Effects of caloric restriction on cell proliferation in several tissues in mice: role of intermittent feeding

1 Department of Nutritional Sciences and Toxicology, Morgan Hall, University of California, Berkeley; and 2 Division of Endocrinology and Metabolism, Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California Submitted 12 August 2004 ; accepted in final form 16 December 2004 Reduced cell proliferation may mediate anticarcinogenic effects of caloric restriction (CR). Using heavy water ( 2 H 2 O) labeling, we investigated the cell proliferation response to CR in detail, including time course, effect of refeeding, and role of intermittent feeding with 5% CR. In the time-course study, 8-wk-old female C57BL/6J mice were placed on a 33% CR regimen (fed 3 times/wk) for varying durations. Compared with responses in controls fed ad libitum (AL), proliferation rates of keratinocytes, mammary epithelial cells, and T cells were markedly reduced within 2 wk of CR. In mice fed 95% ad libitum (C95, fed 3 times/wk), cell proliferation was also reduced in all tissues so that differences from 33% CR were only significant at 1 mo. In the refeeding study, mice were refed a C95 diet for varying durations after 1 mo of 33% CR. Cell proliferation rebounded to a suprabasal rate in all tissues after 2 wk of refeeding and then normalized after 2 mo, although the C95 group again exhibited lower cell proliferation than the AL group. The role of intermittent feeding was studied by comparing 33% CR and C95 animals (both fed intermittently) with animals fed isocalorically either daily or continuously by pellet dispenser. Intermittent feeding had no additive effect on 33% CR but reduced cell proliferation in all tissues at the 95% caloric intake level. In summary, the CR effect on cell proliferation is potent, rapid, and reversible in several tissues, and an intermittent feeding pattern reproduces much of the effect in the absence of substantial CR. stable isotopes; refeeding; keratinocyte; mammary; T cell Address for reprint requests and other correspondence: M. K. Hellerstein, Dept. of Nutritional Sciences and Toxicology, Morgan Hall, Rm. 309, Univ. of California, Berkeley, CA 94720 (E-mail: march{at}nature.berkeley.edu )