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Enzymes Found to Delay Aging Process
Discovery Could Lead to Drugs to Extend Life Span

By Rick Weiss
Washington Post Staff Writer
Monday, August 25, 2003; Page A02

Scientists have found for the first time a way to rev up a potent "anti-aging" enzyme in
living cells, an advance they said could speed the development of drugs to extend
human life span and prevent a wide range of geriatric diseases.

The novel approach has significantly increased the life spans of yeast and human cells in laboratory dishes and extended the lives of flies and worms --organisms that, on the level of  molecular biology, age much as humans do. Indeed, the  researchers said, the compounds seem to have the same anti-aging effect as a drastic reduction in calories, the only strategy ever proven to extend life in mammals but one that most people find difficult to stick to.

It is too soon to say whether the latest findings will ever make the leap from the lab
bench to the geriatrics clinic -- though some may choose not to wait: Of all the
compounds the researchers tested, the one that boosted the anti-aging enzyme the
most was resveratrol, an ingredient in red wine that has been credited with that
beverage's ability to lower the risk of heart disease.

But the findings strengthen an increasingly popular notion among many scientists that
the cellular enzymes at the core of the experiments -- called sirtuins -- are universal
regulators of aging in virtually all living organisms and represent a prime target for new
anti-aging drugs.

"It's looking like these sirtuins serve as guardians of the cell," said Harvard Medical
School researcher David Sinclair, who led the new work published in yesterday's
online edition of the journal Nature. "These enzymes allow cells to survive damage
and delay cell death."

Now the race is on, Sinclair said, to find the most potent sirtuin stimulators -- or
create synthetic ones -- and test their ability to extend the lives not only of cells, flies
and worms but also of mice, monkeys and humans.

Other researchers were more cautious, warning that aging is a complex and poorly
understood process that is unlikely to be slowed by any single drug. As promising as
the research may appear today, they said, sirtuin would not be the first fountain of
youth to prove a mirage.

"Let's face it, aging isn't the same in humans and yeast," said Jef Boeke, a yeast
geneticist at the Johns Hopkins University School of Medicine. Besides, he said,
sirtuins are potent molecules, and in cranking them up, "one would have to be very
careful about potential side effects." The new study caps a three-year string of
discoveries involving sirtuins (pronounced sir-TOO-ins), a class of enzymes that are
found in virtually every organism, including bacteria, plants and people. As with all
enzymes, their job is to promote essential biochemical reactions inside cells.

At first scientists thought sirtuins spent most of their time pulling key molecules off the
proteins that surround DNA -- part of the process by which cells turn their genes on
and off.

But recently researchers learned that sirtuins are also involved in processes with much
more medical -- and commercial -- potential: They are part of a feedback system that
enhances cell survival during times of stress, especially if that stress is a lack of food.

For years researchers have known that life span can be extended by 50 percent or
more in many kinds of creatures, including flies, worms and mice, if the animal is fed a
diet that is nutritious but contains about 30 percent fewer calories than usual. Recently
scientists found that the life-extending benefits of calorie restriction do not occur if the
animal has been genetically altered to lack sirtuins, indicating these enzymes are
crucial to this process.

Now scientists are coming to understand sirtuins' role in that life-extending response.
In people, they seem to halt the normal cellular cycle that ends with old cells
committing suicide and instead help rejuvenate them by beefing up their DNA repair
processes and stimulating production of protective antioxidants.

"What we think is that if a cell is at a point of deciding whether to live or die, these
sirtuins push toward the survival mode and let the cell try a little harder and longer to
fix itself," said Sinclair, who has a financial stake in a new effort to develop
sirtuin-related products with BIOMOL Research Laboratories of Plymouth Meeting,

Leonard Guarente, a researcher at the Massachusetts Institute of Technology in
Cambridge, is also enthusiastic about the compounds' potential as anti-aging aids.

"We're very keen on the idea that this is it" -- that sirtuins are the central regulator of
the aging process -- Guarente said. He is a founder of Elixir Pharmaceuticals of
Cambridge, Mass., which, like Sinclair and BIOMOL, hopes to capitalize on
chemicals that can boost sirtuin activity.

