Stop the Presses
Just a few weeks ago, I learned of this new study linking telomerase to the epigenetic changes that the methylation clock associates with aging.
The implication is that telomerase accelerates aging. It began with an investigation by Steve Horvath’s group (about which I reported last month)
asking, what genetic variations are associated with people who age faster or slower than average, according to the Horvath methylation clock?
They did 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 Horvath clock.
It’s been known for a long time that telomerase has other effects in addition to lengthening telomeres. But this is the first time that telomerase has been reported to affect DNA methylation. So it seems we are presented with a tradeoff, or pleiotropy, or Catch-22, or “damned if you do, damned if you don’t.”
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 Horvath clock. In fact (and remarkably in my opinion) they found no Horvath 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?
Telomere length and the Horvath methylation clock are both correlated with age, but they are not otherwise correlated with each other.
The Horvath clock is a combination of 353 methylation levels that is optimized to correlate maximally with age. The observed correlation is 0.95. Telomere length is not statistically optimized but measured as nature offers it, and its correlation is much weaker (~0.4 according to my estimate, as I have not found this number in print). Thus Horvath clock is an excellent measure of chronological age, and combining information about telomere length can make it potentially a little more accurate yet. But the telomere clock on its own is a very unreliable measure of age.
The Horvath group designed an experiment to separate the direct effect of telomerase on methylation from an indirect effect (telomerase ⇒ telomere length ⇒ methylation age). They found no indirect effect. Telomerase itself affects methylation aging, but telomere length does not.
This raises (what is for me) an uncomfortable question. Many “good” life habits have been associated with telomerase expression, including exercise, meditation, and social integration. Could it be that these habits are simultaneously slowing our telomere aging, while hastening our epigenetic aging?
“While the paradoxical finding cannot be disputed on scientific grounds, its biological interpretation remains to be elucidated.” [
, the same study I’ve been talking about]
(Another finding of this same study: Earlier menopause is associated with epigenetic age acceleration in women, but this is mitigated by hormone replacement therapy. HRT modestly slows aging, as measured by the Horvath clock.)
THUS HORVATH CLOCK MODIFIABLE…EPIGENOME
Antagonistic Pleiotropy turned Upside Down
So, what’s going on? My inclination is always to think in evolutionary terms.
Antagonistic Pleiotropy is the standard explanation for aging, though I have long argued that it doesn’t fit the data. The theory says that some genes enhance fertility and survival early in life, but have detrimental effects late in life. These genes are selected in a Darwinian process because their benefits outweigh their costs. Even though they die younger, those individuals carrying the pleiotropic genes leave more offspring, and that’s what counts for evolution. The crux of the theory is that nature is caught between Scylla and Charybdis, forced by limitations of the available genes to choose either high fertility with short lifespan or low fertility with longer lifespan. Crucial to the theory is the assumption that it is biologically impossible to separate the benefits of these pleiotropic genes (fertility) from their costs, so that there is no way evolution could engineer higher fertility without triggering later senescence.
This theory was formulated by George Williams in 1957, long before anyone had heard of epigenetics. He assumed that if you have a gene, you’re stuck with it for life. We can’t blame Williams for the frame of mind that he brought to the evolutionary question, but we now know that this is very much not the case. The body turns genes on and off in individual tissues and at specific times with exquisite precision. In fact, most of the euklaryotic genome is devoted not to genes, but to epigenetic controls of one kind or another.
Aging as an evolutionary program
Because TERT swithch off in somatic cells, telomere shortening as part of the program. One piece of evidence that supports this claim that the evolutionary origin of telomere shortening can be found in single-celled protozoans. In the ciliates (e.g. paramecium), telomerase is not expressed in mitosis (when the cell copies itself), but only when it conjugates (recombining genes with other individuals) with another. Thus a cell that self replicates without mixing its genes with another is designed to quickly die of cell senescence, it’s mission of self repliction haveing occured. But for cells that self replicate by exchanging genes with a partner, here, teolmerase gets expressed. This mechanisms came about maybe a billion years ago and since has persisted. TS thus insures diseases and death is many species including men, dogs and ctas.
But not mice…pigs or cows
And still other scientists claiming that aging is an evolutionary program based on the shortening process of telomeres, thanks to which diseases and death can occur so as to make room for the younger generation who can continue the self-replication engine with greater gusto.
