Longevity research till date may be riddled with flaws: Study

By Dr. Ananya Mandal, MDSep 22 2011

Research over the last decade showing that proteins called sirtuins can increase lifespan is deeply flawed, according to a new study in Nature that debunks prior claims of a direct causal link.

Till date researchers have worked on experiments on earthworms and fruitflies - commonly used as models to examine the biology of human ageing and suggested that an extra dose of the naturally-occurring enzymes could prolong life by up to 50 percent. These early results unleashed a flood of new research, much of which backed up the original findings.

They also spawned a flourishing market in dubious health products claiming to boost sirtuins, and thus slow down one's biological clock. Many contained resveratrol, a molecule - also found in red wine - thought to activate the enzyme.

However new research led by David Gems at the Institute of Healthy Ageing at the University College London, provides solid evidence that the supposed cause-and-effect relationship between the proteins and longer life is a mirage. Gems and colleagues reproduced benchmark studies to test whether the links might be attributable to other factors besides the allegedly miracle gene, known as Sir2 in worms and flies, and SIRT1 in mammals. “We have re-examined the key experiments linking sirtuin with longevity in animals and none seem to stand up to close scrutiny…Sirtuins, far from being a key to longevity, appear to have nothing to do with extending life,” Gems said.

The main problem with most of these earlier experiments was the failure to account for all the possible differences between genetically manipulated organisms and the “wild” ones against which they compared. For nematode worms, for example, once precautions were taken to ensure that the only difference between normal and test animals was the higher sirtuin levels, the added lifespan disappeared. It turned out that other mutations had occurred but escaped notice. Gems and colleagues then reproduced similar experiments done with fruit flies, again showing that the results attributed to sirtuins were in fact due to other genetic drivers. The researchers also created synthetic fruitfly sirtuin to see if it could be activated by resveratrol, as previously claimed. But neither of two separate laboratories, using multiple techniques, could make it work. Finally, the study refutes the claim that enhanced lifespan due to dietary restriction - itself not in doubt - also depended on sirtuins.

Leonard Guarante of MIT, who conducted some of these pathbreaking studies, acknowledged in a “brief communication,” also published in Nature, that his earlier work had been flawed. 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.

“Studies on yeast lifespan were the first to cast doubt on the role of sirtuins in longevity,” note Carles Canto and Johan Auwerx from the Ecole Polytechnique Federale de Lausanne. The new study “puts a final nail in the coffin,” they wrote in a commentary, also in Nature. But even if sirtuins are not the long hoped-for life-prolonging elixir, they may still confer important health benefits, they added. “SIRT1 activation remains a promising approach to delaying general age-related physiological decline and to treating numerous inherited and acquired diseases,” they argue. The protein may not cause an otherwise healthy animal live longer, in other words, but it could help one who over-eats to reduce related stress on its system.

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.