Dr. O'Connor who heads our mitochondrial mutations obviation lab at SENS Research Foundation wink.png . It also roused significant interest on FightAging! and other Forums.  I'm not terribly impressed with the science underlying the main findings in the report, the analysis is worse (Aubrey notes this albeit in severely compressed form in his comment quoted above), and as niner suspects the concentrations of glycine they used for the cell culture study required are much higher than the physiological range -- high enough that they would be life-threatening if they are even achievable.

The rodent glycine supplementation study was only ever presented as a meeting abstract for a good reason. While the results nominally support a lifespan effect, the study has an exceptionally severe case of the usual problem, with which long-time Longecity members will be familiar because I've hammered at it so often, of short-lived controls — in this case, severely short-lived controls. And even the "extended-life" supplement groups still lived truly miserably abbreviated lifespan. I actually contacted the researchers who conducted this study, and they agree that the short lives of all the cohorts involved makes it impossible to draw any real conclusions from the study.
 
This is just a sketch: there's been enough interest that I'm going to address it more fully in the next "Question of the Month" column.

"What's the 'Question of the Month' column?" you ask? You would know if you subscribed to our Newsletter!
 
 

 

... the easiest and cheapest way to find out is to try some repair treatments and see what happens. Personally I would not mind to repair my MitoDNA even if that was not a cure all. I'm curious, what do you think would happen if you checked all the things on the SENS list of in a human subject? Would they grow even older?


You're talking about "repair treatments" as if such exist. ..or will exist in the foreseeable future.

 


The Aβ and α-synuclein vaccines are in clinical trials now; Cosmicalstorm already noted the senolytics, and other groups are pursuing senescent cell ablation technologies; the catalytic TTR-cleaving antibodies under development with Foundation funding are looking very promising; we're no longer the only group pursuing microbial xenohydrolases as a regenerative therapy against atherosclerosis; stem cell therapy is finally starting to look like it's delivering real treatments in humans. The key point is that you do have to develop the technology to test it — and whether 'foreseeable' means three decades or ten depends on our coming together to push for them.
 

..and the ease with which you commit to repairing your "MitoDNA even if that was not a cure all" speaks of blessed unawareness of complexities involved. Have you given some thought to the side effects of such treatments?


Imagine! Medicine might have side-effects!

 

In any case, interventions that act by removing cellular and molecular damage (which is, by definition, deleterious) rather than interfering with regulating metabolic pathways (which are, by definition, essential to life), are by their intrinsic nature less likely to lead to side-effects.
 

It's worth remembering that the things on the SENS list were authored by a guy with a BS in computer science -- though married to a PhD in biology! :)

 

The things on the SENS list were originally coauthored by Dr. de Grey — who, along with his computer science degree, has a PhD in biology from Cambridge University for work on (wait for it!) the role of mitochondria in aging — along with several distinguished coauthors, and buttressed by subsequent collaborations in SENS roundtables and the progress in the field as a whole.


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#19 alc

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Posted 31 May 2015 - 02:48 AM

@ Michael - about "Question of the month" - where the questions can be submitted?

 

I would like to ask what is your position versus CRISPR/Cas9 and reverse aging, since George Church already mentioned that in one of his presentations.

 

http://casw.org/stud...neering-purpose

 

For me CRISPR/Cas9 and "upgraded" similar technologies have by far a better prospect to achieve reverse aging than almost everything out there (as of now).

 

thanks!



#20 xEva

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Posted 31 May 2015 - 09:53 PM

They do exist, they cleared senescent cells out of mice with Dasatinib+Quercetin quite recently.
 
So do tell me, if a magic spirit appeared in your room and asked you if you wanted to get all those treatments at once via magic, what would be the biological result for you? Would you die? Would you become younger but loose your brain or something?
 
And I believe it would be the cheapest way to find out to develop some repair treatments, Glucosepane, and try them. If they don't work we will be able to pursue more complex goals like whole organism NDNA/MitoDNA/epigenetic/microRNA whatever reprogramming.


Yes, I'm watching with great interest the thread where people experiment with senolytics. But the topic here was more about the mitoSENS, no?

