Most times when I meet old friends who I have not seen for a long time, the old magic comes back. There is new vitality in our new context of relationship. With certain other people met again after many years, memory of the original relationship sees to be the only thing we still have in common. That person usually seems to me to have gone nowhere with his or her life and is not visibly going anywhere now. He or she comes across to me now as having lost all vitality, and now we seem to have little in common except stale memories. Our interaction is flat and listless and I usually don’t want to see that person again.
My relationship with the antagonistic pleiotropy theory of the cause of aging falls in the second category. The theory has an impressive name to throw around in publications and cocktail parties, but that seems to be the main thing going for it. I see it as a fuzzy obsolete theory of the impact of evolution on aging that is no longer particularly informative. I expand on this theme in this blog entry and describe what I see to be the actual impact of evolution – genetic, epigenetic and social – on longevity.
What is antagonistic pleiotropy, anyway?
“The antagonistic pleiotropy hypothesis was first proposed by George C. Williams in 1957 as an explanation for senescence. Pleiotropy is the phenomenon where one gene controls for more than one phenotypic trait in an organism. Antagonistic Pleiotropy is when one gene controls for more than one trait where at least one of these traits is beneficial to the organism’s fitness and at least one is detrimental to the organism’s fitness. The theme of G.C. William’s idea about antagonistic pleiotropy was that if a gene caused both increased reproduction in early life and aging in later life, then senescence would be adaptive in evolution(ref).”
Here are some of the problems I have with Antagonistic Pleiotropy as it was formulated by Williams in ‘57
:a. There are few if any genes that cause both increased reproduction in early life and aging in later life. Multiple papers have been written on genes purported to exhibit Antagonistic Pleiotropy, P53 being among the favorites(ref)(ref). The arguments in those papers tend to befuddle me. Actually the FRAP1 gene involved in activation of the mTOR pathway is probably a better example(ref)(ref). According to the 2010 paper Revisiting the antagonistic pleiotropy theory of aging: TOR-driven program and quasi-program: “A half century ago, the antagonistic pleiotropy (AP) theory had solved a mystery of aging, by postulating genes beneficial early in life at the cost of aging. Recently it was argued however that there are very few clear-cut examples of antagonistically pleiotropic (AP) genes other than p53. In contrast, here I discuss that p53 is not a clear-cut example of AP genes but is rather an aging-suppressor (gerosuppressor). In contrast, clear-cut examples of AP genes are genes that encode the TOR (target of rapamycin) pathway. TOR itself is the ultimate example of AP gene because its deletion is lethal in embryogenesis. Early in life the TOR pathway drives developmental program, which persists later in life as an aimless quasi-program of aging and age-related diseases.”
b. But how TOR operates later in life is highly variable involving many genes and a pathway that is still not fully understood. The idea that any one gene “controls”an important aspect of normal aging is unsubstantiated although we know that mutations in certain genes like WRN can generate abnormal aging phenotypes(ref). Single genes often influence multiple phenotypic traits of an organism, and most-commonly such traits are influenced by multiple genes. One-to-one relationships between genes and complex traits such as are involved in normal aging are rare to nonexistent.
c. The phenotypic traits resulting in part from the activation of any gene is strongly influenced by the state of the pathway the gene is in, and the degree of activation of other genes in that and other pathways having to do with the traits. Whether activation occurs is affected by the epigenetic state of the cell concerned. Age of the organism is only one of multiple factors that determines whether gene activation occurs or its consequences.
So, it makes no sense to hang “causation” of increased reproduction in early life or aging in later life on individual genes.
Antagonistic Pleiotropy as formulated by Williams is too blunt and obsolete a way of looking at aging to be useful. I agree with the author of the 2004 paper Reflections on an unsolved problem of biology: the evolution of senescence and death who wrote “It is suggested that the evolutionary theory of senescence should be focused on those evolutionary principles that have been validated experimentally, and that the notion of antagonistic pleiotropy–which cannot be experimentally validated–be dropped from our thinking about the evolution of senescence.”
