Our lifespan or more importantly our “health span,” as discussed during GEN’s recent The State of Biotech summit, is a complex quantitative parameter influenced by our genes, cells, physiology, and 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 human health span. However, it has been challenging to identify genetic determinants of longevity due to the lack of integrated approaches that leverage multiple lines of evidence linked to complex traits.

A new collaborative study published in the journal Science, identified genes that influence longevity in a sex- and age-specific manner. The insights from the study open doors for hypothesis-driven studies on therapies for aging and age-related diseases.

Maroun Bou Sleiman, PhD, a scientist at the laboratory of integrative systems physiology at EPFL, Switzerland, and Suheeta Roy, PhD, an 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 informatics at UTHSC and Johan Auwerx, PhD, professor of integrative systems physiology at EPFL are co-senior 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 variation of lifespan in a single huge mouse family called the UM-HET3 (more than 3000 progeny),” said Williams. “We discovered a small number of chromosomal regions that modulate lifespan both early and late in life. We then developed general resources for those interested in specific genes that may modulate differences in lifespan both as a function of sex and age.”

The large-scale, multicenter study analyzed DNA variants in 3276 UM-HET3 mice—a genetically diverse mouse model used in aging intervention studies such as the National Institute on Aging’s Interventions Testing Program (NIA ITP).

In a Perspective article published in the same issue of the journal, João Pedro de Magalhães, PhD, a professor of molecular biogerontology at the University of Birmingham noted that although earlier studies have identified over 2000 longevity-linked genes in model organisms, “One underappreciated limitation of such studies is that they are mostly conducted in inbred, genetically homoge­neous animal populations. This means that discoveries in the genetics of aging, as well as dietary and pharmacological manipula­tions, may be strain-specific because there could be genetic background effects.” The use of M-HET3 mice in the current study overcomes this limitation.

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

“We interrogated whether the genetic basis of longevity is sex- and age-dependent, and whether nongenetic factors such as litter size and the effect of early access to nutrients on growth contribute to longevity determination,” the authors noted.

When the researchers analyzed male and female genetic datasets jointly, they identified a region of chromosome 12 linked to longevity that was 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 be detected only when early deaths were eliminated from the dataset. This indicated that in males, some genetic determinants affected longevity only beyond a certain age.

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

Comparing gene expression in the liver, the authors found higher interferon-related gene expression in female mice, and higher immune-related gene expressions in old mice. They then combined their mouse results with data from other model organisms and humans to compile a score-based prioritized list of genes linked to longevity.

Finally, the authors validated five high-scoring, conserved longevity genes by conducting life-span experiments in the microscopic worm 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 have uncovered a handful of loci in this study and many candidate genes that are high priority for downstream analyses,” said Williams. “But by expanding the sample size five times, we would be able to detect roughly 10 to 20 times as many loci and many of these loci would be mapped with much higher positional precision. This would improve the efficiency of subsequent analyses of mechanisms that modulate lifespan and longevity.”

“Because longevity is a complex, 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.