Scientists have known for a long time that rats, mice, and worms that eat very little live longer than those that eat normal diets. Now, the results of research on humans are starting to emerge. It may take decades to prove that people who carefully regulate their calories and eating patterns extend their life span, but at the very least, some scientists say, these people may avoid many health problems associated with aging. This spring scientists issued a report documenting the health benefits on a small group of people between ages 35 and 82 who decided to severely restrict their calorie intake simply on the basis of what is known about laboratory animals. These people have a lower risk of heart disease, as well as reduced chances of having a stroke or getting diabetes. Incidence of these three conditions generally increases markedly as people age. The Calorie Restriction Society Web site has a recipe for “George Bush Salad,” which has no broccoli.

John O. Holloszy of the Washington University School of Medicine, in St. Louis, Missouri, and his colleagues cataloged what they call “profound and sustained beneficial effects” of the calorie restricted diet. Over a three-year period, Holloszy’s team at Washington University compared 18 people who had, in hopes of slowing the aging process, independently eaten a calorie-restricted diet for at least six years, and 18 healthy, non-obese study participants who ate typical Western diets. Their findings appeared the Proceedings of the National Academies of Sciences. The study volunteers consumed from 2,000 to 3,550 calories per day, and the calorie restriction group consumed between approximately 1,000 and 2,000 calories per day. The dietitian-approved meal plan is carefully balanced: The calorie restriction group consumed about 26 percent of their calories from protein, 28 percent from fat, and 46 percent from complex carbohydrates. The fare was enlivened by a nutrient-dense array of fruits, vegetables, legumes, and whole grains. “Calorie restriction is not about starvation,” says Chhanda Dutta, chief of the Clinical Gerontology Branch of the National Institute on Aging in Bethesda, Maryland. “It’s about lowering caloric intake, minus malnutrition.” The calorie-restriction subjects scored vastly better on all major risk factors for heart disease including total cholesterol, triglycerides, and blood pressure. Each of these tends to increase with advancing age. They also have very low amounts of body fat compared to the average person in the control group, who had about 25 percent body fat. This quality protects the calorie restrictors from the type 2 diabetes associated with obesity, Holloszy says. In addition, three people in the calorie restriction group had familial high cholesterol when the study began. According to Holloszy, calorie restriction reduced their cholesterol levels, and they no longer take cholesterol-lowering medication. “The amazing thing is that regardless of their genetic background, they all showed the same response,” he says. And their blood contained negligible amounts of the protein (CRP) known to cause inflammation, which is increasingly believed to be a factor in diseases. Dean Pomerleau estimates that every calorie he avoids adds about 30 seconds to his lifespan.

The idea for the study originated with a letter Holloszy received from a man asking about his research comparing individuals on a calorie-restricted diet with individuals who produce the same calorie deficit by exercise. The man, Dean Pomerleau, followed a calorie-restricted diet and participates in the Caloric Restriction Optimal Nutrition Society. Holloszy realized he had a ready-made test group for the study. Of the 18 participants, many had practiced the calorie restriction diet for years, and kept scrupulous records of their health and food intake. “We’re a ready population they could use to do a quick comparison against a standard population,” says Pomerleau. “It’s hard to get people to volunteer to eat like this.” Since he began “serious” calorie restriction in 2000 at age 35, Pomerleau’s weight has dropped from about 170 to his current lean weight of 123. He calculates that, based on data from the animal studies, every calorie you avoid is worth about 30 seconds of extra life.

