Even more resveratrol news

November 16, 2006

Hi folks,

Seems like we just can't get enough of these resveratrol studies. Look

how much the sales of Longivinex went up!!!!!

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Drug Doubles Endurance, Study Says

By NICHOLAS WADE

Published: November 16, 2006

Given that some athletes will take almost anything to gain a one percent

edge in performance, what might they do for a 100 percent improvement? That

temptation is made somewhat more real by a report today in a leading

journal about a drug that doubles the physical endurance of mice running on

treadmills. And it could only be more tempting, because the drug in

question has also been reported to extend the lifespan of mice.

An ordinary lab mouse will run about one kilometer — five-eights of a mile

— on a treadmill before collapsing from exhaustion. But mice given

resveratrol, a minor component of red wine and other foods, run twice as far.

They also have a reduced heart rate and energy-charged muscles, just as

trained athletes do, according to an article published online in Cell by

Johan Auwerx and his colleagues at the Institute of Genetics and Molecular

and Cellular Biology in Illkirch, France.

“Resveratrol makes you look like a trained athlete without the training,”

Dr. Auwerx (pronounced OH-wer-ix”) said in an interview.

He and his colleagues said the same mechanism seems likely to operate in

humans, based on their analysis, in a group of Finnish subjects, of the

gene that is influenced by the drug.

Their rationale for testing resveratrol was evidence obtained three years

ago that it could activate a genetic mechanism known to protect mice

against the degenerative diseases of aging and to prolong their lifespan by

30 percent.

Dr. Auwerx, whose interest is in the genetic control of metabolism, decided

to see if resveratrol would offset the effects of a high-fat diet,

specifically the metabolic disturbances, known as metabolic syndrome, that

are the precursors of diabetes and obesity.

In his report, he and his colleagues say that very large doses of

resveratrol protected mice from gaining weight and from developing

metabolic syndrome.

Dr. Auwerx attributes this change in large part to the significantly

increased number of mitochondria he detected in the muscle cells of treated

mice.

Mitochondria are the organelles within the body’s cells that generate

energy. With increased mitochondria, the treated mice were able to burn off

more fat and thus avoid weight gain and decreased sensitivity to insulin,

Dr. Auwerx said. He found that their muscle fibers had been remodeled by

the drug into the type more prevalent in trained human athletes.

Dr. M. , a leading expert on the hormonal control of metabolism

at the Salk Institute, said that the report by Dr. Auwerx’s team had “shown

very convincingly that resveratrol improves mitochondrial function” and

fends off metabolic disease.

Dr. described the study as “very important, because it is rare that

we identify orally active molecules, especially natural molecules, that

have such a broad-based, positive effect on a problem as widespread in

society as metabolic disease.”

Dr. Kahn, director of the Joslin Diabetes Center in Boston, said the

research would focus attention on the sirtuins, a recently discovered group

of enzymes that resveratrol is believed to affect. Noting that he is a

scientific advisor to Sirtris, a company developing drugs that activate the

sirtuins, Dr. Kahn said, “Certainly, drugs that act on this class of

proteins have the potential to have major effects on human disease.”

Dr. Auwerx’s study complements one published earlier this month by Dr.

Sinclair of the Harvard Medical School, who found that much more

moderate doses of resveratrol protected mice from the metabolic effects of

a high-calorie diet. Though his mice did not lose weight, they lived far

longer than undosed mice that were fed the same high-calorie diet.

The two studies were started and performed independently, Dr. Auwerx said,

though he obtained supplies of resveratrol from Sirtris, which was

co-founded by Dr. Sinclair, and he has become a scientific advisor to the

company.

A drug that prolongs life, averts degenerative disease and, on top of all

that, makes you into a champion athlete — at least if you are a mouse —

sounds almost too good to be true.

Dr. Christoph Westphal, Sirtris’s chief executive, replied to this

objection with a question: “Is it too good to be true that when you are

young you get no disease?”

