Testing the Mutation Accumulation Theory of Aging through Epistasis in Drosophila

The mutation accumulation (MA) theory of aging stands today as one of the leading theories of senescence, or age-related physiological decline, in the fields of evolutionary biology and gerontology. This theory postulates that senescence is the result of mutations with late-age effects accumulating relatively unchecked by selection over evolutionary time. This is the result of the force of natural selection primarily acting during the reproductive period of an organism's life. Epistasis is a term referring to the biological phenomenon describing the complex and non-additive interactions mutations can have depending on their genetic background. The original theory of epistasis predicts additive interactions among mutations affecting aging within the genome. However, recent theoretical work suggests non-additive interactions can occur between accumulated mutations impacting aging. The current literature displaying non-additive epistatic interactions on aging is limited, mainly due to the inability to experimentally assess this theory. The invertebrate model organism, Drosophila melanogaster, is ideal for examining mutation accumulation because of its short generation time, well-mapped genome, and ability to maintain controlled breeding lines over many generations. Using lines of D.melanogaster we aim to examine the effects of MA as potential evidence of non-additive epistasis and its role in aging. Through our MA protocol, we have accumulated mutations on the D.melanogaster genome for 30 successive generations. Sex- and age-specific impacts of accumulated autosomal mutations will be assessed by measuring reproductive fitness at both early and late-age across various combinations of these mutations in both males and females. The results of this project will offer key experimental insights to refine the MA model through the exploration of epistasis, as well as age- and sex-specificity, ultimately advancing the understanding of the evolutionary biology of aging.