Caloric Restriction and Aging: Studies in Mice and Monkeys

Wisconsin National Primate Research Center, Madison, Wisconsin, USA.
Toxicologic Pathology (Impact Factor: 2.14). 01/2009; 37(1):47-51. DOI: 10.1177/0192623308329476
Source: PubMed


It is widely accepted that caloric restriction (CR) without malnutrition delays the onset of aging and extends lifespan in diverse animal models including yeast, worms, flies, and laboratory rodents. The mechanism underlying this phenomenon is still unknown. We have hypothesized that a reprogramming of energy metabolism is a key event in the mechanism of CR (Anderson and Weindruch 2007). Data will be presented from studies of mice on CR, the results of which lend support to this hypothesis. Effects of long-term CR (but not short-term CR) on gene expression in white adipose tissue (WAT) are overt. In mice and monkeys, a chronic 30% reduction in energy intake yields a decrease in adiposity of approximately 70%. In mouse epididymal WAT, long-term CR causes overt shifts in the gene expression profile: CR increases the expression of genes involved in energy metabolism (Higami et al. 2004), and it down-regulates the expression of more than 50 pro-inflammatory genes (Higami et al. 2006). Whether aging retardation occurs in primates on CR is unknown. We have been investigating this issue in rhesus monkeys subjected to CR since 1989 and will discuss the current status of this project. A new finding from this project is that CR reduces the rate of age-associated muscle loss (sarcopenia) in monkeys (Colman et al. 2008).

