Diet Restriction

Eat Less, Live Longer? - By MICHAEL D. LEMONICK

A few years ago, Harvard researcher Dr. David Sinclair joined the growing ranks of scientists who believe that severely restricting calorie intake can slow down the aging process. Evidence for that surprising phenomenon emerged in the 1930s, when scientists learned that underfed rodents lived up to 40% longer than their well-fed counterparts. The results have since been duplicated in fruit flies, worms, monkeys and other lab animals. And preliminary research on humans suggests that some markers of aging—levels of blood glucose, blood pressure, cholesterol—improve on calorie-restriction (CR) diets.

So Sinclair put himself on the same sort of severe diet that members of the tiny but highly motivated Calorie Restriction Society follow. He lasted a week. "It was too tough," he says. "My hat's off to the calorie restricters. Now I'm hoping to find drugs that can give people the benefits of CR without the diet."

Those drugs haven't been perfected yet, but Sinclair and other researchers are making progress by trying to understand at the molecular level what it is about CR that seems to slow aging. Sinclair has found, for example, that resveratrol, a chemical found in red wine, increases life-spans of yeast and fruit flies. It works by amplifying the action of a molecule called SIRT1, which is present in all life forms and is produced in response to stress. "It's like a cell's 911 center," says Sinclair, and resveratrol is like a false alarm.

That fits with one of the leading theories about why CR works in the first place: starving the body puts it under mild, constant stress, priming it to resist the more severe stresses that make cells age—a sort of self-vaccination against decline. "With resveratrol," says Sinclair, "we're tricking the body into thinking it's not getting enough calories." If he can create a form of resveratrol that's easily absorbed by human cells and can demonstrate that it works without dangerous side effects, Sinclair may eventually come up with what amounts to an antiaging pill.

At the University of California, San Francisco, meanwhile, molecular geneticist Cynthia Kenyon is taking a different approach to aging research, identifying a number of genes in roundworms that help stave off disease and extend life. One such gene directs the action of a receptor for insulin and an insulin-like hormone called IGF-1, and by manipulating it along with other genes, she can increase the worms' life-span sixfold. "It's not so much that they're just living longer," she says. "What's remarkable about these worms is how healthy they are."
But the story is more complex: Kenyon has found that hormones in her long-lived worms actually regulate several unusual genes to increase life-span. One set of genes triggers the worms' cells to make antioxidants, which fight off the ravages of molecules called free radicals, which can damage DNA. Another set directs the creation of proteins called chaperones; they help other proteins fold into their proper shapes. They also detect and destroy improperly folded proteins that can cause such aging-related ailments as Huntington's disease. Other genes affect the transport of fat around the body—which may also have an effect on aging—and create proteins that kill invading microbes. "It's like an orchestra," says Kenyon. "The conductor is the hormones. You have the flutes as the antioxidant genes. The violins would be the chaperones, the cellos the metabolic genes. And maybe the drums would be the antimicrobial genes. So many different kinds of genes can have enormous effects on life and death, and each one on its own could potentially have an effect on human life-span or disease."

At the University of Wisconsin at Madison, gerontologist Richard Weindruch studies deprivation, like Sinclair, but has a different idea about why calorie restriction works. He has been comparing calorie-restricted rhesus monkeys with unrestricted ones and has found striking differences. The CR monkeys have shown no evidence of diabetes, for example, while it affects about half of normal monkeys. Only four of his CR monkeys, moreover, have died from age-related diseases—half the rate of the control group. He believes the explanation lies in the complex activities of fat cells. The CR monkeys have much less body fat, and that—just as with slim vs. obese humans—seems to protect against a wide range of ills.

Calorie restriction has its downside, though, and it's not just hunger. Weindruch's monkeys experience changes in bone density, and other labs have reported changes in libido, menstrual cycles and body temperature in calorie-restricted monkeys. And Sinclair's worms and flies suffer from loss of appetite and fertility. Researchers hope to create drugs based on resveratrol or on the genetic research that would avoid those pitfalls.

In the meantime, members of the CR movement are proceeding with their personal experiments in consumption. Although early CR advocates tried extreme diets, hoping to live to 120 or beyond, most current practitioners take a more moderate approach and have the more modest goal of staving off illness. For the past five years, Andrea Tiktin-Fanti, 61, of Uhrichsville, Ohio, has been adhering to a 1,200-calorie-a-day diet—about half what U.S. women typically eat. Diabetes killed both her parents in their 60s, but her diabetes is under control, thanks to her Spartan diet. "If I live to 85 or 90," she says, "I will have extended my life-span, and I'll be real happy with that."