Excessive adiposity, calorie restriction, and aging

Apr 16 2006

Can eating a low-calorie yet nutritionally balanced diet extend human life? Preliminary research suggests it might, so researchers at Washington University School of Medicine in St. Louis are launching a long-term study to find out.

In an editorial in the Journal of the American Medical Association, Luigi Fontana, M.D., Ph.D., assistant professor of medicine at Washington University and an investigator at the Istituto Superiore di Sanita in Rome, Italy, says calorie-restricted diets point to possible mechanisms of aging and suggest ways to intervene and modify its effects.

In January, Fontana and colleagues found that after an average of six years on calorie restriction, people's hearts functioned like the hearts of much younger people. And a team from the Pennington Biomedical Research Center at Louisiana State University in Baton Rouge is reporting that six months of calorie restriction reduces two key markers of aging: fasting insulin levels and body temperature.

More than a decade ago several researchers, including John O. Holloszy, M.D., professor of medicine at Washington University, demonstrated that stringent and consistent caloric restriction increased the maximum lifespan in mice and rats by about 30 percent and protected them against atherosclerosis and cancer.

Human study has been difficult because calorie restriction requires a very strict diet regimen, both to keep the total number of calories low and to insure that people consume the proper balance of nutrients. Some people from a group called the Calorie Restriction Society are devoted to limiting their caloric intake in hopes of improving their health and extending their lives. Society members, who call themselves CRONies (Calorie Restriction with Optimal Nutrition), have developed ways to eat low calorie/high nutrition diets.

Fontana has done extensive research with CRONies, most recently reporting in the Jan. 17 issue of the Journal of the American College of Cardiology that the hearts of people on calorie restriction appeared more elastic than those of age- and gender-matched control subjects. Their hearts were able to relax between beats in a way similar to the hearts of younger people.

The team from the Pennington Biomedical Research Center reports in the April 5 issue of the Journal of the American Medical Association on a six-month study of men and women between 25 and 50 who were placed on a calorie restriction diet that lowered their daily caloric intake by about 25 percent. The researchers compared those on calorie restriction to subjects who either had not been on a diet, had cut calories by about 12.5 percent and increased the energy they burned through exercise by a like amount, or had spent six months on a standard low-calorie diet of about 1,800 to 2,000 calories per day until they had lost 15 percent of their body weight.

The study, called the Comprehensive Assessment of the Long Term effects of Reducing Intake of Energy (CALERIE), found that all subjects who dieted or increased their exercise lost weight and body fat. But those on a calorie restriction diet ended the study with lower fasting insulin levels and lower core body temperatures. They also had less oxidative damage to their DNA, thought to be a marker of aging at the biochemical and cellular level.

"This study has laid the groundwork for future research into the long-term effects of calorie restriction in humans to see whether it really can extend lifespan," Holloszy says. "It's becoming clear from studies with the CRONies -- and from this brief, prospective study -- that calorie restriction does change some of the markers we associate with aging."

Holloszy and Fontana are getting ready to launch a second phase of the CALERIE study, to look at the effects of calorie restriction over the course of two years.

"We know people on calorie restriction will lose weight," says Fontana. "But this study isn't a weight-loss study. We're hoping to learn more about whether calorie restriction can alter the aging process.

Fontana says, for example, that low-grade, chronic inflammation seems to mediate aging. Overweight and obese people tend to have higher levels of inflammation than lean people, so it makes sense that losing weight might increase average lifespan by lowering the risks of some age-related diseases, such as diabetes and atherosclerosis. But in animal studies not only did more of the animals live longer, the maximum length of a rat's or mouse's life also increased. The CALERIE study hopes to get some clues about whether calorie restriction might do the same thing for humans.

"We want to learn whether calorie restriction can reverse some of these markers of aging in healthy young people," Holloszy says. "It's going to be many years before we know whether calorie restriction really lengthens life, but if we can demonstrate that it changes these markers of aging, such as DNA damage and inflammation, we'll have a pretty good idea that it's somehow influencing the aging process at the cellular level."

Currently, Holloszy and Fontana are beginning to recruit volunteers for Phase II of the CALERIE study.

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