As for your question, I don't even know how to approach it.. The problem is, I don't see how one would go about actualizing those treatments, even one by one, let alone at once, without running into unintended side-effects -- except maybe by sheer magic. ..especially that part about "whole organism NDNA/MitoDNA/epigenetic" reprogramming :) I mean, this may be possible in a zygote, but isn't the idea of SENS "escape velocity" in repairing "damage" in an adult, already aging organism?

Edited by xEva, 31 May 2015 - 09:54 PM.

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#21 xEva

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Posted 31 May 2015 - 10:28 PM

All:


You will not be surprised to learn that we've several inquiries put to Dr. de Grey and/or Dr. O'Connor who heads our mitochondrial mutations obviation lab at SENS Research Foundation wink.png . It also roused significant interest on FightAging! and other Forums. I'm not terribly impressed with the science underlying the main findings in the report, the analysis is worse (Aubrey notes this albeit in severely compressed form in his comment quoted above), and as niner suspects the concentrations of glycine they used for the cell culture study required are much higher than the physiological range -- high enough that they would be life-threatening if they are even achievable.


The Aβ and α-synuclein vaccines are in clinical trials now; Cosmicalstorm already noted the senolytics, and other groups are pursuing senescent cell ablation technologies; the catalytic TTR-cleaving antibodies under development with Foundation funding are looking very promising; we're no longer the only group pursuing microbial xenohydrolases as a regenerative therapy against atherosclerosis; stem cell therapy is finally starting to look like it's delivering real treatments in humans. The key point is that you do have to develop the technology to test it — and whether 'foreseeable' means three decades or ten depends on our coming together to push for them.


The things on the SENS list were originally coauthored by Dr. de Grey — who, along with his computer science degree, has a PhD in biology from Cambridge University for work on (wait for it!) the role of mitochondria in aging — along with several distinguished coauthors, and buttressed by subsequent collaborations in SENS roundtables and the progress in the field as a whole.



First, there no need for the "mitochondrial mutations obviation" project, since, contrary to de Grey's old and failed hypothesis, mitochondrial mutations do NOT accumulate with age. I am aware that long time ago, based on the insufficient data, de Grey proposed that, once damaged, mitochondria should not be able to signal/initiate mitophagy that would take them out. He reasoned that this should lead to accumulation of dysfunctional mitochondria, resulting "in the metabolic derangement of aging and in accelerating the course of the degenerative aging process as a whole" -- as you write on the site. Though it has become apparent years ago --a decade?-- that there are other ways that maintain mitochondrial quality, SENS has apparently remained oblivious of these findings. On the page that you linked it is still stated that accumulation of mitochondrial mutations with age is "inevitable", as if it was a fact. Turns out, it's not.

Now even de Grey himself states that "it has long been very obvious that mito dysfunction in the elderly is hardly at all caused by mutations". Has long been very obvious? -- why would then SENS still finance the project whose specific goal is to express mitochondrial genes allotopically in order "to provide the necessary proteins even when mutations have compromised the mtDNA’s ability to do so"? Don't get me wrong, I'm all for this very interesting research -- it only came up à propos to Reason's frequent laments that limited resources are being wasted on basic research instead of going for more practical "solutions".


Second, was not this failed mitochondrial hypothesis at core of de Grey's publications, for which he got his honorary PhD? (and, incidentally, didn't him getting this honor also coincide with his generous donation to Cambridge?) But the point here is not whether his education makes him "qualified". Biology is not rocket science. ..though it does require a solid base. Unfortunately, that de Grey does not have such a base shines through in his talks and SENS publications. Surely you understand that, if only this was not the case, the question of his education would never even come up! His advocacy efforts are praiseworthy and one could even make a case for his bold, on the border with wackiness, "solutions", along with his beard of course, being a great PR gimmick. The problems only start when some lay people confuse his advocacy efforts with science.


Third, re Aβ and α-synuclein vaccines, not only are they "in clinical trials now", but, as far as I know, at least one such trial has already completed --and!-- though it successfully "ablated" the amyloid from the brains of the AD patients, not only this failed to ameliorate their condition but instead, it appears, hastened their demise. ..which is not particularly surprising in the light of the ever-gaining popularity idea that amyloids are actually accumulations of antimicrobial peptides (a part of the innate immune response to an infection).

