HYPOTHESIS The Response to Calorie Restriction in Mammals Shows Features Also Common to Hibernation: A Cross-Adaptation Hypothesis

The marked elevation in hepatic carbamyl phosphate synthetase I (CPSI) in calorie-restricted mice, and the changes in erythrocyte 2,3-diphosphoglycerate (2,3-DPG) and in hemoglobin oxygen affinity in calorie-restricted and hypoxic humans living in Biosphere 2 suggest similarities between physiologic events in calorie restriction and hibernation. Other data from the literature strengthen this comparison. Accordingly, we hypothesize that the re-sponse to the calorie restriction regime as studied by gerontologists, rather than being a laboratory artifact, is part of a spectrum of responses to food deprivation which have adaptive value in the wild, and whose triggering mecha-nism may primarily involve the neuroendocrine system. IT was demonstrated some years ago that under experi-mental conditions average and maximum life spans in poikilothermic vertebrates (annual fish) could be substan-tially prolonged by lowering body temperature by 3 to 5 °C (Liu and Walford, 1966, 1970, 1972). Comparison of the soluble/insoluble collagen ratios (a "biomarker " of aging) of fish from the different temperature regimes supported the supposition that the life-span differences reflected dif-ferences in rates of aging (Walford et al., 1969). In homeotherms, we observed that young, middle-aged, and old mice on a life-extending calorie restriction regime of "undernutrition without malnutrition " displayed body temperatures 1 to 1.5 °C lower than unrestricted control mice (Weindruch et al., 1979; Cheney et al., 1980). This finding was confirmed and extended by others, both i