Doubt on Anti-Aging Molecule as Drug Trial Stopped

[Guest guest]

By NICHOLAS WADE, New York Times

The pharmaceutical company Sirtris announced last month that it had halted the

last of its clinical trials of resveratrol, the minor ingredient of red wine

that some researchers see as a drug that can extend life.

The decision signifies an apparent divergence of views on the merits of

resveratrol between the current head of the company, which was bought by

GlaxoKline in 2008 for $720 million, and its founders.

Vlasuk, Sirtris's chief executive, said in an interview last week that

SRT501, Sirtris's formulation of resveratrol, " was not an important part of the

acquisition of Sirtris by GSK. " Resveratrol has several features that make it

unsuitable as a drug, he said. These include the fact that it is hard to

maintain a consistent level of resveratrol in the bloodstream and that it seems

to have different effects at different doses.

Resveratrol is thought to work in humans by activating a protein called SIRT1,

but at some doses it actually inhibits SIRT1, Dr. Vlasuk said.

In addition, from a commercial point of view, resveratrol is a natural substance

and not patentable.

Glaxo's purchase of Sirtris, Dr. Vlasuk said, was more because the company

afforded an entry into a new research field, and had developed several small,

synthetic, patentable chemicals that mimic resveratrol in activating SIRT1.

SIRT1 is thought to extend life in mice fed low-calorie diets, and researchers

hope it may do the same in people by enhancing tissue maintenance and postponing

the usual diseases of age.

Sirtris has completed three clinical trials with its synthetic

resveratrol-mimicking drugs and will announce the results next year. These drugs

work fairly specifically on SIRT1, unlike resveratrol, which also affects many

other processes in the cell. " We have much more confidence that we are targeting

SIRT1 and that it's an important target. Resveratrol is not that important any

more, " Dr. Vlasuk said.

But the co-founders of Sirtris, Sinclair and Christoph Westphal, retain

their confidence in resveratrol. Dr. Sinclair, a researcher at the Harvard

Medical School, has long taken resveratrol. Referring to the unpublished results

of a new trial with rhesus monkeys, he said that resveratrol " was and remains an

excellent proof-of-concept molecule. "

Dr. Westphal said he believed there is accumulating evidence that resveratrol

and Sirtris's resveratrol-mimicking chemicals activate SIRT1, and that

sirtuin-activating drugs have beneficial effects in animal and human studies.

Based on preliminary data about the synthetic drugs tested by Sirtris, " I'm as

optimistic about the science and the potential of sirtuin activators as I've

ever been, " Dr. Sinclair said. Sirtuin is the name of a family of proteins of

which SIRT1 is the most important. Humans have seven sirtuins, all with

different roles.

The rhesus monkey trial has been conducted by de Cabo, a researcher at

the National Institute on Aging. It is similar to a study on mice in which he

and Dr. Sinclair showed resveratrol extended the life of obese mice fed on a

high-fat diet, but not of normal mice. Even the normal mice, however, showed

some improvement on measures of heart function and bone loss. Dr. de Cabo said

he could not discuss the results of the study until it is published. It looked

at various markers of disease but did not try to assess resveratrol's effect on

longevity, given that rhesus monkeys live 40 years and it takes a long time

assess any effect on life span.

" Resveratrol is a complex molecule in that it has many targets, and it behaves

differently depending on the tissue and the metabolic status of the organism, "

Dr. de Cabo said. That may make it too complex for a pharmaceutical company,

which must prove to the Food and Drug Administration that a new drug works by a

defined mechanism on a specific target. But resveratrol remains of great

interest to researchers. " What is the actual use for humans still needs to be

discovered, " he said.

Dr. de Cabo said he does not take resveratrol. " I don't think it's a reasonable

thing for people to start consuming these compounds without more information, "

he said.

http://www.nytimes.com/2011/01/11/science/11aging.html?ref=health & pagewanted=pri\

nt