Incidentally, were not you the one who came up with idea for a therapy that would preferentially kill "useless T-cells" that specialize in "non-dangerous viruses"? This craziness is still actively promoted by Reason; and this is precisely what makes one question the education of SENS leaders and their supporters.
 

Imagine! Medicine might have side-effects!

In any case, interventions that act by removing cellular and molecular damage (which is, by definition, deleterious) rather than interfering with regulating metabolic pathways (which are, by definition, essential to life), are by their intrinsic nature less likely to lead to side-effects.


I admit I can't fathom the "intrinsic nature" of such interventions (don't say, nano-machines?) I can't imagine messing with the complexity of an organism --that has been optimizing its functions for hundreds of millions of years-- without inadvertently affecting its essential metabolic pathways. But please do tell us about this "intrinsic nature". I'm all ears :)

Edited by xEva, 31 May 2015 - 11:16 PM.

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#22 corb

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Posted 01 June 2015 - 04:00 PM

Third, re Aβ and α-synuclein vaccines, not only are they "in clinical trials now", but, as far as I know, at least one such trial has already completed --and!-- though it successfully "ablated" the amyloid from the brains of the AD patients, not only this failed to ameliorate their condition but instead, it appears, hastened their demise. ..which is not particularly surprising in the light of the ever-gaining popularity idea that amyloids are actually accumulations of antimicrobial peptides (a part of the innate immune response to an infection).

 

It's is not important if a trial fails. It's important WHY it fails.

 

 

We have identified a direct link between administration of Aβ and loss of consolidated LTM in Lymnaea, a well-established and highly tractable model system for studying evolutionarily conserved cellular and molecular mechanisms of memory function and dysfunction14. Importantly, our study revealed that systemically applied Aβ is able to enter the neurons of the ‘learning ganglia’ and leads to memory impairment at the behavioral level without any evidence for neuronal death. Both 1 μM Aβ 1-42 and 0.1 mM Aβ 25-35 caused significant memory impairment when injected 24 hours after training; however, only 0.1 mM Aβ 25-35 removed the training-induced membrane potential depolarization and lowered membrane resistance of a key neuron of the learning and memory circuitry.

 

http://www.nature.co.../srep10614.html

 

There is no question what causes loss of learning potential in Alzheimer's and geriatrics in general anymore. The only question is whether removing just abeta in late stage Alzheimer's is enough and it probably isn't. That doesn't mean the proposed methodology is wrong, it just means it is insufficient, it means the cause for neuronal death will have to be identified with certainty as well. And it means an optimal way of regenerating the brain will have to be researched for the cases where neuronal death is already significant and prophylaxis is impossible.

 

 

 

I can't imagine messing with the complexity of an organism --that has been optimizing its functions for hundreds of millions of years-- without inadvertently affecting its essential metabolic pathways.

 

I think the point was about affecting metabolism negatively.

If you identify what causes a malfunction and remove it, one can hope the metabolic pathways will return to normal operation, instead of creating an even bigger problem - it might not go that way always but there's no reason why it shouldn't in most cases.

We know malfunctions are caused by elements, or deficiencies new to the system because the system has had a history of working optimally - for most people. This is actually very much in tune with your idea - organisms have self optimized for survival - so by that logic if there is no problem metabolism should work as it is intended to as well. The only way you can remove an irritant or damage, or, again, whatever you decide to call it for the sake of sophistry, and create an even bigger problem is if the system is actively promoting failure.

 

 

"whole organism NDNA/MitoDNA/epigenetic" reprogramming [...] without running into unintended side-effects

 

Epigenetic reprogramming is a constant process absolutely necessary for life which is why most SENS and SENS like method proponents like me think it has little merit as a treatment for the treatment of any disease or sign of aging. My brain reprogrammed it's epigenetic a couple of million times just while I was writing this paragraph, I've been waiting for a couple of years for the epigenetic drift gurus to tell us how exactly they plan on controlling a mechanism so ephemeral with any efficacy and silence is all I get.
As for the rest, if we ignore post mitotic tissues for the time being, every else cell in your body is eventually replaced so zygote or a grown organism it's only a matter of scale. Mosaicism isn't nearly as scary as most biochauvinsts make it out to be, there's thousands of people walking around with someone else's liver or kidney and they're better off than before they became a mosaic.


