By the time it reaches the age of 18 days, the
average roundworm is old, flabby, sluggish and
wrinkled. By 20 days, the creature will likely be
dead�unless, that is, it's one of Cynthia Kenyon's
worms. Kenyon, director of the Hillblom Center for the
Biology of Aging at the University of California, San
Francisco, has tinkered with two genes that turn
simple worms into mini-Methuselahs, with life spans of
up to 144 days. "You can beat them up in ways that
would kill a normal worm�exposing them to high heat,
radiation and infectious microbes�and still they don't
die," she says. "Instead, they're moving and looking
like young worms. It's like a miracle�except it's
science."
Since the days of Ponce de Le�n, if not before,
people have been seeking the elusive Fountain of
Youth. Until recently, such pursuits were the realm of
quacks and charlatans. And there are still plenty of
snake-oil salesmen out there on the Internet and in
so-called anti-aging clinics, hawking everything from
longevity-bestowing Ecuadoran waters (which are
probably harmless) to growth hormones (which could be
downright dangerous for adults). But serious
scientists are now bringing respectability to the
field, unraveling the secrets of aging on a cellular
level and looking for ways to slow it down. And while
the science is still young (so to speak), legitimate
longevity-boosting treatments could be available in 10
to 15 years�although the gains would be more modest
than in Kenyon's worms.
The pursuit is not as quixotic as it may seem. Some
critics of the scientific quest for longevity say it's
God's will that we should die when our time comes. But
in the past century, a clean water supply,
antibiotics, vaccines and improved medical care have
boosted life expectancy at birth by roughly 50 percent
in the United States�from 48 for men and 51 for women
in 1900 to 75 for men and 80 for women today. No one
seems to object to that. "I'm 54," says Felipe Sierra,
director of the division of aging biology at the
National Institute on Aging. "A hundred years ago, I
would have been dead by this age." Others argue that
keeping people alive longer will further strain the
social safety net. Yet for most scientists, the goal
is not to tack years of sickness onto the end of life.
"The goal is to extend youth," says Harvard molecular
biochemist David Sinclair, who is working with a
potential anti-aging compound called resveratrol. "I
want to keep people healthier for longer and lessen
the burden on the economy."
Studies are already yielding important clues on
what produces healthy aging. One obvious answer is a
healthy lifestyle, with plenty of exercise and a diet
that includes lots of fruits, vegetables and whole
grains. Seventh-day Adventists eat a vegetarian diet,
don't smoke and spend a lot of time with family and
church groups, which helps reduce stress. "They
routinely live to 88 or so, which suggests those are
ages most of us could attain with a healthy
lifestyle," says Dr. Thomas Perls, director of the New
England Centenarian Study.
But to make it to 100, like the 1,500 participants
in Perls's study�or 110, like his
"supercententarians"�it takes more than virtuous
behavior and avoiding a collision with a Mack truck. A
person needs genes that slow aging and boost defenses
against age-related diseases. About half a dozen such
genes have been identified out of perhaps 100 or so
that might exist. The exceptional people with these
genes seem to spend very little time sick�even when
they defy all the rules. "We had one man who smoked
three packs of cigarettes a day," says Perls. "He gave
up smoking at 90, but he still drank three martinis a
day�and he was out repairing his roof the day before I
visited him. He died at 103."
Some of these beneficial genes appear to be
involved in metabolic pathways related to growth, as
well as the processing of fat and cholesterol. Kenyon
manipulates a gene in her worms that reduces the
action of insulin and a related hormone called IGF-1.
"Lowering these hormones activates a gene called
Foxo," she says, "which stimulates a whole host of
responses that protect cells�boosting the immune
system, increasing antioxidants, keeping proteins
folded correctly." A study of Ashkenazi Jewish
centenarians this year also found variations in genes
governing IGF-1. A second study found protective
changes in the Foxo genes of healthy 95-year-old men.
If there were no way to achieve these ends without
having rare genes, then there would probably be no
hope for most of us. (Only one in 6,000 Americans
alive today is a centenarian.) But there may be
another route to the same end, even if it's a path
most of us will not want to follow�a severe
low-calorie diet. Mice who eat 30 percent less live
about a third longer. Similar effects in primates are
just becoming available through a decades-long study
in rhesus monkeys.
Obviously, no one can put people in cages, control
their diets and follow them for 80 years to see how it
all works out. But Dr. Luigi Fontana at Washington
University School of Medicine is tracking 45 members
of the Calorie Restriction Society, who voluntarily
put themselves on such a diet. They are people like
Tadd Ottman, 53, a software engineer in California.
Since adopting a calorie-restriction diet in 2002,
he's eaten just 1,500 calories a day, while being
careful to meet nutritional requirements (one factor
that distinguishes the practice from anorexia). He's
dropped from 180 pounds to 130�and learned to cope
with the effects: hunger pangs, reduced libido and
feeling cold. On the bright side, his cholesterol has
fallen from 244 to 169, his blood pressure is just 96
over 66 and he requires 45 minutes less sleep a night.
"I'm like a long-distance runner," he says, "except
that I don't exercise." He doesn't take in enough
calories for much of that.
Fontana has been studying Ottman and 44 others for
an average of 12 years. "Their heart function is 15
years younger than their chronological age," he says.