A new look at what Antagonistic Pleiotropy was tryng to get at
The above having been said, I do think that something like a reformulation of the Antagonistic Pleiotropy hypothesis could be useful. Here is how it would go:
1. Genetic evolution, has operated in most species so as to such as to favor health of the young (animals who bear or still care for offsprings) over health of animals beyond the age where they care for their young. (This says little more than that evolution favors the young over the aged, something we already know).
2. In humans at least, evolution viewed more broadly (genetic, social and epigenomic evolution) is changing the balance between health for-young vs health-for-old, maintaining health of humans in advanced societies for more years and leading to ever-longer life spans.
I articulated this theme in earlier blog posts, particularly in Social ethics of longevity and in Ever-increasing longevity– is epigenomics involved? I repeat a few key passages from those blog entries regarding social evolution and epigenomic evolution. And I show how this reformulation leads to very different conclusions than did the original theory.
Social evolution impacting longevity
‘The argument from evolution — goes like this: Each species, humans included, has evolved characteristic life-spans designed to optimize the survival of that species taking into account resource limitations, a need for protection against predators and diseases, and environmental conditions. Scarce resources need to be devoted to providing for the young and raising new generations and fighting off predators and diseases during the years of rearing the young. According to this argument, need for individual survival diminishes after child-rearing years. Younger animals are stronger and can better fight off predators and diseases than older ones. From the viewpoint of the human species, then, resources are better devoted to raising and protecting children than to keeping old people around, people who are no longer part of the reproductive-child-rearing cycle. According to this argument, extending the lives of old people leads to a misallocation of resources that is counter to survival of the species.”
“The problem with this argument is that it takes biological evolution into account but not social evolution. The argument does not take into account the ever-increasing complexity of our society, the ever-increasing requirement for education that is necessary to function well in society, the ever-increasing cost of rearing young including education, the increase in the time required for young people to become fully functional in society, and the need for people to spend more years working to cover the ever-growing costs for educating their young. As social evolution advances at an exponentially increasing rate and society continues to become more complex, there is an ever-increasing need for people to draw on vast resources of information, deep knowledge and wisdom to survive and advance the society. The time required for basic education continues to grow and continuing education becomes a lifelong necessity. Longer life spans therefore serve the need of social evolution by increasing mobilization of knowledge and wisdom.
In fact, social evolution has been working hard to extend our longevity in recent times. A few hundred years ago people typically died before 40. Now, life expectancy has roughly doubled, to about 78 for US males and 80 for females. All the other typical age-marking numbers have also roughly doubled. Once young males could join their fathers as hunters or warriors or farmers or artisans at the age of 15 and start fully contributing to society shortly thereafter. About twice as much time (30 years) is now required in an advanced society for a male to become a doctor or lawyer or physicist, to become fully engaged in his profession, to get married and have children. Females used to start having babies when they were biologically capable, around 15. Now for educated Western women, the age is roughly 30. The investment required for rearing a child has become enormous – $300,000 – $500,000 or more for a thirty year period when including the cost of preparatory education. All this change has happened in less than 400 years. The key thing to focus on is that the number of productive years – the years between completion of education and retirement – has doubled too. Instead of 20 good working years now the average is more like 40.
So, social evolution requires longer life spans because people have to become ever more sophisticated to accommodate to ever more-complex social conditions. Now as social evolution continues to accelerate at an exponential pace, it is appropriate that life spans also become extended at an accelerating rate. That is what my work is about.
My main point is this: as society becomes exponentially more complex, so a need arises for exponential growth in life expectancy. Life extension is not about older people surviving unproductively longer in retirement communities in Florida or nursing homes. It is about keeping an increasingly complex society workable.”
So, how does social evolution work to increase longevity? The answer is easier than it might seem. All the things we do to increase health and longevity are part of our social evolution. It is useful to recall that in 1850 the streets of London were ladened with fecal matter from horses and dogs and had open ditches running with human sewage. Sanitation as we know it was nonexistent. Wood fires in hundreds of thousands of fireplaces contributed mightily to air pollution. Syphylis was common as Victorian morals led to widespread prostitution. No wonder people died young! All that is behind us now. The second half of the 19th century saw the recognition of the germ theory of disease and the building of the first sewage systems and water treatment plans. The last 40 years saw a turning against cigarette smoking in advanced countries and thrusts for world-wide vaccinations against multiple killer diseases. These and countless other developments contributed significantly to overall longevity. Also contributing are improved diets, food safety laws, cleaning up remaining air pollution, seat belt laws, safer cars, elimination of lead paint, modern medicine and antibiotics. And, in its own small way, this blog contributes to the distribution of knowledge making for greater health and longevity. My writing and your reading and comments are part of that social evolution.