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#23 alc

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Posted 01 June 2015 - 04:45 PM

"I've been waiting for a couple of years for the epigenetic drift gurus to tell us how exactly they plan on controlling a mechanism so ephemeral with any efficacy and silence is all I get."

 

 

 

 

here is something that you might find useful and there are some clues -   a Google search for "epigenetic reprogramming using crispr"

 

https://www.google.c...=utf-8&oe=utf-8

 

one interesting article is: "Synthetic epigenetics—towards intelligent control of epigenetic states and cell identity"

 

http://www.clinicale.../content/7/1/18

 

 

 

 

 


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#24 j87

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Posted 05 June 2015 - 09:43 PM

Are there any studies using topical glycine cream for anti-aging? 


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#25 Steve H

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Posted 08 June 2015 - 11:59 AM

"I've been waiting for a couple of years for the epigenetic drift gurus to tell us how exactly they plan on controlling a mechanism so ephemeral with any efficacy and silence is all I get."

 

 

Blood factors can reprogram cells and reverse the aged phenotype as demonstrated by Irina/Michael Conboy, Rando, Villeda, Corey, Wagers and others. It seems that Stem cells that are Quiescent can be recalled to service by such factors (see recent TGF-Beta study by Conboy) as they reverse the aged phenotype in the Stem cell niche. Plus there are also studies that suggest factors can also stimulate Neurogenesis in the brain. There are also studies which show that things like Androgens activate TERT and thus lengthen Telomeres in cells too so young plasma does contain the cocktail required to epigenetically reprogram cell age. When I say reprogram BTW I am not talking about programmed aging here which is another debate entirely.

 

Aubrey De Grey said recently to me that whilst factors in blood do not directly relate to SENS strategy they could simplify the SENS approach, eg, less strands but still seven damage types. This is a line of thought I agree with and anything to simplify matters is going to help in the long term. Alc is also correct that gene therapy could be used to target key pathways and assist SENS to simplify its task. CRISPR is too early days yet but single gene AAV therapy is perfectly able to up or down regulate target genes as required.

 

So knowing that youthful factors can and do restore function and rejuvenate tissue why not just test this in people? Plasmaspheris is an approved technique and the results could provide interesting data. If results show it has benefits and not just short term ones but helps address the epigenetic drift somewhat then steps could be taken to make an artificial cocktail of key factors or better still use gene therapy to do it without needing to manufacture drugs and the years they take.

If it simplifies the work SENS has to do and improves healthspan as a result then its a win win. If we are very lucky plasma therapy or its analogue may stabilize homeostasis to a manageable level making SENS easier. We just do not know and that is frankly ridiculous given how simple Plasma exchange is though not totally without risk ofc but the last time I checked sitting about aging was also fairly risky. 

 

Regards the original article I believe its a downstream effect and something we could tackle upstream.


Edited by Steve H, 08 June 2015 - 12:08 PM.

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#26 niner

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Posted 08 June 2015 - 01:45 PM

Now even de Grey himself states that "it has long been very obvious that mito dysfunction in the elderly is hardly at all caused by mutations". Has long been very obvious? -- why would then SENS still finance the project whose specific goal is to express mitochondrial genes allotopically in order "to provide the necessary proteins even when mutations have compromised the mtDNA’s ability to do so"? Don't get me wrong, I'm all for this very interesting research -- it only came up à propos to Reason's frequent laments that limited resources are being wasted on basic research instead of going for more practical "solutions".


This is a really good question.  I hope someone from SENS will address this point.  They're continuing the allotopic expression work, so they must have a reason to believe that it's going to do some good.
 

Second, was not this failed mitochondrial hypothesis at core of de Grey's publications, for which he got his honorary PhD? (and, incidentally, didn't him getting this honor also coincide with his generous donation to Cambridge?) But the point here is not whether his education makes him "qualified". Biology is not rocket science. ..though it does require a solid base. Unfortunately, that de Grey does not have such a base shines through in his talks and SENS publications. Surely you understand that, if only this was not the case, the question of his education would never even come up! His advocacy efforts are praiseworthy and one could even make a case for his bold, on the border with wackiness, "solutions", along with his beard of course, being a great PR gimmick. The problems only start when some lay people confuse his advocacy efforts with science.


