An ongoing study at the University of Wisconsin-Madison in which rhesus monkeys are being fed an extremely calorie-restricted diet gives preliminary evidence that the regime prevents age-related diseases. For decades, scientists have known that a diet of about 30-percent fewer calories than normal extends the lifespan of mice by 10 to 20 percent, reduces their incidence of cancer, and prevents the deterioration of learning and memory in the rodents (see “A Clue to Living Longer”). And similar effects have been shown in lower organisms from yeast to fruit flies. But such life extension has not been proven yet in primates.
Researchers at the Wisconsin National Primate Research Center have been studying a group of 76 rhesus monkeys, half of them on calorie restriction and half on a normal diet, for 18 years, to determine whether or not the restricted diet has the same health benefits in primates as it does in other animals. The study will likely go on for at least another decade, since the monkeys are only now entering old age. Captive rhesus monkeys usually live to around 25 years old, which is now about the average age of the monkeys in the study. An age of 40 for a rhesus monkey is similar to 120 for a human–the apparent maximum lifespan.
Although there is now strong evidence that caloric restriction prevents diabetes in the primates (the disease is a major killer of captive rhesus monkeys), it’s still too early to assess the diet’s effects on their lifespan, according to Richard Weindruch, professor of medicine at the University of Wisconsin, who is heading up the study.
But preliminary evidence suggests that the diet is preventing loss of muscle mass, arthritis, menstrual irregularities, and other signs of aging. “Over the next 10 years, survival differences will come out,” predicts Ricki Colman, a scientist on the study. Meanwhile, eight of the monkeys on a normal diet have died of age-related causes such as cancer and diabetes; five on the restricted diet have died of these causes.
As the monkeys enter old age, the researchers are beginning gene expression profiling on them–the first step toward finding the molecular mechanisms that connect the extreme diet to its effects in the animals. The monkeys will also undergo MRIs and be tested for mental acuity, to assess whether or not the diet prevents age-related deterioration of learning and memory.
Even if a diet of 30-percent fewer calories proved to extend healthy human lifespan, however, it’s unlikely that most people could be able to stick with it. (A group of individuals following such a diet, called the Calorie Restriction Society, seem to have some health benefits. See “Human Study Shows Benefits of Caloric Restriction”.)
Researchers studying caloric restriction in animals, including Colman, say that, in general, such a diet is “not a long-term possibility in humans.” Rather, the primary goal of their study, Colman and Weindruch agree, is to learn about aging and to understand how caloric restriction changes metabolism and gene expression.
To make sure the study is as applicable to humans as possible, the Wisconsin scientists provide the monkeys with human-like health care: diabetic monkeys are given insulin; the animals get dental care; and female monkeys suffering endometriosis–a painful condition of the uterine lining common to humans–may undergo surgery. The only other study of caloric restriction in nonhuman primates, at the National Institute on Aging, is larger (120 monkeys) and two years longer-running than the Wisconsin study. However, it may not be as applicable to humans because those monkeys are not given extensive medical care, and were put on their restricted diets at a much younger age, some immediately after weaning, which stunts growth, according to Colman.
The Wisconsin researchers use all human medical equipment on the monkeys, Colman says, including an MRI scanner for upcoming brain-imaging studies. Each monkey will have two scans over a five-year period to monitor changes. Because caloric restriction’s effects on the body seem to be general, there’s no reason it shouldn’t be good for the brain if it’s good for other organs, says Sterling Johnson, assistant professor of medicine at the University of Wisconsin. Normal aging is accompanied by a slight decrease in brain volume, he says.
When the monkeys die, samples of their brain tissue will be saved for future studies of caloric restriction’s effects on gene expression in that organ, Johnson says. As mice age, genes associated with inflammation and the death of brain cells, for example, become more active, while many of those associated with metabolism become less active. Studies of aging in calorie-restricted mice in Weindruch’s lab have demonstrated that the diet prevents about 70 percent of such age-related changes.
In 2001, when the rhesus monkeys were middle-aged, Weindruch published a study showing that, although differences in gene expression existed between those primates on caloric restriction and the control group, the diet did not seem to prevent age-related changes in gene expression. Weindruch expects to get different results when his group does another round of tests, however, now that the monkeys are truly old–and now that technology exists to test specifically for rhesus monkey genes. In the previous round of testing, Weindruch and colleagues had to use chips with human genes on them, since rhesus monkey chips became available only recently.
Whatever the mechanisms turn out to be, “there’s something that happens with that extra reduction of food intake that really affects the aging process,” says Joseph Kemnitz, director of the Wisconsin primate research center. Ultimately, the researchers hope to take what they learn about this process to help people maintain a high quality of life throughout old age.
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