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Background  Longevity and age-specific patterns of mortality are complex traits that vary within and among taxa. Multiple candidate genes for aging have been identified in model systems by extended longevity mutant phenotypes, including the G-protein coupled receptor  methuselah  ( mth ) in  D. melanogaster . These genes offer important insights into the mechanisms of lifespan determination and have been major targets of interest in the biology of aging. However, it is largely unknown whether these genes contribute to genetic variance for lifespan in natural populations, and consequently contribute to lifespan evolution.    Methodology/Principle Findings  For a gene to contribute to genetic variance for a particular trait, it must meet two criteria: natural allelic variation and functional differences among variants. Previous work showed that  mth  varies significantly among wild populations; here we assess the functional significance of wild-derived  mth  alleles on lifespan, fecundity and stress resistance using a quantitative complementation scheme. Our results demonstrate that  mth  alleles segregating in nature have a functional effect on all three traits.    Conclusions/Significance  These results suggest that allelic variation at  mth  contributes to observed differences in lifespan and correlated phenotypes in natural populations, and that evaluation of genetic diversity at candidate genes for aging can be a fruitful approach to identifying loci contributing to lifespan evolution.

Functional Significance of Allelic Variation at methuselah, an Aging Gene in Drosophila