Sirtuins — novel therapeutic targets to treat age-associated diseases (original) (raw)

• Lin, S. J., Defossez, P. A. & Guarente, L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 289, 2126–2128 (2000).
  Article CAS PubMed Google Scholar
• Frye, R. A. Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem. Biophys. Res. Commun. 273, 793–798 (2000).
  Article CAS PubMed Google Scholar
• Cohen, H. Y. et al. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 305, 390–392 (2004). SIRT1 levels are increased in several tissues of calorie-restricted rats.
  Article CAS PubMed Google Scholar
• Heilbronn, L. K. et al. Glucose tolerance and skeletal muscle gene expression in response to alternate day fasting. Obes. Res. 13, 574–581 (2005).
  Article CAS PubMed Google Scholar
• Nisoli, E. et al. Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science 310, 314–317 (2005).
  Article CAS PubMed Google Scholar
• Picard, F. et al. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-γ. Nature 429, 771–776 (2004). In differentiated adipocytes, SIRT1 triggers lipolysis and loss of fat by repressing PPAR-γ.
  Article CAS PubMed PubMed Central Google Scholar
• Bordone, L. et al. SIRT1 transgenic mice show phenotypes resembling calorie restriction. Aging Cell 6, 759–767 (2007).
  Article CAS PubMed Google Scholar
• Boily, G. et al. SirT1 regulates energy metabolism and response to caloric restriction in mice. PLoS ONE 3, e1759 (2008).
  Article PubMed PubMed Central CAS Google Scholar
• Nemoto, S., Fergusson, M. M. & Finkel, T. SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1α. J. Biol. Chem. 280, 16456–16460 (2005).
  Article CAS PubMed Google Scholar
• Rodgers, J. T. et al. Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature 434, 113–118 (2005). SIRT1 modulates ageing in several species and controls the gluconeogenic/glycolytic pathways in the liver through the transcriptional co-activator PGC1α.
  Article CAS PubMed Google Scholar
• Rasbach, K. A. & Schnellmann, R. G. Isoflavones promote mitochondrial biogenesis. J. Pharmacol. Exp. Ther. 325, 536–543 (2008).
  Article CAS PubMed Google Scholar
• Petersen, K. F. et al. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 300, 1140–1142 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Singh, K. K. Mitochondrial dysfunction is a common phenotype in aging and cancer. Ann. NY Acad. Sci. 1019, 260–264 (2004).
  Article CAS PubMed Google Scholar
• Fontana, L., Meyer, T. E., Klein, S. & Holloszy, J. O. Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans. Proc. Natl Acad. Sci. USA 101, 6659–6663 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Hepple, R. T., Baker, D. J., McConkey, M., Murynka, T. & Norris, R. Caloric restriction protects mitochondrial function with aging in skeletal and cardiac muscles. Rejuvenation Res. 9, 219–222 (2006).
  Article CAS PubMed Google Scholar
• Meyer, T. E. et al. Long-term caloric restriction ameliorates the decline in diastolic function in humans. J. Am. Coll. Cardiol. 47, 398–402 (2006).
  Article CAS PubMed Google Scholar
• Minamiyama, Y. et al. Calorie restriction improves cardiovascular risk factors via reduction of mitochondrial reactive oxygen species in type II diabetic rats. J. Pharmacol. Exp. Ther. 320, 535–543 (2007).
  Article CAS PubMed Google Scholar
• Howitz, K. T. et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425, 191–196 (2003).
  Article CAS PubMed Google Scholar
• Baur, J. A. et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444, 337–342 (2006). Resveratrol is shown to increase the healthy lifespan of a mammal by acting as a calorie-restriction mimetic.
  Article CAS PubMed PubMed Central Google Scholar
• Cullen, J. P. et al. Resveratrol, a polyphenolic phytostilbene, inhibits endothelial monocyte chemotactic protein-1 synthesis and secretion. J. Vasc. Res. 44, 75–84 (2007).
  Article CAS PubMed Google Scholar
• Delmas, D., Jannin, B. & Latruffe, N. Resveratrol: preventing properties against vascular alterations and ageing. Mol. Nutr. Food Res. 49, 377–395 (2005).
  Article CAS PubMed Google Scholar
• Lagouge, M. et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell 127, 1109–1122 (2006). Resveratrol is shown to improve insulin sensitivity and prevent liver steatosis in mice fed a high-fat diet.
