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lious and dangerous," he says. "That was the thrill. I think I
was bored." When he was seven years old, he came up with
a list of 10 ways to change the world, and one was to create
inventions to make money. Later, he took up windsur ng and
racing around in cars. He got so many speeding tickets that
he once had his license con scated. "He was always quite
cheeky and could get under your skin if he knew you well
enough," says Mark Sumich, his best friend growing up.
"I think the day I got most scared in my life was when
he showed me his brother s new compound bow," recalls
Sumich, who now owns a market-research company in
Australia. "We went up to the park, and he would shoot it
straight up in the air, and having lost sight of it, we would
scatter for cover. That, to this day, is still the most stupid
thing I have ever done."
Sinclair attended the University of New South Wales
and was studying gene regulation in yeast when he learned
about longevity research during a conversation with Leonard
Guarente, an MIT molecular biologist who was in Australia
giving lectures. Back then---1993---most people assumed that
aging was a complex and inevitable process that could not be
regulated by just a few genes. But that year, Cynthia Kenyon,
a biologist at the University of California, San Francisco, pub-
lished a study showing how manipulating a single gene, daf2,
could double the life span of a tiny roundworm. Guarente
himself was beginning experiments on yeast that would lead
to the discovery of the antiaging gene sir2 in 1995.
The field was so new and unproven, though, that
Guarente talked about it only informally---as, for instance,
when a young Australian scientist sat down next to him dur-
ing a group lunch. "This was incredibly serendipitous," says
Sinclair. Inspired, he sold his Mazda Miata to buy a ticket
to Boston to inter view for a postdoc position in Guarente s
lab. During his inter view, he gave a spirited whiteboard
presentation arguing that scientists studying aging should
look for genes that prolong life rather than genes and mecha-
nisms that end it. He got the job.
While Sinclair was in Guarente s lab in the late 1990s,
he discovered that sir2 prevents aging in yeast by slowing
down the accumulation of ERCs, circular strands of DNA
that build up in organisms as they age, eventually killing
them. Around the same time, others in Guarente s lab made
another crucial discovery: that a link may exist between
sir2 and a molecule critical for metabolizing food, called
NAD. The connection suggested that the longevity gene
might be related to diet---speci cally, Guarente postulated,
to caloric restriction. A nutritionally complete diet contain-
ing 30 to 40 percent fewer calories than normal had long
been known to extend life span in some animals, ramping
up cell defenses and slowing down aging. Guarente and
others theorize that in times of scarcity, such as famine or
drought, this mechanism allows an organism to sur vive---
and postpone reproduction---until the crisis is over. The link
between sir2 and NAD, therefore, suggested to Guarente
that caloric restriction might be a ecting longevity by acti-
vating the antiaging gene.
Colleagues who were students in Guarente s lab dur-
ing this period remember Sinclair as highly ambitious.
Shin-ichiro Imai, then a postdoc, now a molecular biolo-
gist at Washington University in St. Louis, and still a friend,
describes him as "obsessed," with a penchant for aggres-
sively pursuing his ideas. "He is an introvert who becomes
an extrovert for what he s working on," Imai says.
Sinclair s ambition has also complicated his relationship
with his mentor, who helped him secure an appointment
in Harvard Medical School s department of pathology in
1999. Guarente, a lanky man with a shaved head and intense
eyes, says he is proud of his protégé. In 2004, however, an
article in Science described a rivalry between the two men
that began during a meeting at Cold Spring Harbor in New
York, where Sinclair stunned Guarente by disagreeing with
him about how a key gene associated with caloric restric-
tion increases life span in yeast. The two began publishing
competing papers, vying head to head to gure out how
sir2 and, later, other antiaging genes are regulated. "Most
young scientists would not compete directly with their men-
tors, but David did," says Imai.
Sinclair also said no to signing on with Elixir Pharma-
ceuticals, the company cofounded by Guarente and Cynthia
Kenyon in 1999, which for a time he had hoped to join.
By the time Elixir called, he had discovered the e ects of
resveratrol; in 2004 he surprised his former teacher by
cofounding Sirtris, a company whose name incorporated that
of the SIR genes that Guarente had helped to discover.
Both men say that Science overstated the extent of the
rift between them. There was some tension for a couple of
years, they say, but that has died down. They now collabo-
rate on some experiments and articles, and they talk fre-
quently. In a curious turnaround, Guarente left Elixir last
year and has considered working with Sirtris, although he
can t join the company until the fall of 2007 because of a
one-year noncompete clause in his contract with Elixir.
In 2003, one unsolved mystery among the still-small cadre
of longevity researchers was how to modulate genes, such as
SIRT1, that regulate life span. Was there a compound that
could be taken as a pill? Elixir and other companies and labs
were beginning to screen thousands of chemicals to see if one
would work as a gene activator, but none t the bill.
To read a detailed explanation of the science behind resvera-
trol and sirtuins, go to technologyreview.com/sirtuins.
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