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.
“If people should look at the sirtuin literature as a whole, they will come to the conclusion that sirtuins are the most actionable mechanisms for developing drugs to mitigate the diseases of aging,” says Guarente.
David Sinclair, a biologist at Harvard and former collaborator of Guarente’s, dismisses Gems’s interpretation. “The group that published the paper that contradicts the Guarente lab has repeatedly produced data that attacks other groups; this is just another one of those,” says Sinclair. “When I look at the Guarente data, I remain convinced that sirtuins extend lifespan. The debate seems to be over how big the effect is.”
Sinclair has bet big on sirtuins, founding a startup called Sirtris whose premise is that activating the proteins produced by these genes with drugs will help combat such diseases of aging as diabetes, heart disease, and cancer. (Pharmaceutical giant GlaxoSmithKline acquired Sirtris for $270 million in 2008.)
Sinclair had previously discovered that resveratrol—a molecule found in red wine—could activate proteins produced by the sirtuin genes, and his team developed a number of compounds designed to activate sirtuins more powerfully. (In another branch of the debate, some studies have questioned whether resveratrol truly activates sirtuins or whether it acts through its effect on other proteins.)
In practical terms, how much does this argument really matter? The ultimate goal of aging research is to figure out how to improve human health. And drug development efforts that have emerged from the sirtuin research still look encouraging.
Last year, researchers at the National Institute on Aging showed that one sirtuin compound, called SRT-1720, improves health and longevity in mice fed a high-fat diet. Treated fat mice lived more than 40 percent longer than untreated fat mice, though both died sooner than their lean counterparts. The drug did not appear to increase the maximal lifespan of the obese animals.
“I don’t think you need to convince people they are longevity drugs,” says Johan Auwerx, a researcher at the Ecole Polytechnique Federale de Lausanne, in Switzerland, who wrote a commentary accompanying the papers in Nature. “They do control health span, so I still think they are very interesting pharmaceutical targets. Who wants to live forever? You want to live well.”