  Article CAS PubMed Google Scholar
• Marambaud, P., Zhao, H. & Davies, P. Resveratrol promotes clearance of Alzheimer's disease amyloid-β peptides. J. Biol. Chem. 280, 37377–37382 (2005).
  Article CAS PubMed Google Scholar
• Milne, J. C. et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 450, 712–716 (2007). Potent and selective SIRT1 activators improve insulin sensitivity and glycaemia in rodent models of type 2 diabetes.
  Article CAS PubMed PubMed Central Google Scholar
• Nayagam, V. M. et al. SIRT1 modulating compounds from high-throughput screening as anti-inflammatory and insulin-sensitizing agents. J. Biomol. Screen. 11, 959–967 (2006).
  Article CAS PubMed Google Scholar
• Kyselova, V., Peknicova, J., Buckiova, D. & Boubelik, M. Effects of _p_-nonylphenol and resveratrol on body and organ weight and in vivo fertility of outbred CD-1 mice. Reprod. Biol. Endocrinol. 1, 30 (2003).
  Article PubMed PubMed Central Google Scholar
• Dasgupta, B. & Milbrandt, J. Resveratrol stimulates AMP kinase activity in neurons. Proc. Natl Acad. Sci. USA 104, 7217–7222 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Bottner, M., Christoffel, J., Jarry, H. & Wuttke, W. Effects of long-term treatment with resveratrol and subcutaneous and oral estradiol administration on pituitary function in rats. J. Endocrinol. 189, 77–88 (2006).
  Article PubMed CAS Google Scholar
• Bowers, J. L., Tyulmenkov, V. V., Jernigan, S. C. & Klinge, C. M. Resveratrol acts as a mixed agonist/antagonist for estrogen receptors alpha and beta. Endocrinology 141, 3657–3667 (2000).
  Article CAS PubMed Google Scholar
• Lambert, P. D. et al. Resveratrol: a drug to treat human diseases of aging? Annu. Rev. Pharmacol. Toxicol. (in the press).
• Haigis, M. C. et al. SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell 126, 941–954 (2006).
  Article CAS PubMed Google Scholar
• Liszt, G., Ford, E., Kurtev, M. & Guarente, L. Mouse Sir2 homolog SIRT6 is a nuclear ADP-ribosyltransferase. J. Biol. Chem. 280, 21313–21320 (2005).
  Article CAS PubMed Google Scholar
• Landry, J. et al. The silencing protein SIR2 and its homologs are NAD-dependent protein deacetylases. Proc. Natl Acad. Sci. USA 97, 5807–5811 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Imai, S., Armstrong, C. M., Kaeberlein, M. & Guarente, L. Transcriptional silencing and longevity protein Sir2 is an NAD- dependent histone deacetylase. Nature 403, 795–800 (2000).
  CAS PubMed Google Scholar
• Smith, J. S. et al. A phylogenetically conserved NAD+-dependent protein deacetylase activity in the Sir2 protein family. Proc. Natl Acad. Sci. USA 97, 6658–6663 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Vaziri, H. et al. hSIR2 (SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 107, 149–159 (2001).
  Article CAS PubMed Google Scholar
• Tanner, K. G., Landry, J., Sternglanz, R. & Denu, J. M. Silent information regulator 2 family of NAD- dependent histone/protein deacetylases generates a unique product, 1-_O_-acetyl-ADP-ribose. Proc. Natl Acad. Sci. USA 97, 14178–14182 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Civitarese, A. E. et al. Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS Med. 4, e76 (2007).
  Article PubMed PubMed Central CAS Google Scholar
• Fulco, M. et al. Glucose restriction inhibits skeletal myoblast differentiation by activating SIRT1 through AMPK-mediated regulation of Nampt. Dev. Cell 14, 661–673 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Revollo, J. R., Grimm, A. A. & Imai, S. The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltransferase regulates Sir2 activity in mammalian cells. J. Biol. Chem. 279, 50754–50763 (2004). A NAD biosynthetic pathway enzyme can regulate the activity of mammalian Sir2 enzyme in cells, with implications for Sir2 as a potential cellular energy sensor.
  Article CAS PubMed Google Scholar
• Brunet, A. et al. Stress-dependent regulation of OXO transcription factors by the SIRT1 deacetylase. Science 303, 2011–2015 (2004).
