Clues to human longevity found in large-scale mouse genetic study

Our lifespan or, more importantly, our “lifespan”, as discussed during GEN recent summit The State of Biotech, is a complex quantitative parameter influenced by our genes, our cells, our physiology and our environment. Knowing the genes that affect longevity is an important step that could inform the development of treatments, the practice of precision medicine, and potentially extend the span of human health. However, identifying the genetic determinants of longevity has been difficult due to the lack of integrated approaches that take advantage of multiple data sources related to complex traits.

A new collaborative study published in the journal Science, have identified genes that influence longevity in a sex- and age-specific way. The study findings pave the way for hypothesis-driven studies of therapies for aging and age-related diseases.

Maroun Bou Sleiman, PhD, scientist at the Integrative Systems Physiology Laboratory at EPFL, Switzerland, and Suheeta Roy, PhD, assistant professor at the University of Tennessee Health Science Center (UTHSC), are co-lead authors of the study. , while Robert Williams, PhD, professor of genetics, genomics and computer science at UTHSC and Johan Auwerx, PhD, professor of integrative systems physiology at EPFL are co-lead authors of the study.

(Left to right) Maroun Bou Sleiman, PhD, Suheeta Roy, PhD, Robert Williams, PhD, and Johan Auwerx, PhD.

“This is the largest study of the genetics of normal lifespan variation in a single large family of mice called UM-HET3 (over 3000 offspring),” Williams said. “We discovered a small number of chromosomal regions that modulate lifespan early and late in life. We then developed general resources for those interested in specific genes that may modulate differences in lifespan by both sex and age.

The large-scale, multicenter study analyzed DNA variants in 3,276 UM-HET3 mice, a genetically diverse mouse model used in aging intervention studies such as the National Institute on Aging’s Intervention Testing Program. (NIA ITP).

In a Perspective article published in the same issue of the journal, João Pedro de Magalhães, PhD, professor of molecular biogerontology at the University of Birmingham, noted that although previous studies have identified more than 2000 genes linked to longevity in model organisms,” an underestimated limitation of these studies is that they are primarily conducted in inbred and genetically homogeneous animal populations. This means that findings in the genetics of aging, as well as dietary and pharmacological manipulations, can be strain-specific as there could be genetic background effects.The use of M-HET3 mice in the present study overcomes this limitation.

The researchers analyzed changes in liver gene expression with age and genotype, in mice of the same genetic cross to identify genetic loci for further investigation.

“We asked whether the genetic basis of longevity was sex and age dependent, and whether non-genetic factors such as litter size and the effect of early nutrient access on growth contributed to longevity. determination of longevity,” the authors noted.

When the researchers analyzed male and female genetic datasets together, they identified a region of chromosome 12 linked to longevity that had been previously reported. However, when they analyzed the male and female datasets separately, they found a single locus on chromosome 3 linked to longevity in females. Longevity loci in male mice could only be detected when early deaths were removed from the dataset. This indicated that in men, certain genetic determinants only affected longevity beyond a certain age.

The researchers also found that access to nutrients early in life affected growth and was therefore associated with body weight, litter size and longevity. Using Mendelian randomization, scientists summarized the links between early development, adult weight, and longevity in humans.

By comparing gene expression in the liver, the authors found higher interferon-related gene expression in female mice and higher immunity-related gene expression in aged mice. They then combined their mouse results with data from other model organisms and humans to compile a prioritized list based on gene scores related to longevity.

Finally, the authors validated five high-scoring conserved longevity genes by conducting microscopic worm lifespan experiments. Caenorhabditis elegans which normally lives for about three weeks. These include the protein kinases Hipk1 and Pdk1, a gycosyltransferase, Ddost, a heparan sulfate proteoglycan, Hspg2, and a zinc finger protein linked to vascular disease, Fgd6.

“We discovered a handful of loci in this study and many high-priority candidate genes for downstream analyses,” Williams said. “But by increasing the sample size five times, we would be able to detect around 10 to 20 times more loci and many of those loci would be mapped with much higher positional accuracy. This would improve the efficiency of subsequent analyzes of the mechanisms that modulate lifespan and longevity.

“Because longevity is a complex and multifactorial phenotype, it will also be important to elucidate in the future which processes and diseases are affected by genetic variants associated with longevity,” noted de Magalhães.

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