Home' Technology Review : March April 2006 Contents 74 FEATURE STORY
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The vital questions, he says, are what controls that process
and whether we can develop dr ugs to target it. "We don t
assume we know everything about it, but we do strongly
believe that sirtuins are a major component in what could
be a master regulatory system for human health."
The identi cation of the life-extending e ects of sir2 in
yeasts was no accident: Lenny Guarente had been search-
ing for the causes of yeast aging for almost a decade when
he and his MIT graduate students methodically zeroed
in on the gene in 1999. It was an important nding, but
its real signi cance became more apparent over the next
year and a half.
First, Guarente and his students found the sir2 gene in
round worms. Since yeast and worms diverged evolutionarily
billions of years ago, the presence of the same gene in both
organisms suggested that it might be shared by other animals,
including humans. Then came the bombshell. The expres-
sion of the sir2 gene required the presence of another mole-
cule, called NAD; as any biologist knew, NAD is involved
in numerous metabolic reactions in many organisms. "This
nding that sir2 was NAD dependent meant to us that sir2
could connect aging to metabolism and therefore to diet,"
says Guarente. "Once you see this activity, a child could point
out, Maybe this would connect to caloric restriction."
Perhaps not most children, but other molecular biologists
certainly saw the connection, and labs around the world
soon began to puzzle out the e ects of sir2. Scientists knew
that calorie restriction could have an impact on disease. And
now there was evidence of a strong link between sir2 and
calorie restriction. "If you put those together," says Guar-
ente, "you can formulate a hypothesis that sir2 genes will
impact diseases of aging."
Amidst this urry of research, however, it was a 2003
paper in the journal Nature by Sinclair and his collaborators
that really caught the attention of those hoping to turn the
science of sirtuins into drugs. Sinclair identi ed a class of
common chemicals, called polyphenols, that activate sirtu-
ins. The ndings suggested it might be possible to develop
small-molecule dr ugs that could interact with sirtuins and
turn on their apparent bene cial e ects.
Six months after the Nature paper, Sinclair cofounded Sir-
tris with Christoph Westphal, then a partner at Polaris Ven-
ture Partners, a Waltham, MA--based venture capital rm.
[Disclosure: Polaris general partner Robert Metcalfe is on
Technology Review s board of directors.] Less than two years
later, the startup has $45 million in venture nancing and a
series of drug candidates that activate SIRT1 and other sir-
tuins in mammals. Within a few years, says Westphal, now
Sirtris s CEO, the company hopes to begin testing the safety
of the sirtuin activators in humans. "We re aiming to mimic
calorie restriction with small molecules," says Westphal. "The
great break for us was to nd those small molecules."
Meanwhile, members of Sinclair s Har vard lab are busy
conducting experiments on thousands of mice to prove the
bene ts of sirtuins in treating disease and aging. The mice
are stacked in endless rows of small, clean cages packed
into a series of locked rooms. Some of the mice, partly
bald and sti jointed, have been genetically engineered to
age prematurely. Other cages hold animals genetically des-
tined to get colon or prostate cancers, while yet other mice
will develop neurological impairments of a kind associated
with Alzheimer s disease. The researchers crossbreed these
mice with animals genetically engineered to overexpress
one of the sirtuin genes, then monitor how the o spring
fare---whether the sirtuins ght o the diseases or prevent
premature aging. Taken together, it is a massive e ort to
understand the role of sirtuins in mammals, with thousands
of mice providing di erent pieces of the puzzle.
Given that the mice experiments are just a year old,
and mice typically live for around three years, results are
still preliminary. There is not yet any conclusive evidence,
for one thing, that activating or overexpressing sirtuins
increases the life span of the mice. But Sinclair says that
the studies completed so far all show "that the diseases in
the mice have been ameliorated."
Elixir Pharmaceuticals and Sirtris have much in common.
Both rms were founded to discover dr ugs for age-related
diseases, using core technology built around antiaging
genes. Both feature rosters of star antiaging researchers,
with Elixir counting Guarente and Kenyon among its found-
ers. Just a few miles apart, Elixir is at the edge of MIT s
campus, while Sirtris is next to Har vard University.
But despite their similarities, the two companies seem
to have radically di erent outlooks. At Elixir, which was
founded in 1999, there is no evidence of the kind of youth-
ful bravado that characterizes Sirtris. On the whiteboard
in his small o ce, Peter DiStefano, Elixir s chief scien-
ti c o cer, patiently and meticulously diagrams some of
the metabolic pathways that the company is investigating.
Some directly involve SIRT1; some don t. Arrows over-
lap in a complicated mesh; some arrows just wander o ,
pointing to unknown territory. DiStefano s point is clear:
these molecular mechanisms are immensely complicated
and still not completely understood.
"It s hard to say when we will get to a drug development
candidate [based on sirtuins]. It s a little early," he says. He
points to a small sign above his door, positioned so that it s
the last thing you see as you leave the o ce. It reads, "The
animal is always right." The challenge, says DiStefano, is
translating the knowledge of mechanisms at the cellular
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