511. How Science Resolves Disputes: The Longevity Gene Debate

By Nicholas Wade, The New York Times, September 21, 2011

A trans-Atlantic dispute has opened up between two camps of researchers pursuing a gene that could lead to drugs that enhance longevity. British scientists say the longevity gene is “nearing the end of its life,” but the Americans whose work is under attack say the approach remains as promising as ever.

The idea of pursuing a gene that could lead to longevity-enhancing drugs took wing when resveratrol, found in red wine, was reported to activate proteins involved in controlling cells’ metabolism.

The dispute concerns genes that make sirtuins, proteins involved in controlling cells’ metabolism. Because of their metabolic role, the sirtuins may mediate the 40-percent-longer life enjoyed by laboratory rats and mice put on a very low-calorie diet.

People cannot keep to such a low-fat diet, but drugs that activate sirtuin would in principle be a painless way for humans to add years of lean and healthy life. This idea took wing when resveratrol, a substance found in trace quantities in red wine, was reported to activate sirtuin. In 2008 the pharmaceutical company GlaxoSmithKline paid $720 million for Sirtris, a start-up company trying to develop resveratrol-mimicking drugs that activate sirtuins.

Since then, several aspects of the sirtuin story have come under scientific challenge, including doubts as to whether resveratrol’s effects are really exercised through sirtuin, and whether the sirtuins are the real or only mediators of the longevity increase linked to a low-calorie diet.

Despite these concerns, the idea that sirtuins promote longevity appeals to scientists because of experiments that were started in yeast and repeated in two other standard laboratory organisms, the roundworm and the fruit fly.

It is these foundation experiments that have now come under attack by David Gems and Linda Partridge, researchers on aging at University College London. In an article published Wednesday in the journal Nature, they and colleagues have re-examined experiments in which roundworms and flies, genetically manipulated to produce more sirtuin than normal, were reported to live longer.

Both experiments were flawed, they say, because the worms and flies used as a control were not genetically identical to the test organisms. The London researchers report that they have repeated the experiments with proper controls and found that extra sirtuin does not, after all, make the worms or flies live longer.

The genetic study of aging is a relatively new field that has had its fair share of teething problems. In an article in Nature four years ago, Dr. Gems and Dr. Partridge warned of some of the mistakes being commonly made. “The biology of aging is a young field with emerging pitfalls,” they wrote.

The authors of the original worm and fly experiments on the sirtuins fell into one of these traps, the London researchers now write, namely the failure to make sure their test and control animals had the same genetic background in all respects except for the added gene that forced extra production of sirtuins.

In the worm experiment, published by Leonard Guarente of the Massachusetts Institute of Technology in 2001, the strain of worms used had picked up an extra mutation that also had the effect of prolonging life, the London researchers report. When the mutated gene is removed, the worms with extra sirtuin do not live longer, they said.

Dr. Guarente said he did not agree with the thrust of this criticism. The 2001 experiment was done with the best techniques then available, he said. When he heard of the mutated gene two years ago, he redid the experiment, using worms from which the gene had been removed. The worms with extra sirtuin still lived longer, though the effect was less pronounced than before, a finding he also reports in the current Nature.

“We agree there is a glitch in one of the worm strains used in the 2001 paper,” Dr. Guarente said in an interview. “We absolutely do not agree that there is a serious question about whether sir2 extends life span in worms,” he said, using the name for the worm’s version of the sirtuin protein.

“I think the whole thing is a tempest in a teapot,” he said.

Stephen Helfand of Brown University is the author of the fly experiments. Like Dr. Guarente, Dr. Helfand criticized the London researchers for focusing on an old experiment of his and ignoring a subsequent one that reached the same conclusion with a much-improved technique.

In the more recent experiment, published in 2009, he was able to arrange that genes for extra sirtuin were switched on only when the flies were given a drug. The test and control flies were genetically identical, and differed only in whether they got the drug. Those with the drug lived longer, he reported.

Dr. Gems said at first that he had not cited Dr. Helfand’s 2009 experiment because it was “redundant,” and then he said that Nature had limited the number of papers he could cite.

All scientists agree that it is important to correct flawed experiments, but there are differences of opinion as to how this should be done. The London group believes the aging field is full of sloppy experiments done by people new to the field and more interested in publicity than in excluding the factors that confound this difficult subject. The American sirtuin researchers under criticism believe the London group has gone beyond simple correction into “gotcha” science that is not collegial. Usually, they say, if a scientist cannot repeat another’s experiment, he will call up first to find out why instead of putting his objections into print first.

Scientists not involved in the dispute say that sirtuins remain a field of vast interest, even if their relationship to longevity now seems considerably more complex than originally suggested. The theory that resveratrol activates sirtuins, which then prolong life span, is popular because of the notion that drinking red wine can make people live longer, but it “should have been abandoned five years ago,” said Richard A. Miller, who studies aging in mice at the University of Michigan. “But sirtuins are very important proteins which probably have a lot to do with how diseases are controlled.”

Dr. Miller suggested that Nature had given too much attention to resveratrol and sirtuin reports in the past. “Maybe they are trying to make amends by giving equal time to people who have been more careful,” he said.