Antagonistic Pleiotropy and the Puzzle of Aging

The puzzle of aging is less how it happens, given that the scientific community has a good catalog of the forms of cell and tissue damage that cause aging, and can work to prove relevance by repairing that damage, but rather why it happens. Serious attempts to intervene in the aging process have long been a minority concern when compared to the funding and careers devoted to explaining the existence of aging. Understanding why evolution has led to a world dominated by species that age, alongside a tiny number of species that do not, is a thorny problem.

This is in part the case because arguments over the evolution of aging proceed by thought experiment and modeling rather than by examination of data. There is the world as it exists today, a few slim hints about the past, and researchers must deduce how this fantastically complex array of systems came into being over hundreds of millions of years from the minuscule sliver of information provided. There is a great deal of room in which to be wrong. Indeed, everyone involved in any given debate on the evolution of aging may be dramatically incorrect in the details of their models, and there is little that can be done in the short term to prove or disprove their positions.

Insofar as there is any consensus in the field on why we age, it might be found somewhere in the vicinity of the antagonistic pleiotropy hypothesis. Evolution selects for reproductive success in an environment in which mortality from disease and predation is an ugly reality - so the sooner that reproductive success occurs, the better. Selection pressure is much stronger in early life than in later life, and thus mechanisms that achieve early life resilience and success at the cost of later decay are selected for, while the additional expense of long-term resilience and success is selected against, outcompeted. The result is age-related decline. This, needless to say, is an overly simplistic and very high-level description of an area of theory within which are found many variants and dissenting opinions.

The adaptive immune system is a good example of antagonistic pleiotropy. It remembers past threats, making it highly effective in earlier life. But that act of memory consumes resources, requiring cells to be devoted to memory rather than action against new threats. Eventually there is no room left; the system runs out of space and its function declines. We can envisage an adaptive immune system that could work more effectively over longer spans of time, given just a few comparatively simple alterations to the way in which it manages its resources. That didn't evolve, as there is insufficient selection pressure in later life for mechanisms that would make old adaptive immune systems more functional, and no gain in having those mechanisms in younger life where selection pressure is strong.

Is antagonistic pleiotropy ubiquitous in aging biology?

The logic of evolution by natural selection is straightforward. Within any population, the alleles of individuals that produce the most breeding descendants will increase in frequency in successive generations at the expense of the alleles of individuals less successful at reproduction. To be successful at leaving descendants requires that organisms also be successful at surviving - so that they live long enough to reach reproductive age and afterward continue reproducing. By this logic and process, natural selection ultimately produces individuals superbly designed to survive and reproduce in their environment.

From this perspective, aging presents an evolutionary puzzle. If continued survival and reproduction should always be favored by natural selection, why is aging - which in evolutionary terms can be defined as the age-related decline in survival rate and reproduction - nearly ubiquitous in the natural world? Or as George Williams put it, "it is remarkable that after a seemingly miraculous feat of morphogenesis, a complex metazoan should be unable to perform the much simpler task of merely maintaining what is already formed." Why doesn't evolution, in other words, mold the biology of organisms such that aging never occurs?

One possible solution to this conundrum is that evolution does in fact mold the biology of organisms such that they never age in their natural environment, that is, the environment in which they evolved. Aging might seldom occur in nature and only become evident when animals live much longer than they ever would in the wild, such as when we protect them from natural hazards by making them pets or livestock, keeping them in zoos or, as in the case of ourselves, organizing them into climate controlled, predator-free civilizations. Some biomedical gerontologists believe this hypothesis to be the case. But it is not and, in fact, dozens of field studies to date have identified that aging in wild animals is rampant if not close to ubiquitous.

