More Work on DNA Methylation Patterns and Aging

In recent years researchers have made good progress towards a biomarker of age based on patterns of DNA methylation that change over time. The trick here is pulling out meaningful changes that are characteristically related to aging in much the same way in everyone versus the much larger set of changes that vary widely between individuals. As aging is a process of damage accumulation, some of these epigenetic changes in DNA methylation are responses to that damage, meaning that somewhere in all of this is a methodology to rapidly evaluate potential rejuvenation treatments that are based on repair of damage. That is the real significance of this ongoing field of research:

Researchers studied chemical changes to DNA that take place over a lifetime, and can help them predict an individual's age. By comparing individuals' actual ages with their predicted biological clock age, scientists saw a pattern emerging. People whose biological age was greater than their true age were more likely to die sooner than those whose biological and actual ages were the same.

Four independent studies tracked the lives of almost 5,000 older people for up to 14 years. Each person's biological age was measured from a blood sample at the outset, and participants were followed up throughout the study. Researchers found that the link between having a faster-running biological clock and early death held true even after accounting for other factors such as smoking, diabetes and cardiovascular disease.

Researchers measured each person's biological age by studying a chemical modification to DNA, known as methylation. The modification does not alter the DNA sequence, but plays an important role in biological processes and can influence how genes are turned off and on. Methylation changes can affect many genes and occur throughout a person's life. "The same results in four studies indicated a link between the biological clock and deaths from all causes. At present, it is not clear what lifestyle or genetic factors influence a person's biological age. We have several follow-up projects planned to investigate this in detail."

Link: http://www.eurekalert.org/pub_releases/2015-01/uoe-dch013015.php

Comments

Why are you stating that DNA methylation is a response to damage and not damage itself? Is it not? Shouldn't DNA demethylation drugs (They exist- they've been recently developed for cancer treatment) be part of regular rejuvenation therapy?

Posted by: Slicer at January 30th, 2015 2:04 PM

@Slicer: DNA methylation occurs in response to circumstances. Patterns change constantly on a variety of timescales due to environmental changes: temperature, food, etc, etc. Being damaged is just another circumstance, and I'd place epigenetic changes firmly in the consequence rather than cause category for aging. You can still think of it as damage, as all change could be considered damage, but since it's not fundamental root cause damage, but rather a secondary effect, pursuing ways to alter epigenetic changes will not be effective in comparison to actually fixing those root causes.

Posted by: Reason at January 30th, 2015 4:25 PM

Then I guess the only question becomes "The repair of what root cause damage would cause DNA to become less methylated?"

Posted by: Slicer at January 30th, 2015 6:06 PM

@Slicer: All of it, I imagine, with a lot of overlap between specific methylation locations. That's one of those questions that probably won't be answered until repair therapies are implemented. The situation is so complex that the fastest way by far to figure out cause and effect is to remove the cause.

Posted by: Reason at January 30th, 2015 6:26 PM

I believe that epigenetics will be more and more in focus in years to come.
It will be interesting to see what will work of Craig Venter bring. Sequencing million genomes in next five years (although I think/hope it will be sooner) should give us some clues. David Sinclair also announced some interesting results few months ago. He said it should be published soon.

As for SENS...They used to be top story some years ago, but now...
One has to give credit to SENS and De Grey for promoting the whole anti-aging story, but if they want to remain relevant factor in this game they have to provide some results - any kind of results and they have to do it fast.

To be honest, I think that things don't look good for SENS. Just look at the major breakthroughs in last years (and we had some big ones), SENS was not part of any of them.

Posted by: Gellq at January 31st, 2015 3:47 AM

Just to be clear. I know that SENS is doing and funding some research, but I am not talking about that.
I am talking about something that will give them headlines (and investors) - some research that will demonstrate that based on their concept they manged to prolong lifespan of some kind of organism (simple one would do).
The more the time goes by the more I think that SENS is not good strategy to fight aging - please note that I didn't say that their strategy/concept is bad (I still have my doubts)
I never thought that SENS is the the best option, but at least I thought of them as top player.

