Modulation of longevity by diet, and youthful body weight, but not by weight gain after maturity

Diet and environmental factors profoundly modulate lifespan. We measured longevity as a function of diet, and weight gain across a large genetically diverse BXD cohort which segregates for over 6 million variants, making it ideal for the analysis of gene-by-diet interactions that modulate lifespan. We followed 1348 females from parental strains, C57BL/6J and DBA/2J, and 76 BXD progeny strains on a standard low fat diet (CD, 18% calories from fat) or a widely used high fat diet (HFD, 60% calories from fat) across their natural life span. A diet rich in saturated fats shortens lifespan by an average of 85 days (HFD 605 ± 6, n = 685; CD 690 ± 8, n = 663), roughly equivalent to a 7-year decrease in humans. This diet is associated with an average two-fold higher age-adjusted risk of death compared to CD. Individual strains show remarkably wide variation in responses to diet, ranging from -54% on HFD in BXD65 to +37% on HFD in BXD8. Baseline weight and early weight gain on HFD associates negatively with longevity, with a gram increase causing lifespan to decrease by 4 days. By 500 days of age, BXDs on HFD gained 4X more weight than those on CD. However, strain-specific variation in the change in body weight does not significantly correlate with strain-specific life span. Major morbidities appear to be influenced by diet, with cases on HFD showing increased prevalence and severity of cardiovascular disease and lesions. Overall, we find that diet significantly impacts longevity even after adjusting for weight gain.