Scientists Are Changing the Definition of 'Old Age'

If there were a pill that could add two decades to your life, would you swallow it? Not if you're like most people scientist Matt Kaeberlein asks--they see it as an invitation to purgatory.

"Why would I want to be old for an extra 20 years?" they say. But when the University of Washington longevity researcher dangles the prospect that those extra years would be spent spry and hale, not enfeebled and ill, they listen up.

Researchers like Kaeberlein are learning that the aging process--not only how long we live but how well--is remarkably elastic, and that it can be manipulated. The lives of lab animals have been dramatically stretched in several ways--by tweaking their genes, feeding them drugs, changing their diets--that seem to make them age more slowly while prolonging good health.

In theory, these strategies all do the same thing: fool the body into reacting as it would to a harsh environment, going into survival mode. The question is whether such techniques also can be made to work--safely--in humans.

Scientists like Cynthia Kenyon, a geneticist at the University of California-San Francisco, want to try. Kenyon found in the 1990s that by tampering with a single gene associated with aging in nematodes, roundworms no bigger than one of the commas in this sentence, she could double their normal three-week life span. Deactivating the gene, she discovered, kicked in a "fountain of youth" gene that juiced up the worms' defenses against a slew of ills--extreme heat, oxygen deprivation, starvation, and disease. They lived longer and stayed younger; at six weeks, twice the nematodes' usual life span, they looked to be in the prime of life.

It turns out that humans have both of those genes, and certain variations are enriched in centenarians. Now Kenyon is hunting for drugs that could turn on the fountain of youth gene in human cells.

The secret of slowing down human aging would be one of the greatest discoveries in medical history, says S. Jay Olshansky, a biodemographer at the University of Illinois at Chicago. While aging itself is not a disease, postponing it, he says, would simultaneously postpone the risk of our biggest scourges--cancer, heart disease, stroke, diabetes, Alzheimer's. What follows are three hot areas under investigation: cutting calories, developing drugs to mimic a lower-than-normal calorie diet, and deciphering the genetics of the oldest of the old.

FEWER CALORIES

Hundreds of studies since the 1930s have shown that a below-normal intake of calories slows aging and greatly extends healthy life spans in organisms as simple as yeasts and as complex as rats. The journal Science recently reported that rhesus monkeys (our evolutionary cousins) whose daily calories were reduced 30 percent for 20 years had one third the risk of developing age-related illnesses such as diabetes, cancer, heart disease, and brain deterioration compared with normally fed monkeys.

That suggests "quite convincingly" that their aging is being slowed, says Richard Weindruch, a professor of medicine at the University of Wisconsin whose group is leading the ongoing study. (He'll have to wait a good while, however, to see if they live longer, since rhesus monkeys have been known to survive for 40 years.)

In another study, called CALERIE, researchers are investigating the effect of cutting calories by 25 percent for two years for people of roughly normal weight to see if they undergo the same sorts of changes seen in animals. There's reason for thinking they will, says John Holloszy, a professor of medicine at Washington University, St. Louis, MO, and a principal investigator of the study.

Holloszy and a colleague also have been tracking members of the Calorie Restriction Society International, or "Cronies," as some call them, who curtail their calories--typically by about 30 percent--in pursuit of better health and long lives. They are "powerfully protected" against type 2 diabetes and heart disease, says Holloszy, with clean arteries, low blood pressure (60-year-olds have the levels of children), low cholesterol, and much younger hearts than age-matched control subjects who eat a typical American diet.

There's also supporting evidence from an unintentional experiment. After eight people sealed themselves inside an Arizona biosphere in 1991, they were unable to grow enough food to support their arduous daily regimen and had to cut back from the planned 2,500 calories a day to about 2,000. At one point, they fell below 1,800 calories. They, too, seemed to undergo the beneficial bodily changes seen in animals on restricted diets.

Still, we may never know whether calorie restriction can extend human longevity, says Holloszy. He can't imagine getting the government to fund a decades-long definitive study, and he'd have to wait another 40 years to see if the eldest Cronies rival Jeanne Louise Calment of France, whose 1997 death at age 122 made her the longest-lived person ever confirmed. "I won't be around then," says the 77-year-old Holloszy.

Even if restricting calories adds to life and improves health, following such a regimen is "almost impossible," Holloszy says. Constant hunger is common. Sex drive can slump. The body's thermostat can be thrown off--when everyone else is comfortable, the restricted-calorie crowd may pull out the long underwear. And men (women not as much, says Holloszy) often aren't pleased with the gaunt look.

"I was so skinny that I elicited questions like, 'Are you OK? Do you have cancer? Do you have AIDS?' " says CR Society President Brian Delaney, 46. His "vanishing physical presence"--he shriveled from 160 pounds to 129 during four years at 1,700 calories a day--was why he adopted a more manageable cap of 1,950, which he maintains comfortably.

"What most people working in the area of caloric restriction hope is that once we understand how it works, we'll be able to produce the same effects by other methods," says Holloszy. "By taking a drug." If a pill was created that mimics the benefits of calorie restriction, even Delaney admits he would ditch the diet.

