Caloric restriction and aging: studies in mice and monkeys

Wisconsin National Primate Research Center, Madison, Wisconsin, USA.
Toxicologic Pathology (Impact Factor: 1.92). 01/2009; 37(1):47-51. DOI: 10.1177/0192623308329476
Source: PubMed

ABSTRACT 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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    • "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 · 4.50 Impact Factor
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    • "Sirtuin-mediated control of protein acetylation might not be restricted to chromatin packaging and transcriptional modulation, as the mitochondrial sirtuin SIRT3 has been proposed to play an important role in the prevention of agerelated diseases, possibly through modulation of the mitochondrial acetylproteome (Hebert et al., 2013). Of note, in rodents, moderate CR (8%) positively affects median (not maximal) lifespan , but a more severe (30%) dietary restriction increases lifespan by up to 50%, partly by delaying the emergence of chronic diseases (Anderson et al., 2009). Interestingly, a recent report showed that mice with transgenic overexpression of fibroblast growth factor 21 (FGF21), a fasting hormone, have extended lifespan when maintained on an ad libitum diet (Zhang et al., 2012). "
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    ABSTRACT: The phenomenon of aging is an intrinsic feature of life. Accordingly, the possibility to manipulate it has fascinated humans likely since time immemorial. Recent evidence is shaping a picture where low caloric regimes and exercise may improve healthy senescence, and several pharmacological strategies have been suggested to counteract aging. Surprisingly, the most effective interventions proposed to date converge on only a few cellular processes, in particular nutrient signaling, mitochondrial efficiency, proteostasis, and autophagy. Here, we critically examine drugs and behaviors to which life- or healthspan-extending properties have been ascribed and discuss the underlying molecular mechanisms.
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    • "It delays or prevents many age-related diseases such as cardiovascular disease and cancer (Dirks and Leeuwenburgh 2006). CR involves a shift from state of growth and proliferation to maintenance and repair (Yu et al. 1985) and is most effective when caloric intake of animals fed AL is reduced by 20–40% without malnutrition (Anderson et al. 2009). "
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    ABSTRACT: Caloric restriction (CR) has been demonstrated to prolong the life span of a variety of species. CR-induced reduction in core temperature (Tc) is considered a key mechanism responsible for prolonging life span in rodents; however, little is known about the regulation of CR-induced hypothermia as a function of the circadian cycle. We assessed how mild CR that resulted in a 10% reduction in body weight affected the 24 h patterns of Tc as well as heart rate (HR) and motor activity (MA) of the Brown Norway rat. Telemetered rats were allowed to feed for 20 weeks ad libitum (AL) or given a CR diet. Tc, HR, and MA of CR rats exhibited nocturnal reductions and diurnal elevations, opposite to that of AL rats. The effects of CR appeared to peak at ∼4 weeks. Metabolic rate (MR) and respiratory exchange ratio (RER) were measured overnight after 18 weeks of CR. MR and RER were elevated markedly at the time of feeding in CR rats and then declined during the night. We found that the pattern of Tc was altered with CR, characterized by elimination of high nocturnal Tc's typically observed in AL animals. In terms of mechanisms to prolong life span in CR animals, we suggest that the shift in the pattern of Tc during CR (i.e., elimination of high Tc's) may be as critical as the overall mean reduction in Tc. Future studies should address how the time of feeding may affect the thermoregulatory response in calorically restricted rats.
    07/2013; 1(2):e00016. DOI:10.1002/phy2.16
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