Caloric restriction describes a scientific intervention in which total daily calories provided to an animal or organism are limited to about 70% of those of the animal's freely fed counterparts. Sometimes described as "undernutrition without malnutrition," caloric restriction is the only intervention actually documented to extend life span in laboratory animals. Its effects in humans are of course unknown. Scientists would have great difficulty designing experiments that would involve a large enough group of people to be statistically valid, significantly reducing their caloric intake, and then studying them long enough to know the effects on longevity.

But scientists have studied caloric restriction in laboratory animals, with promising results. They have looked at the effects of caloric restriction in each of the major categories of experimental animals mentioned above. For additional information, see the Caloric Restriction Information Center.

Yeast
Roundworms
Fruit flies
Mice
Nonhuman primates

Researchers at Louisiana State University are among the foremost authorities on life span in yeast. They have recently published an article detailing the extension of life span in yeast that they achieved through caloric restriction. They reduced the amount of glucose (sugar) in the medium in which their yeast was cultured and found that life span was increased and the appearance of certain characteristic signs of aging was delayed. They found similar results when they decreased the concentration of amino acids in the yeast culture medium, which suggests that a reduction in total available calories was the important factor in extending life span, not the reduction of one particular nutrient.

Scientists at the Massachusetts Institute of Technology recently published the results of studies showing that two yeast genes, abbreviated as SIR2 and NPT1, might play a role in the life span lengthening effects of caloric restriction in yeast. NPT1 is responsible for the production of a protein important in energy metabolism. SIR2 has many roles; it helps regulate energy metabolism, it controls what proteins the yeast's genes make, and it serves to protect the yeast's DNA from damage. Proteins much like SIR2 are found in more complex animals; understanding its role in increasing yeast longevity might translate into understanding any role it plays in longevity in other organisms.

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In studying roundworms and longevity, scientists have identified several groups of genes that seem to promote longer life spans. One group produces a protein called PABP, another group produces heat shock proteins (proteins that protect the metabolism from the stress of high environmental temperature) and the third group produces proteins that are similar to certain human proteins, although their function is yet undetermined. The genes in the third group were all stimulated to produce their proteins in the face of starvation, suggesting that caloric restriction can induce changes that increase life span in roundworms.

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Demonstrating that even the most serious scientists can have a sense of humor, researchers studying the fruit fly have identified a gene that they have labeled Indy (for "I'm Not Dead Yet"). Indy is analogous to a gene in humans that produces a protein in the kidneys that might be important in the Krebs cycle, a biochemical cascade involved in energy generation. Mutations in the Indy gene in fruit flies result in a doubling of the life span without a reduction in either fertility or physical activity. The researchers speculate that these mutations, which reduce the reutilization of certain substances, produce a physical state that mimics caloric restriction. This indicates that caloric restriction might be effective in increasing longevity in fruit flies.

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A strain of mouse used in the laboratory called AlphaMUPA provides an interesting model for caloric restriction and its effects on the aging process. AlphaMUPA mice spontaneously eat less (by 20%) than wild mice and live about 20% longer than their wild cousins. One interesting feature of their metabolism is that AlphaMUPA mice have a lower average body temperature than wild mice. Though there are some differences between AlphaMUPA mice and mice whose diets have been reduced artificially, they should prove to be a valuable resource for the understanding of caloric restriction as it relates to life span in mammals.

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The National Institute on Aging is conducting long term experiments on nonhuman primates, such as rhesus and squirrel monkeys, in the hopes that their results will increase our understanding of human aging. Among the studies being conducted are several involving caloric restriction. Study animals are given diets with about 30% fewer calories than the diets of the control animals, and they receive nutritional supplements to guard against vitamin deficiencies in order to achieve the goal of undernutrition without malnutrition.

Early results with these primates demonstrate that the calorie-restricted monkeys weigh less than their freely fed counterparts, and they have both less fat and less lean body mass. Like the AlphaMUPA mice, they have lower body temperatures. The calorie- restricted monkeys metabolize glucose (sugar) more efficiently, with better glucose tolerance and greater insulin sensitivity. This improved glucose metabolism suggests that they are less likely to develop diabetes as they age. They also show signs that they are less predisposed to heart disease and cancer, two other diseases of aging. These results are still preliminary. Primates have a rather long life span, and years of study must be conducted before it is known whether these changes seen in the calorie-restricted monkeys will translate into longer average life spans.

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