The goal is to make drugs or nutritional supplements that can fool the body into
thinking it's living on a radically calorie-reduced diet, in effect allowing people to eat
their cake and live longer, too.

The new report from Sinclair's team is the first to show that it is indeed possible to
tweak the sirtuin pathway. The group screened a large number of biologically active
chemicals -- simple compounds that can be made into drugs with relative ease. They
found several that increase sirtuin activity at least two-fold, including resveratrol.

When they added some of these compounds to yeast cells growing in culture dishes,
the cells produced 70 percent more daughter cells than normal -- a common measure
of yeast youthfulness.

Human cells seemed to benefit, too. Those treated with sirtuin boosters enjoyed long
lives in laboratory dishes even after being exposed to ionizing radiation, which
damages DNA and usually shortens a cell's lifespan.

And in experiments not yet completed, Sinclair said, the compounds have shown
evidence of being able to extend the life spans of two full-blown organisms: the
soil-dwelling nematode worm known as C. elegans and the common fruit fly. Both
are popular stand-ins with scientists trying to understand human biological processes.

Sinclair said his group plans to start feeding sirtuin boosters to mice in the next few
months and then move up to testing in monkeys. The immediate goal in people would
be to slow the progression of diseases of aging such as Alzheimer's, because a more
generic slowing of the aging process could take decades to prove.

But others warned against exaggerated expectations. Richard Weindruch, a
gerontologist and expert in calorie restriction at the University of Wisconsin in
Madison, said the work was "very interesting and deserves to be carefully explored in
mammals." But he questioned the relevance of the yeast experiments -- which, strictly
speaking, measured not life span but the number of times a yeast cell could divide and
produce daughter cells.

"Clearly, numbers of generations are related to time, but it's not the same in my mind
as following a single animal over its lifetime," Weindruch said. Indeed, he noted,
"What they are really looking at here is increased proliferative capacity," which he and
others noted is akin to cancer.

David Finkelstein, an expert in metabolic regulation at the National Institute on Aging,
which funded some of Sinclair's work, said the work was "very nice science" but also
warned against leaping to conclusions. "We have results in a lower organism," he said,
"and at this point, there's a lot of hand waving because of how little we know."

Finkelstein also advised against taking the resveratrol results too literally.

"Would the National Institute on Aging recommend you drink red wine every day?
The answer is 'no,' " he said. "If you were to add a glass of red wine every day
without changing your caloric intake, you're going to gain weight. And we know -- we
know -- that if you gain weight, that's going to be harmful while this 'benefit' is a
benefit that may or may not occur."

"People are always looking for a quick fix," Finkelstein said. "Tell people to eat a
healthy diet."

                 © 2003 The Washington Post Company

Chemical in red wine may contribute to longer life

The New York Times
August 25 2003

Biologists have found a class of chemicals that
they hope will make people live longer by activating
an ancient survival reflex.

One chemical, a natural substance known as
resveratrol, is found in red wines, particularly those made in cooler climates like that
of New York.

The finding could help explain the so-called French paradox -- the fact that the
French consume fatty foods considered threatening to the heart but live as long as
anyone else.

Besides the wine connection, the finding has the attraction of stemming from
fundamental research in the biology of aging. However, the new chemicals have not
yet been tested even in mice, let alone people, and even if they work in humans it
will be many years before any drug based on the new findings becomes available.

The possible benefits could be significant. The chemicals are designed to mimic the
effect of a low-calorie diet, which is known to lengthen the life span of rodents.
Scientists involved in the research say human life span could be extended by 30
percent if people respond to the chemicals the way rats and mice do to low calories.
Even someone who started at age 50 to take one of the new chemicals could
expect to gain an extra 10 years of life, said Dr. Leonard Guarente of the
Massachusetts Institute of Technology, one of the pioneers of the new research.

The result was announced last week at a scientific conference in Arolla, a small
village in the Swiss Alps, by Dr. David A. Sinclair of Harvard Medical School. It was
published electronically Sunday in the journal Nature.

