SIRT1 has been shown to be critical in regulating the response to oxidative and hypoxic (low oxygen) stress in endothelial cells. These cells line all the blood vessels in the body (endothelium) and as such are critical gate keepers in maintaining vascular heath. Endothelial cell dysfunction can lead to numerous disorders including atherosclerosis, which can contribute to progressive cardiovascular disease including myocardial infarction, stroke and peripheral arterial disease. Sirtris is currently evaluating one of its NCEs, SRT2104, in a Phase IIa clinical study designed to assess potential cardiovascular benefits by first investigating the impact on endothelial function.

Development of new drugs for the prevention of neurodegenerative disease has been an area of intense activity with very little progress. Discovery of druggable mechanisms with broad application across different neurodegenerative diseases would represent a significant advance in this therapeutic area. Both NCE SIRT1 activators and overexpression of SIRT1 have been shown to slow cell death in cell culture as well as neurodegeneration in animal models. A role for activated SIRT1 in preventing neuronal cell death may be useful for multiple neurodegenerative disorders, such as optic neuritis, ALS and Alzheimer’s disease. Two important publications have solidly implicated SIRT1 in regulating the formation of the two primary pathological components of Alzheimer’s Disease, Aβ-peptide and tau. These data support the idea that SIRT1 activators may be broadly applicable in the treatment of neurodegenerative diseases.

Inflammation is a complex biological response that is caused by a variety of stimuli, such as damaged cells in tissue. Abnormal inflammation is associated with a broad variety of diseases, including inflammatory bowel diseases (IBD) and ophthalmic, respiratory and cardiovascular diseases. SIRT1 has been shown to be a negative regulator of several inflammatory pathways including NFκB, a master regulatory component driving many inflammatory diseases. Thus, activation of SIRT1 may be beneficial for many of these inflammatory diseases.

Sirtris’ new chemical entities (NCEs) have shown efficacy in multiple preclinical models of inflammation and other relevant disease models. Sirtris has evaluated two of its NCEs, SIRT2104 and SRT2379 in separate translational medicine studies of acute inflammation. In these studies low dose, purified bacterial endotoxin or LPS is used to elicit an acute, systemic inflammatory response in healthy human volunteers. The administration of LPS results in changes in clinical parameters including blood pressure and respiratory rate as well as elevations in inflammatory cytokines including tumor necrosis factor (TNF), as well as a transient increase in coagulopathy. The impact of SRT2104 in this setting was presented at the 10th World Congress on Inflammation in Paris, France in June 2011.

Mitochondrial disorders are caused by mutations in mitochondrial DNA (mtDNA) or in nuclear genes important for mitochondrial biogenesis. SIRT1 activation may be beneficial as it has been shown in preclinical models to enhance mitochondrial biogenesis in skeletal muscle and to improve exercise tolerance.

Xia L, Ding F, Zhu JH, Fu GS. Resveratrol attenuates apoptosis of pulmonary microvascular endothelial cells induced by high shear stress and proinflammatory factors. Hum Cell. 2011; 24:127-33.

Wang J, Zhang Y, Tang L, Zhang N, Fan D. Protective effects of resveratrol through the up-regulation of SIRT1 expression in the mutant hSOD1-G93A-bearing motor neuron-like cell culture model of amyotrophic lateral sclerosis. Neurosci Lett. 2011;503: 250-5.

Lei M, Wang JG, Xiao DM, Fan M, Wang DP, Xiong JY, Chen Y, Ding Y, Liu SL. Resveratrol inhibits interleukin 1β-mediated inducible nitric oxide synthase expression in articular chondrocytes by activating SIRT1 and thereby suppressing nuclear factor-κB activity. Eur J Pharmacol. 2011; Oct 25.

Zhu X, Liu Q, Wang M, Liang M, Yang X, Xu X, Zou H, Qiu J. Activation of Sirt1 by resveratrol inhibits TNF-α induced inflammation in fibroblasts. PLoS One. 2011;6: e27081.  
 
Jian B, Yang S, Chaudry IH, Raju R. Resveratrol improves cardiac contractility following trauma-hemorrhage by modulating Sirt1. Mol Med. 2011;Nov 16. doi: 10.2119/molmed.2011.00365.

Chen S, Xiao X, Feng X, Li W, Zhou N, Zheng L, Sun Y, Zhang Z, Zhu W. Resveratrol induces Sirt1-dependent apoptosis in 3T3-L1 preadipocytes by activating AMPK and suppressing AKT activity and survivin expression. J Nutr Biochem. 2011;Nov 30.

Alamdari N, Aversa Z, Castillero E, Gurav A, Petkova V, Tizio S, Hasselgren PO. Resveratrol prevents dexamethasone-induced expression of the muscle atrophy-related ubiquitin ligases atrogin-1 and MuRF1 in cultured myotubes through a SIRT1-dependent mechanism. Biochem Biophys Res Commun. 2011;Dec 7.

Yamashita S, Ogawa K, Ikei T, Udono M, Fujiki T, Katakura Y. SIRT1 prevents replicative senescence of normal human umbilical cord fibroblast through potentiating the transcription of human telomerase reverse transcriptase gene. Biochem Biophys Res Commun. 2011;Dec 14.

Lappas M, Mitton A, Lim R, Barker G, Riley C, Permezel M. SIRT1 is a novel regulator of key pathways of human labor. Biol Reprod. 2011;84: 167-78.

