Calorie Restriction and Aging [Preview]

Eating less--while maintaining adequate nutrition--is a recipe for longer life in many animals. Might it help humans as well?

Intriguing results were also obtained after eight people living in a self-contained environment--Biosphere 2, near Tucson, Ariz.--were forced to curtail their food intake sharply for two years because of poorer than expected yields from their food-producing efforts. The scientific merits of the overall project have been questioned, but those of us interested in the effects of low-calorie diets were fortunate that the late Roy L. Walford of the University of California, Los Angeles, who was an expert on calorie restriction and aging (and was my scientific mentor), was the teams physician. Walford helped his colleagues avoid malnutrition and monitored various aspects of the groups physiology. His analyses reveal that calorie restriction led to lowered blood pressure and glucose levels--just as it does in rodents and monkeys. Total serum cholesterol declined as well.

The results in monkeys and humans may be preliminary, but the rodent data show unequivocally that calorie restriction can exert a variety of beneficial effects. This variety raises something of a problem for researchers: Which of the many documented changes (if any) contributes most to increased longevity and youthfulness? Scientists have not yet reached a consensus, but they have ruled out a few once viable proposals. For instance, it is known that a low intake of energy retards growth and also shrinks the amount of fat in the body. Both these effects were once prime contenders as the main changes that lead to longevity but have now been discounted.

Several other hypotheses remain under consideration, however, and all of them have at least some experimental support. One such hypothesis holds that calorie restriction slows the rate of cell division in many tissues. Because the uncontrolled proliferation of cells is a hallmark of cancer, that change could potentially explain why the incidence of several late-life cancers is reduced in animals fed low-calorie diets. Another proposal is based on the finding that calorie restriction tends to lower glucose levels. Less glucose circulating in the blood would slow the accumulation of sugar on long-lived proteins and would thus moderate the disruptive effects of this buildup.

A Radical Explanation
THE VIEW that has so far garnered the most convincing support, though, holds that calorie restriction extends survival and vitality primarily by limiting injury of mitochondria by free radicals. Mitochondria are the tiny intracellular structures that serve as the power plants of cells. Free radicals are highly reactive molecules (usually derived from oxygen) that carry an unpaired electron at their surface. Molecules in this state are prone to destructively oxidizing, or snatching electrons from, any compound they encounter. Free radicals have been suspected of contributing to aging since the 1950s, when Denham Harman of the University of Nebraska Medical School suggested that their generation in the course of normal metabolism gradually disrupts cells. But it was not until the 1980s that scientists began to realize that mitochondria were probably the targets hit hardest.

The mitochondrial free-radical hypothesis of aging derives in part from an understanding of how mitochondria produce ATP (adenosine triphosphate)--the molecule that provides the energy for most cellular processes, such as pumping ions across cell membranes, contracting muscle fibers and constructing proteins. ATP synthesis occurs by a very complicated sequence of reactions, but essentially it involves activity by a series of molecular complexes embedded in an internal membrane--the inner membrane--of mitochondria. With help from oxygen, the complexes extract energy from nutrients and use that energy to manufacture ATP.

Unfortunately, the mitochondrial machinery that draws energy from nutrients also produces free radicals as a by-product. Indeed, mitochondria are thought to be responsible for creating most of the free radicals in cells. One such by-product is the superoxide radical (O2.–). (The dot in the formula represents the unpaired electron.) This renegade is destructive in its own right but can also be converted into hydrogen peroxide (H2O2), which technically is not a free radical but can readily form the extremely aggressive hydroxyl free radical (OH.–).

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