Gene-by-environment modulation of lifespan and weight gain in the murine BXD family

How lifespan and body weight vary as a function of diet and genetic differences is not well understood. Here we quantify the impact of differences in diet in a genetically diverse family of female mice, split into matched isogenic cohorts fed a low-fat chow (CD, n = 663) or a high-fat diet (HFD, n = 685). We further generate key metabolic data in a parallel cohort sacrificed at four time points. HFD feeding shortens lifespan by 12%— equivalent to a decade in humans. Initial body weight and early weight gains account for longevity differences of ~4–6 days/g. At 500 days, animals on a HFD typically gain 4× as much weight as control, but variation in weight gain does not correlate with lifespan. Classic serum metabolites, often regarded as health biomarkers, are not necessarily strong predictors of longevity. Our data indicate that responses to a high fat diet are substantially modulated by gene-by-environmental interactions, highlighting the importance of genetic variation in making accurate individualized dietary recommendations.