For the subjects in the Calerie experiment, there was little about their diets that seemed freakish. They ate normal foods, hosted dinner parties for friends and generally went about their lives normally. The subjects do not represent a cross section of American society, however. Whereas 66 percent of Americans are currently classified as overweight or obese, no one allowed into the study was seriously overweight by medical definitions: everyone began the experiment with a body-mass index that fell within a normal to slightly overweight range of 22 to 28. There were scientific reasons for this. The effects of calorie restriction may simply be an evolutionary legacy, “a metabolic, hormonal and molecular adaptation” to a world of sparse resources, as Luigi Fontana, one doctor in charge of the Washington University trial who also holds a position at the National Institute of Health in Italy, described it to me. By slowing aging and increasing resistance to disease during periods of food scarcity, the adaptive responses to fewer calories increased the odds that animals and humans that lived short lives might survive until they could reproduce. In laboratory settings, calorie restriction seems to “work” — that is, it seems to influence primary and secondary aging — when the diet of an animal of normal weight is curtailed by a significant percentage. The degree of calorie restriction can’t exceed 50 percent, which is when laboratory animals begin to die. Until that point, however, the more severe the calorie-restriction regimen, the greater the health benefit — a lifespan 50 percent again as long in studies on mice and rats. These results might not apply to the overweight. As Fontana told me, moving a heavyset person’s body-mass index from, say, 35 to 29 might increase his longevity by reducing the risk for diseases like diabetes. Yet it is not “triggering the anti-aging pathways” that have been observed at the cellular and molecular levels in animals of normal weight when placed on a calorie-restricted diet.

And why set the restriction at 25 percent? Why not 20 percent? Or 30 percent? Or why not reduce calorie intake by 10 percent and increase exercise (and calories burned) by 15 percent, so that a subject’s calorie deficit still equals about 25 percent? All were viable options. But the study’s architects determined that 25 percent was both humanly feasible and, based on data from previous experiments, could have noticeable effects on the rate and diseases of aging. It is possible, meanwhile, that a sustained decrease in calories coupled with a sustained increase in exercise might have a potent effect on aging (at the moment there are no large-scale studies under way, Fontana told me). Such a combination, however, could complicate efforts to understand, in isolation, the effects of calorie restriction on humans.

The researchers in Boston, Baton Rouge and St. Louis screened the Calerie recruits in ways other than body-mass index. They looked for subjects who were motivated and highly organized — desirable traits if you have to keep a journal record for two years of every morsel of food you eat. They sought people who had strong moral support at home. They ruled out anyone who counselors surmised might have a predisposition toward anorexia or bulimia — disorders that might conceivably be triggered by the new diet. They also wanted participants who had stable jobs without too much travel, yet were flexible enough to allow them to visit the hospital centers weekly for weigh-ins, counseling and medical tests. All the subjects are being paid: $5,000 at Tufts and Pennington, $2,400 at Washington University. But screeners rejected those who said they were attracted to the study for the money — an unnecessary precaution, perhaps, given that enrollment in Calerie is effectively an arduous part-time job that pays third-world wages. “I figured out that $5,000 for two years for the 70 times I have to come in here worked out to a dollar an hour,” Tom Jacobs, a participant at Tufts, told me.

Getting someone started on a calorie-restriction diet is far more involved than it might first appear. For the past seven years, Fontana has been collecting data on about 50 members of the Calorie Restriction Society; Fontana estimates that these men and women have cut their calories by 25 to 30 percent. Yet this can’t be said with precision or authority. Nor is it clear what their prediet biomarkers or vital signs were. At the start of the Calerie experiment, a first order of business was to rigorously determine how many calories each recruit ate and burned on a typical day. This required a methodical (and expensive) two-week laboratory test: participants drank water containing rare isotopes that, when excreted and analyzed, allowed researchers to discern a subject’s carbon-dioxide production (and his or her calorie burn) to a precise degree. After that, each subject received an individualized target. Most of the subjects I spoke with called this the Number. At the start, researchers determined that Doug Hansen burns (and thus ingests) what he told me was around 2,600 calories a day. So he was put on a diet of 1,950 calories. Jeffrey Peipert, an Ob-Gyn who is nine months into the study in St. Louis, was found to burn 3,300 a day — and thus given a number of just under 2,500. Many of the women, meanwhile, required far fewer calories. Liz Ewen, a molecular biologist who is 18 months into the Tufts study, told me her number was 1,670 calories, down from 2,226. It seemed a common experience that no one had any idea before the study began what his or her caloric requirements were. “My wife and I both took a guess and we both got it wrong,” Peipert told me.

Image Credit... Reinhard Hunger for The New York Times; set design by Sarah Illenberger

At the start, the subjects were informed that although they would receive help with menus and recipes from the study’s dieticians, they would be responsible for buying and cooking all their own meals for the next two years. For each participant’s first 28 days, however, all meals and snacks are free, custom cooked (based on each individual’s calorie requirements) and packaged in large coolers to be picked up every few days and taken home. “That way we can be sure the subjects are getting the exact dietary prescription while they’re learning how to do it,” Morgan Schram, the study manager in St. Louis, told me. The great challenge, at least for that first month, is to create food for the subjects that is simultaneously satiating, appealing and — most crucially — low in calories. At both Tufts and Washington University, meals for new participants are prepared in facilities that resemble laboratory-kitchen hybrids. The food is not particularly exotic: Mediterranean-style combinations of fish with Greek-style potatoes, for instance, or sweet-and-sour chicken with rice. Whether the meals are bad or good is somewhat beside the point. The meals are precise. When I visited the kitchen in St. Louis, a nutritionist was cooking and weighing, to a tenth of a gram, each ingredient of a dish of farfalle with pesto and diced chicken. Most of the recipes seem to steer participants toward foods that are nutrient-rich but low in calories, or what dieticians refer to as “low in energy density.” A number of recent experiments — notably by Barbara Rolls at Penn State — demonstrated that humans tend to eat a consistent weight of food from day to day, but not necessarily a consistent number of calories. For the Calerie study, this has proved a useful tool in the defense against hunger. By building a diet around foods with a low-energy density, especially vegetables, fruits and soups, participants can conceivably ingest the same weight of food as they might on a regular diet while taking in fewer calories.

Apples are superb in this regard. At the medical centers running Calerie, you see a lot of people walking around eating apples. Even subjects who disliked apples have discovered that calorie restriction, which generally has the effect of making food taste better, has given them a surprising desire for the fruit. By contrast, alcohol — many calories, not much nutrition — isn’t much use at all. But it isn’t expressly forbidden. If you wish, you can indulge in drinking or in energy-dense foods (nuts or sweets, for instance), but probably not both nor in excess in either case. “I enjoy a regular glass of wine or drink at the end of the day,” Peipert said. “But I think what I’ve learned on this diet is that I enjoy food more. I’d rather have a Häagen-Dazs bar at 190 calories than a gin and tonic at night at 170.”