  Article CAS PubMed Google Scholar
• Luo, J. et al. Negative Control of p53 by Sir2α promotes cell survival under stress. Cell 107, 137–148 (2001).
  Article CAS PubMed Google Scholar
• Yeung, F. et al. Modulation of NF-κB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J. 23, 2369–2380 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Jing, E., Gesta, S. & Kahn, C. R. SIRT2 regulates adipocyte differentiation through FOXO1 acetylation/deacetylation. Cell. Metab. 6, 105–114 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• North, B. J., Marshall, B. L., Borra, M. T., Denu, J. M. & Verdin, E. The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Mol. Cell 11, 437–444 (2003).
  Article CAS PubMed Google Scholar
• Wang, F., Nguyen, M., Qin, F. X. & Tong, Q. SIRT2 deacetylates FOXO3a in response to oxidative stress and caloric restriction. Aging Cell 6, 505–514 (2007).
  Article CAS PubMed Google Scholar
• Hallows, W. C., Lee, S. & Denu, J. M. Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases. Proc. Natl Acad. Sci. USA 103, 10230–10235 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Schwer, B., Bunkenborg, J., Verdin, R. O., Andersen, J. S. & Verdin, E. Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2. Proc. Natl Acad. Sci. USA 103, 10224–10229 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Ahuja, N. et al. Regulation of insulin secretion by SIRT4, a mitochondrial ADP-ribosyltransferase. J. Biol. Chem. 282, 33583–33592 (2007).
  Article CAS PubMed Google Scholar
• Finnin, M. S., Donigian, J. R. & Pavletich, N. P. Structure of the histone deacetylase SIRT2. Nature Struct. Biol. 8, 621–625 (2001).
  Article CAS PubMed Google Scholar
• Schuetz, A. et al. Structural basis of inhibition of the human NAD+-dependent deacetylase SIRT5 by suramin. Structure 15, 377–389 (2007).
  Article CAS PubMed Google Scholar
• Mostoslavsky, R. et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 124, 315–329 (2006).
  Article CAS PubMed Google Scholar
• Michishita, E. et al. SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin. Nature 452, 492–496 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Kanfi, Y. et al. Regulation of SIRT6 protein levels by nutrient availability. FEBS Lett. 582, 543–548 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Ford, E. et al. Mammalian Sir2 homolog SIRT7 is an activator of RNA polymerase I transcription. Genes Dev. 20, 1075–1080 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Vakhrusheva, O. et al. Sirt7 increases stress resistance of cardiomyocytes and prevents apoptosis and inflammatory cardiomyopathy in mice. Circ. Res. 102, 703–710 (2008).
  Article CAS PubMed Google Scholar
• Alcendor, R. R. et al. Sirt1 regulates aging and resistance to oxidative stress in the heart. Circ. Res. 100, 1512–1521 (2007). Moderate overexpression of SIRT1 is shown to be cardioprotective against oxidative stress.
  Article CAS PubMed Google Scholar
• Cheng, H. L. et al. Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice. Proc. Natl Acad. Sci. USA 100, 10794–10799 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Kim, D. et al. SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis. EMBO J. 26, 3169–3179 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Lombard, D. B. et al. Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation. Mol. Cell Biol. 27, 8807–8814 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• McBurney, M. W. et al. The mammalian SIR2α protein has a role in embryogenesis and gametogenesis. Mol. Cell Biol. 23, 38–54 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Outeiro, T. F. et al. Sirtuin 2 inhibitors rescue α-synuclein-mediated toxicity in models of Parkinson's disease. Science 317, 516–519 (2007).
  Article CAS PubMed Google Scholar
• Parker, J. A. et al. Resveratrol rescues mutant polyglutamine cytotoxicity in nematode and mammalian neurons. Nature Genet. 37, 349–350 (2005).
  Article CAS PubMed Google Scholar
• Sibille, E. et al. Lack of serotonin1B receptor expression leads to age-related motor dysfunction, early onset of brain molecular aging and reduced longevity. Mol. Psychiatry 12, 1042–1056 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Yamamoto, H., Schoonjans, K. & Auwerx, J. Sirtuin functions in health and disease. Mol. Endocrinol. 21, 1745–1755 (2007).
  Article CAS PubMed Google Scholar
• Yang, T., Fu, M., Pestell, R. & Sauve, A. A. SIRT1 and endocrine signaling. Trends Endocrinol. Metab. 17, 186–191 (2006).
