High-content phenotypic analysis of a C. elegans recombinant inbred population identifies genetic and molecular regulators of lifespan

Lifespan is influenced by complex interactions between genetic and environmental factors. Studying those factors in model organisms of a single genetic background limits their translational value for humans. Here, we mapped lifespan determinants in 85 C. elegans recombinant inbred advanced intercross lines (RIAILs). We assessed molecular profiles—transcriptome, proteome, and lipidome—and life-history traits, including lifespan, development, growth dynamics, and reproduction. RIAILs exhibited large variations in lifespan, which correlated positively with developmental time. We validated three longevity modulators, including rict-1, gfm-1, and mltn-1, among the top candidates obtained from multiomics data integration and quantitative trait locus (QTL) mapping. We translated their relevance to humans using UK Biobank data and showed that variants in GFM1 are associated with an elevated risk of age-related heart failure. We organized our dataset as a resource that allows interactive explorations for new longevity targets. [Display omitted] •Mapped lifespan determinants in a C. elegans GRP using multiomics data•Validated three longevity modulators, comprising rict-1, gfm-1, and mltn-1•GFM1 variants linked to age-related heart failure in UK Biobank data Gao et al. mapped lifespan determinants in a C. elegans GRP using multiomics and validated three modulators, including rict-1, gfm-1, and mltn-1. They demonstrated the relevance of these findings to humans by linking GFM1 variants to an increased risk of age-related heart failure in the UK Biobank.