Small-molecule allosteric activators of sirtuins

Annual Review of Pharmacology and Toxicology

Volumn 54, Issue , 2014, Pages 363-380

  Sinclair, David A ^a,b   Guarente, Leonard ^c  

^a HARVARD MEDICAL SCHOOL   (United States)

^b UNIVERSITY OF NEW SOUTH WALES   (Australia)

^c MASSACHUSETTS INSTITUTE OF TECHNOLOGY   (United States)

Author keywords

Aging; Allosteric activation; HDAC; NAD; Sirtuin

Indexed keywords

CHEMICAL COMPOUND; POLYPHENOL; RESVERATROL; SIRTUIN; SIRTUIN 1; SIRTUIN 1 ACTIVATING COMPOUND; SIRTUIN 7; UNCLASSIFIED DRUG;

AGING; ALZHEIMER DISEASE; CELL SURVIVAL; DRUG POTENCY; DRUG SOLUBILITY; ENERGY METABOLISM; EXPERIMENTAL MODEL; HUMAN; IN VITRO STUDY; INFLAMMATION; INFLAMMATORY DISEASE; NEOPLASM; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PRIORITY JOURNAL; REVIEW;

ALLOSTERIC REGULATION; ANIMALS; BENZIMIDAZOLES; DISEASE MODELS, ANIMAL; HUMANS; INFLAMMATION; MOLECULAR TARGETED THERAPY; SIRTUINS; STILBENES;

EID: 84891848670     PISSN: 03621642     EISSN: 15454304     Source Type: Book Series    
DOI: 10.1146/annurev-pharmtox-010611-134657     Document Type: Review

References (126)