  Article CAS PubMed Google Scholar
• Li, X. et al. SIRT1 deacetylates and positively regulates the nuclear receptor LXR. Mol. Cell 28, 91–106 (2007).
  Article PubMed CAS Google Scholar
• Freyssenet, D. Energy sensing and regulation of gene expression in skeletal muscle. J. Appl. Physiol. 102, 529–540 (2007).
  Article CAS PubMed Google Scholar
• Pfluger, P. T., Herranz, D., Velasco-Miguel, S., Serrano, M. & Tschop, M. H. Sirt1 protects against high-fat diet-induced metabolic damage. Proc. Natl Acad. Sci. USA 105, 9793–9798 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Pearson, K. J. et al. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell. Metab. 2 Jul 2008 (doi:10.1016/j.cmet.2008.06.011).
  Article CAS PubMed PubMed Central Google Scholar
• Moynihan, K. A. et al. Increased dosage of mammalian Sir2 in pancreatic beta cells enhances glucose-stimulated insulin secretion in mice. Cell. Metab. 2, 105–117 (2005). Islet-cell-specific SIRT1 overexpression improves glucose tolerance by promoting insulin secretion and protects pancreatic function even with ageing.
  Article CAS PubMed Google Scholar
• Bordone, L. et al. Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells. PLoS Biol. 4, e31 (2006).
  Article PubMed CAS Google Scholar
• Zhang, J. The direct involvement of SirT1 in insulin-induced insulin receptor substrate-2 tyrosine phosphorylation. J. Biol. Chem. 282, 34356–34364 (2007).
  Article CAS PubMed Google Scholar
• Zhang, J. Resveratrol inhibits insulin responses in a SirT1-independent pathway. Biochem. J. 397, 519–527 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Nissen, S. E. & Wolski, K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N. Engl. J. Med. 356, 2457–2471 (2007).
  Article CAS PubMed Google Scholar
• Dentin, R. et al. Insulin modulates gluconeogenesis by inhibition of the coactivator TORC2. Nature 449, 366–369 (2007).
  Article CAS PubMed Google Scholar
• Zhu, J. et al. Anti-inflammatory effect of resveratrol on TNF-α-induced MCP-1 expression in adipocytes. Biochem. Biophys. Res. Commun. 369, 471–477 (2008).
  Article CAS PubMed Google Scholar
• Cullen, J. P. et al. Resveratrol inhibits expression and binding activity of the monocyte chemotactic protein-1 receptor, CCR2, on THP-1 monocytes. Atherosclerosis 195, e125–e133 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Wellen, K. E. & Hotamisligil, G. S. Inflammation, stress, and diabetes. J. Clin. Invest. 115, 1111–1119 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Sharma, S., Kulkarni, S. K. & Chopra, K. Effect of resveratrol, a polyphenolic phytoalexin, on thermal hyperalgesia in a mouse model of diabetic neuropathic pain. Fundam. Clin. Pharmacol. 21, 89–94 (2007).
  Article CAS PubMed Google Scholar
• Tikoo, K., Tripathi, D. N., Kabra, D. G., Sharma, V. & Gaikwad, A. B. Intermittent fasting prevents the progression of type I diabetic nephropathy in rats and changes the expression of Sir2 and p53. FEBS Lett. 581, 1071–1078 (2007).
  Article CAS PubMed Google Scholar
• Dong, F. & Ren, J. Fidarestat improves cardiomyocyte contractile function in db/db diabetic obese mice through a histone deacetylase Sir2-dependent mechanism. J. Hypertens. 25, 2138–2147 (2007).
  Article CAS PubMed Google Scholar
• Holt, I. J., Harding, A. E. & Morgan-Hughes, J. A. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 331, 717–719 (1988).
  Article CAS PubMed Google Scholar
• Wallace, D. C. et al. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 242, 1427–1430 (1988).
  Article CAS PubMed Google Scholar
• Nardin, R. A. & Johns, D. R. Mitochondrial dysfunction and neuromuscular disease. Muscle Nerve 24, 170–191 (2001).
  Article CAS PubMed Google Scholar
• Wallace, D. C. Mitochondrial DNA mutations in diseases of energy metabolism. J. Bioenerg. Biomembr. 26, 241–250 (1994).
