Different genes affect the lifespan of male and female mice

FOr decades, scientists have wrestled with the question: To what extent do genes determine age? Now researchers say, thanks to research published today (September 29) in Sciences, they have evidence that genes directly control how long mice live — and that those genes have orthologues. But female mice, which live longer than males, have different genes linked to a longer lifespan than male mice.

Co-author of the study Robert WilliamsThe study addresses the question of whether “there are genes that control longevity,” says the University of Tennessee geneticist, rather than exerting an indirect effect by reducing disease risk. Based on the findings, he said he and fellow researchers “believe that there are fundamental events that control general aging, not just disease.”

Williams and colleagues used a data set initially collected in 2003 for the Intervention Testing Program (ITP), a research program to determine whether certain dietary interventions can extend the lifespan of mice. The project bred 3,000 genetically diverse animals raised in homogeneous, strictly controlled conditions and from which tissues were collected – an ideal dataset for isolating the effects of genetics on outcomes. Williams explains that mice have been bred “to mimic the genetic diversity seen in human populations”. In several studies on the genetics of longevity, rats were significantly outbred, he explains.

ITP has not analyzed DNA from these animals, but now the authors of the new study have. The team performed quantitative mapping of trait loci, which “links phenotype and genotype,” explains co-author Maroun Bou Sleimana geneticist at the Swiss Federal Institute of Technology in Lausanne, analyzed more than 3,000 ITP mice to identify regions of the genome associated with longer lives.

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 to be specific to males. However, when they took data from male mice that died early in life, they discovered genes associated with longevity in male mice that were different from those in female mice.

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

The researchers also analyzed body weight and litter size data, and found that mice with higher body weights early in life and smaller litter sizes died younger. They concluded that the genes that control body weight and litter size may act over lifespan through these other traits rather than life span directly. But only some of the longevity genes are associated with body weight and litter size, suggesting that other genes may directly influence aging.

Researchers have continued to search for similar genes in other species, including humans. In biobanks of the human genome, they found genes with similar sequences to those of the mice identified. Humans also had similar relationships between early growth and longevity. Finally, the researchers excluded the genes they found to be associated with longevity in both mice and humans in the worms (Caenabordis elegans), allowing them to ask the question whether genes are really necessary for a longer life. They found that some of these genes (which have copies in all three species) affected longevity C. elegans.

The researchers stress that the data set they have created for mice is just a starting point, which they hope will be a valuable resource for other scientists in identifying, characterizing and studying longevity-related genes, with the goal of determining which genes are important for longevity and what molecular pathways they act on.

Caleb FinchD., a researcher at the University of Southern California who was not involved in the study, says the paper is an “important piece of work.” He adds the caveat that the heritability of lifespan may be low in humans – “some studies put it as low as ten percent” – and other things, such as “socioeconomic status, for example, have a significant impact” on lifespan. He says he hopes the authors will continue to identify the genes that lead to longevity, and perhaps study how epigenetics influence this. “There is a lot [of] They can now take more steps.”

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