Small molecule SIRT1 activators for the treatment of aging and age-related diseases

Trends in Pharmacological Sciences

Volumn 35, Issue 3, 2014, Pages 146-154

  Hubbard, Basil P ^a,c   Sinclair, David A ^a,b  

^a HARVARD MEDICAL SCHOOL   (United States)

^b UNIVERSITY OF NEW SOUTH WALES   (Australia)

^c HARVARD UNIVERSITY   (United States)

Author keywords

aging; allosteric activator; cancer; cardiovascular disease; chromatin; deacetylase; diabetes; inflammation; sirtuin; STAC

Indexed keywords

BUTEIN; QUERCETIN; RESVERATROL; SIRTUIN 1; SRT 1460; SRT 1720; SRT 2104; SRT 2183; SRT 3025; THIAZOLE DERIVATIVE; UNCLASSIFIED DRUG;

ABSENCE OF SIDE EFFECTS; AGING; ALZHEIMER DISEASE; ANTIINFLAMMATORY ACTIVITY; ASTHMA; BREAST CANCER; CARDIOVASCULAR DISEASE; CHRONIC OBSTRUCTIVE LUNG DISEASE; COLON CANCER; CROHN DISEASE; DEGENERATIVE DISEASE; DIABETIC NEPHROPATHY; DRUG MECHANISM; DRUG STRUCTURE; EMPHYSEMA; ENZYME ACTIVATION; ENZYME ACTIVITY; HEART INFARCTION; HEART PROTECTION; HUMAN; INFLAMMATION; LIFESPAN; LONGEVITY; LYMPHOMA; METABOLIC DISORDER; MULTIPLE SCLEROSIS; NEOPLASM; NEUROPROTECTION; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; PARKINSON DISEASE; PRIORITY JOURNAL; PROSTATE CANCER; REVIEW; SKIN CANCER;

AGING; ALLOSTERIC ACTIVATOR; CANCER; CARDIOVASCULAR DISEASE; CHROMATIN; DEACETYLASE; DIABETES; INFLAMMATION; SIRTUIN; STAC;

AGING; ANIMALS; CARDIOVASCULAR DISEASES; DIABETES MELLITUS; HUMANS; INFLAMMATION; LONGEVITY; MOLECULAR TARGETED THERAPY; NEOPLASMS; SIRTUIN 1;

EID: 84896739647     PISSN: 01656147     EISSN: 18733735     Source Type: Journal    
DOI: 10.1016/j.tips.2013.12.004     Document Type: Review

References (105)