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Available from: Rozalyn M Anderson, Jun 11, 2015
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    • "It is a nongenetic intervention that consistently promotes longevity in model organisms such as yeast, worms, flies, mice, and nonhuman primates (Mattison et al., 2012; Colman et al., 2009; Fontana et al., 2010). Furthermore, in rodents, dietary restriction significantly delays the onset of many chronic diseases and increases lifespan by up to 60% (Anderson et al., 2009). However, the mechanisms underlying these effects of CR remain poorly understood. "
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    ABSTRACT: To determine the effects and underlying molecular mechanisms of caloric restriction (CR) in C57BL/6 mice. Thirty-six 6-week-old male C57BL/6 mice were assigned to a normal control group (NC, n = 12), a high energy group (HE, n = 12), and a CR group (n = 12), and received a normal diet, a high-calorie diet, or a calorie-restricted diet, respectively, for 44 weeks. Body weight and serum glucose concentration were regularly recorded, and animals were sacrificed and hippocampus tissues were collected for immunohistochemistry (n = 6 per group), western blotting (n = 3 per group) and real-time polymerase chain reaction (n = 3 per group) analysis at the end of the 44-week experimental period. Immunohistochemistry, western blotting and real-time polymerase chain reaction were used to detect changes in hippocampal proteins may be involved in the SIRT1/mTOR pathways. Body weight and serum glucose over the 44 weeks in animals from the CR group were lower than those of HE group. The number of SIRT1-immunoreactive cells in the CR group was significantly higher than in the NC and HE groups, and SIRT1 mRNA expression in the CR group was significantly higher than that in the HE group, but there was no difference in SIRT1 protein expression among the three groups. mTOR and S6K1 protein activation and mTOR and S6K1 mRNA were significantly lower in the CR group than in the NC group. Our findings suggest that a CR diet could lead to activation of SIRT1 and suppression of mTOR and S6K1 activation in C57BL/6 mice. We have shown that the SIRT1/mTOR signaling pathways may be involved in the neuroprotective effect of CR. Copyright © 2015. Published by Elsevier Inc.
    Brain research bulletin 06/2015; 116. DOI:10.1016/j.brainresbull.2015.06.004 · 2.72 Impact Factor
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    • "Caloric restriction (CR) and intermittent fasting (IF) are two procedures of dietary restriction known for several beneficial effects on health and longevity [13] [14]. Several studies in rodents and primates have shown that the reduction of daily caloric intake by 10–40% improves insulin sensitivity, reduces fasting glucose and insulin concentration and prevents obesity, T2D, hypertension and chronic inflammation [15] [16] [17]. In humans, 20% CR improves glucose tolerance and insulin action, and reduces risk factors for T2D, cardiovascular disease and cancer [18] [19]. "
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    ABSTRACT: Caloric restriction and intermittent fasting are known to improve glucose homeostasis and insulin resistance in several species including human. The aim of this study was to unravel potential mechanisms by which theses interventions improve insulin sensitivity and protect from type 2 diabetes. Diabetes-susceptible New Zealand Obese mice were either 10% caloric restricted (CR) or fasted every other day (IF), and compared to ad libitum (AL) fed control mice. AL mice showed a diabetes prevalence of 43%, whereas mice under CR and IF were completely protected against hyperglycemia. Proteomic analysis of hepatic lipid droplets revealed significantly higher levels of PSMD9 (co-activator Bridge-1), MIF (macrophage migration inhibitor factor), TCEB2 (transcription elongation factor B (SIII), polypeptide 2), ACY1 (aminoacylase 1) and FABP5 (fatty acid binding protein 5), and a marked reduction of GSTA3 (glutathione S-transferase alpha 3) in samples of CR and IF mice. In addition, accumulation of diacylglycerols (DAGs) was significantly reduced in livers of IF mice (P = 0.045) while CR mice showed a similar tendency (P = 0.062). In particular, 9 DAG species were significantly reduced in response to IF, of which DAG-40:4 and DAG-40:7 also showed significant effects after CR. This was associated with a decreased PKCε activation and might explain the improved insulin sensitivity. In conclusion, our data indicate that protection against diabetes upon caloric restriction and intermittent fasting associates with a modulation of lipid droplet protein composition and reduction of intracellular DAG species.
    Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 01/2015; 1851(5). DOI:10.1016/j.bbalip.2015.01.013 · 5.16 Impact Factor
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    • "All these genes are located on autosomal chromosomes except for the X-chromosomal gene Kdm6a. Interestingly, for a number of these genes (indicated with §), intestinal expression and/or functioning has been described [55]-[59] but until now sexually dimorphic expression has not been reported. "
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    ABSTRACT: Background There is increasing appreciation for sexually dimorphic effects, but the molecular mechanisms underlying these effects are only partially understood. In the present study, we explored transcriptomics and epigenetic differences in the small intestine and colon of prepubescent male and female mice. In addition, the microbiota composition of the colonic luminal content has been examined. Methods At postnatal day 14, male and female C57BL/6 mice were sacrificed and the small intestine, colon and content of luminal colon were isolated. Gene expression of both segments of the intestine was analysed by microarray analysis. DNA methylation of the promoter regions of selected sexually dimorphic genes was examined by pyrosequencing. Composition of the microbiota was explored by deep sequencing. Results Sexually dimorphic genes were observed in both segments of the intestine of 2-week-old mouse pups, with a stronger effect in the small intestine. Amongst the total of 349 genes displaying a sexually dimorphic effect in the small intestine and/or colon, several candidates exhibited a previously established function in the intestine (i.e. Nts, Nucb2, Alox5ap and Retnlγ). In addition, differential expression of genes linked to intestinal bowel disease (i.e. Ccr3, Ccl11 and Tnfr) and colorectal cancer development (i.e. Wt1 and Mmp25) was observed between males and females. Amongst the genes displaying significant sexually dimorphic expression, nine genes were histone-modifying enzymes, suggesting that epigenetic mechanisms might be a potential underlying regulatory mechanism. However, our results reveal no significant changes in DNA methylation of analysed CpGs within the selected differentially expressed genes. With respect to the bacterial community composition in the colon, a dominant effect of litter origin was found but no significant sex effect was detected. However, a sex effect on the dominance of specific taxa was observed. Conclusions This study reveals molecular dissimilarities between males and females in the small intestine and colon of prepubescent mice, which might underlie differences in physiological functioning and in disease predisposition in the two sexes.
    Biology of Sex Differences 08/2014; 5(1):11. DOI:10.1186/s13293-014-0011-9 · 4.84 Impact Factor
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