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Longevity Genetics Influenced by Age, Sex in Mouse Study

NEW YORK – Findings from a mouse model study appearing in Science on Thursday suggest that the genetics of longevity are influenced by both biological sex and age — a pattern that was explored further in humans.

"We identified common age- and sex-specific genetic effects on gene expression that we integrated with model organism and human data to create a hypothesis-building interactive resource of prioritized longevity and body weight genes," co-senior authors Johan Auwerx, an integrative systems physiology researcher at the Swiss Federal Institute of Technology Lausanne, and Robert Williams, a genetics, genomics, and informatics researcher at the University of Tennessee Health Science Center, and their colleagues wrote.

In an effort to tease out genetic and nongenetic contributors to longevity, along with factors that may mediate their effects, the researchers considered data for nearly 3,000 genetically heterogeneous mice. The animals, which stemmed from four-way mouse strain crosses done for a National Institute on Aging effort called the Interventions Testing Program (ITP), included multiple mice from the same crossing events, they explained, making it possible to dig into the moderating effects of age, sex, growth, litter size, and other factors.

In a combined genetic analysis of male and female mice, for example, the team tracked down a longevity-associated expression quantitative locus (eQTL) on chromosome 12 that had been reported previously. But a sex-specific analysis also uncovered a chromosome 3 eQTL linked to longevity in female mice alone, while other loci appeared to impact male mouse longevity only after weeding out deaths that occurred early on in males.

The researchers found that male and female mice had comparable mortality rates toward the end of the mouse lifespan, although male mice appeared prone to early mortality, lending a longer median lifespan to their female counterparts. Likewise, mouse lifespan showed apparent ties to body weight and early growth patterns, which in part reflected litter size.

By sequencing RNA in nearly three dozen liver tissue samples from young and old male and female mice, the team detected enhanced expression of infection severity-related interferon genes in the female mice, along with an increase in immune gene expression in the aged, 22-month-old mice compared to younger adult mice sampled at six months of age.

When they turned to Mendelian randomization to further explore such patterns in humans, meanwhile, the investigators not only saw potential ties between early growth and longevity but also uncovered longevity-linked eQTL differences that appeared to depend on age and sex.

The team further linked at least five of the candidate genes to longevity by using RNA interference approaches to systematically knock down the genes in lifespan experiments done in the model worm Caenorhabditis elegans.

The investigators combined data from the study with published insights from prior longevity studies done in humans or model organisms to come up with an interactive resource focused on candidate genes that appear to be conserved across different animals, though they noted that additional research will likely uncover still more contributors to aging and longevity.

"Future studies that include more ITP mice as well as denser genetic maps may yield improved QTL results," the authors suggested, noting that "more longitudinal data collection accompanied by extensive phenotyping would be required to shift the focus from longevity to a better understanding of genetics of healthy aging or health span."

In a corresponding perspectives article in Science, University of Birmingham genomics of aging and rejuvenation researcher João Pedro de Magalhães reviewed findings from the study and suggested that the newly generated data "will prove a valuable resource for the study of aging and longevity."

"Because longevity is a complex, multifactorial phenotype," he added, "it will also be important to elucidate in the future which processes and diseases are affected by genetic variants associated with longevity."

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