An Interesting Programmed Aging View on Telomerase and the Epigenetic Clock

The author noted here sees aging as programmed, in the sense that it is an epigenetic program selected for by evolution because shorter life spans prevent population-level ecological issues. His writing is usually a good illustration of how this concept of aging as a selected epigenetic program leads to very different conclusions on the nature of aging as a whole, as well as on any specific research result. In the case of this post, the topic is the role of telomere length and telomerase in aging, and their relationship to the established DNA methylation biomarkers of aging.

The mainstream view of epigenetic change with age is that it is a reaction to accumulated cell and tissue damage, one that evolved in the limited selection pressure thought to characterize post-reproductive life span. Both damage and epigenetic changes are components of a decline that is an accidental outcome of the aggressive selection for success in early life. Evolution produces biological systems that do well initially, then corrode and fail in a haphazard fashion, because there was no selection for long-term function. Thus systems that generate damage as a side-effect of normal operation, and systems that have limited capacity that fills up and causes issues in later life are found everywhere in our biology.

The debate over programmed versus non-programmed aging, and the ordering of cause and effect between cell and tissue damage versus epigenetic change, will be settled over the next decade or two. If one side produces therapies that revert epigenetic changes and the other side produces therapies that repair cell and tissue damage, then simple observation of the results will determine who is right. The greatest extension of life span and health will point the way to the correct interpretation of the process of aging.

Just a few weeks ago, I learned of a new study linking telomerase to the changes in DNA methylation that the epigenetic clock associates with aging. The implication is that telomerase accelerates aging. It began with an investigation asking what genetic variations are associated with people who age faster or slower than average, according to the epigenetic clock? Researchers performed a genome-wide search for statistical correlates and the standout association was telomerase. People who have small genetic variations that support greater telomerase expression tend to have longer telomeres, but they also tend to age faster, as measured by the epigenetic clock.

The association between telomerase and accelerated aging (measured by methylation) was found in the genetic statistics, and then confirmed in a cell culture. When telomerase was artificially activated in the cell culture, the methylation patterns changed in the cells consistent with older age according to the epigenetic clock. In fact (and remarkably in my opinion) they found no epigenetic aging at all in the cell cultures that lacked telomerase. Could it be that telomerase is the one and only driver of epigenetic aging at the cellular level?

So, what's going on? My inclination is always to think in evolutionary terms. Fixed lifespan, (especially when modified conditions of food stress) is helpful in preventing population overshoot that can lead to famines, epidemics, and extinction. But whenever a trait is good for the community and bad for the individual, there is a temptation for the individual to cheat. In this case, cheating would mean evolving a longer lifespan via selfish genes, such as those enabling greater telomerase expression, that spread rapidly through the population. Individual competition would erase aging if left unchecked. The results would be great for individual fitness, but soon would be disastrous for the population. Thus evolution places barriers in the way of individual selection for ever longer lifespan.

My guess is that the connection between telomerase and epigenetic aging is an example of antagonistic pleiotropy crafted by natural selection in its long-term mode. Limiting lifespan has been so important to the viability of the population that evolution has arranged to protect it from leaking away due to cheating, and antagonistic pleiotropy is one of the ways in which this is arranged. I believe that the preponderance of evidence still indicates that activating telomerase has a net benefit for lifespan, but that probably we can add at most a few years by this route. I think that epigenetics is much closer to the core, the origin of aging, and that interventions to modify epigenetic aging will eventually be our holy grail.

Link: https://joshmitteldorf.scienceblog.com/2018/03/19/telomerase-update-and-downgrade/

Comments

"But whenever a trait is good for the community and bad for the individual, there is a temptation for the individual to cheat."

It's no cheat, it's how evolution works. What is cheating is invoking group selection out of thin air, with no real, quantitative mechanism explaining it nor any experimental data. Individual selection has been demonstrated and quantified time and again, in a huge number of examples. A more restricted form of selection above the individual, kin selection, has been observed and modeled in some cases, under special conditions (for example, social insects), but there is no real proof of group selection, and much less a proof that it's so widespread that you can invoke it whenever you wish.

Posted by: Antonio at March 28th, 2018 6:42 AM

I recently read about this group selection concept. The only problem with it is the lack of any substantive mechanism to invoke it. The other issue of group selection is the timing of its development, which was the 60's and 70's. These two factors suggest the group selection is more ideology than real science.

Posted by: Abelard Lindsey at March 28th, 2018 2:37 PM

Despite my previous comments about group selection, I found Josh's book to be quite good. It was especially good at discrediting genomic DNA damage as well as antagonist pleitropy as plausible causes of aging. However, his book does NOT discredit the current mitochondrial DNA mutation cause of aging (the basis of Aubrey de Grey's SENS). It only discusses the original mitochondrial theory of aging from the early 70's that was discredited a long time ago.

