Mutation Accumulation Theory of Aging

Sir Peter Medawar (1915 – 1987) was a noted British professor of zoology and anatomy at the University of London who won the Nobel Prize in medicine (1960) for his work on acquired immunological tolerances.

The mutation accumulation theory is based on Medawar's Hypothesis, which suggests that the evolutionary effect of adverse events declines following the age at which an organism is initially capable of reproduction. Although there is substantial agreement that evolutionary impact of adverse events declines with age, Medawar proposed that it declined to the point of being negligible.

Medawar proposed in 1952 that aging was caused by random mutationscausing adverse aging characteristics. In effect, aging was caused by an assortment of genetic diseases, each of which has adverse symptoms only at advanced ages. Medawardiscussed in this connection human genetic diseases such as Huntington’s chorea, which does have increasing symptoms with age. While Huntington’s and other genetic diseases each individually only affect part of the population, it is easy to imagine that other adverse genetic conditions could have spread to encompass essentially the entire population and thus be considered a “natural” part of aging.

Medawar’s theory was written in response to, and as an alternative for, Weismann’s earlier programmed death theory, and neatly reverses the main disadvantages of Weismann’s theory turning them into advantages. Most importantly, Medawar’s theory does not require a violation of Darwin’s evolutionary mechanics theory. By 1952 (and still to a much lesser extent today) many biologists considered the traditional natural selection theory to be essentially infallible, “a given.” Second, if you reject Weismann's theory because most wild animals do not live long enough to die of old age, and that therefore programmed death cannot be an evolved characteristic, then you should accept Medawar’s idea that mutations can accumulate causing death of old age. These two ideas are opposite sides of the same coin.

Medawar's hypothesis provided an explanation for the enormous differences in life span between different mammal species by tracing those differences to corresponding differences in age of sexual maturity. Indeed, age of sexual maturity correlates moderately well with life span in mammals. The mutation accumulation theory was specifically directed at gradually aging mammals and did not attempt to deal with non-mammals or with instances of sudden death following reproduction.

It is important to note that, unlike the earlier wear out or entropy theories, the mutation accumulation theory does not suppose any fundamental, inescapable, cause of aging. Aging is the result of adverse mutations. If these mutations could be removed or contravened, longevity could be extended, perhaps indefinitely.

Furthermore, aging affects only what might be described as “maintenance” functions, namely, those activities needed merely to maintain the condition of an already developed, fully functional, adult, organism. The scope and difficulty of maintenance would appear to be relatively minor, even trivial when compared to the activities involved in the growth, development, and normal day-to-day functioning of an organism.

Many of the activities involved in maintenance, such as cell division and replacement, would appear to largely duplicate those involved in the original growth and development. Therefore, it is reasonable to believe that a relatively small number of genes are exclusively associated with the maintenance function, such as genes that control initiation of cell division only in a maintenance context. It is only these genes that are affected by the adverse mutations.

Finally, in relatively longer-lived animals, only those few maintenance functions involved in relatively long-term maintenance are adversely mutated since the shorter-term functions are already fully operational. Even the shortest-lived mammal would have needs for maintenance. Wounds heal. Hair and claws grow. Short-lived cells are replaced.

Medawar’s theory therefore suggested that medical intervention that contravened the relatively small number of adversely mutated functions was at least a possibility.

We know from modern genetics that related organisms such as mammals have a very high degree of similarity in their genes, which leads to the conclusion that they share very similar logical processes or “genetic programs.” The differences between different mammals are directed by relatively minor genetic differences that in turn cause differences mainly in degree or magnitude rather than in the logic. In other words, mice and men probably have the same “maintenance program.” It is just that the program in mice is less aggressive and effective than the program in humans so lab mice live perhaps 14 months after reaching maturity and humans live about 60 years after maturity.

We can imagine that even if the evolution process was able to eventually repair or contravene any single mutation, that other mutations would continually appear that also had adverse effect only at advanced age.

The idea that mutations could occur that would cause adverse effects has been verified by substantial work that has been done in an effort to understand human genetic diseases. Many human diseases have been traced to errors that have occurred in genetic code. Symptoms of some genetic diseases are even age-related and tend to increase with age.