Posted by: Gellq at January 31st, 2015 3:58 AM

Everyone better hope that methylation pattern changes are a response to damage and not damage in itself, as fixing dysregulated DNA could be all but impossible for a long time.

Layman speculation, but as cells have systems for dealing with dysregulated DNA (p16 and p52 mediated cell death) it would be pretty surprising if they did not have any systems for dealing with dysregulated DNA methylation.

Posted by: Jim at February 1st, 2015 2:38 AM

@Gellq: Headlines are not the same as efficiency. I don't know of any research that has increased human lifespan. Also, the reasons why SENS is a better strategy than the others still apply. That isn't changed at all by headlines.

Posted by: Antonio at February 1st, 2015 1:19 PM

@Antonio
I think you misunderstood me. Of course headlines and efficiency are not he same.
Often you can hear De Grey talking about lack of funding and what do they do about that?
It's been a long time since millions represented big numbers when it comes to money.
You have governments talking about trillions now. Top 10 companies make a combined profit per year of around 300 billion USD.
It takes you 2 minutes to google all the billionaires that believe in anti-aging science and that invest money in it. And yet, how many of them support SENS? Either SENS don't know how to sell them story or they don't have anything to sell. (I fear it might be the second).
By the way, does Peter Thiel still funds SENS? I have some contradictory info.

Look at latest example with Cohbar and Nir Barzilai. I just mentioned them because they are the latest. Anti-aging is excellent business...

Please note that I said that "damage repair" approach might work (I have my doubts if it is the best near future strategy), but I am not sure about SENS.
What did they give us in last 5 years? And we had some interesting research results, apart from them

And I was not talking about research increasing lifespan for humans. We just have some emerging technologies. To test them it would take 40, 50 years. Instead, science will focus on biomarkers. Just last month we have interesting research published with rapamycin and humans.

I would love (as most of us, I guess) that SENS is a full success. But, they cannot ask people to prove them wrong, they have to demonstrate that they are right. We have a man with expertise in computers who had a revelation one day and he said he figured out how to defeat aging.
If it was that simple we wouldn't have so many different aging theories and you can't say that all the heavyweights in anti-aging science who have different opinion than SENS are stupid or that they just don't get it.

Posted by: Gellq at February 2nd, 2015 2:49 AM

@Gellq:

I think you are mixing two different things:

(1) efficiency of SENS as a therapy or research approach
(2) efficiency of SENS Foundation in obtaining funding.

In the post of yours I replied to, it seems that you are talking about (1):

"As for SENS...They used to be top story some years ago, but now... One has to give credit to SENS and De Grey for promoting the whole anti-aging story, but if they want to remain relevant factor in this game they have to provide some results - any kind of results and they have to do it fast. To be honest, I think that things don't look good for SENS. Just look at the major breakthroughs in last years (and we had some big ones), SENS was not part of any of them."

There you are saying that the other approaches are making good progress in the finding of a good anti-aging therapy and SENS is not. I replied to this in my above post.

Now you seem to be talking of (2):

"Often you can hear De Grey talking about lack of funding and what do they do about that? It's been a long time since millions represented big numbers when it comes to money."

I think SENS Foundation is doing pretty well, given that the NIH only spends around $10M/year on doing something about aging (instead of only understanding it) and SENS spends around $5M/year. It's certainly a small portion of what is needed for SENS to work, but given the opposition of the mainstream in gerontology to SENS, I think they are doing a good job at funding searching.

"but I am not sure about SENS. What did they give us in last 5 years?"

What did the other approaches give us?

"If it was that simple we wouldn't have so many different aging theories and you can't say that all the heavyweights in anti-aging science who have different opinion than SENS are stupid or that they just don't get it."

AFAIK, no one of these heavyweights has been able to prove that SENS is wrong. OTOH, none of them have been able to refute the arguments against the "messing with metabolism" approach (you can find these arguments here and in other websites).

(And SENS is not an aging theory, it's a set of anti-aging therapies. The aging theory SENS is based on, namely the damage accumulation theory, is mainstream.)