The fact is that genes are turned on that dial up fertility and promote robust replacement cell growth early in life, and aging at that time occurs quite slowly. Later in life, these growth and fertility genes are dialed way back, and that is the era in which aging comes at us with a vengeance. This, to me, is a direct refutation of Antagonistic Pleiotropy as a theory.
Nevertheless, many examples pleiotropic genes have been found in studies of aging. The above story of telomerase seems to be a conspicuous example. Telomerase promotes epigenetic aging, while lack of telomerase promotes cellular senescence. “If the ’gaitors don’t getcha then the ’skeeters will.”[ref]
My interpretation of pleiotropy is in my book and some of my academic papers.
It is this: Aging has been built into our genomes by natural selection for the sake of the community. 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 (“cheating” is actually the term used by evolutionary theorists). In this case, cheating would mean evolving a longer lifespan via selfish genes that spread rapidly through the population, because they are more successful at the lowest level of Darwin’s competition.
Individual competition would erase aging if left unchecked. The results would be great for individual fitness, but soon would be disastrous for the population. Overpopulation would ensue, followed by the famines and epidemics mentioned above. Evolution has learned (over a very long expanse of time) to protect the communal interest, placing barriers in the way of individual selection for ever longer lifespan. This is the evolutionary significance of pleiotropy. It provides that no simple mutation can substantially extend any aspect of lifespan without adversely affecting another aspect of lifespan or of fertility. The aging clock has been “purposely” configured so as to be spread out over several different mechanisms, tied not just to other pro-aging mechanisms but to fertility as well. Aging is hard to get rid of “by design”.
In the standard theory that I don’t believe, antagonistic pleiotropy is a precondition, and evolution has had to make the best of a bad deal. In my version, antagonistic pleiotropy has been 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 have modeled this process in numerical simulations of evolution.
My guess is that the connection between telomerase and epigenetic aging is an example of antagonistic pleiotropy in this latter sense–certainly not in the sense of Williams, because on their face telomerase and methylation have little to do with one another.
Bad news for life extension strategies
But whatever the theoretical origins, the pleiotropic connection between telomerase and epigenetic aging complicates any strategy we might devise for slowing the progression of human aging.
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. The caveat is that telomeres are simple, but methylation is complicated, and methylation is just one of many epigenetic mechanisms.
The dominant theory of aging today was conceived at a time when genes were thought to be biological destiny. Handiwork of George Williams, it is called Antagonistic Pleiotropy. Pleiotropy is the idea that one gene can have multiple effects, and the core of the AP theory is that there are genes that give us strength and fertility in youth, but they cause havoc later in life, ultimately destroying the body. Fifty years after Williams, we now know that genes are routinely turned on when and where they are needed, and turned off most of the time. More than 97% of our genome is devoted not to genes but to epigenetics, which is the regulation of gene expression, and a mainstay of 21st century molecular biology. Why should the body ever be stuck with a gene that is doing it harm? Can antagonistic pleiotropy be re-cast to make sense in this age of epigenetics?
In 1957, George Williams proposed an evolutionary theory of aging that later became known as Antagonistic Pleiotropy, and under than name has been the most influential theory of aging to this day. It has formed the basis for interpreting a huge variety of phenomena in aging labs around the world. Pleiotropy is routinely invoked to explain results in genetics, and “evolutionary medicine” is guiding (or misguiding) research priorities for the future of anti-aging science.
Williams began with the idea (still dominant today) that rapid and copious reproductive output is the ticket for evolutionary success. A mathematical measure of time-weighted reproduction is the Malthusian Parameter r, which Williams assumed (many today agree) is as good a mathematical translation as we have for Darwin’s concept of “fitness”.
I have argued that there is more to fitness than reproducing as fast as possible. The very word “fit” came from the notion of traits appropriate to a particular environment, a particular ecosystem. Ecological consequences can’t be separated from individual fitness. Any individual that achieves a growth rate (r) that is higher than species further down the food chain has only a very short-term fitness advantage, because its grandchildren risk starvation. I’ve written about fitness in an ecological context here and in my new book.
Genes “your way”! Tucked away when you don’t need ’em
Today, I am offering another reason to discredit antagonistic pleiotropy. Williams’s theory is rooted in the idea that if a gene is selected in evolution for its advantage early in life, then the bearer of that gene is stuck with it late in life as well. Now that we know how routinely genes are turned on and off in particular tissues, at particular times, for just a few minutes or for years on end, it is no longer credible to imagine that the individual is stuck with a gene at a time when it has become a liability. Can we find a way to make sense of antagonistic pleiotropy in the context of complex and robust epigenetic adaptation?