1. J.G. Wood et al. Sirtuin activators mimic caloric restriction and delay ageing in metazoans Nature 430 2004 686 689
2. J.A. Baur et al. Resveratrol improves health and survival of mice on a high-calorie diet Nature 444 2006 337 342
3. D.E. Harrison et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice Nature 460 2009 392 395
4. R. Strong et al. Evaluation of resveratrol, green tea extract, curcumin, oxaloacetic acid, and medium-chain triglyceride oil on life span of genetically heterogeneous mice J. Gerontol. A: Biol. Sci. Med. Sci. 68 2013 6 16
5. K.T. Howitz et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan Nature 425 2003 191 196
6. B.J. Morris Seven sirtuins for seven deadly diseases of aging Free Radic. Biol. Med. 56 2013 133 171
7. C. Kenyon The first long-lived mutants: discovery of the insulin/IGF-1 pathway for ageing Philos. Trans. R. Soc. Lond. B: Biol. Sci. 366 2011 9 16
8. J.C. Milne et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes Nature 450 2007 712 716
9. M.C. Haigis, and L.P. Guarente Mammalian sirtuins - emerging roles in physiology, aging, and calorie restriction Genes Dev. 20 2006 2913 2921
10. L. Bordone, and L. Guarente Calorie restriction, SIRT1 and metabolism: understanding longevity Nat. Rev. Mol. Cell Biol. 6 2005 298 305
11. G. Blander, and L. Guarente The Sir2 family of protein deacetylases Annu. Rev. Biochem. 73 2004 417 435
12. H.A. Tissenbaum, and L. Guarente Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans Nature 410 2001 227 230
13. B. Rogina, and S.L. Helfand Sir2 mediates longevity in the fly through a pathway related to calorie restriction Proc. Natl. Acad. Sci. U.S.A. 101 2004 15998 16003
14. C. Burnett et al. Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila Nature 477 2011 482 485
15. M. Viswanathan, and L. Guarente Regulation of Caenorhabditis elegans lifespan by sir-2.1 transgenes Nature 477 2011 E1 E2
16. K.K. Banerjee et al. dSir2 in the adult fat body, but not in muscles, regulates life span in a diet-dependent manner Cell Rep. 2 2012 1485 1491
17. Y. Kanfi et al. The sirtuin SIRT6 regulates lifespan in male mice Nature 483 2012 218 221
18. A. Satoh et al. Sirt1 extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH and LH Cell Metab. 18 2013 416 430
19. K.J. Bitterman et al. Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1 J. Biol. Chem. 277 2002 45099 45107
20. S. Imai et al. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase Nature 403 2000 795 800
21. H. Jiang et al. SIRT6 regulates TNF-α secretion through hydrolysis of long-chain fatty acyl lysine Nature 496 2013 110 113
22. J.L. Feldman et al. Activation of the protein deacetylase SIRT6 by long-chain fatty acids and widespread deacylation by mammalian sirtuins J. Biol. Chem. 288 2013 31350 31356
23. R.M. Anderson et al. Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiae Nature 423 2003 181 185
24. S.J. Lin et al. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae Science 289 2000 2126 2128
25. S.J. Lin et al. Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration Nature 418 2002 344 348
26. E.L. Greer, and A. Brunet Different dietary restriction regimens extend lifespan by both independent and overlapping genetic pathways in C. elegans Aging Cell 8 2009 113 127
27. Y. Wang, and H.A. Tissenbaum Overlapping and distinct functions for a Caenorhabditis elegans SIR2 and DAF-16/FOXO Mech. Ageing Dev. 127 2006 48 56
28. R. Raynes et al. Heat shock and caloric restriction have a synergistic effect on the heat shock response in a sir2.1-dependent manner in Caenorhabditis elegans J. Biol. Chem. 287 2012 29045 29053
29. H.Y. Cohen et al. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase Science 305 2004 390 392
30. L. Bordone et al. SIRT1 transgenic mice show phenotypes resembling calorie restriction Aging Cell 6 2007 759 767
31. D. Chen et al. Tissue-specific regulation of SIRT1 by calorie restriction Genes Dev. 22 2008 1753 1757
32. N.L. Price et al. SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function Cell Metab. 15 2012 675 690
33. A. Biason-Lauber et al. Identification of a SIRT1 mutation in a family with type 1 diabetes Cell Metab. 17 2013 448 455
34. C.A. Blum et al. SIRT1 modulation as a novel approach to the treatment of diseases of aging J. Med. Chem. 54 2011 417 432
35. A.A. Sauve et al. Chemical activation of Sir2-dependent silencing by relief of nicotinamide inhibition Mol. Cell 17 2005 595 601
36. J.A. Baur, and D.A. Sinclair Therapeutic potential of resveratrol: the in vivo evidence Nat. Rev. Drug Discov. 5 2006 493 506
37. R. Lamuela-Raventos et al. Direct HPLC;1; analysis of cis- and trans-resveratrol and piceid isomers in Spanish red Vitis vinifera wines J. Agric. Food Chem. 43 1995 281 283
