Evolution of longevity improves immunity in Drosophila

Much has been learned about the genetics of aging from studies in model organisms, but still little is known about naturally occurring alleles that contribute to variation in longevity. For example, analysis of mutants and transgenes has identified insulin signaling as a major regulator of longevity, yet whether variation in this pathway underlies evolutionary changes in lifespan remains largely unclear. Here we have analyzed the genomes of a set of Drosophila melanogaster lines that have been maintained under selection for longevity for over 35 years. We identified many candidate loci shaped by selection for longevity, but – contrary to expectation – we did not find overrepresentation of canonical longevity genes. Instead, we found an enrichment of immunity genes, particularly in the Toll pathway. To test whether this genomic signature is causative, we performed functional experiments. In contrast to control flies, long-lived flies tended to downregulate the expression of antimicrobial peptides upon infection with age yet survived fungal, bacterial and viral infections significantly better, consistent with alleviated immunosenescence. To examine whether genes of the Toll pathway directly affect longevity, we used transgenic RNAi. In adults, ubiquitous RNAi against the Toll receptor or its ligand spätzle extended lifespan, whereas silencing the inhibitor cactus – causing immune hyperactivation – dramatically shortened lifespan. These results suggest that genetic changes in the age-dependent regulation of immune homeostasis contribute to the evolution of longer life.