NEWSWEEK: The search for longer life

[Guest guest]

Never Say Die; Step aside, quacks. The search for longer life is a real

science now.

By Anne Underwood

NEWSWEEK

Dec. 15, 2008

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 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 León, 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 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. 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, GlaxoKline 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

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 s 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, s 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.