Mutation accumulation theory

Mutation accumulation theory is an evolutionary explanation for senescence, first proposed by Peter Medawar in his 1952 lecture "An Unsolved Problem of Biology." It holds that late-acting deleterious mutations — those harmful only after peak reproductive age — escape natural selection and accumulate over generations. Selection pressure declines with age: mutations lethal before reproduction are purged, while those reducing fitness only post-reproduction persist in Medawar's "selection shadow"; genetic drift then raises them to high frequency, eroding physiological function in older individuals. Charlesworth (2001) formalised this in a quantitative genetic model predicting that mean and additive genetic variance of age-specific mortality rates rise exponentially with age, consistent with human and Drosophila data. Turan et al. (2019) provided molecular evidence, detecting an age-related decrease in transcriptome conservation (ADICT) across 16 tissue types in five mammalian species, with late-expressed genes under weaker purifying selection and enriched in apoptosis and inflammatory pathways. The theory differs from antagonistic pleiotropy in requiring no early-life benefit, only late-life harm; which mechanism predominates for any given trait remains empirically unresolved.