MIMETIC DRUGS

A few years ago, the happy prospect of a pill that would make the body behave as if it was being deprived of calories burst into the headlines when researchers reported that a compound found in the skin of red grapes called resveratrol, when fed to fat mice on a high-calorie diet, seemed to counteract the ill effects of their gluttony without them having to lift a paw. The mice stayed fat but, compared with normally fed mice, they had better bones, heart function, and physical performance, fewer cataracts, and extra protection from diabetes. They also lived about 25 percent longer than overstuffed mice usually do.

Resveratrol already was being sold as a supplement, and within weeks of the 2006 report in Nature, it was flying off the shelves even though there was no proof of the slightest benefit in people, says Rafael de Cabo, an investigator at the National Institute on Aging (Bethesda, Maryland) who co-conducted the research. "Everyone went bananas," he notes. A corresponding surge occurred in sales of red wine, although the beneficial mouse doses were tantamount to 1,000 or so glasses a day. When that sank in, the public frenzy ebbed.

Resveratrol's lasting legacy may turn out to be a better understanding of a family of enzymes called sirtuins. Both resveratrol and calorie restriction seem to act at least in part by activating these enzymes, which "regulate the body's defenses against aging and disease," says David Sinclair, a professor of pathology at Harvard Medical School who collaborated with de Cabo on the mouse study.

A company cofounded by Sinclair to investigate the potential of sirtuin activators is conducting early human trials of a resveratrol formulation for people with cancer and type 2 diabetes. So far the drug has been shown to improve insulin sensitivity and lower blood sugar in type 2 diabetics. The company also is developing and testing sirtuin activators claimed by Sinclair to be 1,000 times more potent than resveratrol.

Last summer, scientists reported on another possible calorie-restriction mimetic. Three teams found that feeding older mice a drug called rapamycin, an immunosuppressant used to prevent organ rejection in transplant patients, significantly extended their lives, apparently by inhibiting an enzyme that is linked to the aging process. It was comparable to adding a robust decade to a human life span, says David Harrison, a professor at the Jackson Laboratory, Bar Harbor, Maine, who led an arm of the study. That doesn't mean people "should start popping rapamycin," says Harrison; among the possible side effects is susceptibility to infection. But if several large demographic studies eventually show that longtime rapamycin users seem to be fending off a wide range of age-related diseases and an effective dose is found, says Harrison, "I'm going to start taking it."

Don't expect to see an age-slowing drug approved anytime soon, researchers say. The U.S. Food and Drug Administration does not consider aging a disease; without an illness to treat, there can be no drug to approve. But the research may yield a crop of drugs that could be OK'd for specific conditions, such as diabetes, and then are later found to protect against others.

"If we're slowing aging, then we should be slowing the onset and progression of most, if not all, age-associated disease processes," says Kaeberlein. A picture may gradually emerge, says Steven Austad, a biogerontology professor at the University of Texas Health Science Center, San Antonio, that "hey, this thing seems to keep people from getting cataracts. And wait a second, all those people don't seem to be getting cancer, either."

CLUES FROM THE VERY OLD

Living to 100 didn't get the warm reception Thomas Perls had expected when his book came out in 1999 ("Living to 100: Lessons in Maximizing Your Potential at Any Age"). He thinks the public assumed that anyone that old "must be in terrible shape." But Perls, who directs the New England Centenarian Study, has found that the vast majority of the centenarians in his sample are doing surprisingly well. Most are free of disabilities until the end of their lives--even those contending with significant age-related ailments, like heart disease. And the 1 out of 7 million people who reach the "supercentenarian" age of 110 and beyond (there are 85 in his study) seem to dodge not only the effects of age-related conditions but the illnesses themselves. Or if they do become ill at the end of their lengthy lives, they quickly die rather than languishing in declining health.

What's the secret of the oldest old?

"Our hypothesis is that centenarians get to be 100 because they have some protection against age-related disease and maybe against aging," says Nir Barzilai, director of the Institute for Aging Research at the Albert Einstein College of Medicine in New York, who has studied Ashkenazi Jewish centenarians and their children for a decade. "When you ask them why they live to be so old, you get this fascinating story. ... They've done nothing right. Some have been smoking for 95 years. There's no one who exercises regularly."

Both Barzilai and Perls are hunting for hints to healthy longevity in those who hit 100 to learn what it is about their genetic makeup that seems to help them along and whether that could help those of us with fewer genetic gifts.

Nearly a quarter of Barzilai's 500 centenarians, for example, have a mutation that bestows on them levels of "good cholesterol" as high as triple normal concentration. He has found that those with the mutation also are largely immune from Alzheimer's disease and apparently have lower risk of heart disease, high blood pressure, and diabetes.

Even without miracle drugs, those of us who didn't "win the genetic lottery at birth," as Olshansky puts it, could add many years to our lives. "We are living about 10 years less than our potential ... mostly due to bad health behaviors," says Perls. Evidence comes from groups of similar individuals who do the right thing.

Seventh-Day Adventists, for example, have an average life expectancy of about 88 years, the highest in the United States, he says. (The U.S. average is 78.) Adventists avoid red meat (many are vegetarian), exercise regularly, and don't drink alcohol or smoke. Their focus on religion and family may ease stress, itself a risk factor.

"That's kind of the recipe," says Perls. It's one that doesn't rely on research breakthroughs, either. But even if a means to slow human aging and extend healthy human life spans eventually emerges from the laboratory, says Austad, "You could still get hit by a car or your parachute doesn't open when you're sky diving." Science can't eliminate chance or bad luck.