Wine's anti-aging ingredient

[admin]

For years, Sirtris Pharmaceuticals grabbed headlines for its scientific success in pursuit of a tantalizing goal: drugs that could fight aging itself.

The Cambridge company, built on the discovery that an ingredient found in red wine had life-lengthening effects in yeast, sparked the public imagination and became a biotech success story. In 2008, it was purchased by GlaxoSmithKline for $720 million.

But even as Sirtris and others have published results showing the promise of the ingredient, resveratrol, against diseases of aging, several groups of researchers have questioned whether the original findings that led the company to create a new class of pharmaceuticals really explain why the drugs work.

“It’s complicated right now, and it’s certainly not a clear picture,’’ said Matt Kaeberlein, an assistant professor of pathology at the University of Washington who published a 2005 study that raised questions about the initial test-tube experiment that showed how resveratrol worked.

The original idea about resveratrol is that it mimics the life-prolonging effects of a restricted-calorie diet, by activating an enzyme called SIRT1.

Sirtris crafted drugs that acted like resveratrol, but were unrelated to it and caused more potent activation of SIRT1, and has seen benefits in animal studies, most notably in mice with type 2 diabetes. Two drugs are now being tested in human clinical trials.

But understanding how the drugs work has been controversial.

In January, scientists from Pfizer published a paper in the Journal of Biological Chemistry that concluded resveratrol and several related Sirtris compounds did not directly activate SIRT1. That followed a study published in the journal Chemical Biology and Drug Design last fall, in which Amgen scientists came to a similar conclusion.

And in 2005, Kaeberlein and colleagues suggested the positive results from the initial test used to detect increased SIRT1 activity might be a consequence of the way the studies were done. They showed that resveratrol activated SIRT1 only in the presence of a particular compound with a fluorescent tag used in the experiments, opening the possibility that resveratrol might not work the way people thought.

Sirtris’s chief executive, George Vlasuk, said research soon to be published will provide strong evidence to answer critics’ questions. But the ongoing debate highlights a vexing truth about the quest for new drugs. The industry’s most tantalizing promise in recent years — that researchers could understand a disease so precisely they could custom-design drugs to fight it — has crashed up against the incredible complexity of human biology.

The mechanism of a drug — how it actually works — can remain mysterious after it is developed, tested, and even approved.

This month, for example, a study in the journal Cell Metabolism showed that metformin, a widely used drug approved by the Food and Drug Administration in 1994 to treat type 2 diabetes, works differently than widely thought.