  Article CAS PubMed Google Scholar
• Goto, Y., Nonaka, I. & Horai, S. A mutation in the tRNALeu(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 348, 651–653 (1990).
  Article CAS PubMed Google Scholar
• Kobayashi, Y. et al. A point mutation in the mitochondrial tRNALeu(UUR) gene in MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes). Biochem. Biophys. Res. Commun. 173, 816–822 (1990).
  Article CAS PubMed Google Scholar
• Melov, S., Coskun, P. E. & Wallace, D. C. Mouse models of mitochondrial disease, oxidative stress, and senescence. Mutat. Res. 434, 233–242 (1999).
  Article CAS PubMed Google Scholar
• Chabi, B., Adhihetty, P. J., Ljubicic, V. & Hood, D. A. How is mitochondrial biogenesis affected in mitochondrial disease? Med. Sci. Sports Exerc. 37, 2102–2110 (2005).
  Article CAS PubMed Google Scholar
• DiMauro, S. Mitochondrial myopathies. Curr. Opin. Rheumatol. 18, 636–641 (2006).
  Article CAS PubMed Google Scholar
• DiMauro, S. & Mancuso, M. Mitochondrial diseases: therapeutic approaches. Biosci. Rep. 27, 125–137 (2007).
  Article CAS PubMed Google Scholar
• Taivassalo, T. & Haller, R. G. Exercise and training in mitochondrial myopathies. Med. Sci. Sports Exerc. 37, 2094–2101 (2005).
  Article CAS PubMed Google Scholar
• Lin, J. et al. Transcriptional co-activator PGC-1α drives the formation of slow-twitch muscle fibres. Nature 418, 797–801 (2002).
  Article CAS PubMed Google Scholar
• Das, D. K. & Maulik, N. Resveratrol in cardioprotection: a therapeutic promise of alternative medicine. Mol. Interv. 6, 36–47 (2006).
  Article CAS PubMed Google Scholar
• Labinskyy, N. et al. Vascular dysfunction in aging: potential effects of resveratrol, an anti-inflammatory phytoestrogen. Curr. Med. Chem. 13, 989–996 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Mattagajasingh, I. et al. SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase. Proc. Natl Acad. Sci. USA 104, 14855–14860 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Novakovic, A., Bukarica, L. G., Kanjuh, V. & Heinle, H. Potassium channels-mediated vasorelaxation of rat aorta induced by resveratrol. Basic Clin. Pharmacol. Toxicol. 99, 360–364 (2006).
  Article CAS PubMed Google Scholar
• Stef, G., Csiszar, A., Lerea, K., Ungvari, Z. & Veress, G. Resveratrol inhibits aggregation of platelets from high-risk cardiac patients with aspirin resistance. J. Cardiovasc. Pharmacol. 48, 1–5 (2006).
  Article CAS PubMed Google Scholar
• Zbikowska, H. M., Olas, B., Wachowicz, B. & Krajewski, T. Response of blood platelets to resveratrol. Platelets 10, 247–252 (1999).
  Article CAS PubMed Google Scholar
• Zhang, Y. et al. Resveratrol, a natural ingredient of grape skin: antiarrhythmic efficacy and ionic mechanisms. Biochem. Biophys. Res. Commun. 340, 1192–1199 (2006).
  Article CAS PubMed Google Scholar
• Zhou, B. et al. Silibinin protects against isoproterenol-induced rat cardiac myocyte injury through mitochondrial pathway after up-regulation of SIRT1. J. Pharmacol. Sci. 102, 387–395 (2006).
  Article CAS PubMed Google Scholar
• Teisseyre, A. & Michalak, K. Inhibition of the activity of human lymphocyte Kv1.3 potassium channels by resveratrol. J. Membr. Biol. 214, 123–129 (2006).
  Article CAS PubMed Google Scholar
• Arany, Z. et al. Transcriptional coactivator PGC-1α controls the energy state and contractile function of cardiac muscle. Cell. Metab. 1, 259–271 (2005).
  Article CAS PubMed Google Scholar
• Chen, I. Y. et al. Histone H2A.z is essential for cardiac myocyte hypertrophy but opposed by silent information regulator 2α. J. Biol. Chem. 281, 19369–19377 (2006).
