Common Ingredients
Authors: Beckman Mary 
Published: August 2003

Like an inquisitive baker trying to determine what makes rye and sourdough bread rise the same despite their distinctive flavors, scientists have been looking for the molecular mechanisms common to different manipulations that extend life. Now, a team of researchers has found almost 30 genes that might contribute to two life lengtheners in mice: restricted diet and disrupted hormone signaling. The finding suggests that shared themes might underlie disparate methods of attaining long life.

Mice that eat one-third fewer calories than their indulgent compatriots live about one-third longer. Researchers don't understand how trimming the edibles increases life-span, but they do know that cutting calories reduces concentrations of metabolism-regulating molecules such as IGF-1 and growth hormone. Some genetic alterations that prolong life, such as those in
Snell
and
Ames
dwarf mice, also curtail these hormones. The genetic and dietary manipulations don't work exactly the same way, however. A previous study showed that calorie restriction adds additional months to the lives of Ames mice, suggesting that the strategies operate through independent biochemical means (see
"Dieting Dwarves Live It Up"
). To find out what the two life-enhancers do have in common, biogerontologist Richard Miller of the University of Michigan, Ann Arbor, and colleagues looked for genes that are turned off and on in mice subjected to different life-extending methods.

Miller's team chopped up livers from normal 9-month-old mice that had been on a restricted diet. Using a microarray that contains probes for 2352 mouse genes, the researchers analyzed the samples and looked for genes that cranked out more or less messenger RNA than they did in livers from mice that had stuffed their whiskers. The scientists performed two statistical corrections to guard against fluke results; 352 genes made the cut. They then compared those genes to 72 genes altered by the Snell mutation in dwarf mice, using data from a previous study. They found 29 genes whose production was either pumped up or squelched in both calorie-restricted and Snell mice. The genes ran the gamut from relative unknowns to producers of protein-synthesizing machinery, but none is known to speed up or slow down the aging process.

Additional tests might determine how--or if--each of the genes contributes to long life, says Miller, who predicts that "some will turn out to be important to aging, some not." According to evolutionary geneticist Marc Tatar of Brown University in Providence, Rhode Island, this study is a "learning experience" in how to apply "rigorous" statistics to gene expression array data. In addition, biochemist Stephen Spindler of the University of California, Riverside, says defining the mechanisms that drive different life-extending pathways will help us understand normal aging. "This is the beginning of a very important molecular analysis of life-span extension by dwarf mice," he says. Researchers hope such work will eventually lead them to the core set of genes that control aging, like a baker who learns the secrets of the basic dough.

--Mary Beckman

R. A. Miller, Y. Chang, A. T. Galecki, K. Al-Regaiey, J. J. Kopchick, A. Bartke, Gene expression patterns in calorically restricted mice: Partial overlap with long-lived mutant mice.
Mol. Endocrinol.,
22 August 2002 [e-pub ahead of print].
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