Gene-by-environmental modulation of longevity and weight gain in the murine BXD family

Diet and environment profoundly modulate lifespan. We measured longevity as a function of diet and weight gain across a genetically diverse family of mice that segregates for over 6 million sequence variants. We followed 1348 females from both parental strains-C57BL/6J and DBA/2J-and 76 of their BXD progeny across their natural life span on a standard low fat chow diet (CD, 18% calories from fat) or on a high fat diet (HFD, 60% calories from saturated fat). On average, the HFD shortens lifespan by 85 days or 12%, roughly equivalent to an 8-10 year decrease in humans. This diet is also associated with an average two-fold higher age-adjusted risk of death compared to CD. However, variation among strains in the effect of HFD on longevity is high, ranging from a longevity loss of 54% in BXD65 to a gain of 37% in BXD8. Individual and strain-specific baseline weights and early weight gain are both associated with a mean decrease in longevity of ~4 days/g. By 500 days of age, cases on HFD gained four times as much weight as those on CD. However, strain-specific variation is again substantial and does not correlate well with lifespan. In summary, HFD has a negative effect on longevity, but genetic interactions are a much stronger factor (4% versus 30%). This highlights the unequivocal importance of genetic variation in making dietary recommendations.