  Article CAS PubMed Google Scholar
• Kuningas, M., Putters, M., Westendorp, R. G., Slagboom, P. E. & van Heemst, D. SIRT1 gene, age-related diseases, and mortality: the Leiden 85-plus study. J. Gerontol. A Biol. Sci. Med. Sci. 62, 960–965 (2007).
  Article PubMed Google Scholar
• Potente, M. et al. SIRT1 controls endothelial angiogenic functions during vascular growth. Genes Dev. 21, 2644–2658 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Vahtola, E. et al. Forkhead class O transcription factor 3a activation and Sirtuin1 overexpression in the hypertrophied myocardium of the diabetic Goto–Kakizaki rat. J. Hypertens. 26, 334–344 (2008).
  Article CAS PubMed Google Scholar
• Alcendor, R. R., Kirshenbaum, L. A., Imai, S., Vatner, S. F. & Sadoshima, J. Silent information regulator 2α, a longevity factor and class III histone deacetylase, is an essential endogenous apoptosis inhibitor in cardiac myocytes. Circ. Res. 95, 971–980 (2004).
  Article CAS PubMed Google Scholar
• Crow, M. T. Sir-viving cardiac stress: cardioprotection mediated by a longevity gene. Circ. Res. 95, 953–956 (2004).
  Article CAS PubMed Google Scholar
• Penumathsa, S. V. et al. Statin and resveratrol in combination induces cardioprotection against myocardial infarction in hypercholesterolemic rat. J. Mol. Cell Cardiol. 42, 508–516 (2007).
  Article CAS PubMed Google Scholar
• Pillai, J. B. et al. Poly(ADP-ribose) polymerase-1-deficient mice are protected from angiotensin II-induced cardiac hypertrophy. Am. J. Physiol. Heart Circ. Physiol. 291, H1545–H1553 (2006).
  Article CAS PubMed Google Scholar
• Pillai, J. B., Isbatan, A., Imai, S. & Gupta, M. P. Poly(ADP-ribose) polymerase-1-dependent cardiac myocyte cell death during heart failure is mediated by NAD+ depletion and reduced Sir2α deacetylase activity. J. Biol. Chem. 280, 43121–43130 (2005).
  Article CAS PubMed Google Scholar
• Stokin, G. B. et al. Axonopathy and transport deficits early in the pathogenesis of Alzheimer's disease. Science 307, 1282–1288 (2005).
  Article CAS PubMed Google Scholar
• Fischer, L. R. et al. Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man. Exp. Neurol. 185, 232–240 (2004).
  Article PubMed Google Scholar
• Pallas, M., Verdaguer, E., Tajes, M., Gutierrez-Cuesta, J. & Camins, A. Modulation of sirtuins: new targets for antiageing. Recent Patents CNS Drug Discov. 3, 61–69 (2008).
  Article CAS Google Scholar
• Qin, W. et al. Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction. J. Biol. Chem. 281, 21745–21754 (2006).
  Article CAS PubMed Google Scholar
• Chen, J. et al. SIRT1 protects against microglia-dependent beta amyloid toxicity through inhibiting NF-κB signaling. J. Biol. Chem. 280, 40364–40374 (2005).
  Article CAS PubMed Google Scholar
• Qin, W. et al. Calorie restriction attenuates Alzheimer's disease type brain amyloidosis in Squirrel monkeys (Saimiri sciureus). J. Alzheimers Dis. 10, 417–422 (2006).
  Article CAS PubMed Google Scholar
• Wang, Q. et al. Resveratrol protects against neurotoxicity induced by kainic acid. Neurochem. Res. 29, 2105–2112 (2004).
  Article CAS PubMed Google Scholar
• Hendrie, H. C. et al. Incidence of dementia and Alzheimer disease in 2 communities: Yoruba residing in Ibadan, Nigeria, and African Americans residing in Indianapolis, Indiana. JAMA 285, 739–747 (2001).
  Article CAS PubMed Google Scholar
• Luchsinger, J. A., Tang, M. X., Shea, S. & Mayeux, R. Caloric intake and the risk of Alzheimer disease. Arch. Neurol. 59, 1258–1263 (2002).
  Article PubMed Google Scholar
• Mattson, M. P. Gene–diet interactions in brain aging and neurodegenerative disorders. Ann. Intern. Med. 139, 441–444 (2003).
  Article CAS PubMed Google Scholar
• Patel, N. V. et al. Caloric restriction attenuates Aβ-deposition in Alzheimer transgenic models. Neurobiol. Aging 26, 995–1000 (2005).
