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Publications

Journal Article Preprint Epublish 1 citation

PubMed: 40777243 DOI: 10.1101/2025.04.27.649857

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

bioRxiv

Authors: Danny Arends, David G Ashbrook, Suheeta Roy, Lu Lu, Zachary Sloan, Arthur G Centeno, Kurt H Lamour, João Pedro de Magalhães, Pjotr Prins, Karl W Broman, Saunak Sen, Sarah J Mitchell, Michael R MacArthur, Özlem Altintas Akin, Johan Auwerx, Amandeep Bajwa, Vivian Diaz, David E Harrison, Randy Strong, James F Nelson, Khyobeni Mozhui, Evan G Williams, Richard A Miller, Robert W Williams

Affiliations

  • Department of Applied Sciences, Northumbria University, Newcastle upon Tyne, UK.
  • Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center; Memphis, TN, USA.
  • Department of Entomology and Plant Pathology, The University of Tennessee, Knoxville, Knoxville, TN, USA.
  • Department of Inflammation and Ageing, University of Birmingham, Birmingham, UK.
  • Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison; Madison, WI, USA.
  • Department of Preventive Medicine, University of Tennessee Health Science Center; Memphis, TN, USA.
  • Ludwig Princeton Branch, Princeton University; Princeton, NJ, USA.
  • Lewis-Sigler Institute for Integrative Genomics, Princeton University; Princeton, NJ, USA.
  • Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland.
  • Laboratory of Integrative Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne; Lausanne, Switzerland.
  • Department of Surgery, University of Tennessee Health Science Center; Memphis, TN, USA.
  • Barshop Institute for Longevity and Aging Studies, University of Texas Health San Antonio; San Antonio USA.
  • The Jackson Laboratory; Bar Harbor, ME, USA.
  • Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
  • Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, MI 48109, USA.

Abstract

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 an actuarial approach. We started with an initial population of 6,438 pubescent siblings and ended with a survivorship of 559 mice that lived to at least 1100 days. Twenty-nine Vita loci dynamically modulate the mean lifespan of survivorships with strong age- and sex-specific effects. Fourteen have relatively steady effects on mortality while other loci act forcefully only early or late in life and with polarities of effects that invert. A distinct set of 19 Soma loci shape the negative correlation between weights of young adults with their life expectancies-much more strongly so in males than females. Another set of 11 Soma loci shape the positive correlation between weights at older ages with life expectancies. The Vita and Soma loci share 289 age-dependent epistatic interactions (LODs ≥3.8) but fewer than 4% are common to both sexes. We provide two examples of how to move from maps toward potential mechanisms. Our findings provide an empirical bridge between evolutionary theories on aging and genetic and molecular causes. These loci and their interactions are key to begin to understand the impact of interventions that may extend healthy lifespan in mice and even in humans.

MeSH

Mortality, Life Expectancy, Sex Characteristics, Body Weight, Sex, Survivorship, Sex Differences