Problems with the Mutation Accumulation Theory

However, there are problems with the idea that such mutations cause aging as put forth in the mutation accumulation theory:

The mutation accumulation theory only works if the fitness effect of aging is indeed negligible. Mutation accumulation says that “absence-of-aging” does not evolve because the beneficial effect of absence-of-aging is small enough that mutations that contravene absence-of-aging can accumulate and not be selected out. This would also apply to any other trait that had the same or less beneficial effect. If “slightly longer claws” is very mildly beneficial then “slightly shorter claws” is only very mildly adverse. Evolution is still able to evolve slightly longer claws. Darwin’s theory of tiny incremental steps requires that very small beneficial characteristics can evolve. Medawar’s hypothesis depends on the idea that aging can exist solely because of the declining fitness effect of adverse events with age and therefore depends on the idea that aging has a negligible fitness impact.

Although “death of old age” in the wild probably only occurs frequently in species that have few predators, aging in mammals obviously has effects other than death that would affect fitness and therefore death rate. Aging in mammals affects strength, speed, agility, and other factors that affect fitness even in relatively young animals. It therefore does not appear plausible that aging has a negligible effect on fitness.

If we assume a Medawar scenario in which a species (e.g. mouse) lives in a brutally vicious world where virtually no animals survive long enough to die of old age, then even a very minor difference in a survival trait (speed, strength, etc.) would presumably influence the probability of survival. Such minor differences due to aging could plausibly be expected to appear at very young ages.

If we assume a species (e.g. elephant) that has relatively few predators and therefore lives a relatively peaceful existence in the wild, then presumably death of old age is a fitness factor. These issues led to the subsequent development of the antagonistic pleiotropy theory and other competing theories that suppose that aging is an unavoidable adverse side-effect of some beneficial function.

Another problem is that a number of diverse organisms (e.g. salmon, octopus, marsupial mouse, and bamboo) display instances of death closely following an act of sexual reproduction. Death in these species appears to be controlled by the reproductive function or controlled by whatever triggers reproduction as opposed to calendar age. Aging in most mammals, as a gradual, diffuse, and multi-tissue degradation loosely tied to sexual maturity, could plausibly result from random mutations variably degrading a family of beneficial maintenance characteristics. However, this scenario does not appear to work for bamboo, salmon, marsupial mouse, and other plants and animals that exhibit what appears to be programmed death tied directly to reproduction and clearly not associated with a generalized maintenance function. How could suicidal behavior result from the random mutation degradation of a beneficial characteristic? What beneficial characteristic was degraded to result in biological suicide?

Another difficulty is that we now know that genes are activated or expressed in accordance with a very complex biological program that activates different genes in different tissues at different times during an organism's life. Activation of a gene results in production of a gene-product that accomplishes a function. Genetic diseases result from instances in which genetic flaws prevent the proper product from being produced at the proper time. A genetic disease that only occurs in late life implies the existence of a gene whose product is only needed in late life as well as existence of a program that only calls for expression of that gene in late life. Why would the evolution process have created such a gene? Why would the program extend beyond organism maturity in order to call for expression of different genes in late life?

The basic problem is that mutation accumulation is too simple a mechanism to explain the detail in the observed aging processes of different species.

Some gerontologists think of Medawar as a major prophet, essentially the father of modern gerontology. Some think that eventually Medawar will be found to have had a major negative effect on medicine by pointing many generations of researchers in the wrong direction. Time will tell.

The article Shattered: Medawar's Test Tubes and their Enduring Legacy of Chaos (J. Bowles Medical Hypotheses 54(2) 2000) provides a more extensive criticism of Medawar's theories.

Beginning in 1962 a number of alternative evolutionary mechanics theories were developed in an effort to explain observed organism characteristics other than aging that appeared to conflict with traditional evolutionary mechanics. The alternative theories support programmed aging theories in which the individually adverse effect of aging is offset by a group or evolvability benefit. These theories avoid the logical problems described above. See Aging Theory Overview.

More Issues with Mutation Accumulation Theory