Genes that modulate aging and lifespan

Scientists led by the University of Tennessee Health Sciences Center (UTHSC) and the École Polytechnique Fédérale de Lausanne (EPFL) in Switzerland are exploring the detailed interaction between genes, sex, growth and age and how they affect variance in longevity. Their findings, which are published in the peer-reviewed journal Sciencesis an important step in understanding why some people live longer than others and provides a basis for future studies to improve lifespan.

Robert Williams, PhD, chair of the Department of Genetics and Genomics at UTHSC School of Medicine, along with Johan Auwerx, MD, PhD, professor, and director of the Systems Physiology and Integration Laboratory at EPFL, began the program in 2016 to identify the genetic factors underlying Aging and age. “Finding common molecular pathways that control differences in the rate of aging is critical to our understanding of how individuals differ in their health and age,” said Dr. Williams. “Thoughts like this may help us find ways to intervene rationally.”

Dr.. Williams and Owerks worked with colleagues at the National Institute for Intervention Testing Program on Aging (ITP), which donated DNA from more than 12,000 mice to the project. ITP mice are genetically heterogeneous. Each of the 27,574 mice studied are a full sibling, share half of their genetic inheritance with each other in the program, and each has a known lifespan, making it an ideal study system.

EPFL and UTHSC researchers measured the genetic makeup of more than 3,000 mice, all of whom are genetically brothers or sisters. The mice were then genotyped and allowed to live to their natural death. The researchers then explored the relationship between DNA differences and differences in the lifespan of each mouse. This genetic mapping allowed the teams to identify stretches of DNA in genomes that influence longevity. The results show that DNA segments, or loci, associated with longevity are largely sex-specific, with a region in female chromosome 3 affecting lifespan. When males who died early from causes unrelated to aging were removed from the analysis, additional genetic signals began to emerge, suggesting that some genetic differences only affect life after a certain age.

In addition to finding the genetic determinants of longevity, the researchers explored other contributors. In general, older mice die. Researchers have found that some, but not all, genetic influences on longevity are through influences on growth. One non-genetic effect may be how early access to food affects development. They note that mice with smaller litters tend to be heavier adults and live shorter lives. Mice from larger births that had to share their mother’s milk with more siblings, grew slower and lived longer, on average. The researchers confirmed these trends in early development versus longevity in large human data sets with hundreds of thousands of participants.

In addition to determining how longevity is affected, the researchers worked to find the genes most likely to play a role in determining longevity. They measured the effect of DNA variation on how genes are expressed and compared their analyzes to multiple human and non-human databases. From this, they filtered out a few genes that likely modulate rates of aging. They then tested the effects of manipulating these genes in nematodes and found that a subset of genetic disorders actually affected life span. The results of this study will be a rich source of aging genes that we hope will guide the design of treatments that not only extend life, but also extend health.

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