  Article CAS PubMed Google Scholar
• Wang, J. et al. A local mechanism mediates NAD-dependent protection of axon degeneration. J. Cell Biol. 170, 349–355 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Alvira, D. et al. Comparative analysis of the effects of resveratrol in two apoptotic models: inhibition of complex I and potassium deprivation in cerebellar neurons. Neuroscience 147, 746–756 (2007).
  Article CAS PubMed Google Scholar
• Stull, N. D., Polan, D. P. & Iacovitti, L. Antioxidant compounds protect dopamine neurons from death due to oxidative stress in vitro. Brain Res. 931, 181–185 (2002).
  Article CAS PubMed Google Scholar
• Li, Y., Xu, W., McBurney, M. W. & Longo, V. D. SirT1 inhibition reduces IGF-I/IRS-2/Ras/ERK1/2 signaling and protects neurons. Cell. Metab. 8, 38–48 (2008).
  Article PubMed PubMed Central CAS Google Scholar
• Karabouta, Z., Barnett, S., Shield, J. P., Ryan, F. J. & Crowne, E. C. Peripheral neuropathy is an early complication of type 2 diabetes in adolescence. Pediatr. Diabetes 9, 110–114 (2008).
  Article PubMed Google Scholar
• Coleman, M. P. & Perry, V. H. Axon pathology in neurological disease: a neglected therapeutic target. Trends Neurosci. 25, 532–537 (2002).
  Article CAS PubMed Google Scholar
• Araki, T., Sasaki, Y. & Milbrandt, J. Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration. Science 305, 1010–1013 (2004). The dowstream effector in NMNAT-mediated protection of Wallerian degeneration is SIRT1.
  Article CAS PubMed Google Scholar
• Shindler, K. S., Guan, Y., Ventura, E., Bennett, J. & Rostami, A. Retinal ganglion cell loss induced by acute optic neuritis in a relapsing model of multiple sclerosis. Mult. Scler. 12, 526–532 (2006).
  Article PubMed Google Scholar
• Shindler, K. S., Ventura, E., Rex, T. S., Elliott, P. & Rostami, A. SIRT1 activation confers neuroprotection in experimental optic neuritis. Invest. Ophthalmol. Vis. Sci. 48, 3602–3609 (2007).
  Article PubMed Google Scholar
• Salminen, A. et al. Interaction of aging-associated signaling cascades: Inhibition of NF-κB signaling by longevity factors FoxOs and SIRT1. Cell. Mol. Life Sci. 65, 1049–1058 (2008).
  Article CAS PubMed Google Scholar
• Ghosh, H. S., Spencer, J. V., Ng, B., McBurney, M. W. & Robbins, P. D. Sirt1 interacts with transducin-like enhancer of split-1 to inhibit nuclear factor kappaB-mediated transcription. Biochem. J. 408, 105–111 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Leiro, J. et al. Effect of _cis_-resveratrol on genes involved in nuclear factor kappa B signaling. Int. Immunopharmacol. 5, 393–406 (2005).
  Article CAS PubMed Google Scholar
• Singh, N. P., Hegde, V. L., Hofseth, L. J., Nagarkatti, M. & Nagarkatti, P. Resveratrol (_trans_-3,5,4′-trihydroxystilbene) ameliorates experimental allergic encephalomyelitis, primarily via induction of apoptosis in T cells involving activation of aryl hydrocarbon receptor and estrogen receptor. Mol. Pharmacol. 72, 1508–1521 (2007).
  Article CAS PubMed Google Scholar
• Rajendrasozhan, S., Yang, S. R., Kinnula, V. L. & Rahman, I. SIRT1, an antiinflammatory and antiaging protein, is decreased in lungs of patients with COPD. Am. J. Respir. Crit. Care Med. 177, 861–870 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Yang, S. R. et al. Cigarette smoke induces proinflammatory cytokine release by activation of NF-κB and posttranslational modifications of histone deacetylase in macrophages. Am. J. Physiol. Lung Cell. Mol. Physiol. 291, L46–L57 (2006).
  Article CAS PubMed Google Scholar
• Yang, S. R. et al. Sirtuin regulates cigarette smoke-induced proinflammatory mediator release via RelA/p65 NF-κB in macrophages in vitro and in rat lungs in vivo: implications for chronic inflammation and aging. Am. J. Physiol. Lung Cell. Mol. Physiol. 292, L567–L576 (2007).
