A long — and lean — life for mice missing just one gene

By deleting a single gene, researchers at Yale University were able to dramatically reduce fat mass in mice while expanding their lifespan by 20%. The findings also suggest that the damaging inflammation associated with obesity may not be just a byproduct of the condition, but itself may lead to age-related weight gain and decrease longevity.

“It appears that if you reduce inflammation, this may reduce the growth of fat tissues and therefore have a positive impact on longevity,” said Allon Caanan, associate researcher in genetics at Yale and co-lead author of the study.

The research was headed by scientists at Yale and the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University Tufts University, and will be published in the journal Proceedings of the National Academy of Sciences the week of March 24.

Canaan, working in the lab of Yale’s Sherman Weissman, was interested in using mice without the FAT10 gene to study its role in sepsis, a devastating and sometimes fatal inflammatory response to infection. FAT10 belongs to a family of genes that act as recyclers of cellular proteins and was found to be induced by inflammation. Since older mice and humans are more susceptible to sepsis, Canaan left some mice to age. To his surprise, mice lacking the FAT10 gene aged more slowly than normal mice and were 50% leaner.

Yale and Tufts researchers found that mice lacking FAT10 had an elevated metabolic rate, burned fat as fuel, and exhibited reduced glucose and insulin levels.

“The DNA and protein sequences of the FAT10 gene are highly conserved between man and mouse. If it serves the same functions in humans, then this could be a potential target for new therapies,” Canaan said.

The immune system response that produces inflammation is crucial in warding off infections. “Thus it has short-term beneficial effects on survival but for the long term we may pay a price in a sort of evolutionary tradeoff,” Canaan said.

Canaan’s research was funded by the William Prusoff Foundation, and the Tufts group was funded by grants from the National Institutes of Health.

Yale’s Weissman is senior author of the paper, and Canaan is the corresponding author for this publication and a co-lead author with Jason DeFuria of Tufts. Researchers at Stanford and in Israel also contributed to the research.

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