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Resveratrol's Effects On Sirtuins May Be Mimicked by COPD Drug

By Anette Breindl
Science Editor

Resveratrol, a compound found in minuscule doses in foods including red wine and chocolate, is as close to ambrosia – the food of the ancient Greek Gods that gave them eternal youth – as anyone has come. It activates sirtuins and mimics the effects of caloric restriction, which is the only known way to reliably increase lifespan.

As such, resveratrol, and sirtuin activation more generally, have long been touted as a way to achieve health and longevity without the austerity. It's a promise that led GlaxoSmithKline plc to bet $720 million in acquiring sirtuin-focused Sirtris Pharmaceuticals a few years back. (See BioWorld Today, April 24, 2008.)

And most recently, reports that resveratrol improves metabolic indicators in patients who are at risk of developing metabolic syndrome led to another round of excited chatter.

But for all that, how resveratrol works its magic on sirtuin1 has not been worked out – until now.

"It used to be thought that resveratrol targeted sirtuin1 directly," Jay Chung told BioWorld Today. But in the Feb. 3, 2012, edition of Cell, Chung and his colleagues show that there are several intermediates between resveratrol's arrival on the cellular scene and sirtuin1's activation. And some of those intermediates could potentially be targeted by more specific agents than resveratrol itself, which has a multitude of binding partners.

That multitude of partners was the original reason that Chung and his colleague decided to look for direct partners of resveratrol. "Because resveratrol binds to so many things," he explained, "we didn't know which one or which ones were important."

Chung is chief of the Laboratory of Obesity and Aging Research at the NIH's National Heart, Lung, and Blood Institute. He is the senior author of the Cell paper describing the findings.

In their work, Chung and his team showed that resveratrol could not affect sirtuin1 when another protein, AMP kinase, was blocked, showing that resveratrol's effects on sirtuin were indirect. The direct target of resveratrol turned out to be phosphodiesterases. There are 11 phosphodiesterases, but the critical one in the experiments by Chung and his team turned out to be phosphodiesterase 4.

Phosphodiesterases normally degrade cyclic adenosine monophosphate, or cAMP, a signaling molecule that regulates many aspects of metabolism. When they are blocked by resveratrol, cAMP builds up. Several additional intermediate steps ultimately lead to the activation of sirtuin1.

The findings may show one reason, though clearly not the only one, why physical exercise has health benefits. "When you exercise, cAMP goes up," Chung explained.

And on the practical side, other phosphodiesterase activators may be a more specific way to activate sirtuins than resveratrol itself.

One such inhibitor is rolipram, a phosphdiesterase 4 inhibitor which is approved as an antidepressant. When Chung and his colleagues fed rolipram to mice, its effects were very similar to those of resveratrol. The drug prevented diet-induced obesity in the animals and increased both their mitochondrial activity and their stamina.

Chung and his team, however, want to take another phosphodiesterase 4-targeting drug into the clinic for metabolic indications: roflumilast (Daxas, Daliresp), which was approved for the treatment of chronic obstructive pulmonary disorder in both Europe and the U.S. last year. Roflumilast was developed by German biopharma company Nycomed GmbH, which has since been acquired by Takeda Pharmaceutical Co. Ltd.

Chung hopes that roflumilast may be a more specific alternative to resveratrol itself. His team is "in the process" of starting a clinical trial with the drug to see whether it is effective for preventing the development of Type II diabetes in obese individuals with insulin resistance, and hopes to start treating patients some time this year.

If roflumilast works for halting or slowing the progression from insulin resistance to diabetes, "hopefully, we'll minimize the unwanted side effects," he said. "That's always been the problem with resveratrol, that it binds to so many things."