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More questions arise about "life-extending" proteins

By Genevra Pittman

NEW YORK (Reuters Health) - Proteins that scientists once thought might hold the key to extending life in humans didn't seem to affect how long worms or fruit flies survive in a new study.

But researchers said the proteins may still play a role in treating the diseases of aging, such as diabetes and Alzheimer's, so it's not time to give up hope on them yet.

Much of the original excitement about the proteins, called sirtuins, came from research showing that yeast and worms that made lots of sirtuins lived longer than those with a normal amount. Researchers thought that if a drug could trigger the human body to make more of the proteins, the same might hold true for humans.

Creating a life-extending drug "has been a long-standing dream in aging research," said David Gems, one of the authors of the new study from the Institute of Healthy Aging, University College London. "This seemed like an amazing story."

But researchers have had mixed success in recreating the original experiments showing both that sirtuins can extend life, and that they can be "activated" by a substance called resveratrol, which is currently found in anti-aging creams and under investigation for ailments associated with old age.

"There's been a whole series of these challenges to the sirtuin aging theory," Gems told Reuters Health. "This new study of ours is the latest installment in this long saga."

His team bred nematode worms and fruit flies with high levels of sirtuins. At first look, both of the protein-enhanced strains survived longer than normal worms and flies. But when the researchers went back and controlled for any other genetic differences between the high- and normal-sirtuin strains, there was no longer any difference in lifespan.

That suggested some other genetic variations were behind the survival difference, Gems explained. In worms, his team was able to pinpoint one of the key genes -- a gene involved in nerve growth -- which was already known to affect aging in that species.

"If you do the experiments properly," he concluded, "the sirtuins themselves don't seem to increase lifespan in animals."

In separate experiments, Gems' team also showed that resveratrol didn't stimulate any activity by synthetic versions of the sirtuin proteins.

In a second paper published this week in Nature, the researcher credited with discovering sirtuins' antiaging effects, who is an advisor to a company creating sirtuin-related drugs, found that the proteins did have some effect on worm lifespan -- but a smaller one than previously believed.

Leonard Guarente, a professor at the Massachusetts Institute of Technology and co-chair of the Scientific Advisory Board of Sirtris Pharmaceuticals, owned by GlaxoSmithKline, wrote that the first research on sirtuins "overestimated the extension of lifespan" in a worm with high levels of the proteins. Now, his team calculates, making a lot of sirtuins seems to increase a worm's lifespan by about 10 to 14 percent, all else being equal.

But Guarente said it's not the end of the story for sirtuins. In other strains of worms with extra sirtuins, he told Reuters Health, the added lifespan benefits of the proteins are more established.

Another researcher who has found a positive effect of sirtuins on flies' lifespan, Dr. Stephen Helfand of Brown University, also said that because of methodological differences, Gems' findings don't refute his team's results -- which also took into account unrelated genetic differences.

"To say that sirtuins have nothing to do with aging at this point in time is not correct," Guarente said.

In rodents, he added, sirtuins combined with a calorie-restricted diet have been able to ease some diseases of aging, such as diabetes. That's the direction current research in humans, including drug investigations at Sirtris, is heading.

"I feel that the sirtuins are really the most important and actionable thing to come out of aging research, and I'm very hopeful that we will have drugs in the future based on this work to treat the major diseases of aging," Guarente said.

In an email to Reuters Health, a GlaxoSmithKline representative said, "Our research at Sirtris has been focused on the role of sirtuins in diseases of aging including metabolic, neurodegenerative, cardiovascular and inflammatory diseases, rather than looking at longevity."

"These two publications in lower order species do not have any direct impact on the understanding of the role of sirtuins in human health and disease nor in our drug discovery efforts targeting these enzymes," the representative added.

Gems agreed that research on sirtuins could lead to treatments for diabetes and other metabolic diseases. But he thinks that researchers "got carried away" with the excitement about their anti-aging effects.

SOURCE: http://bit.ly/qFUIUu and http://bit.ly/rpBAAS Nature, online September 21, 2011.

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