Resveratrol has been a good news, bad news compound. The good news is that this component of red wine can extend lifespans in many animals. And it appears to do so by activating the same pathways as caloric restriction, which means there is at least the possibility of achieving a longer lifespan without living, if not in near-starvation, then certainly in greater austerity than most folks who have a choice appear willing to do.

But resveratrol's concentration in wine is such that the amount needed to cause an effect in lab studies is equivalent to what is found in 1,000 bottles of wine - bad news for even the hardiest of drinkers. And though it does exist in pill form, whether it does anything at those doses also is unclear.

Resveratrol works to increase lifespan by activating an enzyme known as sirtuin-1, and academic researchers as well as pharma and biotech companies, including Sirtris Pharmaceuticals, Pharmion and Elixir, have been looking for compounds that can mimic its actions without needing to be taken by the shovelful.

Sirtris Pharma in particular is focused on sirtuins, an enzyme family that potentially can be targeted to fight many diseases of aging. (The company is not focused on aging itself, which the FDA does not consider a disease.)

Sirtris' most advanced compound, SIRT-501, currently is in Phase Ib trials for the treatment of diabetes. And in the Nov 29, 2007 issue, of Nature, Sirtris researchers, together with colleagues from Harvard and the University of California, San Diego, describe additional compounds that activate Sirt1 and "show efficacy in the three gold standard models of diabetes," Sirtris CEO Christoph Westphal told BioWorld Today.

Like SRT501, the new compounds, which for now go by the names of SRT1460, SRT2183 and SRT1720, selectively target Sirt1. But they otherwise have "very distinct characteristics" from SRT501, Westphal said. They are chemically unrelated to resveratrol and a thousand times more potent than resveratrol at activating Sirt1. SRT501, in contrast, is a proprietary reformulation of resveratrol with improved bioavailability.

In their Nature paper, the Sirtris researchers first described the pharmacological properties and molecular mechanism of the three new compounds, and demonstrated that they are selective for Sirt1 over other members of the enzyme family.

The scientists then investigated the effects of SRT1720 in three animal models: mice with either genetically or diet-induced obesity, and a rat model of Type II diabetes and insulin resistance, the Zucker fa/fa rat. They showed that in obese mice, whether they were obese because of bad genes or bad diet, SRT1720 insulin sensitivity, lowered plasma glucose levels and increased the function of mitochondria. In the Zucker rats, the compounds improved glucose homeostasis and insulin sensitivity in fat tissue, muscle and liver.

Westphal said that the company plans to bring one of the new compounds into the clinic in the first half of 2008. In the long run, the company plans to target other sirtuins besides Sirt1. While Sirt1 and the majority of sirtuins are found in the cytoplasm, Sirt3 and Sirt4 are located in the mitochondria. Recent research has shown that mitochondrial sirtuins appear to have an important role in the connection between caloric restriction and longevity, and Westphal said the company also considers Sirt3 "an interesting target." (See BioWorld Today, Sept 24, 2007.)

Ultimately, he envisions targeting the sirtuins for a variety of diseases, with the strength of the activation calibrated to the nature of the disease. "These are the first molecules that have been designed to act on genes that control the aging process," he said. "I think this is a whole new way of targeting the diseases of aging."

Perhaps spurred by the article in Nature, Sirtris stock (NASDAQ:SIRT) finished the day up $1.33, or 7.8 percent, to close at $18.38.

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