November
1, 2006
Substance in Red Wine Extends Life of
Mice
Can you have your cake and eat it? Is there a free lunch after all,
red wine included? Researchers at the
Their report, published electronically today in Nature, implies
that very large daily doses of resveratrol could offset the unhealthy,
high-calorie diet thought to underlie the rising toll of obesity in the
Resveratrol is found in the skin of grapes and in red wine and is
conjectured to be a partial explanation for the French paradox, the puzzling
fact that people in France tend to enjoy a high-fat diet yet suffer less heart
disease than Americans.
The researchers fed one group of mice a diet in which 60 percent
of calories came from fat. The diet started when the mice, all males, were 1
year old, which is middle-aged in mouse terms. As expected, the mice soon
developed signs of impending diabetes, with grossly enlarged livers, and
started to die much sooner than mice fed a standard diet.
Another group of mice was fed the identical high-fat diet but with
a large daily dose of resveratrol. The resveratrol did not stop them from
putting on weight and growing as tubby as the other fat-eating mice. But it
averted the high levels of glucose and insulin in the bloodstream, which are
warning signs of diabetes, and it kept the mice’s livers at normal size.
Even more strikingly, the substance sharply extended the mice’s
lifetimes. Those fed resveratrol along with the high-fat diet died many months
later than the mice on high fat alone, and at the same rate as mice on a
standard healthy diet. They had all the pleasures of gluttony but paid none of
the price.
The researchers, led by David Sinclair
and Joseph Baur at the
The researchers hope their findings will have relevance to people
too. Their study shows, they conclude, that orally taken drugs “at doses
achievable in humans can safely reduce many of the negative consequences of
excess caloric intake, with an overall improvement in health and survival.”
Several experts said that people wondering if they should take
resveratrol should wait until more results were in, particularly safety tests
in humans. “It’s a pretty exciting area but these are early days,” said Dr.
Ronald Kahn, president of the
The mice were fed a hefty dose of resveratrol, 24 milligrams per
kilogram of body weight. Red wine has about 1.5 to 3 milligrams of resveratrol
per liter, so a 150-pound person would need to drink from 1,500 to 3,000
bottles of red wine a day to get such a dose. Whatever good the resveratrol
might do would be negated by the sheer amount of alcohol.
Dr. Richard Hodes, director of the National Institute on Aging,
which helped support the study, also said that people should wait for the
results of safety testing. Substances that are safe and beneficial in small
doses, like vitamins, sometimes prove to be harmful when taken in high doses,
he said.
One person who is not following this prudent advice, however, is
Dr. Sinclair, the chief author of the study. He has long been taking
resveratrol, though at a dose of only 5 milligrams per kilogram. Mice given
that amount in a second feeding trial have shown similar, but less dramatic,
results as those on the 24 milligram a day dose, he said.
Dr. Sinclair has had a physician check his metabolism, because
many resveratrol preparations contain possibly hazardous impurities, but so far
no ill effects have come to light. His wife, his parents, and “half my lab” are
also taking resveratrol, he said.
Dr. Sinclair declined to name his source of resveratrol. Many
companies sell the substance, along with claims that rivals’ preparations are
inactive. One such company, Longevinex, sells an extract of red wine and
knotweed that contains an unspecified amount of resveratrol. But each capsule
is equivalent to “5 to 15 5-ounce glasses of the best red wine,” the company’s
Web page asserts.
Dr. Sinclair is the founder of a company, Sirtris Pharmaceuticals, that has developed several chemicals
designed to mimic the role of resveratrol but at much lower doses. Sirtris has
begun clinical trials of one of these compounds, an improved version of
resveratrol, with the aim of seeing if it helps control glucose levels in
people with diabetes. “We believe you cannot reach therapeutic levels in man
with ordinary resveratrol,” said Dr. Christoph Westphal, the company’s chief
executive.
