Mutation accumulation theory

Despite Charles Darwin's completion of his theory of biological evolution in the 19th century, the modern logical framework for evolutionary theories of ageing wouldn't emerge until almost a century later. Though August Weismann did propose his theory of programmed death, it was met with criticism and never gained mainstream attention.[3] It wasn't until 1930 that Ronald Fisher first noted the conceptual insight which prompted the development of modern ageing theories. This concept, namely that the force of natural selection on an individual decreases with age, was analysed further by J. B. S. Haldane, who suggested it as an explanation for the relatively high prevalence of Huntington's disease despite the autosomal dominant nature of the mutation. Specifically, as Huntington's only presents after the age of 30, the force of natural selection against it would have been relatively low in pre-modern societies.[2] It was based on the ideas of Fisher and Haldane that Peter Medawar was able to work out the first complete model explaining why ageing occurs, which he presented in a lecture in 1951 and then published in 1952[1]

(a) The survival rate within a population decreases with age, while the reproduction rate remains constant. (b) The reproduction probability peaks early in life, at sexual maturity, and then steadily decreases as an individual ages, with the remaining share of the population decreasing with age as they enter the selection shadow.

Amongst almost all populations, the likelihood that an individual will reproduce is related directly to their age.[1] Starting at 0 at birth, the probability increases to its maximum in young adulthood once sexual maturity has been reached, before gradually decreasing with age. This decrease is caused by the increasing likelihood of death due to external pressures such as predation or illness, as well as the internal pressures inherent to organisms that experience senescence. In such cases deleterious mutations which are expressed early on are strongly selected against due to their major impact on the number of offspring produced by that individual.[3] Mutations that present later in life, by contrast, are relatively unaffected by selective pressure, as their carriers have already passed on their genes, assuming they survive long enough for the mutation to be expressed at all. The result, as predicted by Medawar, is that deleterious late-life mutations will accumulate and result in the evolution of ageing as it is known colloquially.[2] This concept is portrayed graphically by Medawar through the concept of a "selection shadow". The shaded region represents the 'shadow' of time during which selective pressure has no effect.[4] Mutations that are expressed within this selection shadow will remain as long as reproductive probability within that age range remains low.

Under most assumptions, the mutation accumulation theory predicts that mortality rates will reach close to 100% shortly after reaching post-reproductive age.[10] Experimental populations of Drosophila Melanogaster, and other organisms, however, exhibit age-specific mortality rates that plateau well before reaching 100%, making mutation accumulation alone an insufficient explanation. It is suggested instead that mutation accumulation is only one factor among many, which together form the cause of ageing. In particular, the mutation accumulation theory, the antagonistic pleiotropy hypothesis and the disposable soma theory of ageing are all believed to contribute in some way to senescence[11]

Somatic accumulation of protein truncating variants (PTVs), a form of deleterious or loss of function mutations, may account for only a small fraction of mortality and morbidity acceleration in humans.[12] Since the estimate provides little support for causal role mutation accumulation in human aging, damaging mutations, germline and somatic, can only contribute to aging as a result of higher-order effects including interactions of multiple forms of damage.