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Evolution of Aging

Mutation Accumulation Theory Of Aging

The mutation accumulation theory of aging, suggested by Peter Medawar in 1952, considers aging as a by-product of natural selection (similar to the evolutionary explanation for the blindness of cave animals). The probability of an individual reproducing depends on his age. It is zero at birth and reaches a peak in young adults, after which it decreases due to the increased probability of death linked to various external (predators, illnesses, accidents) and internal (senescence) causes. In such conditions, deleterious mutations expressed at a young age are severely selected against, due to their high negative impact on fitness (number of offspring produced). On the other hand, deleterious mutations expressed only later in life are rather neutral to selection, because their bearers have already transmitted their genes to the next generation.

Mutations can affect fitness either directly or indirectly. For example, a mutation increasing the risk for leg fracture, due to a low fixation of calcium, may be indirectly as deleterious to fitness as a mutation directly impairing the eggs nesting in the uterus. From an evolutionary perspective, it does not really matter exactly why the organism is at risk not to reproduce—either because many spontaneous abortions occur, or because it becomes an easy prey for a predator (in nature) or for a criminal (in society).

According to this theory, persons loaded with a deleterious mutation have fewer chances to reproduce if the deleterious effect of this mutation is expressed earlier in life. For example, patients with progeria (a genetic disease with symptoms of premature aging) live only for about twelve years, and, therefore, they cannot pass their mutant genes to the next generation. In such conditions, the progeria stems only from new mutations and not from the genes of parents. By contrast, people expressing a mutation at older ages can reproduce before the illness occurs, as it is the case with familial Alzheimer's disease. As an outcome, progeria is less frequent than late diseases, such as Alzheimer's disease, because the mutant genes responsible for the Alzheimer's disease are not removed from the gene pool as readily as progeria genes, and can thus accumulate in successive generations. In other words, the mutation accumulation theory predicts that the frequency of genetic diseases should increase at older ages.

Mutation accumulation theory allows researchers to make several testable predictions. In particular, this theory predicts that the dependence of progeny life span on parental life span should not be linear, as is observed for almost any other quantitative trait demonstrating familial resemblance (e.g., body height). Instead, this dependence should have an unusual nonlinear shape, with increasing slope for the dependence of progeny life span on parental life span for those with longer-lived parents. This prediction follows directly from the key statement of this theory that the equilibrium gene frequency for deleterious mutations should increase with age at onset of mutation action because of weaker (postponed) selection against later-acting mutations. (The term equilibrium gene frequency refers here to the ultimate time-independent gene frequency, which is determined by mutation-selection balance [equilibrium between mutation and selection rates]; see Charlesworth, 1994).

According to the mutation accumulation theory, one would expect the genetic variability for life span (in particular, the additive genetic variance responsible for familial resemblance) to increase with age. (Additive gene variance refers to a variance of additive genetic origin; that is, a variation due to additive effects of genes on the studied trait in genetically heterogeneous populations. This variance increases with an increase in mutation frequencies.) The predicted increase in additive genetic variance could be detected by studying the ratio of additive genetic variance to observed phenotypic variance. This ratio (the so-called narrow-sense heritability of life span) can be easily estimated as the doubled slope of the regression line for the dependence of offspring life span on parental life span. Thus, if age at death were indeed determined by accumulated late-acting deleterious mutations, one would expect this slope to become steeper with higher parental ages at death. This prediction was tested through the analysis of genealogical data on familial longevity in European royal and noble families, data well known for their reliability and accuracy. It was found that the regression slope for the dependence of offspring life span on parental life span increases with parental life span, exactly as predicted by the mutation accumulation theory (see Gavrilova et al.). Thus, the current status of the mutation accumulation theory could be characterized as a productive working hypothesis, pending further validation.

Additional topics

Medicine EncyclopediaAging Healthy - Part 2Evolution of Aging - Evolution Of Scientific Ideas On The Evolution Of Aging, Mutation Accumulation Theory Of Aging, Antagonistic Pleiotropy Theory Of Aging ("pay Later" Theory)