Epigenomic evolution affecting longevity
The entire field of gene regulation is new and existed in only very crude form when Williams formulated the original Antagonistic Pleiotropy theory. But, gene regulation is all-important. The same genes exist in your brain neuron cells, your red and white blood cells, in your heart, and in your toe muscle cells. The difference between these cells are due to regulation of gene expression, not due to the genes themselves. The same genes exist in the cells of an ambryo, the resultant child at the age of 2, the young adult of 22 and the same person at an old an of 90. The resulting age phenotypes have also to do with gene regulation. And an important determinant of gene regulation is the epigenetic/epigenomic state of the cell, including histone acetylation and DNA methylation patterns and other chromatin modifications. These changes are present in our DNA but not in the genes themselves, result from the experience of the cell, typically vary with age, and are to some extent heritable. For background, see the blog post Epigenetics, Epigenomics and Aging, and Histone acetylase and deacetylase inhibitors. Clearly, epigenetic states have a great deal to do with disease suscptibility and aging. See the blog post Epigenetics, inflammation, cancer, immune system, neurological and cardiovascular disease and aging. Regarding the heritability of epigenetic changes, you can check out the references in this list.
So, my hypothesis is that inheritable epigenomic changes are happening in our DNA that are leading to greater longevity. I first put this suggestion forward in the blog entry Ever-increasing longevity– is epigenomics involved? which cites astounding increases in longevity throughout the developed world.
Insofar as epigenomic modifications are heritable, they are subject to evolution just as genomic modifications are. The important factor to emphasize in this discussion is that epigenomic evolution and social evolution happen on a much shorter time scale than genetic evolution. Our genome is pretty much the same as it was millions of years ago but our social habits affecting longevity have changed drastically in the last 200 years and are continuing to evolve rapidly. And epigenomic changes can be inherited from one generation to the next. Why are kids who grow up in developing countries where there is newfound prosperity 6 inches to a foot taller than their parents? The answer lies in social and epigenomic evolution. For fun reading, see also my blog post Longevity Genes and Two Fantasies
Wrapping it up
If you accept the reformulation of Antagonistic Pleiotropy that I suggest above including consideration of social and epigenomic evolution, you come out with quite a different perspective consistent with what we experience:
· Human physical evolution did not stop 2 million years ago; it appears to be accelerating.
· Most of the new evolution results from social evolution and evoution in the epigenome, not in our genes
.· The evolutionary process has been leading to altered bodytypes and longer lifespans in developed countries.
· We can affect the evolutionary process individually and collectively through social activism and applying knowledge of health and longevity.
None of these statements are true for the original theory of Antagonistic Pleiotropy. That is why I say we should stop torturing ourselves about this outdated conjecture and let it rest in its crypt in history where it belongs.
Very interesting, was waiting for this. Thank you.
Somthing that increases reproduction in the young and decreases life for the old!
Protein fits this model. Insects and animal studies show lower protein reduces or eliminates reproduction (Fecundity) but higher protein enhances fecundity.
Glycerol also fits. Insects reduce fecundity but increase life with added glycerol while when glycerol is removed the fecundity is increases and life shorter.
And if tested I think mannoheptulose whould be demonstrated to lower fecundity and increase longevity.
As humans we should be able to overcome the fecundity issues and if like the flies at the human equivalent age of 60 change our diets when fecundity is not a worry but life and health span are the issue.
I quite agree with the point you make it in your final paragraph. Indeed, that is the thrust of the firewalls section in my treatise. There seems to be still very much to be learned.
Antagonistic pleiotropy revisited e2 80 93 for the last time.. Reposted it 🙂