Home' Technology Review : September October 2007 Contents 82 FEATURE STORY
TECHNOLOGY REVIEW /
In Febr uary 2003, in what was then his small, shoestring
lab at Harvard, Sinclair was doing his own screening when
he lear ned that scientists at Biomol Research Laboratories,
a biotech company in Plymouth Meeting, PA, had observed
that SIRT1 was activated by certain polyphenols, including
resveratrol. Sinclair and Konrad Howitz, Biomol s director of
molecular biology, collaborated to isolate resveratrol and test
it in yeast and fr uit ies. "Never in my wildest dreams did I
think we would nd an activator of sir2," says Sinclair.
In a 2004 Science inter view, Sinclair added to his reputa-
tion as a zealot, calling resveratrol "as close to a miraculous
molecule as you can nd." "One hundred years from now,"
he said, "people will maybe be taking these molecules on a
daily basis to prevent heart disease, stroke, and cancer."
That same year, two scientists who were students in
Guarente s lab when Sinclair was there published a paper
casting doubt on the underpinning of Guarente s hypothesis
that caloric restriction activates sir2---a hypothesis that is crit-
ical to Sinclair s own theories. ("I have independent-minded
students, I guess," Guarente told me with a wry smile.)
The for mer students, Brian Kennedy and Matt Kaeberlein,
both biologists at the University of Washing-
ton, claimed that, at least in yeast, caloric
restriction could exert antiaging e ects in
the absence of sirtuins---the enzymes pro-
duced by sir2 and its mammalian homo-
logues (such as SIRT1). Studies published
soon after posed a more direct challenge to
Sinclair s contention that resveratrol mimics
caloric restriction by activating sirtuins. Peter
DiStefano, a coauthor of one of these studies and the chief
scienti c o cer of Elixir, told me in 2005 that resveratrol
does wondrous things, but it is unlikely to be an activator
of the SIRT1 enzyme.
That skepticism, however, didn t deter Sinclair. In 2004
he set out to prove that resveratrol indeed mimicked some
e ects of caloric restriction, joining with Rafael de Cabo of the
National Institute on Aging to test the chemical on mice.
Mice live about two to three years; when I rst visited
Sinclair s lab, in 2005, his test mice were about a year old.
Sinclair was already ecstatic, because the resveratrol-fed
mice seemed healthier than the controls; their cells were
also aging remarkably slowly, even though the mice were
being fed a fatty, unhealthy diet. When the paper on these
experiments came out the following year in Nature, the
results supported the claims Sinclair had been making about
resveratrol in mammals. They showed that mice on a high-
fat diet fed large doses of resveratrol were as healthy as mice
on a regular diet. Resveratrol also improved the mice s insu-
lin sensitivity and increased their energy production.
The mice were given very high doses of resveratrol---
22 milligrams per kilogram of weight. In comparison, a
liter of red wine delivers 1.5 to 3 milligrams. To consume
resveratrol at the same rate as the mice, a 150-pound human
would need to drink roughly 1,500 bottles of wine (or take
scores of pills) each day.
Sinclair s paper came out within days of a study in Cell
from the lab of Johan Auwerx of the Institute of Genetics
and Molecular and Cellular Biology in Illkirch, France.
Auwer x s team, which was partially funded by Sirtris
(Auwerx is on the company s scienti c advisory board),
had given mice even higher doses of resveratrol---400 milli-
grams per kilogram. These mice stayed slender and strong
on a high-fat diet, with the energy-charged muscles and
reduced heart rate of athletes. The number of mitochon-
dria in their cells increased, which improved the cells
Sinclair s and Auwerx s success in extending the life span
and improving the health of mice has partly assuaged crit-
ics doubts that resveratrol can work in mammals. "Both
studies are extremely exciting," says Kaeberlein; it s "pretty
clear" that resveratrol modi es certain proteins, such as
mitochondrial proteins associated with energy production.
Kaeberlein points out, however, that the tests involved mice
on a high-fat diet and should be duplicated with mice on
a normal diet.
And Kaeberlein is not yet convinced that resveratrol is an
activator of the SIRT1 enzyme. "We were unable to repro-
duce the work from the Sinclair lab in yeast," he says, add-
ing that results have been mixed in ies, wor ms, and other
animals. He also still disagrees that sir2 is the pathway by
which caloric restriction increases longevity in yeast. "Sir2
regulates longevity, and caloric restriction regulates lon-
gevity," he says. But it doesn t follow that caloric restriction
necessarily increases life span by activating sir2.
Critics point out, too, that no one yet knows whether
resveratrol will work in humans. According to Har vard
population biologist Lloyd Demetrius, the evolutionary
forces determining life span are so radically di erent in
mice and humans that mechanisms responsible for slower
aging in mice are unlikely to have much e ect in people.
Demetrius has studied caloric restriction, not resveratrol,
but he s still skeptical of the chemical s viability as a dr ug.
"I think its e ects on the maximal life span in humans will
be almost zero," he says.
"This will impact humans within a decade.
That's why I don't think there is anything
more important than this quest. That's why
I take chances, and why the controversy is
worth it: because I think we are right."
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