The new development has roused the enthusiasm of many biologists who study
aging because caloric restriction, the process supposedly mimicked by the
chemicals, is the one intervention known to increase longevity in laboratory animals.
A calorically restricted diet -- including all necessary nutrients but 30 percent fewer
calories than usual -- has been found to extend the life span of rodents by 30
percent to 50 percent. Scientists hope, but do not yet know, that the same will be
true in people.

A similar mechanism exists in simpler forms of life, which has led biologists to
believe that they are looking at an ancient strategy, formed early in evolution and
built into all animals. The strategy allows an organism to live longer and postpone
reproduction when food is scarce, and to start breeding when conditions improve.

Two experiments to see if caloric restriction extends life span in monkeys are at
about their halfway point -- rhesus monkeys live about 25 years in captivity -- and
the signs so far are promising, though not yet statistically significant. But even if
caloric restriction should extend people's life span, the current epidemic of obesity
suggests how hard it would be for most people to stick with a diet containing 30
percent fewer calories than generally recommended.

Biologists have therefore been hoping to find some chemical or drug that would
mimic caloric restriction in people by tripping the same genetic circuitry that a
reduced-calorie diet does and provide the gain without the pain. Sinclair and his
chief co-author, Dr. Konrad T. Howitz of Biomol Research Laboratories in Plymouth
Meeting, Pa., say they have succeeded in finding a class of drugs that mimic
caloric restriction in two standard laboratory organisms, yeast and fruit flies. Both
mice and humans have counterpart genes that are assumed to work in a similar
way, though this remains to be proved.

Independently, Elixir Pharmaceuticals of Cambridge, Mass., had found a different
set of chemicals that mimic caloric restriction, said Ed Cannon, Elixir's chief
executive. Because of testing and regulatory requirements, he said, his company is
"eight to 10 years away from having an approved drug."

After presenting his results for the first time, Sinclair said in an interview from Arolla,
"I've been waiting for this all my life."

"I like to be cautious," he said, "but even as a scientist it is looking extremely

So far Sinclair and his colleagues have shown only that resveratrol, the chemical
found in red wine, prolongs life span in yeast, a fungus, by 70 percent. But a
colleague, Dr. Mark Tatar of Brown University, has shown, in a report yet to be
published, that the compound has similar effects in fruit flies. The National Institute
of Aging, which sponsored Sinclair's research, plans to start a mouse study later in
the year.

Despite the years of testing that will be needed to prove that resveratrol has any
effect in people, many of the scientists involved in the research have already started
drinking red wine. "One glass of red wine a day is a good recommendation. That's
what I do now," Sinclair said. Resveratrol, he said, is unstable on exposure to the air
and "goes off within a day of popping the cork."

Tatar, asked if he had changed his drinking habits, said, "No, I have always
preferred red wine to white."

Health authorities have not yet had time to make a detailed evaluation of the
research. Dr. David Finkelstein, the project officer at the National Institute of Aging,
said he would not advise anyone to start drinking red wine.

"At this point we have no indication that there will be a benefit in people," Finkelstein
said, adding that the calories in a glass of wine could lead to weight gain.

Dr. Toren Finkel, who is in charge of cardiovascular research at the National Heart,
Lung and Blood Institute, said: "I would be cautious in sending out the message that
one glass of wine a day will make you live 10 years longer. The concentration of
resveratrol in different wine differs. As a drug, it is not ready for prime time." But the
concept of a drug that mimics caloric restriction "is a great idea," he said.

Sinclair said that he and Howitz were working on chemical modifications of
resveratrol that would be more stable. Ownership of the patent will be split evenly
between their parent institutions, Harvard Medical School and Biomol.

Resveratrol is synthesized by plants in response to stress like lack of nutrients and
fungal infection. It exists in the skin of both red and white grapes but is found in
amounts 10 times as high in red wine as in white because of the different
manufacturing process.

According to "The Oxford Companion to Wine" pinot noir tends to have high levels of
the chemical, cabernet sauvignon lower levels. "Wines produced in cooler regions or
areas with greater disease pressure such as Burgundy and New York often have
more resveratrol," the book says, whereas wines from drier climates like California
or Australia have less.

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İMatt Mitchell