Sci. Aging Knowl. Environ., 4 December 2002
Multiple DNA-wrapping proteins might execute calorie restriction's life-extending effects in fruit flies
Key Words: deacetylation acetylation histone
An enzyme that helps put unused genes in mothballs could bring the mechanics of calorie restriction out of the closet. Reducing food consumption lengthens life in numerous species, but the molecular workings of this phenomenon remain mysterious. According to new research, Rpd3, an enzyme that alters the way DNA and proteins pack together, influences aging in Drosophila melanogaster and possibly provides a tool with which calorie restriction works its life-extending magic.
Tightly wrapping DNA around proteins called histones stores genes not currently in use, and enzymes that remove acetyl groups from histones facilitate this process and influence life-span. One such enzyme, Sir2, prolongs life in yeast and worms (see Kaeberlein Perspective), and another, Rpd3, might cut it short in yeast. Earlier work suggests that calorie restriction delivers its benefits to yeast through Sir2 and Rpd3, so Rogina and colleagues wanted to probe whether these molecules contribute to the dietary regimen's ability to increase fly life-span.
Although previous studies showed that the insects can't survive when Rpd3 is absent, reduced amounts of the protein prolong their life-span, the researchers found. For example, male flies with only one functioning copy of the rpd3 gene made about half as much Rpd3 as normal and gained almost half a lifetime over normal flies. Females, on the other hand, needed more of the protein to stretch their days: Cutting their Rpd3 ration by 50% produced only modest life-span benefits, but when engineered to keep 60% of their usual Rpd3 allotment, they gained as much time as the males did. Although the researchers don't understand the reason for the gender-based discrepancy, it might arise from the energy demands of laying eggs, they speculate. Further observations support that notion: Virgin females lay far fewer eggs and live longer than do females that have mated.
To peek into the relation between Rpd3 and calorie restriction, the researchers diluted the long-lived mutant flies' food. The regimen failed to extend life-span further, suggesting that reducing calorie intake extends life-span by curbing Rpd3 activity. Previous evidence showing that normal flies on the restricted diet decrease Rpd3 production supports this model. The researchers then showed that underfed animals and those with a defective rpd3 gene doubled their production of Sir2, implicating Sir2 for the first time in fly longevity. "It's satisfying to see a hint that the results in yeast are conserved at least up to Drosophila," says geneticist David Sinclair of Harvard Medical School in Boston.
Calorie restriction could slow down manufacture of Rpd3, which somehow spurs Sir2 production, the researchers propose. Molecular biologist Scott Pletcher of University College London says it's "very cool" that these proteins could be involved in calorie restriction. "It's nice to have some more explanation of what's going on here," he says. "It looks quite promising." By controlling how tightly DNA is wound, both Sir2 and Rpd3 affect the production of other proteins, which might in turn step up or rein in still other proteins. Understanding which genes Rpd3 and Sir2 control could give scientists a way to put aging away for a while.
B. Rogina, S. L. Helfand, S. Frankel, Longevity regulation by Drosophila Rpd3 deacetylase and caloric restriction. Science 298, 1745 (2002). [Full Text]
December 4, 2002 Citation: C. Seydel, Domino Effect. Science's SAGE KE (4 December 2002), http://sageke.sciencemag.org/cgi/content/full/sageke;2002/48/nw162
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