Posted by: Antonio at February 4th, 2015 3:32 PM

@Slicer: as Reason says, a cell needs to alter the methylation of the promoters for many genes in order to change the expression of many genes, so any change in the cell's internal or external environment to which the cell responds will lead to changes in its DNA methylation pattern; aging causes a massive amount of change in every cell, in its neighbors, and in the systemic environment (viz. parabiosis work, etc), so it's entirely to be expected that DNA methylation status will change sweepingly with age. Most obviously, when looking at blood cells: as "everybody knows," inflammation and oxidative stress in the blood rises with age for a variety of reasons (senescent cell accumulation, accumulation of cells homoplasmic for large mitochondrial DNA deletions, unresolved injury, age-related autoimmunity, rising burden of atherosclerotic lesions, etc, plus a variety of specific diseases of aging); oxidative stress both dysregulates expression of many genes, and elicits adaptive gene expression responses, while inflammation is itself mediated by gene expression (most clearly and consistently of interleukin-6). And we also know that levels of multiple hormones and other blood-borne signaling factors (TGF-β, GDF-11, etc) are also altered by aging damage; their signaling effects, too, are often mediated by changes in methylation of genes. At the same time, blood cells themselves are suffering damage that leads to changes in gene expression and accompanying methylation status, such as cellular senescence (driven by telomere attrition, oxidative stress, aberrant oncogene expression, etc) and involving in many cases demethylation of the p16 promoter) and the accumulation of anergic T-cells. (Contrariwise, there is now rather strong evidence that p16 hypermethylation can be detected in DNA in the blood of patients with some cancers (especially esophageal cancer): this is because tumor DNA escapes into the blood, and reflects the true mutations and epimutations that allow the cancer to escape senescence).

@Gellq: while I agree that some quick headline-generating results would be useful for fundraising, especially in the short term, the kind of result you're suggesting (the extension of lifespan of a model organism) simply can't be achieved in the short term through the SENS "damage-repair" strategy. This is because multiple kinds of aging damage contribute to the degenerative aging process, and in order for the rejuvenation biotechnologies that SENS Research Foundation is working to develop to effect lifespan extension, we will require the development of a suite of rejuvenation biotechnologies: one each to remove, repair, replace, or render harmless one of the particular forms of aging damage whose accumulation plays an important role in setting a currently-normal lifespan. But the suite as a whole must be sufficiently comprehensive, or it will exert only a modest effect on lifespan. If you only rehabilitate foam cells in atherosclerotic lesions, or only reverse the age-related stiffening of major arteries, or only reverse thymic involution by developing engineered thymus tissue to restore naïve T-cell production, you will benefit the great majority aging people (or rodents) a little bit (and a very small number of people quite dramatically), but the average person (or mouse) won't actually live much longer, simply because of the "weakest link in the chain" problem. If heart attack doesn't get you, then it's cancer, or stroke, or Alzheimer's disease — or a hip fracture brought when your central vision is so blocked by the early stages ofmacular degeneration that you don't see the cat, trip across it, and then send your osteoporosis-weakened bones crashing to the floor.trip on and go crashing to the floor.

Olshansky, for instance, has calculated that  a complete and final cure for all ischemic heart disease would only gain an average person who has already made it to age 50 (and thus avoided death in childhood etc) ≤ 3.55 years of life.(1) Similarly, eradicating cancer nets ≤ 3.2 years; both together ("if one doesn't get you, the other will") ≤ 7.83 years; and both, plus ALL circulatory diseases and diabetes, 15.3 years (1). Dr. de Grey subsequently zeroed in on the key point in the specific context of development of rejuvenation biotechnologies:

[Critics] note that no SENS intervention — in isolation — has ever been shown to extend any organism's lifespan. I do not recall Henry Ford alerting potential customers that the components of a car — in isolation — remain obstinately stationary when burning petrol is poured on them, nor do I recall his being castigated for this omission. Similarly, if engineers followed scientists’ lead in regarding the most direct evidence as the most valuable, we would still be trying to fly by flapping.