38. H. Dai et al. SIRT1 activation by small molecules: kinetic and biophysical evidence for direct interaction of enzyme and activator J. Biol. Chem. 285 2010 32695 32703
39. B.P. Hubbard et al. Evidence for a common mechanism of SIRT1 regulation by allosteric activators Science 339 2013 1216 1219
40. M.T. Borra et al. Mechanism of human SIRT1 activation by resveratrol J. Biol. Chem. 280 2005 17187 17195
41. M. Kaeberlein et al. Substrate-specific activation of sirtuins by resveratrol J. Biol. Chem. 280 2005 17038 17045
42. M. Pacholec et al. SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1 J. Biol. Chem. 285 2010 8340 8351
43. S.J. Park et al. Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases Cell 148 2012 421 433
44. J.J. Smith et al. Small molecule activators of SIRT1 replicate signaling pathways triggered by calorie restriction in vivo BMC Syst. Biol. 3 2009 31
45. R.K. Minor et al. SRT1720 improves survival and healthspan of obese mice Sci. Rep. 1 2011 70
46. M. Lakshminarasimhan et al. Sirt1 activation by resveratrol is substrate sequence-selective Aging (Albany NY) 5 2013 151 154
47. M. Gertz et al. A molecular mechanism for direct sirtuin activation by resveratrol PLoS ONE 7 2012 e49761
48. D.R. Valenzano et al. Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate Curr. Biol. 16 2006 296 300
49. B. Rascon et al. The lifespan extension effects of resveratrol are conserved in the honey bee and may be driven by a mechanism related to caloric restriction Aging (Albany NY) 4 2012 499 508
50. L. Guarente Sir2 links chromatin silencing, metabolism, and aging Genes Dev. 14 2000 1021 1026
51. J.L. Barger et al. A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice PLoS ONE 3 2008 e2264
52. M. Liu et al. Resveratrol protects against age-associated infertility in mice Hum. Reprod. 28 2013 707 717
53. K.J. Pearson et al. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span Cell Metab. 8 2008 157 168
54. C.X. Deng SIRT1, is it a tumor promoter or tumor suppressor? Int. J. Biol. Sci. 5 2009 147 152
55. G. Boily et al. SirT1-null mice develop tumors at normal rates but are poorly protected by resveratrol Oncogene 28 2009 2882 2893
56. R. Firestein et al. The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth PLoS ONE 3 2008 e2020
57. B.B. Aggarwal et al. Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies Anticancer Res. 24 2004 2783 2840
58. D.J. Boocock et al. Phase I dose escalation pharmacokinetic study in healthy volunteers of resveratrol, a potential cancer chemopreventive agent Cancer Epidemiol. Biomarkers Prev. 16 2007 1246 1252
59. D. Chauhan et al. Preclinical evaluation of a novel SIRT1 modulator SRT1720 in multiple myeloma cells Br. J. Haematol. 155 2011 588 598
60. K. Suzuki et al. SRT1720, a SIRT1 activator, promotes tumor cell migration, and lung metastasis of breast cancer in mice Oncol. Rep. 27 2012 1726 1732
61. A.A. Qureshi et al. Inhibition of nitric oxide and inflammatory cytokines in LPS-stimulated murine macrophages by resveratrol, a potent proteasome inhibitor Lipids Health Dis. 11 2012 76
62. G. Lanzilli et al. Anti-inflammatory effect of resveratrol and polydatin by in vitro IL-17 modulation Inflammation 35 2012 240 248
63. N. Elmali et al. Effects of resveratrol in inflammatory arthritis Inflammation 30 2007 1 6
64. D.W. Park et al. Resveratrol inhibits inflammation induced by heat-killed Listeria monocytogenes J. Med. Food 15 2012 788 794
65. M. Zhou et al. [Effect of resveratrol on chronic obstructive pulmonary disease in rats and its mechanism] Yao Xue Xue Bao 43 2008 128 132
66. K. Rahal et al. Resveratrol has antiinflammatory and antifibrotic effects in the peptidoglycan-polysaccharide rat model of Crohn's disease Inflamm. Bowel Dis. 18 2012 613 623
67. Y. Jimenez-Gomez et al. Resveratrol improves adipose insulin signaling and reduces the inflammatory response in adipose tissue of rhesus monkeys on high-fat, high-sugar diet Cell Metab. 18 2013 533 545
68. H. Yao et al. SIRT1 protects against emphysema via FOXO3-mediated reduction of premature senescence in mice J. Clin. Invest. 122 2012 2032 2045
69. T. Ichikawa et al. Sirtuin 1 activator SRT1720 suppresses inflammation in an ovalbumin-induced mouse model of asthma Respirology 18 2013 332 339
70. J.P. Zheng et al. Resveratrol induces p53 and suppresses myocardin-mediated vascular smooth muscle cell differentiation Toxicol. Lett. 199 2010 115 122
71. A. Csiszar et al. Age-associated proinflammatory secretory phenotype in vascular smooth muscle cells from the non-human primate Macaca mulatta: reversal by resveratrol treatment J. Gerontol. A: Biol. Sci. Med. Sci. 67 2012 811 820
72. M.E. Ferrero et al. Activity in vitro of resveratrol on granulocyte and monocyte adhesion to endothelium Am. J. Clin. Nutr. 68 1998 1208 1214
73. C. Tong et al. Impaired SIRT1 nucleocytoplasmic shuttling in the senescent heart during ischemic stress FASEB J. 27 2013 4332 4342
