Genome-wide RNAi analysis in adult Caenorhabditis elegans unveils genes controlling age-related fat accumulation

Fat accumulation with aging occurs in adults across species, yet its underlying mechanisms remain poorly understood, partly due to limited number of studiesspecifically targeting adulthood. Here, we present the first genome-wide analysis of age-associated fat accumulation during adulthood in Caenorhabditis elegans. Unprecedently, our adult-specific RNAi screen identified a limited subset of genes influencing adult fat dynamics, contrasting with the extensive gene sets uncovered in prior developmental RNAi screens. This disparity suggests a unique genetic architecture governing age-related lipid deposition. Central to this network is the evolutionarily conserved transcription factor DAF-16/FoxO, which progressively accumulates in nuclei during aging. Genetic ablation of daf-16 abolished adult fat accumulation, while its adult-specific knockdown reduced adiposity without compromising healthspan or longevity, highlighting its therapeutic potential. Critically, knockdown of the top hits, pals-17 and rege-1, markedly attenuated the nuclear localization of DAF-16 and failed to reduce the adult fat content daf-16-deficient animals, establishing DAF-16 as their essential effector. Overall, our work uncouples developmental and adult lipid regulatory mechanisms and highlights potential targets for understanding and managing adult-onset obesity.