Calorie Restriction Extends Life Span— But Which Calories?

E vidence that calorie restriction (CR) retards aging and extends median and maximal life span was fi rst described in the 1930s by McCay et al. [1]. Since then, similar observations have been made in a variety of species including rodents, fi sh, fruit fl ies, worms, and yeast [2]—and although they are not yet defi nitive, results from ongoing longevity studies in monkeys suggest that CR will also extend life span in longer-lived species [3,4]. There are many theories explaining the mechanisms by which CR extends life span. An early hypothesis was that delayed sexual maturation might be a mechanism. However, it has since been shown that CR initiated in older animals also increases life span [5]. Reduced metabolic rate—with consequent reduction in free radical production—was another early, leading hypothesis to explain the anti-aging effects of CR. But there are many other metabolic effects that have been associated with CR, including altered insulin sensitivity and signaling, stress resistance, altered neuroendocrine function, and changes in nutrient signaling. Any, or a combination, of these biological changes may retard aging. However, recent studies seem to favor a highly conserved stress response that evolved early in most species to increase an organism's chance of surviving adversity (such as CR) by triggering concerted physiological responses [6]. Previous studies in rodents have shown that the effects of CR on extending life span are dose dependent, with a 20% reduction in calorie intake producing a smaller increment in life span as compared to a 40% reduction in food intake [7]. From this work and others, the reduction in calories was recognized to be of paramount importance in the longevity response, and alterations in the nutrient content of diets were considered irrelevant. However, a recent study in PLoS Biology by Mair et al. challenges this long-held concept of CR [8]. In the study by Mair et al., the authors examined life span in fruit fl ies (Drosophila melanogaster) fed one of four different diets: (1) a combination of yeast and sugar (control), (2) restricted in yeast only, (3) restricted in sugar only, and (4) restricted in yeast and sugar. The authors observed that in the restricted sugar group, as compared to the controls, maximal life span was unchanged and median life span was increased by only 12%. On the other hand, both maximal and median life spans were increased substantially in the restricted yeast group and in …