The debate over the workings of an anti-ageing chemical in red wine called resveratrol resembles a rally between Rafael Nadal and Novak Djokovic. The latest scud comes today, from a scientist who has shown the benefits of resveratrol in lab organisms and who started a drug company to exploit them in humans.

Resveratrol, which is abundant in the skins of grapes, spares mice from the harmful effects of a fatty diet, and work in yeast, fruitflies and roundworms has suggested that the chemical lengthens the lives of these organisms by activating proteins called sirtuins.

Competing work has challenged the assertion that resveratrol directly activates sirtuins (see ‘Health benefits of red wine chemical unclear‘) and raised the possibility that the chemical’s anti-ageing effects rely on other proteins (see ‘Questions hang over red wine chemical‘). Meanwhile, recent research now questions whether activating sirtuins makes worms and flies live longer (see ‘Longevity genes challenged)’.

My colleague Heidi Ledford’s fantastic 2010 feature ‘Much ado about ageing‘ offers a fuller run-down of the debate.

David Sinclair, a molecular biologist at Harvard Medical School in Boston, and his team have struck back in a paper published online today in Cell Metabolism showing that mice that lack a pivotal sirtuin gene, SIRT1, do not enjoy many of the metabolic benefits of resveratrol.

Sinclair co-founded Cambridge, Massachusetts-based Sirtris Pharmaceuticals, which the drug giant GlaxoSmithKline bought for US$720 million in 2008. The company stopped developing resveratrol as a drug, but molecules believed to activate SIRT1 are being tested in humans against diabetes and other ageing-related diseases.

Sinclair’s latest experiment is an obvious one. If resveratrol needs SIRT1 to improve health, then animals lacking the gene should not get any benefits from the chemical. His lab published that experiment in yeast in 2003. But mice lacking SIRT1 die in the womb, or they are born with developmental defects such as blindness. To get around that problem, Sinclair’s team engineered “conditional knockout” mice whereby SIRT1 can be inactivated in adulthood. “It took us two weeks to do the experiment in yeast, and five years in mouse, but finally we’re there,” he says.

Work with the mice would seem to confirm a role for SIRT1 in resveratrol’s benefits. In normal mice, resveratrol combated the effects of a high-fat diet by boosting the efficiency of energy-generating organelles called mitochondria in skeletal muscle tissue. This effect vanished in adult mice without a working version of SIRT1.

Yet SIRT1 wasn’t responsible for all the beneficial effects of resveratrol in Sinclair’s study. Resveratrol stabilized the blood glucose levels of both normal and SIRT1-lacking mice on fatty diets. The chemical also improved liver health in mice without SIRT1.

Sinclair also contends that a lot the confusion over how resveratrol works comes down to dosage. At very high doses it binds other proteins besides SIRT1, he says. “Resveratrol is a dirty, dirty molecule, very non-specific.” For instance, a signalling protein called AMPK is also important to resveratrol’s beneficial effects on metabolism. Sinclair found that low doses of resveratrol boosted AMPK levels in various cells that expressed SIRT1, but not cells without the sirtuin. Much higher doses of resveratrol, however, activated AMPK irrespective of whether the cells expressed SIRT1.

Jay Chung, an endocrinologist at the National Heart Lung and Blood Institute in Bethesda, Maryland, who earlier this year proposed that resveratrol works by blocking proteins called phospho-diesterases, questions Sinclair’s interpretation. SIRT1 and AMPK both rise in response to resveratrol treatment, so “you don’t know what’s the chicken and what’s the egg,” Chung says. “This question may never get answered to everyone’s full satisfaction. ”

Matt Kaeberlein, a biochemist at the University of Washington in Seattle who has questioned whether resveratrol acts on SIRT1 in the past, writes via e-mail: “Testing the effects of resveratrol in the SIRT1 knockout is a good experiment, and this study supports the model that resveratrol requires SIRT1 to modulate AMPK and mitochondrial function, at least at lower doses. Interpretation is complicated by the fact that we don’t really know how loss of SIRT1 alters the overall metabolic network, and it doesn’t rule out the possibility that this is still an indirect effect.”

It’s hard not to ask if this debate amounts to little more than academic rubber-necking, but Sinclair disagrees. Spelling out just how resveratrol lengthens lifespan and improves health is crucial, he says, “because we want to know how to make better molecules than resveratrol. And unless we know the targets, that is extremely difficult.”

Image via Wikimedia Commons