1. Zorn JA, Wells JA. 2010. Turning enzymes ON with small molecules. Nat. Chem. Biol. 6:179-88
2. Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, et al. 2003. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425:191-96
3. Feige JN, Lagouge M, Canto C, Strehle A, Houten SM, et al. 2008. Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. Cell Metab. 8:347-58
4. Nayagam VM, Wang X, Tan YC, Poulsen A, Goh KC, et al. 2006. SIRT1 modulating compounds from high-throughput screening as anti-inflammatory and insulin-sensitizing agents. J. Biomol. Screen. 11:959-67
5. Wu J, Zhang D, Chen L, Li J, Wang J, et al. 2013. Discovery and mechanism study of SIRT1 activators that promote the deacetylation of fluorophore-labeled substrate. J. Med. Chem. 56:761-80
6. Hoffmann E, Wald J, Lavu S, Roberts J, Beaumont C, et al. 2013. 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. 75:186-96
7. Libri V, Brown AP, Gambarota G, Haddad J, Shields GS, et al. 2012. A pilot randomized, placebo controlled, double blind phase I trial of the novel SIRT1 activator SRT2104 in elderly volunteers. PLoS ONE 7:e51395
8. Kaeberlein M, McVey M, Guarente L. 1999. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev. 13:2570-80
9. Sinclair DA, Guarente L. 1997. Extrachromosomal rDNAcircles-a cause of aging in yeast. Cell 91:1033-42
10. Unal E, Kinde B, Amon A. 2011. Gametogenesis eliminates age-induced cellular damage and resets life span in yeast. Science 332:1554-57
11. Stumpferl SW, Brand SE, Jiang JC, Korona B, Tiwari A, et al. 2012. Natural genetic variation in yeast longevity. Genome Res. 22:1963-73
12. Tissenbaum HA, Guarente L. 2001. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 410:227-30
13. Rogina B, Helfand SL. 2004. Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc. Natl. Acad. Sci. USA 101:15998-6003
14. Viswanathan M, Guarente L. 2011. Regulation of Caenorhabditis elegans lifespan by sir-2.1 transgenes. Nature 477:E1-2
15. Banerjee KK, Ayyub C, Ali SZ, Mandot V, Prasad NG, Kolthur-Seetharam U. 2012. dSir2 in the adult fat body, but not in muscles, regulates life span in a diet-dependent manner. Cell Rep. 2:1485-91
16. He W, Newman JC, Wang MZ, Ho L, Verdin E. 2012. Mitochondrial sirtuins: regulators of protein acylation and metabolism. Trends Endocrinol. Metab. 23:467-76
17. Houtkooper RH, Pirinen E, Auwerx J. 2012. Sirtuins as regulators of metabolism and healthspan. Nat. Rev. Mol. Cell Biol. 13:225-38
18. Imai S, Armstrong CM, Kaeberlein M, Guarente L. 2000. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403:795-800
19. Peng C, Lu Z, Xie Z, Cheng Z, Chen Y, et al. 2011. The first identification of lysine malonylation substrates and its regulatory enzyme. Mol. Cell. Proteomics 10:M111.012658
20. Jiang H, Khan S, Wang Y, Charron G, He B, et al. 2013. SIRT6 regulates TNF-α secretion through hydrolysis of long-chain fatty acyl lysine. Nature 496:110-13
21. +-dependent deacetylases. J. Biol. Chem. 277:12632-41
22. Tanner KG, Landry J, Sternglanz R, Denu JM. 2000. Silent information regulator 2 family of NADdependent histone/protein deacetylases generates a unique product, 1-O-acetyl-ADP-ribose. Proc. Natl. Acad. Sci. USA 97:14178-82
23. Sauve AA, Wolberger C, Schramm VL, Boeke JD. 2006. The biochemistry of sirtuins. Annu. Rev. Biochem. 75:435-65
24. Anderson RM, Bitterman KJ, Wood JG, Medvedik O, Sinclair DA. 2003. Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiae. Nature 423:181-85
25. Lin SJ, Defossez PA, Guarente L. 2000. Requirement of NADand SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 289:2126-28
26. Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, et al. 2004. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 305:390-92
27. Bordone L, Cohen D, Robinson A, Motta MC, van Veen E, et al. 2007. SIRT1 transgenic mice show phenotypes resembling calorie restriction. Aging Cell 6:759-67
28. Guarente L, Picard F. 2005. Calorie restriction-the SIR2 connection. Cell 120:473-82
29. Guarente L. 2008. Mitochondria-a nexus for aging, calorie restriction, and sirtuins? Cell 132:171-76
30. Sinclair D, Verdin E. 2012. The longevity of sirtuins. Cell Rep. 2:1473-74
31. +/- mice: a role of lipid mobilization and inflammation. Endocrinology 151:2504-14
32. Gillum MP, Erion DM, Shulman GI. 2011. Sirtuin-1 regulation of mammalian metabolism. Trends Mol. Med. 17:8-13
33. Rodgers JT, Puigserver P. 2007. Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1. Proc. Natl. Acad. Sci. USA 104:12861-66
34. Jing E, Emanuelli B, Hirschey MD, Boucher J, Lee KY, et al. 2011. Sirtuin-3 (Sirt3) regulates skeletal muscle metabolism and insulin signaling via altered mitochondrial oxidation and reactive oxygen species production. Proc. Natl. Acad. Sci. USA 108:14608-13
35. Verdin E, Hirschey MD, Finley LW, Haigis MC. 2010. Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling. Trends Biochem. Sci. 35:669-75
36. Hirschey MD, Shimazu T, Goetzman E, Jing E, Schwer B, et al. 2010. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 464:121-25
37. Picard F, Kurtev M, Chung N, Topark-Ngarm A, Senawong T, et al. 2004. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-γ. Nature 429:771-76
38. Hebert AS, Dittenhafer-Reed KE, Yu W, Bailey DJ, Selen ES, et al. 2013. Calorie restriction and SIRT3 trigger global reprogramming of the mitochondrial protein acetylome. Mol. Cell 49:186-99
39. Qiu X, Brown K, Hirschey MD, Verdin E, Chen D. 2010. Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. Cell Metab. 12:662-67
