Scientists have discovered a surprising link in the trade-off between reproducing and aging -- fat metabolism. A fat-burning enzyme in Caenorhabditis elegans is activated after germline stem cells stop proliferating, leading to leaner and longer-lived worms, according to research published today (Nov. 6th) in Science.

"It has been known for a long time that there is a positive correlation between lifespan and caloric restriction, [but] how fat storage, lifespan, and reproduction are intertwined remains quite mysterious," Kaveh Ashrafi, a molecular physiologist at the University of California, San Francisco, who was not involved in the research, said in an E-mail. This study "starts unraveling the complex molecular mechanisms that link stem cells in the reproductive system to fat regulation and lifespan determination."

Molecular geneticist Gary Ruvkun and his colleagues at the Massachusetts General Hospital in Boston first stumbled upon their findings by accident. The worm's gonad divides much more frequently than its somatic tissue does, so germline stem cells require a large amount of energy. Thus, in the absence of reproduction, Ruvkun expected that worms would burn less fat and plump up.

Yet when Ruvkun's team knocked out the germline -- either by laser ablation or in sterile mutants -- they found that worms stored around 50% as much fat as wild-type or untreated animals. Conversely, mutant worms with overactive germlines showed a 70% increase in fat storage. Further, blocking germline profileration resulted in worms living significantly longer.

"You can put fat into the embryo, or you can put it in yourself," said Ruvkun. "We're getting at the switches and endocrine signals that control the decision on what kind of metabolism to have."

"This sort of twists everything upside-down, because it says if you arrest the germline, the worms are thinner instead of fatter," Heidi Tissenbaum, a molecular geneticist at the University of Massachusetts Medical School in Worcester, who did not participate in the research, told The Scientist. "And they show that's an actual physiological process."

To sleuth out how germline stem cells regulate fat storage and longevity, Ruvkun's team screened 163 metabolic genes using RNA interference. They turned up a single triglyceride lipase, K04A8.5, that, when eliminated in germline-depleted mutant worms, increased fat storage and suppressed the enhanced longevity. When the lipase was overexpressed in the intestine, however, worms lived 24% longer. Ruvkun's team concluded that germline stem cells regulate the activity of K04A8.5 to mediate both lipid hydrolysis and longevity.

"It was surprising that one lipase was going to do it all," said Ruvkun. "I would have thought there's a huge gene repertoire that's responding to [germline proliferation]." Still, he thinks that they've only scratched the surface of the genetic pathway involved, and there are probably many other transcription factors and co-factors involved. Ting Xie, a developmental biologist at the Stowers Institute in Kansas City, who wrote the accompanying review article in Science, agrees. "This may be the major regulator, but I don't think it's that simple," he said.