SINCE PUBLICATION of this article a decade ago, the calorie-restriction (CR) field has become "hot," with great progress made on several fronts. One striking example is the use of short-lived "model organisms," such as yeasts, flies and worms, to rapidly obtain mechanistic insights into CRs effect on life span. The ease of genetic manipulation of these models has enabled the identification of key pathways and regulators of the response to CR. It is not surprising that most of these pathways involve aspects of energy metabolism. The core feature of CR is, after all, energy intake restriction.
New technology has also fueled rapid advances in the understanding of CR. The human genome comprises some 30,000 genes. Before 1998 one could evaluate the activity of only one gene at a time, by measuring the level of the messenger RNA molecule that it encodes. With the development of microarray technology, in a single experiment one can now evaluate the activities of thousands of genes. My colleagues and I were the first to implement the use of this technology in the context of aging and CR, by providing a global view of the activities of more than 6,000 genes in mouse muscle. Subsequently, this approach has been widely used in aging research.
The ultimate goal of the field is to understand the potential of CR in humans. Along the way, we hope to determine whether CR can slow the aging process in nonhuman primates, including species that share much of their genetic makeup with us. We have been comparing the effects of CR and a control diet on rhesus monkeys since 1989 and 1994 (two sets of studies were begun, with animals that were between eight and 14 years old at the outset). The monkeys on CR display signs of improved health and an emerging survival advantage compared with their age-matched controls. But the rhesus monkeys at our primate center have an average life span of about 27 years and a maximum life span of about 40 years, so it may be another 25 years before we obtain full survival data.
Progress has also been made on understanding the effects of long-term CR in humans. Direct evidence comes from studies of long-term practitioners of CR who display markedly improved risk-factor profiles for cardiovascular disease, including reductions in circulating insulin and glucose levels. These individuals also display fewer signs of deterioration in diastolic heart function. Additional progress in human CR is expected; the National Institute on Aging has funded three sites to conduct long-term CR investigations in humans.
The impressive accrual of knowledge on multiple aspects of CR can be expected to continue, and its pace to hasten, as increasing numbers of investigators focus on this fascinating intervention. The mechanistic understanding of calorie restriction will increase the likelihood of the development of drugs or nutrients that mimic the effects of CR in people consuming a normal diet. And if researchers can find a safe way to curb appetite, widespread practice of CR may become possible. Either way, calorie restriction appears well situated to contribute to aging retardation in humans.
RICHARD WEINDRUCH, who earned his Ph.D. in experimental pathology at the University of California, Los Angeles, is professor of medicine at the University of WisconsinMadison and a researcher at the Veterans Administration Geriatric Research, Education and Clinical Center in Madison. He has devoted his career to the study of calorie restriction and its effects on the body and practices mild restriction himself. He has not, however, attempted to put his family, his dog or his two cats on the regimen.