[tt] The Longevity Pill?

[Hughes, James J.]

http://www.technologyreview.com/read_article.aspx?id=19776

Wednesday, November 28, 2007

The Longevity Pill?

Drugs much more powerful than the resveratrol found in red wine will
soon be tested in humans to treat diabetes.

By Emily Singer

A novel group of drugs that target a gene linked to longevity could
provide a way to turn back the clock on the diseases of aging. The
compounds are 1,000 times more potent than resveratrol, the molecule
thought to underlie the health benefits of red wine, and have shown
promise in treating rodent models of obesity and diabetes.

Human clinical trials to test the compounds in diabetes are slated to
begin early next year, according to Sirtris Pharmaceuticals, based in
Cambridge, MA, which developed the drugs. "As far as I'm aware, this is
the first anti-aging molecule going into [testing in] man," says David
Sinclair, a biologist at Harvard Medical School, in Boston, and
cofounder of Sirtris. (See "The Enthusiast.") "From that standpoint,
this is a major milestone in medicine."

The new drugs target an enzyme called SIRT1, which belongs to a class of
proteins known as sirtuins that have been shown to lengthen life span in
lower organisms. Sinclair and others theorize that activating these
enzymes, which play a role in cell metabolism, mimics the effects of
caloric restriction--a low-calorie but nutritionally complete diet that
dampens disease and boosts longevity in both invertebrates and mammals.

For several years, scientists have been on the hunt for a drug that
could bring the benefits of caloric restriction without the strict diet.
(See "The Fountain of Health.") Last fall, Sinclair and his colleagues
took a first step when they showed that mice given resveratrol, a
molecule that activates SIRT1, stayed healthy when fed high-fat foods.
(See "A Life-Extending Pill for Fat Mice.") But there was a catch: mice
were dosed with the human equivalent of more than 1,000 wine bottles'
worth of the compound, an amount not possible for humans to imbibe or
take in pill form.

Now a team at Sirtris, led by CEO Christoph Westphal, has identified a
group of compounds that activate SIRT1 1,000 times more potently than
resveratrol does. According to findings published today in the journal
Nature, the compounds bind to the enzyme and dramatically increase its
activity. Because the new compounds are more powerful, much lower doses
are likely needed to achieve the same beneficial effects. "We believe
doses needed in humans for the novel compounds are probably on the order
of hundreds of milligrams, similar to many marketed drugs," says
Westphal.

The Sirtris team focused initial animal tests on type 2 diabetes, a
disease that results from the impaired ability to use insulin, and whose
risk increases with aging. They found that the drugs improved insulin
sensitivity and blood glucose levels in three rodent models:
diet-induced obese mice, genetically obese mice, and a rat model of type
2 diabetes. "Theoretically, this is a perfect drug," says Charles
Burant, head of the Michigan Metabolomics and Obesity Center at the
University of Michigan, in Ann Arbor. "Animals seem to have no change in
weight, yet they have improved metabolic status."

Still, Burant and others caution that it's too soon to tell how well the
drug will work in humans, whose metabolism drastically differs from that
of rodents. Sirtris is also testing a resveratrol-like compound in
clinical trials for treating diabetes, with initial results expected
later this year or early next year.

Both Sinclair and Westphal have high hopes for the drugs, in part
because they appear to mimic the effects of caloric restriction, which
has been shown to delay or slow the progression of a variety of
age-related diseases. So the novel SIRT1 activators might have the
potential to treat illnesses ranging from Alzheimer's disease to heart
disease to cancer. "The big news here is that maybe all big diseases of
aging fall into the same category and can be treated with sirtuin
activators," says Leonard Guarente, an MIT biologist whose lab
discovered the first sirtuin gene. Guarente recently joined Sirtris's
advisory board.

Initial studies suggest that activating SIRT1 can slow
neurodegeneration, and tests of the compounds' impact on animal models
of different diseases are ongoing.

However, many questions remain to be answered. While Sinclair and
Guarente argue that the new findings support the idea that sirtuins lie
at the heart of caloric restriction's health and longevity benefits, not
everyone agrees. And the issue that has garnered the most media
attention--whether or not such compounds will provide a molecular
fountain of youth--is still unclear. While the diabetes research is
promising, says Burant, "the life-extension part of this story is still
incomplete."

In fact, that question may remain open for a few more years. Sinclair's
team is testing the compounds' effect on life span, "but we may know if
they can treat a disease in humans before we know if mice live longer,"
he says.

Copyright Technology Review 2007.