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Knocking Out Germline Stem Cells in Worms Turns Up Fat Metabolism, Longevity

It makes evolutionary sense for reproduction to be tied to longevity, but the question has always been how. HMS researchers have found what could be the missing link: fat metabolism.

The lab of Gary Ruvkun, HMS professor of genetics at Massachusetts General Hospital, found that germline stem cells in the worm inhibit a fat-burning enzyme inside of intestinal cells. Worms lacking germline cells store less fat and also live significantly longer than normal worms. The study, published in the Nov. 7 issue of Science, suggests that fat metabolism may be a key go-between in an intercellular dialog that modulates reproduction and longevity.

Ruvkun and first author, research fellow Meng Wang, began this study by ablating germline stem cells in worms, making it impossible for them to produce eggs. They expected to see a marked increase in fat storage. “Think of the chicken egg and how fat that yolk is,” said Ruvkun. It stands to reason that an animal that is not making eggs might have extra fat to put into storage.

But that is not what Ruvkun and Wang observed. The treated worms stored half as much fat as controls. Further experiments showed that these lean worms had no significant change in appetite. The evidence suggests that germline cells influence the kind of metabolism that goes on inside the worms, said Ruvkun.

To tease this information out of the intestinal cells, which store fat in the worm, the researchers used RNA interference to knock down the activity of 163 metabolic genes. The inactivation of one gene, K04A8.5, increased fat storage in mutant worms lacking germline cells. This gene encodes a fat-burning lipase that is normally inhibited by signals from germline cells. Though it is not yet clear what signals the germline cells send, without them, the intestinal cells unleash the lipase and burn up the fat.

The researchers then linked fat metabolism to aging in the worm by observing that worms engineered to always produce this lipase lived 24 percent longer than control animals. Using RNA interference again, they found that the lipase is activated through an insulin-signaling pathway that is known to be connected with longevity. This pathway is also highly conserved from the worm to the human.

This study contains “major novel findings and very exciting links to the emerging appreciation of the role of adipose tissue in the control of aging in mammals,” said Andrzej Bartke, professor of physiology at Southern Illinois University School of Medicine. He and Ruvkun agree, however, that more work is needed to determine if these findings have direct parallels in mammals.

Students may contact Gary Ruvkun at ruvkun@molbio.mgh.harvard.edu for more information on this and other lab projects.

Conflict Disclosure: The authors declare no conflicts.

Sources of Funding: The Life Sciences Research Foundation, Ellison Medical Foundation, and Human Frontier Science Program fellowships and the National Institutes of Health.