Thus, there is a real puzzle to be solved as to how aging develops in natural populations. Fortunately, evolutionary biologists have cracked this mystery. An evolutionary mechanism of aging was hypothesized 60 years ago to be the genetic trade-off between early life fitness and late life mortality. Genetic evidence supporting this hypothesis was unavailable then, but has accumulated recently. These tradeoffs, known as antagonistic pleiotropy, are common, perhaps ubiquitous. George Williams' 1957 paper developed the antagonistic pleiotropy hypothesis of aging, which had previously been hinted at by Peter Medawar. Antagonistic pleiotropy, as it applies to aging, hypothesizes that animals possess genes that enhance fitness early in life but diminish it in later life and that such genes can be favored by natural selection because selection is stronger early in life even as they cause the aging phenotype to emerge.

No genes of the sort hypothesized by Williams were known 60 years ago, but modern molecular biology has now discovered hundreds of genes that, when their activity is enhanced, suppressed, or turned off, lengthen life and enhance health under laboratory conditions. Does this provide strong support for Williams' hypothesis? What are the implications of Williams' hypothesis for the modern goal of medically intervening to enhance and prolong human health? Overall, whenever antagonistic pleiotropy effects have been seriously investigated, they have been found. However, not all trade-offs are directly between reproduction and longevity as is often assumed. The discovery that antagonistic pleiotropy is common if not ubiquitous implies that a number of molecular mechanisms of aging may be widely shared among organisms and that these mechanisms of aging can be potentially alleviated by targeted interventions.

Comments

Hi There ! Just a 2 cents.

''Why doesn't evolution, in other words, mold the biology of organisms such that aging never occurs?''

Because there are so few resources, and reproduction (cost) gets them first, for specie survival (gain).
Since those resources are relocated from somatic tissue maintenance and repair/longevity towards sexual reproduction/fitness, then that means less resources for longevity and more for reproduction capability. Because, for evolution, the latter is more than the former; specie survival is dependent on reproduction, longevity is just a side effect of animals reducing reproduction for increased longevity (resource relocation). Long-lived humans make less children but live longer lives by longevous genes; thus there is less reproduction and specie survival is maintained even so;
becuase everyone lives long (instead of dying prematurely, early; like fast living species whom continuously 'replace their short-living/dying numbers' by extreme reproduction and rapid entry to puberty (endocrinal/growth 'to adult maturity'/hormonal control for sexual reproduction capacity).
It's why mice can have large litters of babies; they live 2 years; that makes fast specie decimation in short term. Humans live up to 120-122, no need for huge litters; specie survives by long lives, women have very little children (and studies in pregnant women by repetition showed that they have higher mitochondrial oxidized lesions - having children is not free/is costly to host. Centenarian women generally had about 1 or 1.5 children tops; many centenarian women had no kids and were Single, their whole life (no drama, no stress, no relationship, no man in their life, boring life but; they lived a 100 years and more); women whome have over 4 kids can shorten their life dramatically with each subsequent child. This was demonstrated though not with 100% confirmation, with Euneuchs, people whom would have their testicules removed lived longer lives (not always though, beause of frailty from sexual amorphism creating possible frailty; loss of testosterone is equal to andropause which is can cause disease arrival and immune weakening through lowered telomerase), but, in general, yes, there was a trend - the sexual organs that were removed from you (earlier) meant that your body would not spend 'sexual resources' on them; thus, divert these resources toward somatic tissue maintenance and longevous gene activation, which would mean a longer lifespan - think of it like a form of 'CR' (calorie restriction), but let's call it 'SR'
(sexual restriction); who knew that there was good to being chast/chastity like. But, I would not advice that to people (like for example, it was found that men whom did not engage in sexual activity - some times - had a enlarging prostate creating possible prostate cancer because there is not making pre-semen fluid; thus your prostate can't 'be dormant' or else it will dysfunction and hypertrophy despite you not using it; a small prostate is a working/used prostate in moderation),
when you look at people with sexual amorphism they may display other problems and even health degradation/frailty because fitness is tied
tp sexual capability (mTOR/IGF, IGF works with endocrine system)), and when you look at midget people (very small people), they may show IGF/HGH defects/pineal gland defects, thyroid defects, and even have gonadal amorphism (no or very small sexual organs, microtesticules or noovaries);
their sexual capability may be lesser - yet, some of these dwarvism/short people have lived long lives (again due to IGF/resource relocation);
you see this is certain populations of people, like quechua/pueblo/people of south american native ancestry that may live long lives (some reach centenarian) but are small or some dwarf (defect in growth/IGF defect). It's been in shown in Ashkenazi women and men, many of these ethnic jewish people are 'small' stature...and live to a 100 years old, demonstrating HGH defect just like in mice GH-knockout, meaning IGF knockout (studies showed that these people have reduced insulin signaling and growth hormone activation).
IT's the same thing with women .in general as the female gender, women being smaller size, hollower BMD,
smaller sexual organ, a limited number of ovule eggs, all this is sexual 'limitation' resourcse to put more resources into longevity
(grand-mother longevity-genes-inheritance theory) for women, and why women at 10 times more likely to reach a 110 years old than a man; becaus a man can produce
sperm all life - that's not free/costly sexual resourcse that is 'not for repair' but for sexual output instead; which means a body that will get damaged quicker - later; thus, die earlier since repair resources are limited and diverted into sexual ones. So women get more
repair resources while men get more sexual resources...makes sense, men can impregnate many women - at the same time : improve specie survival by many women making children....women cannot 'impregnate men' by the thousands...they, and only they, make the children come alive
through their body and there is a need for 9 months...each time...thus severly limited. Hence, why, evolution chose women as indispensable (for specie continuation by birrthing)
and man dispensable (once has reached puberty and reproduced with thousands of women (hypergamous/polygamous, monogamous is just something we choose artificially/humans are polygamous by nature and can have sex anyone anytime)..so 'purpose done'); and gave women the longevity boost (XX) and men the sex boost (XY).