Posted by: Abelard Lindsey at March 28th, 2018 2:41 PM

Hi there ! Very Interesting and confusing. Just my 2 cents. TL DR : too much stuff to say.

I think we are seeing just how much aging is vastly more nuanced (and paradoxical/contradictory) than we thought. I still feel that both epigenetic aging and damage aging are responsible in near equal measure and are dependent and independent (depending of the situation and health) of each other. It's not one, or, the other; it's both, at the same time; like identical twins they go together and resemble each other (a lot, like carbon copy) but they can differentiate once a while (to keep their 'uniqueness' and not feel a clone of 'me too - I'm you' bro/sis; trust me I know (I am a twin, albeit not identical - two of me would be too much (jk)). But as studies in identical twins shown (such as Danish Twin epigenome aging studies), one twin ends up rather quite different and with a different DNA methylation profile/epigenetic clock aging (by Horvath's clock CpG methyl measure). Thus, identical twins end up with a different epigenetic age that is modeled by external factors (lifestyle diet/CR, environment, exercise, anti-aging supplements, and so) and by internal factors (unknown mostly, but this the 'program' with got at birth and continues on; in identical twins it is nearly same program; thus extrinsic elements are stronger factors for diverging epigenetic aging in these specific twin people; since they are so similar, intrinsic wise). And, indeed, that is what the studies showed; when the twin are separated - different environments - shapes different epigenetic aging; thus external forces in action shaping the other twin isolated elsewhere and exposed to new stimulis/problem/stress/pathogens/'environment' as a large umbrella word and all it encompasses etc.

It is very confusing, now that they show telomerase actually increases DNA methyl clock aging; it is difficult to put that into context with what we know so far. We had known that telomerase did create chromosomal unstability when used in excess; I'm guessing in people with long telomerese of leukocytes it is rather Very active; or perhaps too much which would then promote advancement of clock.
Why would it do so, the longest lived animals - have Long Telomeres, not short ones; is that not enough explanation. Short telomeres, become uncapped and activate inflammasome/DDR, not exactly good news.
I think that if short telomeres are maintained - enough - and capped enough, then they can be viable but it does not change the fact that many problems will appear as replative senescence approaches in the 2-3kb region. Telomeres might be more (or not) than just replicative counters, but also genomic integrity barometers; it makes sense, they are the end termini DNA On Chromosomes, in the cell nucleus; thus, yes they would regulate integrity/stability (and it is why demethylated telomeres become uncapped, and are often, short and unstable (creating telomere fusion/homologuous recombination/ALT/SCEs chromatic exchanges events that can undermin the genome integrity)).
Methylation does not just touch the epigenetic clock, it touches the telomeres too.
With that said, there is much blurry 'grey' shades between epigenetic clock and telomeres; they can be totally uncoupled. because they are in a sort permissive/loose relation where are depedent, but in certain instances, become independent.

Also, this in contradiction with iPSCs whom shown DNA methyl clock age reversal - and show telomere elongation reset ; and mostly likeyl have strong telomerase boost. Yet, they say that fœtus or babies have rapid DNA methylation aging, even if they are very Young. And it's rather sort of ironic, because there is a dramatic drop in telomere length at that specific age (like 16kb down to 12 kb in the space of like 2 months following birth; which later 4kb equals nearly a full lifespan). This ties with accelerated growth of the human at birth, accelerated growth (through IGF/mTOR/SIR/DAF) activâtes the mTOR cascade which activates geroconversion to senescence. Yet, by the same token, you need growth otherwise your are on a downhill slope, which is what happens after menopause/andropause/female menarc or male puberty. Sexual reproduction/Adult onset entry with sexual capability means that growth has reach max potential and now it will enter the phase of 'letting go'; such as menopause then showing.
At what's even more stranger, is that the studies showed that women whom had hormonal therapy (estrogen/17b-estradiol) at a lower DNA methyl age in many tissues/fluid like buccal tissue, blood or saliva - than women who took none and were more aged by the clock measure. And we do know that sexual reproduction is costly and is throught the Growth Hormone endocrinal axis that connects to CR/nutrient sensing (IGF/mTOR/estrogenes/androgenes/steroidogenics testosterogenics); basically mTOR is behind this as sensing and forcing insulin signlaling and growth/fitness - either muscle formation or sexual reprod virgor by ovary capacity and spermatogenesis (of course, not just IGF, EGF, VEGF, and every other growth factor Under the sun). It's also interesting, because estrogen and testosterone (after aromatase conversion back to estrogen) are capably of activating telomerase - and strangely, women who took them - have less DNA methyla clock age. Not so strage after all. It means, that not only telomerase is in concert/contact with DNA methyl clock; it controls it, partly. In the study it advance aging, my wager is that telomerase is an antagonistic element - it'S good only in specific instances (conditional, once more); the rest of the time it can promote age acceleration and that is, an Obvious imposed limit because it would Not do that, it Should revert DNA methyl age but it does not (at least, in these people whom their clock was measured). Since it increases DNA methyl age when used ()and in people with Long leukocytes TElomeres), then evolution decided that humans would not benefit from telomerase as in certain animals (such as near eternal Jelly fish that need telomerase for their supposed eternal life); yet, all these animals continues to Grow. Growth loss is in concert with after puberty/after menopause entry. Loss of IGF, increase in frailty, increase in sexual amorphism and infertility (Sexual senescence, remeber that paratised salmon that lives 13 years vs a regular salmon that lives 3 years, the regular one becomes sexually senescent while the long lived ones does not). And yet, again, the studies showed that women who birther the youngest - died the youngest - Too Early entry in sexual reproduction - too much mTOR, less telomerase - for later. Sexual reproduction delaying is a feature of the longest lived animals (some aquatic animals are having children at over 100 years old, thus have extrmely later puberty), tis was aging corrobrated in NMRs whom have protracted brain edevelopmet and sexual repdocution entry/puberty. Growth is Necessary, as seen in NMRs, but growth must be Steady- and Slow. but never stopping as what happens after menopause/andropaus/puberty. If an animal if delayed in growth it could grow as big as a bowhead whale or clam; talking about developmental growth. Mice grow rapidly - much faster than humans, bowhead whales or clams - we are late 'late' LATE bloomers, pubery is so late while these 'ultra-reproducing' animals, like mouse or rat, live short lives and have huge population numbers to offset the losses from very short lives. WE are the total inverse, : living long, very little kids (no need, they live long - no loss of population/just an 'aging/old' population), we have sex Years later; these animals it's like Boom The are Born and Boom They are in The Bed the NExt DAy with Mate.