I'll say biology isn't rocket science!  Rocket science is child's play compared to biology.  The complexity of biology makes rockets look like... rocks.  The fact that you say this presumably derives from the fact that you aren't trained in the biological or molecular sciences.  Nothing wrong with that, until you start claiming that people who have a vastly deeper understanding of biology than you do are unqualified.
 

Third, re Aβ and α-synuclein vaccines, not only are they "in clinical trials now", but, as far as I know, at least one such trial has already completed --and!-- though it successfully "ablated" the amyloid from the brains of the AD patients, not only this failed to ameliorate their condition but instead, it appears, hastened their demise. ..which is not particularly surprising in the light of the ever-gaining popularity idea that amyloids are actually accumulations of antimicrobial peptides (a part of the innate immune response to an infection).

I'm not sure where the antimicrobial peptide idea is gaining traction, but my guess would be in internetland.   Recently Biogen's aducanumab, an AB antibody, has showed that removing AB can slow progression.  These are different days in the Alzheimers world.  There is growing evidence that AB is a major driver (though not the only one) of the disease.  A couple years ago some people were declaring the amyloid hypothesis dead because a couple high profile trials of AB-related therapies failed.  The problem is, those trials were flawed.  It's only recently that we've been able to distinguish between people whose dementia is due to AB versus other causes, and the trial population was mixed.  It's relatively recently that we've figured out that AB accumulation starts 15 years before symptoms.  In a vicious-cycle disease like Alzheimers, you can't start treatment at the end and expect great results.  To paraphrase Samuel Clemens:  Reports of the amyloid hypothesis' death are greatly exaggerated...
 


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#27 xEva

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Posted 09 June 2015 - 01:38 AM

I'm not sure where the antimicrobial peptide idea is gaining traction, but my guess would be in internetland.


oh niner! your duties as a mod here must leave you with not enough time to keep up. I noticed this a while ago, when it turned out that you still! went by the old de Grey's hypothesis on mitochondria (discussed above), of which even de Grey himself now says "has long been very obvious" (also above).

Re amyloid-beta being an antimicrobial peptide, here is the well-publicized paper from 2010 (5 years ago! -- though the original idea first appeared in 2006): The Alzheimer's Disease-Associated Amyloid β-Protein Is an Antimicrobial Peptide

Since then, pubmed lists 84 papers referencing it, and CrossRef 123. Of course not all the papers referencing it are relevant (or even agree with it -- maybe not!) but the titles of some of them, picked at random, are very telling:
  • Infectious Agents and Neurodegeneration
  • Microbial manipulation of the amyloid fold
  • The 21st century epidemic: infections as inductors of neuro-degeneration associated with Alzheimer’s Disease
  • Periodontal disease associates with higher brain amyloid load in normal elderly
  • Chlamydia pneumoniae infection of monocytes in vitro stimulates innate and adaptive immune responses relevant to those in Alzheimer’s disease
  • Alzheimer's Associated β-Amyloid Protein Inhibits Influenza A Virus and Modulates Viral Interactions with Phagocytes
  • Emerging roles of pathogens in Alzheimer disease
  • Do β-Defensins and Other Antimicrobial Peptides Play a Role in Neuroimmune Function and Neurodegeneration?
  • Dementia: A link between microbial infection and cognition?
That's the "internetland" for you :)

But seriously, it pays to read something else besides SENS publications.

Edited by xEva, 09 June 2015 - 01:58 AM.

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#28 HighDesertWizard

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Posted 09 June 2015 - 03:00 AM

I understand that I sound like a crazed one trick pony but, it's not my fault that, Glycine turns out to be an NF-kB Transcription Inhibitor...

