Antagonistic Pleiotropy Theory of Aging

George Williams, then a professor at Michigan State University, published a paper in 1957 titled Pleiotropy, Natural Selection, and the Evolution of Senescence (Evolution 11 398-411). Pleiotropy is defined as a situation in which a single gene controls more than one trait. In human genetic diseases, a defect in a single gene often can affect a number of traits and have simultaneous diverse symptoms such as nerve and vision problems, bone deficiencies, and skin changes. In general, a single gene can be activated in more than one tissue and therefore a defect in a single gene can affect more than one tissue.

Williams specifically criticized Medawar’s earlier assumption that the adverse effect of aging on evolutionary fitness was negligible:

“No one would consider a man in his thirties senile, yet, according to athletic records and life tables, senescence is rampant during this decade. Surely this part of the human life-cycle concerns natural selection. … It is inconceivable in modern evolutionary theory that senescence, such as operates in man between the ages of thirty and forty is selectively irrelevant.”

Williams proposed that aging was caused by the combined effect of many pleiotropic genesthat each had a beneficial effect in an animal’s youth but also had an adverse side effect in older age.

Williams’ concept added to Medawar’s hypothesis in that it built on the idea that adverse effects have a progressively smaller impact on fitness as an animal gets older relative to its age of reproductive maturity. A gene resulting from natural selection could have a rather catastrophic negative effect (e.g. death) on an older animal if the negative effect was balanced by an even relatively minor beneficial effect to younger animals.

Williams’ theory, like Medawar’s earlier mutation accumulation theory, provided a better fit to the observed inter-species variations in mammal aging than the simple deterioration theories while simultaneously avoiding conflict with traditional evolutionary mechanics theory and did not depend on accumulation of adverse mutations in equilibrium with out-selection. Williams’ theory avoided the apparent difficulty in the mutation accumulation theory that required the negative fitness effect of aging to be negligible because the assumed beneficial effect of the pleiotropic genes balanced the negative (aging) effect. Williams predicted that species with younger age of sexual maturity and more vigorous reproduction traits would tend to have shorter life spans.

One consequence of Williams’ theory was that prospects for any significant treatment of the fundamental causes of aging were considered negligible because of the assumed large number of antagonistic genes and the assumption that the harmful aging genes had beneficial and possibly essential functions in youth. Hopes that only a relatively small number of factors causing aging would be eventually found and successfully treated as suggested by the mutation accumulation theory were therefore, according to Williams, misplaced. Williams said it this way:

“Any such small number of primary physiological factors is a logical impossibility if the assumptions made in the present study are valid. This conclusion banishes the “fountain of youth” to the limbo of scientific impossibilities where other human aspirations, like the perpetual motion machine and Laplace’s ‘superman’ have already been placed by other theoretical considerations.” [Emphasis added.]

Clearly, believers in Williams’ theory, which is still popular, also believe that anti-aging research is a fundamentally foolish endeavor, a "chase after the fountain of youth."

Problems with the Antagonistic Pleiotropy Theory

The antagonistic pleiotropy theory has a number of difficulties.

One problem with the antagonistic pleiotropy theory is that the force of natural selection, although apparently progressively smaller in older individuals is not zero, even according to the traditional model. This of course was the genesis of the antagonistic pleiotropy theory. Evolution would therefore presumably be trying to find ways of accomplishing the beneficial effects without the adverse (aging) side effects. Why would it not succeed? One obvious answer is that there is no way to accomplish the presumably essential beneficial effect without the side effect, (a conclusion that is very pessimistic regarding successful treatment of aging or age-related conditions such as cancer).

It seems implausible that this “unavoidable side effect” issue would only affect maintenance of the condition of an adult organism when the tasks that have to be performed in the development, growth, and day-to-day operation of an organism are apparently so much more complex and difficult.

Another difficulty with the antagonistic pleiotropy theory is the very great variation in observed life spans between otherwise very similar animals such as similar birds and fish. If aging is a side effect of genes that have a beneficial effect in youth, then why would the adverse side effects of such presumably similar genes be so different? If the side effect is an unavoidable consequence of the beneficial effect, then why would a very similar animal need a different gene and display a different side effect? What is stopping the shorter lived animal from evolving the same longer life span as the longer-lived but otherwise similar animal?

The antagonistic pleiotropy theory also appears to have a fundamental conflict with modern genetics as follows. The “antagonistic” aspect of the theory works. Essentially any design feature of an organism has tradeoffs. Faster is antagonistic to stronger.

“Pleiotropy” somewhat works (see below). Genes are known to often affect multiple tissues. The problem is that this theory proposes a sort of time-sequential antagonistic pleiotropy in which the same gene has beneficial net value at one stage in an animal’s life and adverse net consequences at another stage.

