Calorie restriction, SIRT1 and metabolism

Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Nature Reviews Molecular Cell Biology (Impact Factor: 37.81). 05/2005; 6(4):298-305. DOI: 10.1038/nrm1616
Source: PubMed


Calorie restriction (CR) is the only experimental manipulation that is known to extend the lifespan of a number of organisms including yeast, worms, flies, rodents and perhaps non-human primates. In addition, CR has been shown to reduce the incidence of age-related disorders (for example, diabetes, cancer and cardiovascular disorders) in mammals. The mechanisms through which this occurs have been unclear. CR induces metabolic changes, improves insulin sensitivity and alters neuroendocrine function in animals. In this review, we summarize recent findings that are beginning to clarify the mechanisms by which CR results in longevity and robust health, which might open new avenues of therapy for diseases of ageing.

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    • "The SIRT1, a NAD-dependent deacetylase, has been shown to be important for sustaining clock network, cellular energy metabolism and aging (Bordone and Guarente, 2005). SIRT1 is implicated in circadian gene regulation by enhancing Bmal1 and Clock transcription (Fonseca Costa and Ripperger, 2015). "
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    ABSTRACT: Although age-related hypofunction of Leydig cells is well illustrated across species, its circadian nature has not been analyzed. Here we describe changes in circadian behavior in Leydig cells isolated from adult (3-month) and aged (18- and 24-month) rats. The results showed reduced circadian pattern of testosterone secretion in both groups of aged rats despite unchanged LH circadian secretion. Although arrhythmic, the expression of Insl3, another secretory product of Leydig cells, was decreased in both groups. Intracellular cAMP and most important steroidogenic genes (Star, Cyp11a1 and Cyp17a1), together with positive steroidogenic regulator (Nur77), showed preserved circadian rhythm in aging although rhythm robustness and expression level were attenuated in both aged groups. Aging compromised cholesterol mobilization and uptake by Leydig cells: the oscillatory transcription pattern of genes encoding HDL-receptor (Scarb1), hormone sensitive lipase (Lipe, enzyme that converts cholesterol esters from lipid droplets into free cholesterol) and protein responsible for forming the cholesterol esters (Soat2) were flattened in 24-month group. The majority of examined clock genes displayed circadian behavior in expression but only a few of them (Bmal1, Per1, Per2, Per3 and Rev.-Erba) were reduced in 24-month-old group. Furthermore, aging reduced oscillatory expression pattern of Sirt1 and Nampt, genes encoding key enzymes that connect cellular metabolism and circadian network. Altogether circadian amplitude of Leydig cell's endocrine function decreased during aging. The results suggest that clock genes are more resistant to aging than genes involved in steroidogenesis supporting the hypothesis about peripheral clock involvement in rhythm maintenance during aging.
    Full-text · Article · Nov 2015 · Experimental gerontology
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    • "In humans, Sirt3 expression was associated with an extended lifespan (Albani et al., 2014). Sirt1 is also an extensively studied sirtuin for its role in longevity (Bordone and Guarente, 2005) and whole body energy metabolism (Boutant and Canto, 2014; Fernandez-Marcos and Auwerx, 2011), maintaining pancreatic beta cell integrity and function (Luu et al., 2013), reducing myocardial hypertrophy (Planavila et al., 2011), and providing neuroprotection (Jiang et al., 2012). However, the effects of endocrine disruptors on these epigenetic regulators are largely unknown. "
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    ABSTRACT: The plasticizer benzyl butyl phthalate (BBP) is a well-known endocrine disruptor. Widespread human exposure to phthalates has raised substantial public concern due to its detrimental health effects. However, molecular mechanisms of the phthalates effect require elucidation. In this study, we analyzed: 1) the binding interaction of several phthalates and persistent organic pollutants with epigenetic regulator sirtuins and 2) the effect of BBP on the sirtuins in HepG2 cells. AutoDock molecular docking analysis showed that BBP binds to Sirt1 and Sirt3 proteins similarly to the native ligands with shortest binding free energies (ΔGb) of -7.35 and -8.3kcal/mol, respectively; and inhibition constants (Ki) of 4.07μM and 0.82μM, respectively. Furthermore, BBP was superimposed onto the co-crystallized ligands within the least root-mean-square deviation (RMSD) of 0.96Å and 1.55Å for Sirt1 and Sirt3, respectively, and bound into the sites with a sufficient number of hydrogen bonds, implying the best fit compared to other sirtuins. In HepG2 cells, BBP significantly down-regulated Sirt1 and Sirt3 (p<0.05) gene expression at a concentration as low as 10nM; other sirtuins remained unaffected. Consistent with decreased gene expression, Sirt1 and Sirt3 protein levels were significantly decreased at 48h (p<0.05). In addition, mitochondrial biogenesis regulators PGC-1α, NRF-1, and NRF-2, were decreased (p<0.05). SiRNA studies showed that BBP did not regulate PGC-1α via sirtuin and BBP requires sirtuin's presence to regulate NRF-1 or NRF-2. BBP significantly increased ROS production (p<0.05) and ROS may be chiefly regulated by NRF-1 and NRF-2 in HepG2 cells under Sirt1 and Sirt3 silenced condition. This is the first report to demonstrate that BBP selectively disrupts specific sirtuins in HepG2 cells. In conclusion, our study suggests that BBP can impair two vital epigenetic regulators and mitochondrial biogenesis regulators in liver cells.
    Full-text · Article · Nov 2015 · Toxicology
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    • "Diet has profound effects on longevity, and caloric restriction (CR) without malnutrition extends lifespan in most animals thus far tested (Testa et al., 2014). CR of 20–40% extends lifespan in many organisms (Bordone and Guarente, 2005; Fontana et al., 2010; Mair and Dillin, 2008; Sinclair 2005), including rotifers (Gribble and Mark Welch, 2013; Snell, 2014). The comparative approach using a variety of model organisms has been productive in advancing understanding of the mechanisms of aging (Austad, 2009; Deweerdt, 2012). "
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    ABSTRACT: Diet has profound effects on animal longevity and manipulation of nutrient sensing pathways is one of the primary interventions capable of lifespan extension. This often is done through caloric restriction (CR) and a variety of CR mimics have been identified that produce life extending effects without adhering to the rigorous CR dietary regimen. Glycerol is a dietary supplement capable mimicking CR by shifting metabolism away from glycolysis and towards oxidative phosphorylation. Glycerol supplementation has a number of beneficial effects, including lifespan extension, improved stress resistance, and enhanced locomotory and mitochondria activity in older age classes. Using rotifers as a model, we show that supplements of 150–300 mM glycerol produced 40–50% extension of mean lifespan. This effect was produced by raising glycerol concentration only three times higher than its baseline concentration in rotifer tissues. Glycerol supplementation decreased rotifer reliance on glycolysis and reduced the pro-aging effects of glucose. Glycerol also acted as a chemical chaperone, mitigating damage by protein aggregation. Glycerol treatment improved rotifer swimming performance in older age classes and maintained more mitochondrial activity. Glycerol treatment provided increased resistance to starvation, heat, oxidation, and osmotic stress, but not UV stress. When glycerol was co-administered with the hexokinase inhibitor 2-deoxyglucose, the lifespan extending effect of glycerol was enhanced. Co-administration of glycerol with inhibitors like 2-deoxyglucose can lower their efficacious doses, thereby reducing their toxic side effects.
    Full-text · Article · Sep 2014 · Experimental Gerontology
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