Genetic Modulation of Lifespan: Dynamic Effects, Sex Differences, and Body Weight Trade-offs

The dynamics of lifespan are shaped by DNA variants that exert effects at different ages. We have mapped genetic loci that modulate age-specific mortality using a new actuarial method. We started with 6,438 pubescent mice and ended with a survivorship of 559 mice that lived to at least 1100 days of age. Twenty-nine Vita loci dynamically modulate lifespan and have strong age-delimited effects after correction for multiple tests. Fourteen loci have relatively steady but genotype-dependent effects on mortality from pubescence to old age and are candidate aging rate modulators. Other loci act most forcefully over shorter periods of life, and the polarities of their genetic effects often invert with age and differ by sex. We detect 41 epistatic interactions among these Vita loci, all exclusive to males or females, and with strong signatures of sexual reciprocity. A distinct set of 19 Soma loci shape the negative correlation between larger body size in young adults with their subsequent life expectancies. These loci are direct evidence that antagonistic pleiotropy modulates mortality early in life. Another set of 11 Soma loci shape the positive correlation between heavier body weight at older ages and longer life expectancies. We provide exemplars of how to move from maps to mechanisms for two tractable loci. Our findings provide a solid empirical bridge between evolutionary theories on aging and their molecular causes. The 59 loci are keys to understand the impact of interventions on healthy lifespan in mice and humans.