He believes that activation of the sirtuins is what keeps the body healthy

in youth, but that these enzymes become less powerful with age, exposing

the body to degenerative disease. That is the process that he says is

reversed by resveratrol and, he hopes, by the more powerful

sirtuin-activator drugs that his company is developing, though many years

of clinical trials will still be needed to demonstrate whether they work

and are safe to use.

The developing buzz over sirtuin activators has captivated some scientists

who do research on the aging process, several of whom are already taking

resveratrol themselves. Dr. Sinclair has said that he has been swallowing

resveratrol capsules for three years, and that his parents and half his lab

staff do the same.

So does Dr. Tomas Prolla at the University of Wisconsin. “The fact that

investigators in the field are taking it is a good sign there is something

there,” he said.

But many others believe taking the drug now is premature, including Dr.

Leonard Guarente of M.I.T. whose 15-year study of the sirtuins laid the

basis for the field of study. It was after working in Dr. Guarente’s lab as

a postdoctoral student that Dr. Sinclair found in 2003 that resveratrol was

a sirtuin activator.

Though resveratrol has long been known to be a component red wine and other

foods, it is present there in only minuscule amounts, compared with the

very large doses used in experiments. Dr. Sinclair dosed his mice daily

with 22 milligrams of resveratrol for each kilogram of weight, and Dr.

Auwerx used up to 400 milligrams. No one could drink enough red wine to

obtain such doses.

Resveratrol is now available in capsules that contain extracts of red wine

and giant knotweed, a plant found in China. One manufacturer of such

capsules is Longevinex, whose president, Bill Sardi, said today that demand

for the product had increased by a factor of 2400 since Nov. 1. But even

Longevinex’s capsules, which at present contain 40 milligrams of

resveratrol each, would have to be gulped in almost impossible quantities

for a human to obtain doses equivalent to those used in mice. “It’s like

eating a whole bottle of Tums every day,” Dr. said.

Whether much lower doses would benefit athletic performance is not clear,

Dr. said. And higher doses may not be as safe as the lower doses

found now in foods and “nutraceuticals” like the extract capsules.

Besides these uncertainties over what a safe and effective dose of

resveratrol might be, the science underlying the field is still in full

flux. Many central details are still unclear. The principal theory

developed by Dr. Guarente and others is that the sirtuins somehow sense the

level of energy expenditure in living cells and switch the body’s resources

from reproduction to tissue maintenance when food is low.

This is an ancient strategy, Dr. Guarente believes, that allows an organism

to live through famines and postpone breeding until good times return. The

switch to tissue maintenance involves specific action to stave off the

major degenerative diseases of aging, such as cancer, diabetes, heart

disease and neurodegeneration.

Though resveratrol is in the spotlight, the central focus of researchers is

on how the sirtuins are activated and what they do. One serious uncertainty

is whether, in the mouse experiments, resverattrol in fact acted through

the sirtuins or by some other unknown mechanism. In the latter case, Dr.

Sinclair’s and Dr. Auwerx’s mouse experiments would offer less support to

the sirtuin theory.

Dr. Auwerx cites evidence that resveratrol does activate sirtuin, but Dr.

said the case was not yet fully convincing.

Dr. Bruce Spiegelman, a Harvard Medical School expert on fat metabolism,

said Dr. Auwerx’s paper was “pretty good.” Dr. Auwerx believes resveratrol

activates sirtuin, which in turn activates a factor known as PGC1-alpha in

a manner first described by Dr. Spiegelman and his colleagues last year.

Subsequent actions by PGC1-alpha then stimulate cells to produce more

mitochondria.

Increased energy production by mitochondria generates potentially dangerous

reactive chemicals that are known to damage cells. So it has long been

puzzling that exercise, in which energy is expended, is good for health,

not bad.

Dr. Auwerx noted that Dr. Spiegelman showed in a report in the journal Cell

last month that PGC1-alpha not only increases mitochondria, but at the same

time generates chemicals that detoxify the energy by-products.

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