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For decades, scientists have wrestled with the question: To what extent do genetics determine lifespan? Researchers now say that, thanks to research published today (September 29) in Science, they have evidence that genes directly control how long mice live—and that these genes have human orthologs. But female mice, which live longer than males, have different genes associated with longer life spans than male mice.

Study coauthor Robert Williams, a geneticist at the University of Tennessee, says that the study addresses the question of whether “there are actually genes that control longevity,” as opposed to exerting an indirect effect by lessening disease risk. Based on the results, he says he and his fellow investigators “think there are fundamental events controlling generic aging, rather than just disease.”

Williams and his colleagues used a dataset initially gathered in 2003 for the Interventions Testing Program (ITP), a research program to determine whether certain dietary interventions could increase lifespan in mice. The project raised 3,000 genetically diverse animals raised in tightly-controlled, homogenous conditions and collected tissue from them—an ideal dataset for isolating the effects of genetics on outcomes. The mice were bred to “mimic the genetic diversity seen in human populations,” explains Williams. In many studies on the heritability of longevity, mice have been highly inbred, he explains. 

The ITP didn’t analyze the DNA from these animals, but now the authors of the new study have. The team performed quantitative trait locus mapping, which “associates phenotype and genotype,” explains coauthor Maroun Bou Sleiman, a geneticist at the Swiss Federal Institute of Technology in Lausanne, on more than 3,000 ITP mice to determine which regions of the genome were associated with longer life.

Looking across all the mice, the researchers pinpointed several genetic loci associated with longevity. They also linked several loci to longevity in female mice, but initially found none that were male-specific. However, when they took out data from male mice that died early in life, they turned up genes associated with longevity in male mice that were distinct from those in the female mice. 

 “It just shows you that sex is an important thing to consider in these studies,” says Sleiman. 

The researchers also analyzed body weight and litter size data, finding that mice with higher body weights early in life and smaller litter sizes died younger. They conclude that genes that control body weight and litter size might be acting on lifespan through these other traits instead of on lifespan directly. But only some longevity genes correlated with body weight and litter size, indicating that other genes might directly influence aging. 

The researchers went on to search for similar genes in other species, including humans. In human genome biobanks, they found genes with similar sequences to the identified mouse genes. Humans also had similar relationships between early growth and longevity. Finally, the researchers knocked out genes they’d found to be associated with longevity in both mice and humans in worms (Caenabordis elegans), which allowed them to ask the question if the genes were indeed necessary for longer life. They found that some such genes (for which versions exist across all three species) influenced longevity in C. elegans. 

The researchers stress that the dataset they’ve generated for mice is just a starting point, one that they hope will be a valuable resource for other scientists in identifying, characterizing, and studying genes related to lifespan, with the goal of determining which genes are important for longevity and what molecular pathways they act on.  

Caleb Finch, a researcher at the University of Southern California who did not participate in the study, says that the paper “is an important piece of work.” He adds the caveat that in humans, heritability of lifespan may be low—“some studies put it as low as ten percent”—and other things, like “socioeconomic status, for example, have a huge influence” on lifespan. He says he hopes that the authors will continue to pinpoint genes that drive longevity, and perhaps study how epigenetics factors into it. “There’s a lot [of] further steps they can take now,” he says.