"They have the blood pressure of teenagers." Their
C-reactive protein�a measure of damaging, chronic
inflammation�is a fraction of normal. The only way
they fall short of calorie-restricted mice (other than
extended life span, which has not yet been
demonstrated) is that they do not have lower levels of
the hormone IGF-1, which is believed to play a major
role in aging and cancer. "IGF-1 doesn't fall, because
25 percent of their calories come from protein, versus
the recommended 15 percent," he says. "We don't see
this in vegetarians."
Extreme calorie restriction is not a practice that
most people should try. Too many people are likely to
simply yo-yo out of any initial weight loss. And
pregnant women and children should never attempt it,
lest they hinder development.
But Harvard's Sinclair is hoping to develop pills
that will mimic the benefits of calorie
restriction�without depriving us of chocolate or
crumpling our sex drive. In 2006, he published a
much-heralded study in Nature on a compound from red
wine called resveratrol. Obese mice that received
concentrated doses were just as healthy as skinny
mice. They also lived longer and had superior
endurance. "They were Lance Armstrong mice, except
they were fat," he says. In a study this year, lean
mice on resveratrol also had less heart disease, fewer
cataracts, stronger bones and better motor
function�though they did not live longer than normal.
To the extent that resveratrol mimics calorie
restriction and exercise, it may be because all three
activate a protein called SIRT1, a member of the
sirtuin family of enzymes. SIRT1 increases the
formation of new mitochondria, the power plants of
cells, and it revs up existing ones. Last month
Sinclair published a study showing that SIRT1 also
repairs chromosome breaks, helping to keep youthful
genes switched on and aging genes turned off. And
Kenyon says that SIRT1 boosts the same metabolic
pathway that she enhances in her worms.
None of this proves that SIRT1 extends human life.
But both Kenyon and Sinclair have helped set up
businesses to pursue clinical applications of their
work. Any drugs that result will not be approved for
longevity, since the FDA approves drugs only to treat
illnesses. Instead, both Sinclair's Sirtris
Pharmaceuticals and Kenyon's Elixir Pharmaceuticals
are pursuing pills for diabetes, one of the leading
diseases of aging. Sirtris's formulation of
resveratrol has been shown in early trials to lower
blood sugar and insulin in patients with type 2
diabetes, and the company is entering trials with
synthetic sirtuin activators that are up to 1,000
times more potent than resveratrol. Though 60 to 90
percent of drugs at these stages of testing ultimately
fizzle out, GlaxoSmithKline purchased Sirtris over the
summer for $720 million. "Half a dozen major drug
companies are working on sirtuins," says Dr. Christoph
Westphal, CEO of Sirtris. "Because they affect many
diseases of aging, the potential market is huge."
Other future blockbusters could be drugs that
repair telomeres, the DNA caps on the ends of
chromosomes. Every time a cell divides, the telomeres
become shorter. When they shrink too much, cells stop
replicating and start to function poorly. The result
is wrinkling and general deterioration�well-known
problems of aging. But scientists hope to forestall
the effects by boosting telomerase, an enzyme that
rebuilds telomeres. "There are rare families with very
low telomerase," says molecular biologist Elizabeth
Blackburn of UC San Francisco. "They never make it to
old age. They die first of infections, cancers or lung
fibrosis."
That doesn't prove that boosting telomerase extends
years of health. But it's a reasonable hypothesis.
Last month the first evidence in mammals surfaced in a
study from Spain. Mice that were bred to have enhanced
levels of telomerase lived 40 percent longer�and had
better glucose sensitivity and motor function,
stronger skin and less inflammation. The relevance to
humans is open to debate. But UCLA immunologist Rita
Effros also published a study last month on immune
cells that were drawn from people with HIV. The cells
were treated in the lab with a telomerase activator
from Geron Corp. "Sure enough, they killed viruses
better, divided longer and acted more youthful,"
Effros says. It's not just people with HIV who stand
to benefit. "Many diseases of aging involve a weakened
immune system," she says. But because too much
telomerase could theoretically boost cancer risks, "it
will be a long and difficult job to make sure a
telomerase drug is safe," says Blackburn.
Some folks aren't waiting. Telomere biologist Bill
Andrews of Sierra Sciences is taking a
telomerase-boosting supplement called TA-65. "I
believe it's safer than driving my car to work," he
says. Since he started taking it a year and a half
ago, Andrews says he has moved from the back of the
pack to the front in 100-mile runs known as
ultramarathons. But don't expect to find TA-65 at your
local Vitamin Shoppe. It is available only from TA
Sciences�for $25,000 a year. And customers have to
undergo a battery of tests every six months to gauge
the results, none of which have been published yet.
It might be smarter to save the $25,000 and modify
your lifestyle. Last month Blackburn published a study
showing that 30 men on Dr. Dean Ornish's program (an
ultralow-fat diet, exercise and stress reduction)
increased their telomerase levels by 30 percent.
"According to the World Health Organization, 80
percent of heart disease and 40 percent of cancers
could be prevented with a healthy diet and lifestyle,"
says Fontana. For those of us in the wrong end of the
gene pool, healthy habits may be the best life
preserver around.
With Karen Springen