 

Glycine suppresses TNF-α-induced activation of NF-κB in differentiated 3T3-L1 adipocytes

 

Cysteine, histidine and glycine exhibit anti-inflammatory effects in human coronary arterial endothelial cells

 

A glycine-rich region in NF-kappaB p105 functions as a processing signal for the generation of the p50 subunit

 

Dietary glycine inhibits activation of nuclear factor kappa B and prevents liver injury in hemorrhagic shock in the rat

 


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#29 alc

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Posted 10 June 2015 - 10:37 PM

"It would be good if SENS supporters would also show the same flexibility. Otherwise, the impression I get from my exchanges with niner starts making this community appear sorta sect-like. I mean, the smallest criticism is promptly countered with and-wtf-are-you adhoms -- as if SENS is infallible commandments cast in stone.

 

But I always thought that it was just an approximate plan. I mean, it's naïve to expect such am ambitious proposal, created years ago amid vastly insufficient data, to work out"

 

 

That is exacly what others are thinking too! If you look for example  at FA blog, the only story you read between lines, is that whatever SENS does, is good/great and works, whetever others are doing is doubtful/not working, etc. Really? is that the case? I do not think that is how SENS or its supporters should be, they should be open minded and analyze all new serious findings and try to integrate new serious developments into their work.

 

I mentioned in one of my posts that if people believe that what SENS laid out a decade ago is working,  to me that seems more like a prophecy than real science. In this field things get discovered in a daily basis.

 

Another big question here is why Calico did not licensed SENS's technologies? This is about business and nothing else. And I'm pretty sure Calico is after any serious rejuvenation technology.

 

Please keep in mind that I make all these comments as aperson that do support SENS and I even donate small sums to them. More than that I want them to succeed, but not going this path becoming more like a cult and their zealots hit everybody that challange their path. 

 

For past years I started to like more and more George Church's work then SENS' especially that now he and his team are looking into rejuvenation.


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#30 Steve H

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Posted 11 June 2015 - 11:46 AM

It's good to see de Grey being flexible about SENS and I'm glad they are supporting Conboy research. I find her work most fascinating.

It would be good if SENS supporters would also show the same flexibility. Otherwise, the impression I get from my exchanges with niner starts making this community appear sorta sect-like. I mean, the smallest criticism is promptly countered with and-wtf-are-you adhoms -- as if SENS is infallible commandments cast in stone.

But I always thought that it was just an approximate plan. I mean, it's naïve to expect such am ambitious proposal, created years ago amid vastly insufficient data, to work out to the t. To the contrary, I expected that, as soon as evidence for a better plan will appear, this community will gladly embrace it and adjust their plans accordingly. After all, what's the goal here? (personally, I don't believe in living forever but simply don't like the idea of getting old and decrepit, and whatever works is fine with me  :)) So what's all this ideology? I mean, look, even your question to de Grey that you quote above sounds like but what about the party line?

 

 

I am not sure I could be said to be following the party line to be fair as I often debate SENS where I feel it's not right or information is conflicting hence I questioned why SENS is funding work that messes about with Metabolism as Reason frequently says in articles of this nature. The above response from ADG actually made sense in how it works with SENS so as you say it is good to see him modifying his ideas as new information comes in, I think it is important to be willing to modify your strategy over time.

 

Another big question here is why Calico did not licensed SENS's technologies? This is about business and nothing else. And I'm pretty sure Calico is after any serious rejuvenation technology

 

.
It suggests to me they either have technology that does similar, they have no agreed a deal with SENS, they do not think SENS is a viable strategy or they are not trying to fully rejuvenate the body as SENS is. I have heard rumors Calico is working on the FOXO pathway so if that is an example of their approach (ie, signalling pathways and pharma solutions) I can understand why they might not be interested in SENS. Of course it is all speculation and as I have said before, I don't care who runs the race to solve aging as long as someone does!

Regards programmed aging vs stochastic aging I think far too much time is being wasted by the community arguing about that instead of focusing on the problem and what both schools of thought do have in common. Not wishing to get into a debate about programmed vs stochastic aging as I consider everyone in the field as working on the same problem albeit from different directions, There are clearly crossover points where everyone can work together so why not do that?

 

Regards CMV I think removing it is a good idea, anything that put a burden on the immune system is bad regardless of the exact mechanics involved. It should be removed by whatever method is effective.


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