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Two papers published today in Nature present contradictory evidence about a promising approach to understanding and manipulating the biology of aging: boosting expression of a gene called Sir2. One of the papers calls into question whether boosting Sir2 expression truly enhances longevity in animals; the other suggests that it does, though to a lesser extent than previously thought. Research into Sir2 and related genes, called sirtuins, has captured attention among both scientists and the public because of the implications for anti-aging drugs. Several such drugs are now being tested in humans.

Nonetheless, a scientific imbroglio has long surrounded sirtuins. More than a decade ago, Leonard Guarente, director of the Glenn Laboratory for the Science of Aging at MIT, and collaborators discovered that tweaking Sir2 prolonged lifespan in yeast. The findings, later replicated in worms and flies, triggered thousands of research papers investigating the role of sirtuins in longevity and disease, along with a billion-dollar search for drugs that mimicked the effect.

Still, some scientists have questioned whether sirtuins really play a central role in aging. Studies in mice have yet to show that boosting sirtuins increases lifespan. And in one of the new studies, David Gems, a biologist at University College London, and colleagues crossed worms and flies that had been genetically engineered to express high levels of Sir2 and that were long-lived with other strains. (This procedure gets rid of background mutations that might influence lifespan.) After the crosses, the enhanced lifespan disappeared. In worms, the researchers found that the longevity increase was linked to a secondary mutation, rather than the increase in Sir2.

Gems interprets his results as evidence against the importance of sirtuins in aging.  “A lot of time, effort, and money have gone into sirtuins to try to understand aging,” he says.  “I think with hindsight, that energy was invested in the wrong place.”

The other new study, by Guarente and collaborators, was similar and repeated some of their earlier work using a new strain of worms. They too found that a secondary mutation played a role in longevity. However, the worms with higher levels of Sir2 still lived longer than their counterparts—about 10 to 15 percent longer, rather than the 30 percent they had previously reported.

However, Guarente says, the new findings are a minor technical blip. “It was a problem with the strain, and that has been fixed,” he says. “It does not invalidate the conclusions.” He adds that other labs have since replicated the link between Sir2 and longevity, and shown a 20 percent increase in lifespan in worms using newer methodology. 

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Tagged: Biomedicine, aging, longevity, anti-aging, sirtuins

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