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

ABSTRACT 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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    • "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.
    Experimental Gerontology 09/2014; 57:47–56. DOI:10.1016/j.exger.2014.05.005 · 3.49 Impact Factor
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    • "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). "
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    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.
    Frontiers in Aging Neuroscience 05/2014; 6:95. DOI:10.3389/fnagi.2014.00095 · 4.00 Impact Factor
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    • "In addition, there are changes in hormone levels like insulin, glucagon, adipokines, and glucocorticoids that are coupled with changes in the concentration of regulatory proteins like peroxisome proliferator-activated receptor (PPAR)g, forkhead protein (FOXO), and silent information regulator-1 (SIRT1). The SIRT1 gene belongs to the sirtuin gene family that is involved in nutrient sensing, DNA damage sensing and responses, and cancer in mammals [15]. Most sirtuins act in the same pathway that is regulated by TOR (target of rapamycin) genes and extend life by similar mechanisms as DR [17]. "
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    ABSTRACT: It has been two decades since 1993 when research on the biology of rotifer aging was last reviewed by Enesco. Much has transpired during this time as rotifer biologists have adapted to the "omics" revolution and incorporated these techniques into the experimental analysis of rotifers. Rotifers are amenable to many of these approaches and getting adequate quantities of DNA, RNA, and protein from rotifers is not difficult. Analysis of rotifer genomes, transcriptomes, and proteomes is rapidly yielding candidate genes that likely regulate a variety of features of rotifer biology. Parallel developments in aging biology have recognized the limitations of standard animal models like worms and flies and that comparative aging research has essentially ignored a large fraction of animal phylogeny in the lophotrochozoans. As experimentally tractable members of this group, rotifers have attracted interest as models of aging. In this paper, I review advances over the past 20 years in the biology of aging in rotifers, with emphasis on the unique contributions of rotifer models for understanding aging. The majority of experimental work has manipulated rotifer diet and followed changes in survival and reproductive dynamics like mean lifespan, maximum lifespan, reproductive lifespan, and mortality rate doubling time. The main dietary manipulation has been some form of caloric restriction, withholding food for some period or feeding continuously at low levels. There have been comparative studies of several rotifer species, with some species responding to caloric restriction with life extension, but others not, at least under the tested food regimens. Other aspects of diet are less explored, like nutritional properties of different algae species and their capacity to extend rotifer lifespan. Several descriptive studies have reported many genes involved in rotifer aging by comparing gene expression in young and old individuals. Classes of genes up or down-regulated during aging have become prime targets for rotifer aging investigations. Alterations of gene expression by exposure to specific inhibitors or RNAi knockdown will probably yield valuable insights into the cellular mechanisms of rotifer life extension. I highlight major experimental contributions in each of these areas and indicate opportunities where I believe additional investigation is likely to be profitable.
    International Review of Hydrobiology 03/2014; 99(1-2):84-95. · 0.97 Impact Factor
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