74. Y.N. Zhao et al. Resveratrol improves learning and memory in normally aged mice through microRNA-CREB pathway Biochem. Biophys. Res. Commun. 435 2013 597 602
75. D. Kim et al. SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis EMBO J. 26 2007 3169 3179
76. D.D. Lofrumento et al. Neuroprotective effects of resveratrol in an MPTP mouse model of Parkinson's-like disease: possible role of SOCS-1 in reducing pro-inflammatory responses Innate Immun. 2013 10.1177/1753425913488429
77. K.S. Shindler et al. Oral resveratrol reduces neuronal damage in a model of multiple sclerosis J. Neuroophthalmol. 30 2010 328 339
78. P. Marambaud et al. Resveratrol promotes clearance of Alzheimer's disease amyloid-β peptides J. Biol. Chem. 280 2005 37377 37382
79. S.S. Karuppagounder et al. Dietary supplementation with resveratrol reduces plaque pathology in a transgenic model of Alzheimer's disease Neurochem. Int. 54 2009 111 118
80. J. Graff et al. A dietary regimen of caloric restriction or pharmacological activation of SIRT1 to delay the onset of neurodegeneration J. Neurosci. 33 2013 8951 8960
81. K. Higashida et al. Effects of resveratrol and SIRT1 on PGC-1α activity and mitochondrial biogenesis: a reevaluation PLoS Biol. 11 2013 e1001603
82. B. Jiang et al. Resveratrol attenuates early diabetic nephropathy by down-regulating glutathione S-transferases mu in diabetic rats J. Med. Food 16 2013 481 486
83. Y. Yamazaki et al. Treatment with SRT1720, a SIRT1 activator, ameliorates fatty liver with reduced expression of lipogenic enzymes in MSG mice Am. J. Physiol. Endocrinol. Metab. 297 2009 E1179 E1186
84. S. Venkatasubramanian et al. Cardiovascular effects of a novel SIRT1 activator, SRT2104, in otherwise healthy cigarette smokers J. Am. Heart Assoc. 2 2013 e000042
85. J.L. Fiori et al. Resveratrol prevents β-cell dedifferentiation in non-human primates given a high fat/high sugar diet Diabetes 62 2013 3500 3513
86. J.M. Smoliga et al. Resveratrol and health - a comprehensive review of human clinical trials Mol. Nutr. Food Res. 55 2011 1129 1141
87. H. Ghanim et al. A resveratrol and polyphenol preparation suppresses oxidative and inflammatory stress response to a high-fat, high-carbohydrate meal J. Clin. Endocrinol. Metab. 96 2011 1409 1414
88. S. Timmers et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans Cell Metab. 14 2011 612 622
89. J. Yoshino et al. Resveratrol supplementation does not improve metabolic function in nonobese women with normal glucose tolerance Cell Metab. 16 2012 658 664
90. + cosubstrate specificity of a Sir2 enzyme Mol. Cell 17 2005 855 868
91. +-dependent Sir2 histone/protein deacetylases Proc. Natl. Acad. Sci. U.S.A. 101 2004 8563 8568
92. B.C. Smith, and J.M. Denu Mechanism-based inhibition of Sir2 deacetylases by thioacetyl-lysine peptide Biochemistry 46 2007 14478 14486
93. T. Asaba et al. Inhibition of human sirtuins by in situ generation of an acetylated lysine-ADP-ribose conjugate J. Am. Chem. Soc. 131 2009 6989 6996
94. J.M. Villalba, and F.J. Alcain Sirtuin activators and inhibitors Biofactors 38 2012 349 359
95. F. Medda et al. Novel cambinol analogs as sirtuin inhibitors: synthesis, biological evaluation, and rationalization of activity J. Med. Chem. 52 2009 2673 2682
96. D. Rotili et al. Identification of tri- and tetracyclic pyrimidinediones as sirtuin inhibitors ChemMedChem 5 2010 674 677
97. J.M. Solomon et al. Inhibition of SIRT1 catalytic activity increases p53 acetylation but does not alter cell survival following DNA damage Mol. Cell. Biol. 26 2006 28 38
98. +-dependent deacetylation mechanism Proc. Natl. Acad. Sci. U.S.A. 110 2013 E2772 E2781
99. Y. Zhang et al. Deacetylation of cortactin by SIRT1 promotes cell migration Oncogene 28 2009 445 460
100. X. Zhou et al. Sirtuin 1 inhibition delays cyst formation in autosomal-dominant polycystic kidney disease J. Clin. Invest. 123 2013 3084 3098
101. P. Gresele et al. Resveratrol, at concentrations attainable with moderate wine consumption, stimulates human platelet nitric oxide production J. Nutr. 138 2008 1602 1608
102. P.J. Elliott, and M. Jirousek Sirtuins: novel targets for metabolic disease Curr. Opin. Investig. Drugs 9 2008 371 378
103. L.M. Howells et al. Phase I randomized, double-blind pilot study of micronized resveratrol (SRT501) in patients with hepatic metastases - safety, pharmacokinetics, and pharmacodynamics Cancer Prev. Res. (Phila.) 4 2011 1419 1425
104. E. Hoffmann et al. Pharmacokinetics and tolerability of SRT2104, a first-in-class small molecule activator of SIRT1, after single and repeated oral administration in man Br. J. Clin. Pharmacol. 75 2013 186 196
105. V. Libri et al. A pilot randomized, placebo controlled, double blind phase I trial of the novel SIRT1 activator SRT2104 in elderly volunteers PLoS ONE 7 2012 e51395