Behind the resveratrol test is a considerable degree of scientific
theory, some of it well established and some yet to be proved. Dr. Sinclair’s
initial interest in resveratrol had nothing to do with red wine. It derived
from work by Leonard Guarente of the Massachusetts
Institute of Technology, who in 1995 found a gene that controlled the
longevity of yeast, a single-celled fungus. Dr. Guarente and Dr. Sinclair, who
had come from
Dr. Guarente then found that the gene’s protein needs a common
metabolite to activate it and he developed the theory that the gene, by sensing
the level of metabolic activity, mediates a phenomenon of great interest to
researchers in aging, the greater life span caused by caloric restriction.
Researchers have known since 1935 that mice fed a calorically
restricted diet — one with all necessary vitamins and nutrients but 40 percent
fewer calories — live up to 50 percent longer than mice on ordinary diets.
This low-calorie-provoked increase in longevity occurs in many
organisms and seems to be an ancient survival strategy. When food is plentiful,
live in the fast lane and breed prolifically. When famine strikes, switch
resources to body maintenance and live longer so as to ride out the famine.
Researchers had long supposed that the increase in longevity was a
passive phenomenon: during famine or on a low-calorie diet, organisms would
have lower metabolism and produce less of the violent chemicals that oxidize
tissues. But Dr. Guarente and Dr. Sinclair believed that longer life was
attained by an active program that triggered specific protective steps against
the diseases common in old age. It was because these diseases were averted in
calorie restriction, they believed, that animals lived longer.
Most people find it impossible to keep to a diet with 40 percent
fewer calories than usual. So if caloric restriction really does make people as
well as mice live longer — which is plausible but not yet proved — it would be
desirable to have some drug that activated the SIRT-1 gene’s protein, tricking
it into thinking that days of famine lay ahead.
In 2003 Dr. Sinclair, by then in his own lab, devised a way to
test a large number of chemicals for their ability to mimic caloric restriction
in people by activating SIRT-1. The champion was resveratrol, already well
known for its possible health benefits.
The experiment reported today tests one aspect of caloric
restriction, the reduction in metabolic disease. Calorically restricted mice
also suffer less cancer and heart disease, and there is some evidence that
neurodegenerative diseases are also held at bay.
Critics point out that resveratrol is a powerful chemical that
acts in many different ways in cells. The new experiment, they say, does not
prove that resveratrol negated the effects of a high-calorie diet by activating
SIRT-1. Indeed, they are not convinced that resveratrol activates SIRT-1 at
all. “It hasn’t really been clearly shown, the way a biochemist would want to
see it, that resveratrol can activate sirtuin,” said Matt Kaeberlein, a former
student of Dr. Guarente who now does research at the University of Washington
in
Dr. Sinclair said experiments at Sirtris have essentially wrapped
up this point. But they have not yet been published, so under the rules of
scientific debate he cannot use them to support his position. In his Nature
article he therefore has to concede, “Whether resveratrol acts directly or
indirectly through Sir2 in vivo is currently a subject of debate.”
Given that caloric restriction forces a tradeoff between fertility
and lifespan, resveratrol might be expected to reduce fertility in mice. For
reasons not yet clear, Dr. Sinclair said he saw no such effect in his
experiment.
If resveratrol does act by prodding the sirtuins into action, then
there will be much interest in the new class of sirtuin activators now being
tested by Sirtris. Dr. Westphal, the company’s chief executive, has no
practical interest in the longevity-promoting effects of sirtuins and caloric
restriction. For the Food and
Drug Administration, if for no one else, aging is not a disease and death
is not an end-point.
Generally, the F.D.A. will only approve drugs that treat diseases
in measurable ways, so Dr. Westphal hopes to show his sirtuin activators will
improve the indicators of specific diseases, starting with diabetes.
“We think that if we can harness the benefits of caloric
restriction, we wouldn’t simply have ways of making people live longer, but an
entirely new therapeutic strategy to address the diseases of aging,” Dr. Guarente
said.