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," he 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.
[See how cutting calories by as much as 80 percent on alternate days may help shed weight.]
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 who coconducted the research. "Everyone went bananas." 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.