Or, Pomerleau says, putting it another way, “I’m more than willing to give up a piece of pizza to live another three hours.” Eating Every Other Day As the legions of lapsed dieters can attest, even modest calorie restriction can be hard to sustain. And not everyone who wants to be healthy and long-lived wants or needs to be stick thin. Mark Mattson, a researcher at the National Institute on Aging in Baltimore, Maryland, thinks an alternate route may be through what he calls intermittent fasting. Health benefits in mice that eat only every other day are similar to those for mice that eat a calorie restricted diet—they live 30 percent longer, Mattson says. And, he adds, "We see vast improvements in variables that indicate risk of disease." The calorie intake of the mice is not restricted—during the “on” days, they can eat as much as they like. With colleagues, Mattson plans to study how this kind of eating pattern affects humans. Mattson already knows that some people do make the switch to intermittent fasting, with apparently little pain. After publishing a report last year on the diet’s benefits in mice, Mattson received calls and emails from people who, for a variety of reasons, decided to try intermittent fasting. Mattson’s objective is not weight loss (though the ad hoc fasters happily report pounds lost, as well as other health benefits including reduced allergy sensitivity and more energy). Nor is Mattson especially interested in extending life span. Instead, he wants to boost what he calls the human “healthspan”—the period of a life in which a person enjoys good health, even into the eighties or nineties. Indeed, Mattson's findings suggest that one can enhance health parameters by regulating diet, even without losing weight. Intermittent fasting, like calorie restriction, may circumvent the aging process by reducing free radicals in the cells. Mattson explains that these highly reactive molecules can damage cells, and with age, the cells become less adept at eliminating them. Numerous studies show that free radicals are involved in a host of age-related diseases including cardiovascular disease, diabetes, and neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s. Although calorie restriction and intermittent fasting seem to induce similar health benefits, Mattson suspects the two approaches differ somewhat in their metabolic effects. Based on his cellular studies, he says, “Fasting seems to increase the resistance of cells to various types of stress that can cause disease, while calorie restriction may be more effective at curtailing free radicals.” Clues in Stress and in Free Radicals There are two main theories to explain what’s going on. The first theory says that calorie restriction reduces the amount of glucose that comes into cells over time, curtailing production of free radicals in the mitochondria —organelles that contain many enzymes important for metabolism. The second theory says that dietary restriction increases life span because it imposes mild stress on the organism. The mouse or rat—or human—who learns to exist on a curtailed diet is better able to cope with more severe stress at the cellular level and to resist diseases that are associated with certain types of stress. There is also abundant research into what triggers these protective mechanisms, and how. In a fast-paced and competitive search for answers, researchers, for now, are focused on two main possibilities. Over the past few years, Leonard Guarente of the Massachusetts Institute of Technology in Cambridge has suggested that an organism responds to food scarcity—stress—by slowing aging and reproduction, so as to survive and be able to reproduce when conditions improve. The key to this adaptive response, Guarente and others believe, is a set of genes known as sirtuins that help cells to withstand stress by regulating the pace of aging based on the availability of nutrients. Guarente’s lab is focusing on one sirtuin, SIR2, which is associated with metabolism. Sirtuins have attracted such intense interest because studies have shown that, when stimulated, sirtuins can extend the life span of cells, and of worms. What’s more, this effect is greater when calories are cut. In a recent essay, Guarente noted that SIR2 genes can regulate life span for organisms that diverged long ago in evolutionary terms, “even if they age by different mechanisms.” “We don’t know that this is the only gene that may be responsible for regulating so many fundamental processes tied to aging. But it does seem to be the first that exerts so many effects related to life span in so many organisms,” Guarante wrote in an email. Other scientists, including Guarente’s former protégé David Sinclair, now at Harvard Medical School in Boston, Massachusetts, also think that SIR2 is involved, but they hypothesize that the key lies in biological processes involving a vitamin B precursor called nicotinamide and a gene called PNC1. Sinclair and others also are studying resveratrol—an antioxidant abundant in grapes, red wine, and other plants—that also activates sirtuin proteins in many organisms. Cut Calories with a Pill? Because it is difficult to study longevity in humans, the National Institute on Aging is focusing on a more immediate goal: insights into how various eating regimens affect human health. With federal funds, researchers at Washington University Medical School, Pennington Biomedical Research Center in Baton Rouge, Louisiana, and the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University in Boston, Massachusetts, are wrapping up the first part of a three-phase study of the effects of calorie restriction on humans at different ages. Using a variety of protocols, the researchers also are trying in a systematic, carefully controlled way to tease out how calorie restriction in humans affects certain age-related pathologies, such as weakened immune function or insulin resistance, which is a common precursor of diabetes. “The question is: can calorie restriction prevent, or even delay, onset of age-related pathologies?” Dutta says. She points out that “things are not consistent as you go up the food chain” and that while Holloszy’s results are intriguing, there is much to learn about side effects and long-term effects of calorie restriction. So there is still no panacea, no fountain of youth. Not surprisingly, some of the research teams trying hardest to decipher how calorie restriction affects the genes and extends life span are also spinning off companies. Firms founded by Guarente and Sinclair, for instance, are in direct competition to develop a drug that best stimulates the activity of sirtuins. In the meantime, it seems unlikely that most Americans will opt to lower their calorie intake significantly. Nor is calorie restriction for everyone. Holloszy, for instance, is in his seventies and does not restrict his calories, though he’s always eaten “very carefully.” “It’s dangerous to decrease calorie intake, or reduce weight after age 65, when one is already losing muscle and lean tissue,” he cautions. Still, he adds wistfully, most people would benefit “tremendously” from even moderate calorie restriction. “You wouldn’t get the extreme improvement, but you would get small improvement in the same direction: reduced incidence of diabetes, clogged arteries, high blood pressure, and so on,” says Holloszy. Related GNN story: Protein Structure Provides Clue to Long Life Holloszy, John O. et al. Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans. Proceedings of the National Academy of Sciences 101, 6659-6663 (April 27, 2004). Mattson, M. P. et al. Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from calorie intake. Proceedings of the National Academy of Sciences 100, 6216-6220 (May 13, 2003). Guarente, L. et al. Mammalian SIRT1 Represses Forkhead Transcription Factors. Cell 116, 551-563, 20 February 2004.

Top Stories Personalized Medicine in Cancer: Matching Patients and Drugs Yellowstone Microbe Cleans Up Wastewater The Complex Genetics of Down Syndrome Heart Disease, Stroke Linked to Gene Mutations Cause Rare Form of Parkinson's Back to GNN Home Page