Caloric restriction, touted as a possible way to increase human life span, has gotten a lot of press lately. Research on rats and mice has shown that reducing their food consumption by 50 percent, while maintaining adequate nutrition, can lead to a 30 percent increase in longevity. Because the human mean life span in the United States is 75 years and the maximum life span potential is 120 years, caloric restriction might add 15 and 20 years, respectively, to those numbers. But will what works for mice also work for men?

Lloyd Demetrius, an associate of the department of population genetics in the Museum of Comparative Zoology, writes in the current issue of the Journal of Gerontology that the answer lies in understanding just how caloric restriction (CR) acts on an organism to extend its life. Traditionally, CR has been thought to work by lowering the metabolic rate, the rate of oxygen consumption. This "rate of living" theory, as it is sometimes called, was advanced in 1928 by biostatistician Raymond Pearl, who observed the effects of CR on domestic animals. Extrapolating from a very small sample, Pearl argued that metabolic rate determines longevity, and the slower the rate of metabolism, the longer an organism will live. (The phrase "Live fast, die young" emerged from that idea, says Demetrius.) In 1954, Dr. Denham Harmon proposed a mechanism to explain how the rate of living theory might work, postulating that oxygen radicals cause damage resulting in aging and death. This gave "a certain molecular respectability" to Pearl's idea, Demetrius says.

But the empirical evidence does not support Pearl's theory: antioxidant supplementation does not increase longevity. Some birds with twice the rate of metabolism of equivalent-size mammals, which should live half as long, instead live at least three times longer. Furthermore, Pearl's qualitative theory predicts that caloric restriction should reduce the metabolic rate across all living species. But in some experiments, CR has had no effect on metabolism, and might even increase it. If a slowed metabolism is not the reason mice and rats on a restricted diet live longer, how can the phenomenon be explained?

Demetrius believes he has the answer, one that suggests human beings will respond differently to caloric restriction than rats and mice do. A mathematical biologist, Demetrius argues analytically that the rate of aging is determined not by metabolic rate but by metabolic stability, which is a measure of a cell's ability to maintain stable ratios of certain critical cellular metabolites in the face of stress. "In order for a cell to perform its function," he says, "it must maintain the ratio of these cellular metabolites within a certain range." Otherwise, the cell's function is compromised. Caloric restriction increases metabolic stability. An organism's metabolic stability, he argues, is determined by its evolutionary history, so researchers can predict what the metabolic stability of a species will be if its history is known  and hence predict just how much CR might extend its life.

Mice and rats, for example, are "opportunistic species," says Demetrius. They experience periods of relative food abundance punctuated by prolonged periods of scarcity, and therefore undergo episodes of rapid, exponential population growth followed by periods of decline. Such species are characterized by early sexual maturity, a narrow reproductive span, and large litter size, all traits reflecting a survival strategy for coping with feast-or-famine circumstances. Humans, on the other hand, are what Demetrius calls an "equilibrium species." "Evolution has tended to modify our life history so that we mature late sexually, have fewer offspring, and spread our reproductive activity over a long period," he explains. Experiments have shown that human cells are much more resistant to the effects of stressors than the cells of rodents are: they are inherently more stable, more able to resist random perturbations of cellular homeostasis.

Although evolutionary processes do not act directly on the metabolic stability of cells, says Demetrius, they lead to changes in the stability of the organism's cells by changing the aforementioned traits of a species' life history. "Metabolic stability," he says, "is going along for the ride."

The bad news (or perhaps good news, depending on your fondness for food) is that our already high metabolic stability means caloric restriction will not lead to dramatic life extension, as it does for mice. Demetrius predicts a one- to five-year gain in human life span at most, largely attributable to reductions in rates of cardiovascular disease and diabetes. Mice, with their low metabolic stability, have "lots of room for improvement."

Demetrius cautions that studies on caloric restriction and longevity were done on healthy-weight animals. Being obese is not healthy. "Drastic changes in the eating habits of healthy-weight individuals," he says, "will not make any critical difference in longevity," but that should not be considered carte blanche for feasting: "People should be wary of too many helpings of Häagen-Dazs!"

~Jonathan Shaw

Lloyd Demetrius e-mail address: ldemetr@oeb.harvard.edu