I am very confused about telomeres, it's so wishywashy and all over the place; one minute it's good one minutes it's bad. For now, it's less Usefull, it might make telomeres longer but at a cost of accelerated epiegentic aging; and that is Very bad. Bad, because studies showed it - telomeres do not correlated (at least, as well) to mortality and aging to the same precision that the DNA methyl clock does. It is far more precise and predictive of your death in subsequent years.

Aging is all about context and situation; in one situtaion it's bad and the same thing, in another is good; that is how dualistic, 'antagonistic (pleiotropy)', agonistic, double-bladed, ironistic, double-dippingistic, 2-facedistic, 2-timingistic... oh and double-standardistic it is because it's a balance and obviously, it will balance in, out, back and forth till it finds what works - at that specific moment which seems opportunistic also, evol has a nack for cheating too but it likes to calls it a 'balance'; so it becomes very hard to predict anything about aging; rather, I think now we are better at 'seeing' the 2 extremities and so we can roughly 'gauge' where it will fall between these two.

Just a 2 cent. (K it might be more like a 3 cent).

PS:
This study has verified DNA methylation clock of mouse and, it shows me, that if mice die with LONG(er) telomeres than humans in a very short life of 2 years - while progeric mice die evenn quicker and show faster telomere loss - then it means telomeres are just a 'barometer' of health and a counting limit to cell replication before entering replicative senescence. They are not the true intrinsic element of aging; that is far more the DNA methyl clock - And the damages/IC EC junk (espeically, DNA damage, 8-oxodG lesions in the mitochondrial DNA and less so in the nuclear DNA, mainly; and telomeric DNA foci damage y-H2AX is not nearly as important).

1. Multi-tissue DNA methylation age predictor in mouse
https://genomebiology.biomedcentral.com/articles/10.1186/s13059-017-1203-5

Posted by: CANanonymity at March 28th, 2018 5:21 PM

It all makes perfect sense to me... telomerase, gene transcription of growth factors, cell division and growth tend to punch holes in the epigenome surrounding the chromatin. These areas then become hypomethylated, exposing growth genes that should be closed during adulthood in aging organisms. Instead, these areas of the physical epigenome should be tightly closed to gene transcription, in other words those areas of the epigenome should be tightly hypermethylated to preserve the epigenetic clock.

Posted by: Biotechy at March 29th, 2018 9:45 AM

I don't see how longer lifespan necessarily equates to lost resources and thus programmed aging was selected for. This is an argument that doesn't hold up for me, logically. Longer lifespan has always been associated with slower reproduction rates hasn't it? Also, isn't overpopulation a myth? We're talking hundreds of thousands of years ago, when our ape like ancestral populations were pretty low compared to the 7 billion humans today. How would environmental pressures like famine select for short lifespans? I guess maybe if shorter lifespans result in more reproduction then perhaps you end up with a larger population to help with the probability of going extinct in cases of disaster. I think the issue with longer lifespans in terms of selection is purely a problem of population size, the shorter the lifespan the larger the size of population which means greater probability of survival.

Regardless of the above, I really hope we can solve this epigenetic, methylation clock problem because I agree, it's likely that this, rather than telomeres alone, is at the very root of aging.

Posted by: Nathan at March 29th, 2018 9:51 AM

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