Genetic regulation of fasting-induced longevity effects.

Dietary interventions such as caloric restriction and periodic fasting improve metabolic health and extend lifespan in preclinical models, yet individuals differ widely in their physiological responses-variation that remains poorly understood but is critical for safe and effective translation to humans. We applied a 2 days per week intermittent fasting (IF) regimen to 10 inbred strains from the Collaborative Cross (CC), a genetically diverse, reproducible panel ideal for dissecting genetic effects on intervention responses. Using longitudinal phenotyping, we measured hundreds of traits, including lifespan. Our results show that sex and genetic background shape physiological responses to IF across metabolic, hematologic, and immunologic domains. Lifespan effects were also sex specific and varied among strains. These findings demonstrate that IF response is genetically determined in a mammalian model with human relevant physiology. We further compared CC results with a parallel study in Diversity Outbred mice, identifying shared predictors of health and lifespan as well as key differences between inbred and outbred populations. Overall, our work highlights the central role of genetics in shaping dietary intervention outcomes and informs efforts to translate IF benefits to human health and longevity.