How does calorie restriction work?

For almost 70 years, calorie restriction has been known to extend life span. Despite the extensive physiological characterization of this dietary regimen, the molecular basis for the slowing in aging remains unsolved. Recent findings have pinpointed a few molecular pathways that appear to regulate the aging process. In this review, we propose a molecular model for how calorie restriction works that incorporates these recent findings. Calorie restriction (CR) refers to a dietary regimen low in calories without undernutrition. It was first noted in the 1930s that food restriction significantly extends the life span of rodents (McCay et al. 1935). This longevity results from the limitation of total calories derived from carbohydrates, fats, or proteins to a level 25%–60% below that of control animals fed ad libitum (Richardson 1985; Weindruch et al. 1986). The extension in life span can approach 50% in rodents (Sohal and Weindruch 1996). CR extends life span in a remarkable range of organisms, including yeast, rotifers, spiders, worms, fish, mice, and rats (Weindruch and Walford 1988). Emerging data show that its effect may also apply to nonhuman primates (Lane et al. 2001). CR delays a wide spectrum of diseases in different experimental animals; for example, kidney disease, a variety of neoplasias, autoimmune disease, and diabetes (Fernandes et al. 1976; Sarkar et al. 1982; Fernandes and Good 1984; Kubo et al. 1984; Engelman et al. 1990; Shields et al. 1991; Johnson et al. 1997). CR reduces ageassociated neuronal loss in most mouse models of neurodegenerative disorders such as Parkinson’s disease (Duan and Mattson 1999) or Alzheimer’s disease (Zhu et al. 1999). However, beneficial effects in a mouse model for amyotrophic lateral sclerosis were not observed (Pedersen and Mattson 1999). The CR regimen also prevents age-associated declines in psychomotor and spatial memory tasks (Ingram et al. 1987) and loss of dendritic spines necessary for learning (Moroi-Fetters et al. 1989) and improves the brain’s plasticity and ability for selfrepair (Mattson 2000). Why does CR exert these effects? Because CR delays reproduction and promotes survival in times of scarcity, it may have been evolutionarily adaptive during boom/ bust cycles (Harrison 1989; Holliday 1989). Despite the plausibility of this reasoning, several challenges to the significance of CR studies in the laboratory have been made. Perhaps the restricted animals live longer simply because controls are overfed to the point of ill health. However, regimens in which animals are fed controlled amounts of food rather than ad libitum still show beneficial effects of low calories (Weindruch and Walford 1988). Another objection is that inbred strains of rodents are not representative of animals in the wild. For example, lab strains are selected for rapid reproduction and large litters (Miller et al. 1999). It has been argued that these animals may accordingly have shorter life spans than wild strains. By this reasoning, CR may simply correct a defect that has been created by domestication. However, the generality of CR in many different organisms, as mentioned above, supports the argument against this criticism. Even though benefits of CR have been known for many years, the mechanism(s) of its action remains unclear. Its complexity lies in multiple effects including metabolic, neuroendocrine, and apoptotic changes, which vary in intensity and exhibit striking differences among specific organ systems. Several major models to explain CR exist, but none satisfactorily integrates all of CR’s effects. In this review, we address the question of how CR might function to extend life span. We begin with a summary of several aging theories and classical views about the action of CR. Then we discuss how CR extends the life span in Saccharomyces cerevisiae. We extrapolate these findings from yeast to mammals and consider metabolic, neuroendocrine, and apoptotic shifts that may trigger longevity in the higher organisms. We conclude with a model of CR that integrates its effects on mammals.