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

Abstract

Reduced cell proliferation may mediate anticarcinogenic effects of caloric restriction (CR). Using heavy water ( 2 H2O) 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 CALORIC RESTRICTION (CR), defined as undernutrition without malnutrition (45), was first discovered in 1935 to extend maximal life span in rats (29). Since then, similar findings have been reported in mice, fish, flies, worms, and yeast (45). A range of 30 -70% extension of maximal life span has been achieved using variations on CR regimens (45), including both early-and adult-onset CR (44,46). CR also exerts a number of other beneficial health effects, including reduced carcinogenesis, enhanced insulin sensitivity, and reduced cardiovascular disease risk (15). The inhibitory effect of CR on carcinogenesis is of particular interest, because CR effectively inhibits spontaneous tumor formation as well as neoplasias in knockout/ transgenic models of cancer-and chemically induced tumorigenesis (18,19,45). The mechanisms by which CR extends life span and inhibits carcinogenesis remain unknown (15,19).CR could affect several steps in the multistage carcinogenesis model (18). CR may function as an anti-initiator by decreasing carcinogen activation, enhancing carcinogen detoxification, scavenging reactive oxygen species, or enhancing DNA repair (18). CR could also function as an antipromoter by reducing mitoses of initiated cells, altering expression of cancer-related genes, decreasing inflammation, enhancing immune competence, or stimulating apoptosis (18). Reductions in cell proliferation might be expected in view of ob...

Caloric restriction attenuates the age-associated increase of adipose-derived stem cells but further reduces their proliferative capacity

“…Coupled with our finding in lin − SVF showing that telomerase activity, a marker of cellular youth, is at near adult ad lib levels in the aged CR group, it would seem most likely that CR maintains the ASC population in a quiescent state. This effect would be consistent with studies demonstrating that CR decreases the proliferation rates of dividing non-stem cells such as keratinocytes, mammary epithelial cells and T cells (Hsieh et al 2005). The idea that CR maintains stem cell population in a quiescent state is consistent with the idea that CR reduces the rate of cellular turnover.…”

Effects of modified alternate-day fasting regimens on adipocyte size, triglyceride metabolism, and plasma adiponectin levels in mice

“…The heavy water ( 2 H 2 O) labeling protocol has been described previously (16). In brief, mice were administered 2 H 2 O starting at the beginning of week 3 (day 14) and throughout the last two weeks of the study (days [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]). An initial priming dose of 99.9% 2 H 2 O (0.18 ml/10 g body weight) was given via intraperitoneal injection to bring the 2 H 2 O content of body water up to ?5%.…”

“…ADF regimens consist of ad libitum feeding for a 24 h period (feed day), alternated with a 24 h fast (fast day). Although studied less frequently than traditional CR, ADF reproduces many of the beneficial effects of daily CR (14), including reductions in global cell proliferation (15). ADF is a potentially attractive strategy for implementing CR in humans, particularly if the ADF regimens can be modified (i.e., through varying degrees of energy restriction on the fast day alternated with ad libitum feeding on the feed day) while still retaining their beneficial effects.…”

Potential Mechanisms of Cancer Prevention by Weight Control

“…It showed the proliferation rates of mammary epithelial cells and T cells were markedly reduced within 2 weeks with calorie restriction regimen when compared to that of ad libitum fed mice. Two weeks after refeeding, the cell proliferation rates rebounded to the basal level (Hsieh et al, 2005). We found that the percentage of PCNA in skin epithelial cells was significantly lower in 20% of calorie restricted mice than ad libitum fed mice, as shown by immunohistochemistry staining (Xie et al, 2007).…”

“…Using a heavy water labeling, Hsieh et al (2005) investigated a time-course of the effects of calorie restriction on cell proliferation rates in female C57BL/6J mice. It showed the proliferation rates of mammary epithelial cells and T cells were markedly reduced within 2 weeks with calorie restriction regimen when compared to that of ad libitum fed mice.…”