Thus, there is no quick-and-easy lifespan headline in the offing: to have a convincing impact on lifespan using SENS "damage-repair" therapeutics will require the assembly of not one therapy, but a sufficiently comprehensive panel of rejuvenation biotechnologies that have first been validated individually in rodent proof-of-principle studies, then tweaked as necessary to allow for joint administration to mice, and finally tested in mice as a combination rejuvenation protocol. Of course, only a limited subset of such therapies exist at present, and a lot of them are still undergoing the first steps of development in cell models, so that first goal is the immediate focus of SENS Research Foundation's work.

Once we have a comprehensive panel of rejuvenation biotechnologies assembled and ready to administer them all to mice, it will (by definition) take up to four years to show life extension — although, for reasons scientific, practical, PR-related, and political,  we will in practice want to use mice that are already in early seniority, to effect the goal of "Robust Mouse Rejuvenation" (RMR). The actual testing will therefore take more like 2-3 years: on the one hand, the mice will only have 1 year of "naturally" remaining life expectancy, but on the other hand, the goal of RMR will only really be demonstrated with a doubling or trebling of that remainder, as a small (10-30%) lifespan extension will be compared unfavorably to CR or rapamycin, nullifying its power as a demonstration of the potential of the "damage-repair" approach.

Let me remind everyone that from the very first days of cofounding the Methulselah Foundation, Dr. de Grey has always estimated that it would take at least a decade of research with adequtate funding to achieve this goal — meaning, dedicated investment of $10 million annually for 10 years, for a total of $1 bn. A more detailed analysis has now revised that estimate to more like $4.5 bn. Now, let there be no misunderstanding or slack-jawed incredulity: this does not mean that the SENS Research Foundation budget has to be raised by an order of magnitude to achieve RMR in ten years! It is perfectly fine if much of the research is done (and much of the investment flows) through government health research institutes like the NIH, and/or through universities, and/or through other biomedical charities that are not focused on the degenerative aging process, and/or pharmaceutical companies and biotech startups (such as those developing vaccines against intracellular aggregates including beta-amyloid and α-synuclein, which are now in human clinical trials, and now moving into vaccines against aberrant tau species). Strategically, much of our focus is on critical path investments into exactly those planks in the SENS platform that are not being actively pursued by industry or government sources (and thus usually in their most preliminary stages), so as to bring them closer to the stage of development of the planks that are nearest to the clinic; this allows us to make the most efficient (least redundant) investments, and mitigates the risk that the success of the platform as a whole stymied by the inavailability of some single, neglected element when the rest of it is already ready to be rolled out.

Of course, this focus on making investments in cash-starved, early-stage rejuvenation research also comes with the downside that those aspects of SENS are (by definition) statistically going to be the farthest from even proof-of-principle in rodents — and thus, the least least likely to garner us headlines, except by dint of being the first and at least initially sole mover in a space. (A lot of these  issues were explored in a previous dialog with members of the FA! community).

To be proleptic: I expect that from you (or someone) may wonder if it would be better to drop the relatively longevous laboratory mouse as a test subject and shoot for quick results in something with the courtesy to develop age-related disease and die much more quickly — nematode worms, for instance, or fruitflies. These organisms are both fast-aging and genetically very tractable, and are thus useful for basic science exploration of some of the the genetic determinants of "normal" species-specific lifespan and the organism's dynamic range of modulation of the rate of aging by Calorie restriction (CR) and similar manipulations. However, invertebrate species are wholly inappropriate for actual testing of rejuvenation biotechnologies, because they age so much differently from mammals. Fruit flies, for instance, don't develop cancer (no WILT or any other cancer therapy); their entire bodies (aside for the gonads) are composed of postmitotic cells, so no endogenous stem cell pools to rejuvenate or repopulate; they lack hearts or circulatory systems as they occur in mammals, and thus don't have large arteries to de-stiffen or foam cells to rehabilitate; they don't accumulate mitochondrial mutations as they age that can be rescued with allotopic expression; etc. In other words, since many of the key forms of damage targeted by rejuvenation biotechnologies — including the main ones we're attacking at the moment! — don't occur in these organisms or can't be repaired in them.