The difficulty with this is that we now know that genes are activated and deactivated in accordance with a very complex genetically controlled system of logic or program. Essentially any gene would have adverse consequences if activated in the wrong tissue, or under the wrong circumstances, or at the wrong stage in an organism’s life just as failure to activate the gene at the proper times in the proper tissues has adverse consequences. Many genetic diseases result from failure to produce the proper gene product at the proper time.

The genetic program is apparently capable of coordinating the vastly different activities that must take place in the various developmental stages of an organism. Grossly different combinations of genes must be activated during, say, embryonic development than in late childhood because of the grossly different growth activities that must be performed. There does not appear to be any plausible reason to believe that the activation program would fail to deactivate a gene that would cause a problem in later adulthood if it worked so well in programming the differences between all the other stages in an animal’s life, especially when the differences between other stages are so much greater than between “adult” and “older adult.” Why wouldn’t time-sequential antagonistic pleiotropy generally be more of a problem in early development where there is a greater need for age sequential changes? What is the difference between mature animal and older mature animal that requires different genes to be activated?

Williams uses "pleiotropy" as a justification for the idea that an individually beneficial quality could be permanently, rigidly, unavoidably linked to the adverse characteristics that cause aging such that evolution could not find a way to accomplish the benefit without incurring the cost of aging. Indeed, single genes often control diverse phenotypic characteristics of an organism. However, it is wrong to assume that this suggests widespread rigid linkages such as he describes. The other side of the "pleiotropy coin" is that many different genes can affect a given phenotypic quality, essentially a simultaneous equation situation. By making the right changes to many genes, the evolution process could, in general, modify an individual phenotypic parameter without a rigid linkage to some other parameter. Try the following thought exercise: Imagine all the right fore-limbs of all of the mammals. Imagine all the different foot (or hand) parameters represented there. There are big toes on small feet, small toes on big feet, more toes, less toes, no toes, retractable claws, dewclaws, pads, hoofs, opposable thumbs, etc. etc. Somehow, the mammal genetic information system must be able to independently specify all these foot/hand parameters. Somehow the evolution process has been able to independently vary all those parameters in accordance with the evolutionary needs of the particular species. Somehow the evolution process has been able to do that even within the very short evolutionary time span occupied by mammals. Why would we therefore suspect the sort of rigid linkage leading to Williams' conclusion? Aging is a characteristic that has existed for a long evolutionary period and applies to most animals. Wouldn't evolution have been able to overcome the alleged pleiotropy problem during such a long period?

The "antagonistic pleiotropy" problem is apparently just severe enough to prevent a given mammal species from evolving a longer life span but, coincidentally, is not severe enough to prevent another mammal species, possessing very similar genes and very similar biochemistry, from evolving a longer life span. Apparently the rigid linkage is only just rigid enough to explain the first case while flexible enough to explain the second case! As a further somewhat amazing coincidence, the symptoms of aging are very similar in different mammals having very different life spans. Humans and housecats both suffer from cataracts, deafness, muscle atrophy, cancer, and heart disease, and share other manifestations of aging.

Note that single-gene genetic diseases commonly have multiple, diverse, adverse symptoms, but it is essentially unheard-of for a genetic disease to produce a manifestation that anyone would consider beneficial alongside the various adverse symptoms.

In many ways, Williams’ theory is a restatement of Darwin’s circular “explanation”: There must be some hidden individual benefit compensating for the individual disadvantage of aging merely and entirely because traditional evolutionary mechanics theory says so.

Despite the rather massive difficulties, the antagonistic pleiotropy theoryis respected among some current scientists. This has a serious negative impact on anti-aging research since, according to Williams, anti-aging medicine is impossible. The antagonistic pleiotropy theory is one of a family of theories that all hold that aging is an unavoidable individually adverse side effect of some individually beneficial function. They typically have similar difficulties in explaining why the alleged beneficial effect is unavoidably, rigidly, linked to the adverse effects of aging and also in providing experimental evidence of such rigid linkage.

When the antagonistic pleiotropy theory was developed (1957) it was widely thought that it was literally "impossible" that traditional evolutionary mechanics theory could be incorrect or even less than perfectly comprehensive. Development of a biological aging theory was therefore an exercise in producing the least implausible theory that maintained compatibility with traditional mechanics. Antagonistic pleiotropy only had to compete with other theories following the same criterion such as disposable soma or mutation accumulation, which had similar degrees of implausibility. However, since then multiple alternative evolutionary mechanics theories have been developed in response to various observed issues other than aging. The newer alternative theories support programmed theories of aging that provide a better fit to observations and avoid the logical flaws described above.

More Issues with Antagonistic Pleiotropy Theory