ABSTRACT: As global populations age, understanding the genetic basis of variation in lifespan becomes increasingly important. We used an outbred population derived from 37 inbred, sequenced lines from the Drosophila Genetic Reference Panel. We performed whole genome sequencing on pools of young and old flies, separately for males and females, to identify variants and genes associated with increased lifespan. We identified 742 variants in females and 428 in males, most of which were sex-specific; only 53 genes and 6 variants were shared between males and females, with some variants exhibiting sexually antagonistic patterns. Of the 1,117 mapped genes, 665 had human orthologs and many were associated with disease phenotypes. Gene Ontology analyses revealed enrichment for genes affecting nervous system development and mitochondrial functions. We conducted RNA sequencing of male and female heads, bodies, and reproductive tissues weekly up to 10 weeks of age. We identified nearly 2,600 genes with significant age-related changes, that were enriched in mitochondrial, metabolic, immune, and neuronal pathways. A total of 185 of these genes had variants associated with lifespan from the first study. Construction of interaction networks using all age-significant genes and their interacting partners revealed 25 xQTL-containing hub genes with human orthologs, including blw, klu, Dronc, ATP5PD, mEFTu1, levy, and Socs36E. Context-dependent correlation analysis revealed tissue- and sex-specific expression patterns among age-associated genes, highlighting xQTL genes with strong tissue-specific regulation. These findings illustrate how systems genetics can identify conserved pathways and candidate genes relevant to human aging and longevity.