Moreover, even when it comes to old-school, "messing-with-metabolism" biogerontology, you always have to wait for validation in mice before you assume that the results can be translated to mammals. both Drosophila and C. elegans have a single, unified insulin/insulin-like growth factor signaling system, whereas the two pathways are separated in mammals, and while CR extends life in invertebrates just as it does in mammals, the reasons why it works are quite different: CR affects the initial mortality rate immediately on implementation in Drosophila, whereas in mice and rats, CR retards the rate of acceleration of mortality with age. As the linked paper notes, this fact "indicates that the biology underlying the life-extending effect of DR in rodents likely involves attenuated accumulation of damage, which contrasts with the acute effect of DR on mortality reported for Drosophila." And there are a zillion things along these lines (including many dietary and genetic antioxidant manipulations, or even putting the little pests in the 'fridge!) that extend the lives of simple model organisms that just don't work in mammals. So there are an awful lot of premature, breathless headlines about such research in the press.

On another point, I'd also be cautious about making comparisons between philanthropic investments in SENS Research Foundation and business investments in companies working with pathways involved in the regulation of aging. As we have seen over and over again for the last decade and a half (Geron, Eukarion, Elixir, Sirtris, Genescient, Centagenetix (HLI, take heed!), Rejuvenon, etc), most of the early investment flowing into these companies rests on hopes of a quick and profitable IPO rather than any real desire to see the therapies actually intervene in the human degenerative aging process, and rapidly lose patience with the company's original vision. This impatience rapidly leads to a "strategic repositioning" into metabolic therapies (in most cases against diabetes), and soon thereafter the company shuttes due to investor impatience, or because the very nature of the metabolism-modulation approach makes them unable to deliver. Aging damage accumulates gradually; "gerontological" therapies can only retard but not reverse its accumulation; disease is a late indication, and geriatrics do not interface with gerontology. (There has been one rather dramatic exception on the IPO front, of course, but it's no secret that the prominent buyer did fare well from the purchase and no further development is under way).

As to what SENS Research Foundation delivered in the last five years, I'd encourage you to read our Annual Reports. SRF/MF funded research (a bit more than 5 years ago, just prior to the formal institutional division) led to reversal of blindness induced by allotopic mitochondrial DNA mutations in mice, and subsequently our sponsored research has developed candidate rejuvenation therapies that alleviate the cytotoxicity of the key oxysterol 7-ketocholesterol; has brought us close to development of the Maximally-Modifiable Mouse; has gone a substantial way toward development of engineered thymus tissue to restore naïve T-cell production; and has had substantial success (quite recently, and still unreported) in allotopic expression of up to two new mitochondrial DNA genes. With the support of our donors, David Spiegel's group at Yale have successfully completed the first-ever synthesis of glucosepane (and anticipates the ability to use the same approach to synthesize its biologically-significant isomers and pentosinane, another AGE crosslink that may have been mistakenly neglected), which will in turn enable the development of synthetic glucosepane-crosslinked peptides that can be used to develop antibodies against glucosepane, which will make it orders of magnitude faster and cheaper to look for it in biological tissues, as well as to do high-throughput screening of potential crosslink-breakers and to test potential glucosepane crosslink breakers in vivo.

But (again) this is long-term work, and we are grossly underfunded relative to the amount of neglected work there is to do: headlines attracted is not the appropriate metric to evaluate efficacy. (I know that you (Gellq) disavowed such equivalence in some of your comments, but others of your comments do suggest that you intuitively link the two). This is expensive, time-consuming work, and maddening as it is, it just requires (and I'm genuinely sorry to say it) patience and ongoing support from donors and supporters of SENS, SENS Research Foundation, and rejuvenation biotechnology. (Relatedly, and to answer another of your questions: yes, Mr. Theil remains one of the biggest and most enthusiastic donors to the Foundation).

Reference
1. Olshansky SJ, Carnes BA, Cassel C
In search of Methuselah: estimating the upper limits to human longevity.
Science 1990 Nov 2;250(4981):634-40
PMID: 2237414

Posted by: Michael at February 4th, 2015 7:09 PM

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