Sci. Aging Knowl. Environ., 14 April 2004
Puzzling Out the Pieces
Dieting and dwarfism work together and separately at the molecular level to boost longevity
Solving a particular jigsaw puzzle from a mound of pieces poses a challenge, especially when the pieces are from multiple puzzles. Scientists face a similar hurdle when fitting together the mechanisms of two well-studied life-extending methods, given the huge number of molecules in an organism. Using gene-chip technology, they have now pulled out some probable key components. The work supports the notion that two life-extension pathways harness some of the same molecules, and it also focuses researchers on specific genes that participate in these pathways.
Certain hormone-deficient dwarf mice live unusually long (see Bartke Perspective). Genetically normal mice, too, can postpone death--if they cut calories (see Masoro Review). Dwarves and dieters share a physiological signature: They usually have lower blood concentrations of glucose and insulin than do control rodents, and their cells take up glucose more readily when prodded by insulin. These observations suggested that dwarfism and calorie restriction slow aging through similar biochemical pathways. That hypothesis suffered a blow in 2001 when researchers showed that hungry dwarves lived even longer than did animals that were either dwarves or calorie-restricted (see "Dieting Dwarves Live It Up"). This result supports the idea that some of the mechanisms that prolong youth in the two groups of animals can act additively, but the molecular basis for this effect remained unclear and the work did not resolve whether the two pathways also share some components.
To probe these issues, biochemist Stephen Spindler of the University of California, Riverside, and colleagues tracked gene activity in the livers of dwarf and normal siblings that ate without restriction, as well as dwarf and normal siblings that consumed low-calorie fare. They analyzed 12,000 genes, representing about a third of the genome. Activities of 212 or 77 genes changed only in dwarves or dieters, respectively; those of another 95 genes were influenced by both conditions. All three sets included genes involved in physiological pathways that are already linked to life-span regulation, such as cell death, stress defense, and metabolism of glucose, insulin, and lipids. Few obvious trends emerged from the analysis, although, for example, the activity of genes that drive lipid transport and cell proliferation dropped only in the dwarves. These findings provide evidence that dwarfism and dieting boost longevity in both similar and unique ways, says Spindler.
"The study is statistically well done, with good experimental design and results that make biological sense," says Kevin Becker, a molecular biologist at the National Institute on Aging in Baltimore, Maryland. He praises, in particular, the use of large sample sizes and the validation of gene activity changes using other methods, adding that the strength of the study lends confidence to the findings. As a result, they provide "a concrete, believable listing of candidate genes" that should help explain how calorie restriction and the dwarf mutation extend life. These pieces will likely help clarify the emerging picture of aging.
April 14, 2004
Suggested by James M. Harper.
Science of Aging Knowledge Environment. ISSN 1539-6150