Dynamics of genetic and somatic trade-offs in ageing and mortality
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.
Authors
- Robert W. Williams (ORCID: https://orcid.org/0000-0001-8924-4447)
- Khyobeni Mozhui (ORCID: https://orcid.org/0000-0002-6623-4112)
- James F. Nelson (ORCID: https://orcid.org/0000-0002-7439-3033)
- Randy Strong (ORCID: https://orcid.org/0000-0001-6643-3288)
- Pjotr Prins (ORCID: https://orcid.org/0000-0002-8021-9162)
- Suheeta Roy (ORCID: https://orcid.org/0000-0002-5996-6905)
- David G. Ashbrook (ORCID: https://orcid.org/0000-0002-7397-8910)
- Xiaoxu Li (ORCID: https://orcid.org/0000-0001-5121-9190)
- Zachary Sloan (ORCID: https://orcid.org/0000-0002-8099-1363)
- Michael R. MacArthur (ORCID: https://orcid.org/0000-0003-3593-6995)
- Arthur G. Centeno (ORCID: https://orcid.org/0000-0003-3142-2081)
- Amandeep Bajwa (ORCID: https://orcid.org/0000-0003-0517-8871)
- David E. Harrison
- Richard A. Miller (ORCID: https://orcid.org/0000-0001-9266-9649)
- Karl W. Broman (ORCID: https://orcid.org/0000-0002-4914-6671)
- Śaunak Sen (ORCID: https://orcid.org/0000-0003-4519-6361)
- Danny Arends (ORCID: https://orcid.org/0000-0001-8738-0162)
- Ozlem Altintas Akin
- Kurt H. Lamour
- Evan G. Williams
- Johan Auwerx (ORCID: https://orcid.org/0000-0002-5065-5393)
- Lu Lu
- Sarah J. Mitchell
- Vivian Diaz
- João Miguel Brito Magalhães (ORCID: https://orcid.org/0000-0002-6363-2465)
Institutions
- University of Wisconsin–Madison (US)
- University of Tennessee Health Science Center (US)
- The University of Texas at San Antonio Health Science Center (US)
- University of Luxembourg (LU)
- Princeton University (US)
- University of Michigan (US)
- Northumbria University (GB)
- ETH Zurich (CH)
- Longevity Biotech (United States) (US)
- Jackson Laboratory (US)
- École Polytechnique Fédérale de Lausanne (CH)
- University of Tennessee at Knoxville (US)
- University of Birmingham (GB)
- University of Edinburgh (GB)
Publication Details
- Journal
- Nature
- Published
- 2026-04-22
- DOI
- https://doi.org/10.1038/s41586-026-10407-9
- Primary Topic
- Genetics, Aging, and Longevity in Model Organisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00