I’ll say this much for pleiotropy: some of the genes most detrimental to the body do indeed have “legitimate” functions (good for the individual or her reproduction). I have come to see the proximate cause of aging as a re-balancing of hormones, some turned up and some turned down, with detrimental effect. Inflammation is turned up too high. Apoptosis is turned up generally, causing loss of perfectly good muscle and nerve cells, but the strong apoptosis signals that kill cancer cells before they can become tumors becomes less effective with age. Melatonin (for the circadian clock) and glutathione (antioxidant) and CoQ10 (cellular energy) are all in progressively shorter supply as we age.
It is common to call this rebalancing “dysregulation” and ask what went wrong [example, another, a third]. But I don’t think evolution makes such big mistakes. I see not dysregulation but re-regulation or even re-purposing of a system that protects the body, toward the end of self-destruction.
Mikhail Blagosklonny has written often about a theory in which aging comes from the body’s inability to turn off the genetic program that led to development and growth early in life. He knows his stuff, and writes convincingly about particular genes (notably mTOR) and the evidence that they are being kept on later in life, when their main consequence is to increase inflammation, promote disease and shorten lifespan. I question only the part of Blagosklonny’s theory that says this is an accident. I see it as one of the many instances in which genetic machinery is repurposed. How does Blagosklonny explain this mistake? “A potential switch that would turn off the developmental program cannot be selected, because most animals die from accidental death before they have a chance to die from senescence. A program for development cannot be switched off, simply because there is no selective pressure against aging.” This idea has a venerable past, but no future. Indeed, there is selective pressure against aging, and the cost of aging in the wild can be as high as 70% of fitness, though it is typically about 20-30% [ref]. This idea that aging comes about because no animals in the wild live long enough to die of old age was a brilliant insight due to a Nobel immunologist sixty years ago; but today it is no longer tenable.
Oft-cited Example of Antagonistic Pleiotropy
A classic example used to illustrate pleiotropy is Huntington’s Disease. This is a congenital syndrome caused by a gene variant that actually increases fertility early in life, but typically around age 40, neurological symptoms begin, affecting coordination and causing mood swings. Brain cells die, and Huntington’s is eventually fatal. Huntington’s is not normal aging, of course, but the idea is that there are other genetic variants that are so common we don’t think of them as diseases but they are also promoting fertility early in life and degeneration later on.
In this case, it is not the timing of the gene but the version of the gene (allele) that is caused. Is Huntington’s Disease truly an example of antagonistic pleiotropy? Yes, in the sense that the allele causing Huntington’s Disease has both a benefit and a cost, and the cost is connected to disease and death later in life. But no, in the sense that natural selection has actually rejected the Huntington’s gene time and again. The Huntington’s mutation is one that occurs spontaneously in one child, and then is transmitted to children and grandchildren. It lasts for several generations, but would disappear from the population were it not for the fact that it is constantly being re-introduced by fresh mutations. Here is an allele with early benefits and late costs that is being rejected by natural selection on an ongoing basis. So should Huntington’s be considered a counter-example to the AP theory?
Grade inflation for (some) scientific theories
Nowhere in science are theories given a pass when contradicted so frequently and so flagrantly as in evolutionary theory of the selfish gene. Manuscripts describing evidence against the selfish gene, or theories based on group selection are routinely rejected for publication. (This situation isn’t nearly as bad as it was 15 years ago.) But Antagonistic Pleiotropy continues to get by with a “gentleman’s C”, because (like the Ivy League preppies), the theory has a pedigree.
“Direct experimental evidence for age-specific effects of mutations comes from only a handful of reports” [Scott Pletcher and Jim Curtsinger] These geneticists actually mutated fruitflies at random and went looking for gene variations that could cause benefits at one stage of life and costs at another. And they found them! Except, curiously, they were all at early stages of life, and none affecting old age [ref]. “The main evolutionaty models of senescence are antagonistic pleiotropy and mutation accumulation, neither of which has substantial experimental support.”  Yes, that was written move than 20 years ago. The difference today is that we now have a huge body of evidence contradicting each of these theories.
May we live to see the day when scientists look back at the theory of Antagonistic Pleiotropy, scratch their heads and say, “I wonder why people would have believed that!”