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1 Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA, USA
* To whom correspondence should be addressed. E-mail: march{at}nature.berkeley.edu.
Reduced cell proliferation may mediate anti-carcinogenic effects of caloric restriction (CR). Using heavy water (2H2O) labeling, the cell proliferation response to CR was investigated in detail, including the time course, effect of refeeding, and role of intermittent feeding with 5% CR. In the time course study, 8-week-old female C57BL/6J mice were placed on a 33% CR regimen (food given 3 times/week) for varying durations. Compared to ad libitum fed controls (AL), proliferation rates of keratinocytes, mammary epithelial cells and T-cells were markedly reduced within 2 weeks of CR. In mice fed 95% of ad libitum (C95, fed 3 times/week), cell proliferation was also reduced in all tissues so that the differences from 33% CR were only significant at 1 month. In the refeeding study, mice were refed a 95% ad libitum diet for varying durations after 1 month of 33% CR. Cell proliferation rebounded to a supra-basal rate in all tissues after 2 weeks of refeeding, then normalized after 2 months, although the C95 group again exhibited lower cell proliferation than AL. The role of intermittent feeding was studied by comparing 33% CR and C95 (both fed intermittently) to 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.
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