Counting Up the Calories, Holding Back the Years?

Dietary restriction prolongs rodents' lives, but its effects on humans are not yet predictable

At the Academy Awards ceremony in March, host Steve Martin introduced an attractive young presenter saying, "I would do anything to look like him--except, of course, eat right and exercise." Those who look to science to extend their lives might face the same dilemma. The only intervention known to slow aging in a variety of animals would, for Haagen-Dazs-loving humans, border on torture: Consume one-third fewer calories every day for life.

Calorie restriction (CR), as the regimen is called, differs from the diets of the Hollywood stars or anyone trying to squeeze into last year's bikini. Weight-loss programs benefit their practitioners by reducing obesity and the incidence of life-threatening ailments such as heart disease and diabetes. But CR is not about shedding pounds; it's about extending one's life span and avoiding the chronic health problems of the later years.

If humans respond as lab animals do, cutting calories could add decades to their lives: Rats and mice fed 30% less live 30% longer than those that eat their fill. They are lean and sleek and remain healthier than their fully fed kin. Preliminary studies suggest that the same holds true for primates--and that old humans share some of the physiological changes that occur in restricted rhesus monkeys, hinting that CR should work in people too. Yet researchers who study CR suspect that, when it comes to following such a drastic diet, most people will be like Steve Martin: unwilling to bear near-perpetual hunger pangs, no matter how fabulous it makes them look--or how long it makes them live. Furthermore, even if we decide to eat like lab mice, we might face some distasteful side effects.

But those same researchers say that studying CR--and determining how it works--is important because this intervention provides the most promising avenue of research on forestalling aging. In the United States, the number of people over 65 is expected to double by 2030, drastically increasing health care costs. Although longer life spans could add to this problem, scientists believe that CR or compounds that mimic its effects could prevent or postpone maladies associated with aging--cancer and Alzheimer's disease, for example--thus increasing the individual's "health-span."

As CR research matures, science and society face two big questions, says Thomas Johnson, a molecular geneticist at the University of Colorado, Boulder. First, will CR work in humans? Second, should we try to use it? To begin to answer these questions, researchers have launched a pilot study for the first major clinical trial of CR in humans. Researchers at the National Institute on Aging (NIA) in Bethesda, Maryland, have put a handful of people on a moderate CR diet, reducing their calorie intake by about 10%. If the program proves safe and practical, NIA will start a 2-year trial whose results might arrive around 2007, says NIA gerontologist Evan Hadley. The research is timely, because scientists such as George Roth, a gerontologist formerly at NIA, predict that a "CR mimetic"--a compound that simulates the biochemical consequences of CR--could enter trials or even reach market in as little as 3 years.

Should CR benefit humans, one obvious response would be to lower the current U.S. recommended daily allowance (RDA) of 2000 to 3000 calories. But researchers say that it would be hard to predict exactly how they should be modified.

Furthermore, the effects of CR are not all positive. Animals on a CR diet are smaller and less muscular, more susceptible to bacterial infection, slower to heal wounds, and less fertile than their well-fed counterparts. And people who are currently practicing CR report chills, irritability, loss of sex drive, and--not surprisingly--constant hunger.

Any diet or compound that scientists come up with must deliver the benefits of CR while avoiding its side effects. Johnson and his colleagues are working with 77 strains of mice to try to determine which genes are responsible for CR's advantages and which might underlie its drawbacks. Unfortunately, the pain might be inseparable from the gain, he says.

That possibility hasn't stopped biotech companies from searching for mimetics. Roth, who is also CEO of GeroTech Inc., is studying a naturally occurring compound that might alter metabolism and hormone concentrations in ways that imitate CR. If all goes well, the mimetic will carry few of the side effects of CR, and GeroTech will make it available as a "nutraceutical," a natural product that would not be subject to time-consuming regulatory approval.

The availability of such a supplement could have unforeseen consequences. Roth says he hopes that CR mimetics would extend both life span and health-span, minimizing the social cost of aging. But the reality could be more complicated. Like any potential age-retarding treatment, CR or its pharmaceutical equivalent pose ethical concerns (see "Extending Life or Compounding Misery?"). But CR raises unique issues as well. The treatment is most effective in lab animals when begun at an early age. If CR stunts growth or impairs fertility in humans, parents might have to decide for their children whether longer life is worth delaying puberty, reducing size and vigor, and perhaps even sacrificing the ability to reproduce.

For organisms as complex as humans, and with societies struggling to support the elderly, the effects of boosting longevity are hard to predict. Factor in possible alterations to fundamental human behaviors--such as dining, romancing, and forming families--and the ramifications seem infinite. That uncertainty might explain why few researchers who are excited about CR are willing to offer policy-related recommendations beyond the most general advice. "Policy-makers really better start looking at this research," Johnson says. If they don't, the future--populated by 150-year-olds that look (and eat) like 20-year-old starlets--might catch them unprepared.

Ben Shouse is a newspaper reporter in Sioux Falls, South Dakota. He plans to volunteer as a control subject for future calorie restriction experiments.