Sci. Aging Knowl. Environ., 27 July 2005
Vol. 2005, Issue 30, p. nf59
[DOI: 10.1126/sageke.2005.30.nf59]


Fat-Free Longevity

Mutation spurs fat accumulation and longevity through separate paths

R. John Davenport

Living long and slimming down figure prominently on many people's wish lists, and new results bolster hope for achieving both. Worms without a particular gene retain fat and cheat death, but different molecular pathways control the two outcomes. The study helps flesh out connections between fat and longevity.

Obesity promotes diabetes and stresses the heart, yet storing fat doesn't always kill. For example, worms with flaws in daf-2, a component of an insulin-like signaling pathway, stockpile fat and live long. To probe the connection between life span and fat, molecular geneticist Heidi Tissenbaum and colleagues at the University of Massachusetts Medical Center in Worcester investigated a gene called tubby. Defects in tubby cause obesity in humans; mice and worms without the gene also retain fat. The TUBBY protein is made in neurons, suggesting that it performs some important function in these cells, which control metabolism and feeding. Tissenbaum's group tested whether tubby deficits stretch worm life span.

Worms without their version of tubby, tub-1, lived about 20% longer than normal. Worms with daf-2 glitches persist and horde fat only if they carry intact versions of the DAF-16 protein. The researchers found that tub-1 and daf-2 likely act in the same pathway, so they wanted to find out whether DAF-16 is required for tub-1's functions. Animals with mutations in tub-1 and daf-16 died sooner than did those missing only tub-1. The creatures stored fat, however, suggesting that worms without TUB-1 need DAF-16 for extended longevity but not for fat accumulation.

To understand more about how TUB-1 works, the researchers sought proteins that grab it. One, named RBG-3, resembles molecules that help shuttle small membrane bubbles called vesicles within cells; these compartments transport molecules. Further experiments revealed that TUB-1 and RBG-3 appear in the same types of neurons, supporting the notion that they collaborate. Hampering production of RBG-3 kept worms with tub-1 defects from storing fat but did not shorten their life span. Together, the results suggest that TUB-1 influences life span through DAF-16 and fat metabolism through RBG-3. In addition, the team found that TUB-1 moves along the lengths of neurons, as vesicles do, supporting the connection to cellular transport.

"It's the first [study] that implicates tubby ... in life span," says molecular biologist Anne Brunet of Stanford University in Palo Alto, California. The work shows that different pathways control longevity and fat storage, suggesting that people might be able to manipulate TUBBY's workings to prolong life without adding girth, she adds. However, questions remain about TUBBY's machinations, says structural biologist Lawrence Shapiro of Columbia University in New York City. Researchers have observed TUBBY in the nucleus of mammalian cells, but the current findings reveal that TUB-1 lurks in the cytoplasm of worm cells. The protein seems to "behave in fundamentally different ways" in mammals and nematodes, he says. Next, investigators should probe whether mice without tubby also live long, says Shapiro. In addition, researchers need to test whether tubby directly influences metabolism or whether it enhances the health of neurons that serve that purpose, says Shapiro. Such efforts should clarify how life span can swell without an expanding waistline.

July 27, 2005
  1. A. Mukhopadhyay, B. Deplancke, A. J. M. Walhout, H. A. Tissenbaum, C. elegans tubby regulates life span and fat storage by two independent mechanisms. Cell Metab. 2, 35-42 (2005). doi:10.1016/j.cmet.2005.06.004 [CrossRef][Medline]
Citation: R. J. Davenport, Fat-Free Longevity. Sci. Aging Knowl. Environ. 2005 (30), nf59 (2005).

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