Knight, CM, Gutierrez-Juarez, R, Lam, TKT, Arrieta-Cruz, I, Huang, l, Schwartz, G, Barzili, N and Rossetti, L. Mediobasal hypothalamic sirtuin 1 is essential for resveratrol's effects on insulin action in rats. Diabetes 2011; 10.2337/db10-0987

Minor, RK, Baur, JA, Gomes, AP, Ward, TM, Csiszar, A, Mercken, EM, Abdelmohsen, K, Shin, Y-K, Canto, C, Scheibye-Knudsen, M, Krawczyk, M, Irusta, PM, Martin-Montalvo, A, Hubbard, BP, Zhang, Y, Lehrmann, E, While, AA, Price, NL, Swundell, WR, Pearson, KJ, Becker, KG, Bohr, VA, Gorospe, M, Egan, JM, Talan, MI, Auwerx, J, Westphal, CW, Ellis, JL, Ungvari, Z, Vlasuk, GP, Elliott, PJ, Sinclair, DA and de Cabo, R. SRT1720 improves survival and healthspan of obese mice. Sci. Rep. 2011; 1, 70; DOI:10.1038/srep00070

Shakibaei, M, Buhrmann, C and Mobasheri, A. Resveratrol-mediated SIRT1 interactions with P300 modulate RANKL-activation of NF-κB signaling and inhibit osteoclastogenesis in bone-derived cells. J. Biol. Chem. 2011; 286: 11492-11505

Vetterli, L, Brun, T, Giovannoni, L, Bosco, D and Maechler, P. Resveratrol potentiates glucose-stimulated insulin secretion in INS-1Eb-cells and human islets through a SIRT1-dependent mechanism. J. Biol. Chem. 2011; 286: 6049-6060

Lee, S-J and Kim M-M. Resveratrol with antioxidant activity inhibits matrix metallo[roteinase via modulation of SIRT1 in human fibrosarcoma cells. Life Sci. 2011; 88: 465-472

Hori, YS, Kuno, A, Hosoda, R, Tanno, M, Miura, T, Shimamoto, K.and Horio, Y. Resveratrol ameliorates muscular pathology in the dystrophic mdx mouse, a model for duchenne muscular dystrophy. J. Pharm. Exp. Therap. 2011; 338: 784-794

Kim, DH, Jung, YJ, Lee, JE, Lee, AS, Kang, KP, Lee, S, Park, SK, Han, MK, Lee, SY, Ramkumar, KM, Sung, MJ, and Kim, W. SIRT1 activation by resveratrol ameliorates cisplatin-induced renal injury through deacetylation of p53. Am. J. Physiol. Renal Physiol. 2011; 301: F427-F435

Yang, J, Wang, N, Li, J, Zhang, J and Fenf, P. Effects of resveratrol on NO secretion stimulated by insulin and its dependence on SIRT1 in high glucose cultured endothelial cells. Endocr. 2010; 37: 365-372

Park, J-M, Kim, T-H, Bae, J-S, Kim, M-Y, Kim, K-S and Ahn, Y-H. Role of resveratrol in FOXO-mediated gluconeogenic gene expression in the liver.  Biochem. Biophys. Res, Comm. 2010; 403:329-334

Yoshizaki T, Schenk S, Imamura T, Babendure JL, Sonoda N, Bae EJ, Oh da Y, Lu M, Milne JC, Westphal C, Bandyopadhyay G, Olefsky JM. SIRT1 inhibits inflammatory pathways in macrophages and modulates insulin sensitivity. Am J Physiol Endocrinol Metab. 2010; 298(3):E419-28

Funk JA, Odejinmi S, and Schnellmann RG, SRT1720 Induces mitochondrial biogenesis and rescues mitochondrial function after oxidant injury in renal proximal tubule cells. J. Pharmacol Exp Ther. 2010; 333:593-601

He W, Wang Y, Zhang MZ, You L, Davis LS, Fan H, Yang HC, Fogo AB, Zent R, Harris RC, Breyer MD, Hao CM. SIRT1 activation protects the mouse renal medulla from oxidative injury. J. Clin Invest. 2010; 120:1056-1068

Fischer-Posovszky P, Kukulus V, Tews D, Unterkircher T, Debatin KM, Fulda S, Wabitsch M. Resveratrol regulates human adipocyte number and function in a SIRT1-dependent manner. Am J Clin Nutr. 2010; 92: 5-15

Boily G, He XH, Pearce B, Jardine K, McBurney MW. SIRT1-null mice develop tumors at normal rates but are poorly protected by resveratrol. Oncogene, 2009; 28(32):2882-93

Yoshizaki T, Milne JC, Imamura T, Schenk S, Sonoda N, Babendure JL, Lu JC, Smith JJ, Jirousek MR, Olefsky JM. SIRT1 exerts anti-inflammatory effects and improves insulin sensitivity in adipocytes. Mol Cell Biol, 2009; 29:1363-74

Feige JN, Lagouge M, Canto C, Strehle A, Houten SM, Milne JC, Lambert PD, Mataki C, Elliott PJ, Auwerx J. Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. Cell Metab, 2008; 8:347-58

Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P, Geny B, Laakso M, Puigserver P, Auwerx J. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell, 2006; 127(6):1109-22

Picard F, Kurtev M, Chung N, Topark-Ngarm A, Senawong T, Machado De Oliveira R, Leid M, McBurney MW, Guarente L. SIRT1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature, 2004; 429:771-776

Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature, 2003; 425(6954):191-6