Researchers at EPFL and UTHSC are studying the interaction between genes, gender, growth and age

Researchers at EPFL and UTHSC are studying the interaction between genes, gender, growth and age

Scientists led by the University of Tennessee Health Science Center (UTHSC) and the École Polytechnique Fédérale de Lausanne (EPFL) in Switzerland explore the complex interplay of genes, gender, growth and age and how they influence variation in longevity. Their findings, published in the journal Science, are an important step toward 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 the College of Medicine at UTHSC, along with Johan Auwerx, MD, PhD, professor and director of the Integrated Physiology and Systems Physiology Laboratory at EPFL, launched a program in 2016 to define the genetic factors underlying aging and lifespan.

Finding common molecular pathways that control differences in the rate of aging is crucial to our understanding of how individuals differ in their health and lifespan. Such insights can help us find ways to intervene rationally.”

Robert Williams, PhD, chair of the Department of Genetics and Genomics in the College of Medicine at UTHSC

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

Researchers at EPFL and UTHSC 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 examined the connection between DNA differences and differences in the lifespan of each mouse. This genetic mapping allowed teams to define stretches of DNA in genomes that impact longevity. The results show that the DNA segments, or loci, associated with longevity are largely sex-specific, with women having a region in chromosome 3 that influences lifespan. When the men who died early for non-age-related reasons were removed from the analysis, additional genetic signals emerged, suggesting that some genetic variations only affect lifespan after a certain age.

In addition to looking for genetic determinants of longevity, researchers also examined other factors. In general, larger mice die sooner. The researchers found that some, but not all, genetic effects on longevity are due to growth. One of the non-genetic effects could be how early access to food affects growth. They observed that mice from smaller litters tended to be heavier adults and have shorter lifespans. Mice from larger litters that had to share breast milk with more siblings grew more slowly and lived longer on average. The researchers confirmed these trends between early growth and longevity in large human datasets with hundreds of thousands of participants.

Beyond characterizing the effects on longevity, researchers worked to find genes most likely to play a role in determining longevity. They measured the impact of DNA variation on the expression of genes and compared their analyzes to several human and non-human databases. They then nominated some genes that likely modulate aging rates. They then tested the effects of manipulating these genes in roundworms and found that a subset of gene disorders actually affected lifespan. The results of this study will be a rich resource of aging genes that will hopefully guide the development of therapies that not only extend lifespan but also health.

The project was funded by the NIA, EPFL, the European Research Council, the Swiss National Science Foundation and the Glenn Foundation for Medical Research. The article, titled “Sex- and age-dependent genetics of longevity in a heterogeneous mouse population,” appears in the October 2022 issue of Science.

Source:

University of Tennessee Health Sciences Center

Reference:

Sleiman, MB, et al. (2022) Sex- and age-dependent genetics of longevity in a heterogeneous mouse population. Science. doi.org/10.1126/science.abo3191.

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