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!”