Biological Effects of Calorie Restriction: Implications for Modification of Human Aging

Abstract

Caloric restriction (CR), the consumption of fewer calories without malnutrition, and reduced insulin and/or IGFI intracellular signaling, can extend the lifespan and delay many deleterious age-related physiological changes in animals as phylogenetically diverse as nematodes and mice. The lifespan effects of CR are directly proportional to the duration and intensity of the regimen in rodents. Mice and flies can shift readily between the control and CR physiological states. In humans and nonhuman primates, CR produces nearly all of the physiologic, hematologic, hormonal, and biochemical changes produced in other animals. In humans, CR appears to provide protection from type 2 diabetes, cardiovascular and cerebral vascular diseases, immunological decline with age, malignancy, hepatotoxicity, liver fibrosis and failure, sarcopenia, systemic inflammation, and DNA damage. CR also reduces fat mass, including cardiovascular disease-related visceral fat mass, enhances muscle mitochondrial biogenesis, affords neuroprotection, and according to some retrospective epidemiological human studies, extends mean and maximum lifespan. Many of these benefits can be induced by relatively brief periods of CR in flies, rodents, monkeys and humans. In mice, CR rapidly induces powerful antineoplastic effects, even when initiated late in life. However, CR also has negative effects. In humans, these include loss of lean body mass and muscle strength, decreased VO₂ max, decreased bone mineral density, reduced reproductive activity and libido in males.

The composition of the CR diet appears to be of secondary importance to its health and longevity effects in rodents. However, protein, methionine, or tryptophan restriction also can extend lifespan, apparently in part by downregulating circulating levels of insulin and IGFI. Manipulation of a few other dietary components have been credibly reported to extend the lifespan of control fed rodents. Most such studies are confounded by uncontrolled food intake. Many reports of extended lifespan are probably due to CR induced by unpalatable or anoretic dietary additives.

The potent anticancer effects of CR and disrupted insulin/IGFI receptor signaling may have evolved as a byproduct of the role of many mitotically competent cells and tissues as reservoirs of metabolic energy. Daily cycling between postprandial anabolic periods and postabsorptive catabolic periods is intensified in CR animals, which have lower energy reserves. Protein, lipid, organelle and cellular (in mitotic tissues) breakdown and resynthesis are strongly driven by these cycles in CR animals. This enhances tissue and cell renewal, and is likely a key molecular mechanism for the longevity and health effects of CR. In mitotically competent tissues, apoptotic cell death, driven by nutritional scarcity and reduced circulating levels of insulin and IGFI, preferentially removes preneoplastic and neoplastic foci, thereby producing the potent anticancer effects of CR. Evidence suggests that decreased core body temperature may be integral to the beneficial health and longevity effects of CR. Exercise shares many of the positive effects of CR on physiology, including the extension of mean lifespan. However, for reasons that remain unclear, exercise in rats and humans does not increase maximum lifespan, as does CR.

Elevated body weight leads to an increased incidence of cardiovascular diseases and cancer. Knockout mouse studies suggest adipose tissue may secrete a cytokine or hormone that antagonizes longevity. Paradoxically, low body weight in middle aged and elderly humans is associated with increased early mortality from cancer and cardiovascular diseases. Although there are a number of potential confounds to these studies, they challenge the view that human CR leads to lifespan extension as robust as that found in rodents. For this reason, further enhancement of human longevity may require pharmaceutical intervention in the hormonal and signaling pathways mediating robust lifespan extension in other species.