While, in other species, like mice; the females can be much more 'active' and they can make Huge Litters, like some female animals make like 100 babies or so each litter...so this means very strong pressure/selection on 'reproduction'/sexual capability to improve specie survival (demographic numbers).

''Does this provide strong support for Williams' hypothesis?
What are the implications of Williams' hypothesis for the modern goal of medically intervening to enhance and prolong human health?...
However, not all trade-offs are directly between reproduction and longevity as is often assumed''.

Yes, it definitely demonstrates and supports his hypothesis. Now, there are outliers and variations, but its 'a 'trend'... and makes sense. Resources are limited and specie survival is paramount in the face of predatorial competition to 'see who will survive and who die', hence why things happen the way they do (aging/dying). It's meant and nasty like that.

But, we are changing in that in the lab, we are feminizing the body for a longer lifespan (as was demonstrated in silver foxes in a
1940s Russian study of wild silver fox domestication; animals became feminized with domestication and reduction of 'agression'/testosterone... their bodies became smaller, their paws too, their fur changed color towards less aggresive 'Warning patterns' or 'Sex Mate Calling Patterns'
this means more estrogen exposure in womb and less testosterone exposure. While, all this, made these foxes live long lives, 'grand-mother longevity hypothesis', the reduction of stress (remove male agression stress due to testosterogenic and (cortico)steroidal/adrenaline/androgene exposure) and the diverting of sexual resources to somatic repair meant longer life.

I think in the future we will able to preserve our gender identities and increase lifespan, by making sure we work on where it matters; not sexual reproduction, not tissue repair (though that matters of course, it is not the sole determinant of lifespan), but onthe many clocks in us that determine if we live or not because they are responsible for this genetic (de)orhestration with the years.
'Gene silencing/expression/activation', we could not crack this nut, so now we are trying to repair damages (we assume that damages repair/removal should stop aging on the clock, assumptions); I think now we can hope for long healthy lives but the LEV thing shall remain illusory till we crack these clocks (cause I don't see use winning over them, they control us so we must (re)rig them/control them) and get back time so we remain Young ('by the clock' that is), for however long we can and hence, push back death forever; if possible. Just a 2 cents.

Posted by: CANanonymity at December 19th, 2018 9:15 PM

CANanonymity: Have you considered creating your own blog? Your reply is longer than the post!

Posted by: Antonio at December 20th, 2018 2:12 AM

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