A Mechanistic Basis for the Beneficial Effects of Caloric Restriction On Longevity and Disease: Consequences for the Interpretation of Rodent Toxicity Studies

Abstract

Caloric restriction in rodents has been repeatedly shown to increase life span while reducing the severity and retarding the onset of both spontaneous and chemically induced neoplasms. These effects of caloric restriction are associated with a spectrum of biochemical and physiological changes that characterize the organism's adaptation to reduced caloric intake and provide the mechanistic basis for caloric restriction's effect on longevity. Here, we review evidence suggesting that the primary adaptation appears to be a rhythmic hypercorticism in the absence of elevated adrenocorticotropin (ACTH) levels. This characteristic hypercorticism evokes a spectrum of responses, including reduced body temperature and increased metabolic efficiency, decreased mitogenic response coupled with increased rates of apoptosis, reduced inflammatory response, reduced oxidative damage to proteins and DNA, reduced reproductive capacity, and altered drug-metabolizing enzyme expression. The net effect of these changes is to (1) decrease growth and metabolism in peripheral tissues to spare energy for central functions, and (2) increase the organism's capacity to withstand stress and chemical toxicity. Thus, caloric restriction research has uncovered an evolutionary mechanism that provides rodents with an adaptive advantage in conditions of fluctuating food supply. During periods of abundance, body growth and fecundity are favored over endurance and longevity. Conversely, during periods of famine, reproductive performance and growth are sacrificed to ensure survival of individuals to breed in better times. This phenomena can be observed in rodent populations that are used in toxicity testing. Improvements over the last 30 years in animal husbandry and nutrition, coupled with selective breeding for growth and fecundity, have resulted in several strains now exhibiting larger animals with reduced survival and increased incidence of background lesions. The mechanistic data from caloric restriction studies suggest that these large animals will also be more susceptible to chemically induced toxicity. This creates a problem in comparing tests performed on animals of different weights and comparing data generated today with the historical database. The rational use of caloric restriction to control body weight to within preset guidelines is a possible way of alleviating this problem.