  Article CAS PubMed Google Scholar
• Pruitt, K. et al. Inhibition of SIRT1 reactivates silenced cancer genes without loss of promoter DNA hypermethylation. PLoS Genet. 2, e40 (2006).
  Article PubMed PubMed Central CAS Google Scholar
• Firestein, R. et al. The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth. PLoS ONE 3, e2020 (2008).
  Article PubMed PubMed Central CAS Google Scholar
• Chen, W. Y. et al. Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses. Cell 123, 437–448 (2005).
  Article CAS PubMed Google Scholar
• Cohen, H. Y. et al. Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis. Mol. Cell 13, 627–638 (2004).
  Article CAS PubMed Google Scholar
• Dai, J. M., Wang, Z. Y., Sun, D. C., Lin, R. X. & Wang, S. Q. SIRT1 interacts with p73 and suppresses p73-dependent transcriptional activity. J. Cell Physiol. 210, 161–166 (2007).
  Article CAS PubMed Google Scholar
• Dryden, S. C., Nahhas, F. A., Nowak, J. E., Goustin, A. S. & Tainsky, M. A. Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle. Mol. Cell Biol. 23, 3173–3185 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Hiratsuka, M. et al. Proteomics-based identification of differentially expressed genes in human gliomas: down-regulation of SIRT2 gene. Biochem. Biophys. Res. Commun. 309, 558–566 (2003).
  Article CAS PubMed Google Scholar
• Bigner, S. H. & Vogelstein, B. Cytogenetics and molecular genetics of malignant gliomas and medulloblastoma. Brain Pathol. 1, 12–18 (1990).
  Article CAS PubMed Google Scholar
• Cleveland, D. W., Mao, Y. & Sullivan, K. F. Centromeres and kinetochores: from epigenetics to mitotic checkpoint signaling. Cell 112, 407–421 (2003).
  Article CAS PubMed Google Scholar
• Inoue, T. et al. SIRT2, a tubulin deacetylase, acts to block the entry to chromosome condensation in response to mitotic stress. Oncogene 26, 945–957 (2007).
  Article CAS PubMed Google Scholar
• Kamel, C., Abrol, M., Jardine, K., He, X. & McBurney, M. W. SirT1 fails to affect p53-mediated biological functions. Aging Cell 5, 81–88 (2006).
  Article CAS PubMed Google Scholar
• Solomon, J. M. et al. Inhibition of SIRT1 catalytic activity increases p53 acetylation but does not alter cell survival following DNA damage. Mol. Cell Biol. 26, 28–38 (2006). Potent inhibitors of the deacetylase activity of SIRT1 altered the acetylation state of p53, but effects on cell survival were not evident in multiple cell lines following DNA damage.
  Article CAS PubMed PubMed Central Google Scholar
• Stunkel, W. et al. Function of the SIRT1 protein deacetylase in cancer. Biotechnol. J. 2, 1360–1368 (2007).
  Article CAS PubMed Google Scholar
• Michishita, E., Park, J. Y., Burneskis, J. M., Barrett, J. C. & Horikawa, I. Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. Mol. Biol. Cell 16, 4623–4635 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Narala, S. R. et al. SIRT1 acts as a nutrient-sensitive growth suppressor and its loss is associated with increased AMPK and telomerase activity. Mol. Biol. Cell 19, 1210–1219 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Masoro, E. J. Overview of caloric restriction and ageing. Mech. Ageing Dev. 126, 913–922 (2005).
  Article CAS PubMed Google Scholar
• Sinclair, D. A. & Guarente, L. Unlocking the secrets of longevity genes. Sci. Am. 294, 48–51, 54–57 (2006).
  Article CAS PubMed Google Scholar
• Chen, D., Steele, A. D., Lindquist, S. & Guarente, L. Increase in activity during calorie restriction requires Sirt1. Science 310, 1641 (2005). Elevation in physical activity in response to diet restriction is evident in wild-type mice but not in Sirt1 -knockout mice.
  Article CAS PubMed Google Scholar
• Lombard, D. B., Schwer, B., Alt, F. W. & Mostoslavsky, R. SIRT6 in DNA repair, metabolism and ageing. J. Intern. Med. 263, 128–141 (2008).
  Article CAS PubMed PubMed Central Google Scholar