Age-dependent genetic effects contribute to immunosenescence in Drosophila melanogaster

Immunosenescence, the age-related decline in immune function, varies widely among individuals. Although both genetic and environmental factors contribute to variation in immunosenescence, the extent to which age-specific genetic effects shape age-related immune decline remains poorly understood. Here, we tested whether age-related variation in bacterial clearance is shaped by age-dependent genetic effects by measuring clearance of Escherichia coli infection in 175 genotypes at 1 week of age and 183 genotypes at 5 weeks of age. Clearance ability declined with age, but the magnitude of decline differed markedly among genotypes. Age-specific genetic effects explained substantially more phenotypic variation than age-independent genetic differences, and the genetic correlation in clearance ability across ages was modest, indicating that genetic effects on immune performance were only partially shared across ages. Consistent with these findings, genome-wide analyses identified largely distinct sets of candidate genes associated with clearance in young and old flies, including genes exhibiting genotype-by-age effects. Network and gene ontology analyses revealed enrichment for plasma membrane-associated genes and pathways involved in cell adhesion and cell migration. Functional follow-up of 14 candidate genes using hemocyte-specific RNA interference produced limited effects overall but confirmed that nebulosa contributes to bacterial clearance. Together, our results demonstrate that immunosenescence is shaped by age-dependent genetic effects and identify conserved pathways and candidate genes for future mechanistic studies of age-related immune decline.