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Subjects

- Biomarkers

- Genetic linkage study

- Genetic variation

Abstract

DNA variants modulate mortality risks across an entire lifespan but their dynamic age-dependent effects have not been resolved in any species for either sex. Here we mapped variants that shape mortality using an actuarial approach, starting with a base population of 6,438 pubescent mice and ending with 559 survivors that lived beyond 1,100 days of age. Twenty-nine Vita loci influence lifespan with strong age- and sex-specific effects. Most act during distinct stages with polarities that often invert with age, but a minority have consistent age-dependent effects in one or both sexes. A separate set of 30 Soma loci influence correlations between body mass and life expectancy. Nineteen Soma loci mediate higher mortality in larger young mice, whereas 11 mediate lower mortality in larger old mice. All effects are stronger in male mice than in female mice. Vita and Soma loci form epistatic networks split strictly by sex. These findings provide a genetic bridge between evolutionary theories of ageing and molecular mechanisms that can guide interventions to extend healthy lifespan.

Main

We do not yet understand the genetic, molecular, cellular and organismal processes that shape the intrinsic variability in rates of ageing, lifespan and all-cause mortality in humans, mice or other model organisms1,2,3,4,5,6,7,8,9,10,11. Although thousands of variants modulate risks of age-related diseases, the great majority influence proximate causes of death and not the core mechanisms that influence ageing rates per se12,13. To disentangle causes from consequences and to define those variants that modulate mortality across entire lifespans, we developed actuarial methods that map variation in lifespan of progressively older survivorships—equivalent to a range from 12 to 94 years in humans14. This approach has been tested4,15,16,17, but has not been applied systematically in any organism. The closest human parallels are biometric studies of age-dependent changes in heritability of lifespan in Scandinavian twin cohorts born between 1870 and 191018. Our study is a complementary dissection resolved at the level of discrete genetic effects—59 well-defined loci that dynamically interact to influence mortality rates and lifespan. We address four sets of questions in geroscience:

What DNA variants influence mortality rates, and how and when do they act? Which have persistent effects, which have transient effects, and which act only late in life?

How do these loci align with sex differences in mortality during and after reproduction? Is there evidence of genotype-by-sex (G × S) interactions, genotype-by-genotype (G × G) interactions, or even genetic antagonism between the sexes?

What loci account for the strong negative association between larger body size early in life and shorter lifespans versus larger body size late in life and longer lifespans? Are these loci discrete sets?

How do the dynamics and action of loci and their many interactions support or refute predictions made by major evolutionary theories of ageing—the mutation accumulation theory19, the antagonistic pleiotropy theory20 and the longevity-assurance/disposable soma theory21?

To dissect age-localized genetic effects on mortality and lifespan we relied on the largest study of mouse ageing—the National Institute on Aging’s Interventions Testing Program (ITP)22. For more than two decades, teams at three sites have used a population of genetic siblings called the University of Michigan Heterogeneous Cohort 3 (UM-HET3) to study effects of drug interventions on longevity22,23. These mice are effectively one large sibship segregating for 11 million DNA variants. In earlier work we mapped lifespan using 3,055 mice and detected seven lifespan loci17. Here we have doubled the sample size to 6,438 mice, quadrupled numbers of genetic markers, and introduced a more powerful actuarial mapping method. The result has been a fourfold increase in numbers of lifespan loci (Vita type) and the confirmation of six of seven loci that we had previously mapped. In addition, we have mapped 30 loci of a new type that specifically influence correlations between body mass and life expectancies in males and females (Soma type loci) as a function of age. We also comprehensively analysed age-dependent heritability changes, and the strong sex- and age-dependent epistatic interactions among all loci.

The dynamics of Vita and Soma loci are highly complex. Some act almost exclusively at younger or older ages. A subset modulates life expectancies more uniformly and includes DNA variants that may act as pacemakers of ageing24. Many have marked and even complementary or antagonistic sex differences, as do almost all epistatic partnerships. Some loci have effects that are predicted by the theory of antagonistic pleiotropy19,25,26, whereas others have effects long after the reproduc

Dynamics of genetic and somatic trade-offs in ageing and mortality | Nature