NY Times article about Resveratrol

[Guest guest]

Hi all,

Just a new piece from the NY Times about the latest resveratrol-mouse

feeding study being published today in Nature. I'll have to go find that

article as well....

-Will

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Substance in Red Wine Could Extend Lifespan, Researchers Say

By NICHOLAS WADE

<http://topics.nytimes.com/top/reference/timestopics/people/w/nicholas_w

ade/index.html?inline=nyt-per>

Published: November 1, 2006

Can you have your cake and eat it? Is there a free lunch after all, red

wine included? Researchers at the Harvard Medical School and the

National Institute of Aging report that a natural substance found in red

wine, known as resveratrol, offsets the bad effects of a high-calorie

diet in mice and significantly extends their lifespan.

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

United States and elsewhere, should people respond to the drug as mice

do.

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 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 Sinclair and ph Baur at the Harvard

Medical School and by de Cabo at the National Institute of Aging,

also tried to estimate the effect of resveratrol on the mice's physical

quality of life. They gauged how well the mice could walk along a

rotating rod before falling off, a test of their motor skills. The mice

on resveratrol did better as they grew older, ending up with much the

same staying power on the rod as mice fed a normal diet.

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. Kahn, president of the Joslin Diabetes Center in Boston.

Information about resveratrol's effects on human metabolism should be

available a year or so, he said, adding, " Have another glass of pinot

noir - that's as far as I'd take it right now. "

The mice were fed a hefty dose of resveratrol, 24 milligrams per

kilogram of body weight. Red wine has about 1.5 to 3 mg of resveratrol

per liter, so a person would need to drink from 10 to 20 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. Hodes, director of the National Institute of 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

<http://topics.nytimes.com/top/reference/timestopics/organizations/m/mas

sachusetts_institute_of_technology/index.html?inline=nyt-org> , who in

1955 found a gene that controlled the longevity of yeast, a

single-celled fungus. Dr. Guarente and Dr. Sinclair, who had come from

Australia to work as a post-doctoral student in Dr. Guarente's lab,

discovered the mechanism by which the gene makes yeast cells live

longer. The gene is known as sir-2 in yeast, sir standing for silent

information regulator, and its equivalent in mice is called SIRT-1.

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

<http://topics.nytimes.com/top/reference/timestopics/organizations/u/uni

versity_of_washington/index.html?inline=nyt-org> in Seattle. Sirtuin is

the protein produced by the SIRT-1 gene.

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

<http://topics.nytimes.com/top/reference/timestopics/organizations/f/foo

d_and_drug_administration/index.html?inline=nyt-org> , if for no one

else, aging is not a disease and death is not an end-point. 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.

Jewell, Ph.D.

Campus Mass Spectrometry Facilities

UC

cmsf.ucdavis.edu