Insulin receptor substrate chico acts with the transcription factor FOXO to extend Drosophila lifespan.

Although extensively studied in Caenorhabditis elegans, no work has yet demonstrated for Drosophila melanogaster whether reduced insulin/IGF signaling (IIS) requires the FOXO transcription factor (foxo) to extend lifespan. Here, we conduct genetic epistasis analysis to determine whether foxo is required for chico mutants (insulin receptor substrate) to reduce age-specific mortality and thus extend lifespan. The mutant chico(1) allele strongly extends lifespan relative to wild-type sibs. A mutant of foxo eliminates most of this chico survival benefit. In addition, we used a factorial proportional hazard analysis to formally study the main effects of chico and of foxo and to determine how these genes interact to influence mortality. We document that foxo indeed contributes to how chico increases lifespan, but part of the convergence in survival between chico genotypes in the foxo-mutant background may occur because chico mutation exacerbates the negative effects of foxo mutation.