Recent progress in the biology and physiology of Sirtuins

Translational Medicine Branch, National Heart Lung and Blood Institute, US National Institutes of Health, Bethesda, Maryland 20892, USA.
Nature (Impact Factor: 41.46). 08/2009; 460(7255):587-91. DOI: 10.1038/nature08197
Source: PubMed


The sirtuins are a highly conserved family of NAD(+)-dependent enzymes that regulate lifespan in lower organisms. Recently, the mammalian sirtuins have been connected to an ever widening circle of activities that encompass cellular stress resistance, genomic stability, tumorigenesis and energy metabolism. Here we review the recent progress in sirtuin biology, the role these proteins have in various age-related diseases and the tantalizing notion that the activity of this family of enzymes somehow regulates how long we live.

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Available from: Raul Mostoslavsky, Apr 19, 2014
    • "We next investigated the gene expression of sirtuins and genes involved in insulin/IGF-1 action and intermediary metabolism in skeletal muscle, the tissue accounting for the most of the body's energy expenditure. Sirtuins control stress resistance, genomic stability and energy metabolism, and contribute to lifespan determination and some of the sirtuin mouse knockout models display reductions in lifespan (Finkel et al., 2009). Furthermore, SIRT1 may be an important genetic determinant of fetal programming during malnutrition, influencing type 2 diabetes risk later in life (Botden et al., 2012), and SIRT1 gene expression levels are altered in a rat model of perinatal low-protein undernutrition (MartinGronert et al., 2008). "
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    ABSTRACT: Prenatal and early postnatal life determines future health, and intrauterine growth restriction (IUGR) - associated low birth weight predisposes to metabolic syndrome in adulthood. We hypothesize here that IUGR might induce hormonal and gene expression alterations predisposing to metabolic disease. Using a porcine model of spontaneous IUGR, we determined in utero (71, 112 days post-conception) and early-postnatal (2 days post-birth) IGF-1, insulin and leptin levels, and in parallel we investigated, in skeletal muscle, the developmental expression patterns of sirtuins and metabolic and signaling genes IRS1, GLUT4, HK2 and GAPDH. IUGR was associated with impaired IGF-1 plasmatic levels. Gene expression of sirtuin 1, 5, 6, 7, GLUT4 and HK2 exhibited significant correlations with gestational age or body weight. SIRT1 and HK2 expression displayed an age- and weight-dependent downregulation in controls, which was lost in IUGR pigs. Conversely, SIRT2 and GLUT4 were upregulated in IUGR pigs. Within the set of genes studied, we found a significant correlation between IGF-1 levels and gene expression in control, but not IUGR samples, indicating that lower IGF-1 may be a limiting factor in IUGR. IUGR-dependent gene alterations were partly linked to epigenetic changes on histone H3 acetylation and methylation. Overall, our data indicate that several sirtuins and metabolic genes display specific gene expression trajectories during fetal and early postnatal life. Gene expression alterations observed in IUGR are correlated to IGF-1 dysregulation. Given the importance of the genes studied in metabolic control, their perinatal alterations might contribute to the predisposition to metabolic disease of adulthood.
    No preview · Article · Jan 2016 · General and Comparative Endocrinology
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    • "The list depicted in Table 1 is by no means comprehensive since new in vivo substrates and specificities are discovered every day. The most studied human isoform is SIRT1, a nuclear protein reported to regulate critical physiological processes and associated with chronic inflammatory diseases and metabolic dysfunctions like diabetes, obesity, aging, and even cancer [7]. "
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    ABSTRACT: Sirtuins are a conserved family of NAD-dependent protein deacylases. Initially proposed as histone deacetylases, it is now known that they act on a variety of proteins including transcription factors and metabolic enzymes, having a key role in the regulation of cellular homeostasis. Seven isoforms are identified in mammals (SIRT1–7), all of them sharing a conserved catalytic core and showing differential subcellular localization and activities. Oxidative stress can affect the activity of sirtuins at different levels: expression, posttranslational modifications, protein-protein interactions, and NAD levels. Mild oxidative stress induces the expression of sirtuins as a compensatory mechanism, while harsh or prolonged oxidant conditions result in dysfunctional modified sirtuins more prone to degradation by the proteasome. Oxidative posttranslational modifications have been identified in vitro and in vivo , in particular cysteine oxidation and tyrosine nitration. In addition, oxidative stress can alter the interaction with other proteins, like SIRT1 with its protein inhibitor DBC1 resulting in a net increase of deacetylase activity. In the same way, manipulation of cellular NAD levels by pharmacological inhibition of other NAD-consuming enzymes results in activation of SIRT1 and protection against obesity-related pathologies. Nevertheless, further research is needed to establish the molecular mechanisms of redox regulation of sirtuins to further design adequate pharmacological interventions.
    Full-text · Article · Jan 2016 · Oxidative medicine and cellular longevity
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    • "In addition, since the action of ALR2 on glucose metabolism is linked to depletion into the cells of the cofactor NAD+ [11] and SIRT1 is a NAD1-dependent protein deacetylase which belongs to a class of proteins that lead to improved energy consumption, limitation of oxidative stress, and reduced DNA damage [12] [13], the second aim of the study was to investigate whether there is an involvement of the sirtuin 1 (SIRT1) in the cardiac effects of BF-5m. SIRT1 is one of the better characterized sirtuins with multiple protective actions in many pathological conditions, through involvement of several molecular pathways, deacetylation of mediators of oxidative stress, inflammation, apoptosis, and transcription factors, and plays an important role in the regulation of glucose consumption by regulating insulin expression in vivo [14] [15]. "
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    ABSTRACT: This study investigated the effects of the new aldose reductase inhibitor benzofuroxane derivative 5(6)-(benzo [ d ] thiazol-2-ylmethoxy)benzofuroxane (BF-5m) on the prolongation of cardiac QT interval and increase of coronary perfusion pressure (CPP) in isolated, high glucose (33.3 mM D-glucose) perfused rat hearts. BF-5m was dissolved in the Krebs solution at a final concentration of 0.01 μ M, 0.05 μ M, and 0.1 μ M. 33.3 mM D-glucose caused a prolongation of the QT interval and increase of CPP up to values of 190 ± 12 ms and 110 ± 8 mmHg with respect to the values of hearts perfused with standard Krebs solution (11.1 mM D-glucose). The QT prolongation was reduced by 10%, 32%, and 41%, respectively, for the concentration of BF-5m 0.01 μ M, 0.05 μ M, and 0.1 μ M. Similarly, the CPP was reduced by 20% for BF-5m 0.05 μ M and by 32% for BF-5m 0.1 μ M. BF-5m also increased the expression levels of sirtuin 1, MnSOD, eNOS, and FOXO-1, into the heart. The beneficial actions of BF-5m were partly abolished by the pretreatment of the rats with the inhibitor of the sirtuin 1 activity EX527 (10 mg/kg/day/7 days i.p.) prior to perfusion of the hearts with high glucose + BF-5m (0.1 μ M). Therefore, BF-5m supplies cardioprotection from the high glucose induced QT prolongation and increase of CPP.
    Full-text · Article · Dec 2015 · Journal of Diabetes Research
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