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.
"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. "
[Show abstract][Hide abstract] 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.
"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). "
[Show abstract][Hide abstract] 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.
"In summary, major effects are associated with its scavenging activity as well as in the activation of SIRT1 (see Bordone and Guarente, 2005; Herskovits and Guarente, 2014 for extensive reviews on the topic). The presence of non-SIRT1 neuronal targets of resveratrol is debated, suggesting that resveratrol in vivo may act on other uninvestigated biological targets (Herskovits and Guarente, 2014). "
[Show abstract][Hide abstract] ABSTRACT: Cognitive impairment is the final outcome of a complex network of molecular mechanisms ultimately leading to dementia. Despite major efforts aimed at unraveling the molecular determinants of dementia of Alzheimer type (DAT), effective disease-modifying approaches are still missing. An interesting and still largely unexplored avenue is offered by nutraceutical intervention. For instance, robust epidemiological data have suggested that moderate intake of red wine may protect against several age-related pathological conditions (i.e., cardiovascular diseases, diabetes, and cancer) as well as DAT-related cognitive decline. Wine is highly enriched in many polyphenols, including resveratrol. Resveratrol is a well recognized antioxidant which may modulate metal ion deregulation outcomes as well as main features of the Alzheimer's disease (AD) brain. The review will discuss the potentiality of resveratrol as a neuroprotectant in dementia in relation to the oxidative stress produced by amyloid and metal dysmetabolism.
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