Red Wine Aging Drug

In recent years, scientists have zeroed in on the genes activated by caloric restriction, which turn out to improve metabolic function by affecting the energy centers of cells, the mitochondria.

A family of genes that make proteins called sirtuins have emerged as frontrunners.

Sirtris researchers screened thousands of small molecules for those that can activate the sirtuin genes. Their first candidate, which turns on the SIRT1 gene, is an enhanced version of the red wine compound resveratrol. They showed it can control diabetes in animals and are now testing it in people with diabetes.

"This is not science fiction anymore," Westphal says. "We are actually talking about real drug candidates in human studies targeting diseases of aging by targeting the genes that control the aging process. This is not 20, 30, 40 years away. We believe actually we may be on the market within the next five to seven years."

Sirtris founder, Harvard's David Sinclair, who showed in 2006 that reseveratrol could reverse the complications of obesity and diabetes in animals, acknowledged taking resveratrol, resulting in major web attention like this.

But Westphal says taking resveratrol supplements might not do much for lifespan or diabetes. "Resveratrol, which is currently found as a nutraceutical supplement, we believe, cannot reach therapeutic levels," he says. "You would have to take hundreds of pills a day, we believe, to have a therapeutic effect. That’s because native reserveratrol can't reach your bloodstream. It's not absorbed by your gut."

So the company enhanced it to make it more bioavailable. They recently announced unpublished results of their early human trials of that drug, SRT-501 that they say demonstrated safety, as well as hinted at efficacy. "We reached statistical significance," Westphal says, adding that they plan to publish the data, along with early results from additional trials, in scientific journals. They published their preclinical trial results in the journal Nature.

They found that, "You could treat diabetes in the three key models–these are animal models of diabetes where it's very predictive when you see effects [such as] lowering blood sugar and improving insulin sensitivity–that you will see similar effects in human patients," he says.

And as they reported in Nature, they've now discovered other molecules that, in animal tests are a thousand times more potent. "We showed that you could develop molecules that had the same activity, but at 1000th the dose," says Westphal. "So these are the kind of things that you could imagine taking one small pill once a day. "

While longevity researchers have come to view aging itself as a host of diseases of failing metabolism, Westphal explains that they're focusing on one disease of aging–diabetes, because the FDA doesn't classify aging itself as a disease.

"Sirtris is focused on developing drugs that would be approved by the Food and Drug Administration, we're very focused initially on developing drugs to treat diabetes," he says. But since these genes have also been shown to stop other diseases of aging, like cancer and Alzheimer's, he adds that the company is well aware of the possibilities.

"What's particularly exciting is, when you target the genes that control the aging process, you seem to be able to treat all diseases of aging in a new and safe way. Diseases of aging include diabetes, Alzheimer's, cancer, inflammation. So, if we're right, this is actually potentially of profound importance for a number of the major killers of Western society," says Westphal.

The company also has some competition. Elixir Pharmaceuticals, also based in Cambridge, is targeting the sirtuins and other genes for treating obesity and diabetes. And it may well turn out that existing drugs that already have the FDA seal of approval will turn out to extend lifespan.

This research was published in Nature, Nov. 29, 2007 and funded by Sirtis Pharmaceuticals.