EPFL and UTHSC researchers explore the interplay between genes, sex, growth, and age

Scientists led by the University of Tennessee Health Science Center (UTHSC) and the École Polytechnique Fédérale de Lausanne (EPFL) in Switzerland are exploring the elaborate interplay between genes, sex, growth, and age and how they influence variation in longevity. Their findings, which are being published in the peer-reviewed journal Science, are an important step in understanding why some people live longer than others and provide a basis for future studies to improve healthspan.

Robert Williams, PhD, chair of the Department of Genetics and Genomics in UTHSC's College of Medicine, along with Johan Auwerx, MD, PhD, professor and director of the Laboratory for Integrated and Systems Physiology at EPFL, started a program in 2016 to define genetic factors underlying aging and lifespan.

Finding common molecular pathways that control differences in rate of aging is critical to our understanding of how individuals differ in their health and lifespan. Such insights may help us work out ways to intervene rationally."

Robert Williams, PhD, Chair of the Department of Genetics and Genomics in UTHSC's College of Medicine

Drs. Williams and Auwerx worked with colleagues at the National Institute on Aging's Interventions Testing Program (ITP), which donated DNA of over 12,000 mice to the project. ITP mice are genetically heterogeneous. Each of the 27,574 mice studied is a full sibling, sharing half its genetic inheritance with each other mouse in the program, and each has a known lifespan, making them an ideal system to study.

EPFL and UTHSC researchers measured the genetic makeup of more than 3,000 mice, all of them genetic brothers or sisters. The mice were then genotyped and allowed to live until their natural death. The researchers then explored the relationship between DNA difference and differences in the lifespan of each mouse. This genetic mapping allowed the teams to define stretches of DNA in genomes that affect longevity. The results show the DNA segments, or loci, associated with longevity are largely specific to sex, with females having a region in chromosome 3 that affects lifespan. When the males who died early due to non-aging-related reasons were removed from the analysis, additional genetic signals started to emerge, suggesting some genetic variations only affect lifespan after a certain age.

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In addition to finding genetic determinants of longevity, the researchers explored other contributors. In general, bigger mice die younger. The researchers found that some, but not all, of the genetic effects on longevity are through effects on growth. One of the non-genetic effects may be how early access to food affects growth. They observed that mice from smaller litters tended to be heavier adults and live shorter lives. Mice from larger litters that had to share their mother's milk with more siblings, grew more slowly and lived longer on average. The researchers corroborated these trends of early growth versus longevity in large human datasets with hundreds of thousands of participants.

Beyond characterizing how longevity is affected, the researchers worked to find genes most likely to play a role in longevity determination. They measured the effect of DNA variation on how genes are expressed and compared their analyses with multiple human and non-human databases. From this they nominated a few genes likely to modulate aging rates. They then tested the effects of manipulating these genes in roundworms and found that a subset of gene perturbations did in fact affect the lifespan. The results of this study will be a rich resource of aging genes that will hopefully guide the design of therapies that not only extend lifespan, but also healthspan.

Funding for the project was provided by the NIA, EPFL, the European Research Council, the Swiss National Science Foundation, and the Glenn Foundation for Medical Research. The paper, titled "Sex- and age-dependent genetics of longevity in a heterogeneous mouse population," is in the October 2022 issue of Science.