Deleterious age-amplified mutations and the evolution of ageing

Ever since Medawar and Williams published their tremendously influential theories of the evolution of ageing half a century ago (Mutation Accumulation [MA] and Antagonistic Pleiotropy [AP], respectively), evolutionary geneticists have been locked into the idea that ageing is exclusively generated by two specific subclasses of mutations.

Both classes cause ageing through late-life deleterious effects, but differ in how they affect early-life performance (MA neutrally and AP positively).

Evidence in favor of each class have been found, but consistent observations of positive pleiotropy between early- and late-life performance are difficult to reconcile with either theory.

This proposal is centered around the novel hypothesis that deleterious mutations show increasing negative effects with age, a possibility predicted from recent ageing theory, indirectly supported by past experiments, and directly supported by preliminary data from my laboratory.

Deleterious mutations with age-amplified negative effects resolve the paradox of how ageing evolves under positive pleiotropy, and in contrast to established theories suggest that virtually all deleterious mutations may contribute to ageing.

In this proposal I outline a research program designed to comprehensively test this novel hypothesis, using several Drosophila melanogaster model systems.

The proposed research promises to transform our understanding of ageing: one of the most fundamental yet least understood biological processes.