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New research challenges work on a longevity gene

Many defend quest for anti-aging drug

By Carolyn Y. Johnson
Globe Staff / September 22, 2011

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Two papers published yesterday in a leading science journal challenge some of the key research that identified a longevity gene in worms and flies and helped lay the foundation for the search for drugs that fight human aging.

In one of the papers, a prominent MIT researcher corrects his influential 2001 paper that showed that a genetic mechanism could prolong life in microscopic worms, finding that the life extension is much smaller than first reported. In the other paper, an international team reports that after correcting problems in how some experiments were conducted, increasing the activity of the gene in worms and fruit flies did not result in longer lifespans.

The original research drew immense scientific and public attention to proteins called sirtuins, and the field heated up as later studies showed that an ingredient found in red wine could activate those proteins. Sirtris Pharmaceuticals of Cambridge began a race to create drugs that could target sirtuins, and the pharmaceutical company GlaxoSmithKline took a big bet on the approach when it bought the biotech company for $720 million.

Whether the new papers will undermine this biomedical juggernaut is uncertain. The findings are in flies and worms, and over the years a growing body of evidence that is not currently in question has established the effects of sirtuins in diseases of aging in mammals. Clinical trials of sirtuin-activating compounds are already proceeding.

The studies bring to the fore a long-simmering and polarized debate among biologists about the strength of various aspects of the red wine hypothesis. Still, even critics dubious of claims that have been made about the biology of sirtuins and the red wine ingredient, resveratrol, acknowledge that more recent studies in mice have produced exciting results and may lead to promising drugs for diseases like diabetes.

“One of the things that has always been true of aging research . . . is there was a lot of emotionality,’’ said Tom Johnson, a professor of behavioral genetics at the University of Colorado at Boulder. “This field has been marked by both conscious and unconscious interpretation and, let me say. tremendous over-interpretation of very limited datasets . . . What I think is going on is the field now is starting to reexamine itself.’’

The search for longevity genes sprang from the discovery that animals from yeast to mice live longer when placed on a very low-calorie diet. Scientists hypothesized that these animals had genes that allowed them to survive at times of famine and that these genes might be responsible for the life extension they were observing. Further research suggested that sirtuin genes played a key role in this mechanism and that resveratrol could trigger the mechanism, without the dieting.

The assault on this idea began in earnest in 2005, when scientists at the University of Washington in Seattle questioned whether resveratrol activated sirtuins. That line of research has spawned papers on either side, muddying up what had seemed to be a tidy scientific explanation. The new papers appear to be set to do the same.

Leonard Guarente, a biology professor at MIT and a member of the scientific advisory board of Sirtris, has coauthored a brief paper in the journal Nature showing that because of a previously unknown mutation in a strain of worms his laboratory was studying in 2001, the life extension caused by increasing the activity of a gene was not 50 percent, but 10 to 15 percent.

“It’s a tempest in a teapot,’’ Guarente said, arguing that his new paper does not undermine the idea that sirtuins play a role in longevity. “This has happened every three to four years in sirtuins. . . . I think part of the problem is sirtuins were really highly promoted at the beginning, and so that created a backlash, and the backlash shows itself periodically.’’

But the second Nature paper casts a darker shadow, finding fault with experiments that showed lifespan extension in flies and worms, including Guarente’s work. When researchers repeated those experiments with better methods, they found no increase in longevity. They also put flies on a diet that was extremely calorie-restricted and found that the flies’ lives were extended even if they were missing the sirtuin gene.

“It’s quite a saga,’’ said David Gems, a geneticist working on the biology of aging at University College London who led the work. “It’s a very unlovable thing to do. It’s boring, and it makes you unpopular. But you have to do it, because false facts - they lie around and lots of other scientists kind of run afoul of them. . . . They’re like land mines.’’

But Stephen Helfand, a biology professor at Brown University who did the fruit fly experiment attacked by Gems’s team, said that he had already redone the experiment using a better method that addressed their concerns and still found lifespan extension. His results were published in 2009.

Scientists in the field said there is little consensus about what is going on.

“I can give you my views on it, but I can’t give you answers,’’ said Brian Kennedy, head of the Buck Institute for Research on Aging in California and once a graduate student in Guarente’s lab.

On one hand, Kennedy said, there are more than 100 genes in worms that cause lifespan extension, so even if there is a 10 to 15 percent increase by activating sirtuins, he said, “you have to wonder if it’s a central player.’’ But at the same time, he said, there is a tremendous amount of data on the important role the proteins play in mammals.

In a statement, Melinda Stubbee, a spokeswoman for GlaxoSmithKline, said the new results in flies and worms do not directly affect the questions the company is studying.

“There is a wealth of scientific evidence validating the role sirtuins play in health and multiple diseases of aging in mammals, including humans,’’ Stubbee wrote in an e-mail.

A paper published this summer found that obese mice on a high-fat diet lived longer and healthier lives when given one of the sirtuin-activating compounds developed by Sirtris.

David Sinclair, a professor of genetics at Harvard Medical School and cofounder of Sirtris, said that the paper by Gems’s group “doesn’t overturn the years of work that have been done in the field by any stretch.’’

“This group of researchers makes a living out of putting out these negative papers,’’ he said, “and it’s not the first time they’ve done this and overreached with their conclusions.’’

Carolyn Y. Johnson can be reached at cjohnson@globe.com. Follow her on Twitter @globecarolynyj.