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Yeast Yield Secret of Aging

8 May 2003 (All day)
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Yellowing with age. A single protein, Pnc1, appears to tie food restriction and stressors into a single life-extension pathway in yeast.

Many techniques can bestow Methuselah-like life spans on yeast and other lab creatures: heating their environments, tinkering with their genes, or restricting their food, for example. New work suggests that, at least in yeast, a single enzyme could explain how diverse stimuli stall aging. No one knows whether the findings will extend to other creatures, but they support a theory of aging that has been proposed for mammals: Stress makes them endure.

Some yeast show their age by becoming infertile, and researchers commonly measure life span by counting how many times a new Saccharomyces cerevisiae cell can bud to create daughter cells. Giving yeast less glucose makes them more fertile; this treatment is used as a model of calorie restriction, which enhances longevity in many animals.

A necessary part of this pathway is an enzyme called Sir2: Without it, hungry yeast have normal life spans. Moreover, adding extra copies of the gene for Sir2 promotes longevity in yeast and worms. Sir2 helps DNA pack more tightly. This tightening prevents DNA from reshuffling, which normally ages yeast.

Three years ago, researchers found that Sir2 requires a small molecule called NAD to perform its duties. This observation raised the possibility that NAD slows aging in yeast. To test this idea, David Sinclair of Harvard Medical School in Boston and colleagues added NAD precursors to yeast. To their surprise, they found that a compound called nicotinamide--which cells transform into NAD--prevented the tight packing of DNA rather than encouraging it, and shortened life span. Even miniscule concentrations did the trick; Sir2's activity had apparently "evolved to be very sensitive to nicotinamide levels," says Sinclair.

To test whether lowering nicotinamide quantities lengthen life, the researchers engineered yeast to overproduce an enzyme called Pnc1 that breaks down nicotinamide. This manipulation dramatically slowed aging. Pnc1 is also needed for prolonging life by glucose reduction, the team reports in the 8 May issue of Nature. The researchers then discovered that Pnc1 appears to be the linchpin in other life-extending treatments. Its production rose in cells subjected to low glucose, amino acid restriction, heat, or salt. Further tests suggested that Pnc1 enlivens Sir2 by consuming nicotinamide rather than by boosting NAD quantities. The results support a new scenario in which diverse stressors induce Pnc1 to destroy nicotinamide, which in turn allows Sir2 to prolong the lives of yeast.

"I think it's really exciting that ... one gene seems to increase longevity in response to many stress signals," says Leonard Guarente, a molecular biologist at Massachusetts Institute of Technology in Cambridge, although he's not convinced that nicotinamide is the whole story.

Related sites
The Sinclair lab
Leonard Guarente's site
A more detailed article about the research on Science's SAGE KE
An article on caloric restriction from SAGE KE

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