Sex- and age-dependent genetics of longevity in a heterogeneous mouse population

DNA variants that modulate life span provide insight into determinants of health, disease, and aging. Through analyses in the UM-HET3 mice of the Interventions Testing Program (ITP), we detected a sex-independent quantitative trait locus (QTL) on chromosome 12 and identified sex-specific QTLs, some of which we detected only in older mice. Similar relations between life history and longevity were uncovered in mice and humans, underscoring the importance of early access to nutrients and early growth. We identified common age- and sex-specific genetic effects on gene expression that we integrated with model organism and human data to create a hypothesis-building interactive resource of prioritized longevity and body weight genes. Finally, we validated Hipk1, Ddost, Hspg2, Fgd6, and Pdk1 as conserved longevity genes using Caenorhabditis elegans life-span experiments. Description Long live the mice (and humans) The question of what determines our longevity has preoccupied humans throughout the ages, and different researchers have tried to address this in a variety of ways. Bou Sleiman et al. approached this question on a large scale, examining the growth patterns and genetics of thousands of mice from a multicenter study of aging (see the Perspective by Magalhães). From this analysis, the authors identified the contributions of various genes to the animals’ longevity, which differed between male and female mice. The genes involved were well conserved between species, as evidenced by the finding of similar effects in humans and worms. In addition to genetics, early-life nutrition appeared to play a major role. —YN Variation in life span is the consequence of sex- and age-dependent genetic effects and early access to nutrients. INTRODUCTION Aging is the progressive decline in physical, mental, and reproductive capacities that is accompanied by multiple morbidities and associated with increased mortality. Despite advances in identifying aging pathways and drugs that extend life span in model systems, an integrative understanding of the interplay between genetics, sex, and environment in aging and life-span determination is largely lacking. RATIONALE Although there is no single measure of aging, studies depend on surrogate or related traits such as longevity, life history, age-related disease onset, and physiological markers. Characterizing genetic and nongenetic determinants of longevity at the population level may identify genes and pathways involved in aging, providing avenues for targeted anti-aging therapies and extension of healthy longevity. We set out to query genetic regulators of longevity in a total of 3276 UM-HET3 mice used in longevity studies by the National Institute on Aging’s Interventions Testing Program (NIA ITP). We interrogated whether the genetic basis of longevity is sex and age dependent, and whether nongenetic factors such as litter size and the effect of early access to nutrients on growth contribute to longevity determination. We characterized the age- and genotype-dependent changes in liver gene expression in mice from the same genetic cross. Finally, we integrated these results with orthogonal datasets to obtain a resource of prioritized candidate genetic loci and genes for further investigation. RESULTS When jointly analyzing males and females, we obtained a single, previously described, longevity locus on chromosome 12. However, when analyzed separately, males and females had distinct genetic determinants of longevity. In females, a single locus on chromosome 3 was uncovered, whereas in males, loci were detected only when early deaths were excluded, suggesting that some genetic variations had an effect on longevity beyond a certain age. Increased body weight associated with earlier death and some of the variation in adult body weight are explained by litter size. Hence, early access to nutrients may affect mouse longevity through its effect on growth. We used Mendelian randomization to replicate the relationships between early growth, adult size, and longevity in humans. To prioritize genes under the longevity loci, we profiled liver gene expression of adult and old mice to look for sex-, age-, and genetically driven differences in expression. Female livers had higher interferon-related gene expression, and older mice had overexpressed immune-related genes. Genetic regulation of gene expression was assessed, with the majority being conserved across sexes and age. We combined our results with data from multiple sources in model organisms and humans to compile an interactive resource for conserved longevity gene prioritization (https://www.systems-genetics.org/itp-longevity). Worm life-span experiments validated some of the most highly scoring genes and identified Hipk1, Ddost, Hspg2, Fgd6, and Pdk1 as candidates. CONCLUSION This study provided insights into determinants of longevity, highlighting genetic mediators that can be sex or age specific, and nongenetic effects such as early access to nutrients. The combined body of information assembled from this study and the external data constitute a hypothesis-building resource for future studies on, and therapies for, aging, age-related disease, and longevity. Genetic analyses in UM-HET3 mice used in the Interventions Testing Program highlight sex- and age-specific longevity loci. Body weight associates with longevity, as does litter size, through its effect on body weight. Mendelian randomization in humans recapitulated these relationships between early growth and life span. Gene expression analyses, cross-species integration, and Caenorhabditis elegans life-span experiments highlight candidate longevity genes and provide a resource for further investigation.