40. Someya S, Yu W, Hallows WC, Xu J, Vann JM, et al. 2010. Sirt3mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell 143:802-12
41. Chen D, Steele AD, Lindquist S, Guarente L. 2005. Increase in activity during calorie restriction requires Sirt1. Science 310:1641
42. Boily G, Seifert EL, Bevilacqua L, He XH, Sabourin G, et al. 2008. SirT1 regulates energy metabolism and response to caloric restriction in mice. PLoS ONE 3:e1759
43. Kume S, Uzu T, Horiike K, Chin-Kanasaki M, Isshiki K, et al. 2010. Calorie restriction enhances cell adaptation to hypoxia through Sirt1-dependent mitochondrial autophagy in mouse aged kidney. J. Clin. Investig. 120:1043-55
44. Ramadori G, Fujikawa T, Anderson J, Berglund ED, Frazao R, et al. 2011. SIRT1 deacetylase in SF1 neurons protects against metabolic imbalance. Cell Metab. 14:301-12
45. Satoh A, Brace CS, Ben-Josef G, West T, Wozniak DF, et al. 2010. SIRT1 promotes the central adaptive response to diet restriction through activation of the dorsomedial and lateral nuclei of the hypothalamus. J. Neurosci. 30:10220-32
46. Donmez G, Wang D, Cohen DE, Guarente L. 2010. SIRT1 suppresses β-amyloid production by activating the α-secretase gene ADAM10. Cell 142:320-32
47. Banks AS, Kon N, Knight C, Matsumoto M, Gutierrez-Juarez R, et al. 2008. SirT1 gain of function increases energy efficiency and prevents diabetes in mice. Cell Metab. 8:333-41
48. Pfluger PT, Herranz D, Velasco-Miguel S, Serrano M, Tschop MH. 2008. Sirt1 protects against high-fat diet-induced metabolic damage. Proc. Natl. Acad. Sci. USA 105:9793-98
49. Hsu CP, Odewale I, Alcendor RR, Sadoshima J. 2008. Sirt1 protects the heart from aging and stress. Biol. Chem. 389:221-31
50. Qin W, Yang T, Ho L, Zhao Z, Wang J, et al. 2006. Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction. J. Biol. Chem. 281:21745-54
51. Oberdoerffer P, Michan S, McVay M, Mostoslavsky R, Vann J, et al. 2008. SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell 135:907-18
52. Firestein R, Blander G, Michan S, Oberdoerffer P, Ogino S, et al. 2008. The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth. PLoS ONE 3:e2020
53. Kanfi Y, Naiman S, Amir G, Peshti V, Zinman G, et al. 2012. The sirtuin SIRT6 regulates lifespan in male mice. Nature 483:218-21
54. Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, et al. 2006. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell 127:1109-22
55. Shi T, Wang F, Stieren E, Tong Q. 2005. SIRT3, a mitochondrial sirtuin deacetylase, regulates mitochondrial function and thermogenesis in brown adipocytes. J. Biol. Chem. 280:13560-67
56. Hirschey MD, Shimazu T, Jing E, Grueter CA, Collins AM, et al. 2011. SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome. Mol. Cell 44:177-90
57. Chalkiadaki A, Guarente L. 2012. High-fat diet triggers inflammation-induced cleavage of SIRT1 in adipose tissue to promote metabolic dysfunction. Cell Metab. 16:180-88
58. Gillum MP, Kotas ME, Erion DM, Kursawe R, Chatterjee P, et al. 2011. SirT1 regulates adipose tissue inflammation. Diabetes 60:3235-45
59. Yoshizaki T, Milne JC, Imamura T, Schenk S, Sonoda N, et al. 2009. SIRT1 exerts anti-inflammatory effects and improves insulin sensitivity in adipocytes. Mol. Cell. Biol. 29:1363-74
60. Chen Y, Zhao W, Yang JS, Cheng Z, Luo H, et al. 2012. Quantitative acetylome analysis reveals the roles of SIRT1 in regulating diverse substrates and cellular pathways. Mol. Cell. Proteomics 11:1048-62
61. Li X. 2013. SIRT1 and energy metabolism. Acta Biochim. Biophys. Sin. 45:51-60
62. Newman JC, He W, Verdin E. 2012. Mitochondrial protein acylation and intermediary metabolism: regulation by sirtuins and implications for metabolic disease. J. Biol. Chem. 287:42436-43
63. Toiber D, Sebastian C, Mostoslavsky R. 2011. Characterization of nuclear sirtuins: molecular mechanisms and physiological relevance. Handb. Exp. Pharmacol. 206:189-224
64. Mills KD, Sinclair DA, Guarente L. 1999. MEC1-dependent redistribution of the Sir3 silencing protein from telomeres to DNA double-strand breaks. Cell 97:609-20
65. McAinsh AD, Scott-Drew S, Murray JA, Jackson SP. 1999.DNAdamage triggers disruption of telomeric silencing and Mec1p-dependent relocation of Sir3p. Curr. Biol. 9:963-66
66. Sauve AA, Moir RD, Schramm VL, Willis IM. 2005. Chemical activation of Sir2-dependent silencing by relief of nicotinamide inhibition. Mol. Cell 17:595-601
67. Pace-Asciak CR, Hahn S, Diamandis EP, Soleas G, Goldberg DM. 1995. The red wine phenolics transresveratrol and quercetin block human platelet aggregation and eicosanoid synthesis: implications for protection against coronary heart disease. Clin. Chim. Acta 235:207-19
68. Bhat KPL, Kosmeder JW II, Pezzuto JM. 2001. Biological effects of resveratrol. Antioxid. Redox Signal. 3:1041-64
69. Morselli E, Galluzzi L, Kepp O, Criollo A, Maiuri MC, et al. 2009. Autophagymediates pharmacological lifespan extension by spermidine and resveratrol. Aging 1:961-70
70. Yang H, Baur JA, Chen A, Miller C, Adams JK, et al. 2007. Design and synthesis of compounds that extend yeast replicative lifespan. Aging Cell 6:35-43
71. Jarolim S, Millen J, Heeren G, Laun P, Goldfarb DS, Breitenbach M. 2004. A novel assay for replicative lifespan in Saccharomyces cerevisiae. FEMS Yeast Res. 5:169-77
72. Zarse K, Schmeisser S, Birringer M, Falk E, Schmoll D, Ristow M. 2010. Differential effects of resveratrol and SRT1720 on lifespan of adult Caenorhabditis elegans. Horm. Metab. Res. 42:837-39
73. Viswanathan M, Kim SK, Berdichevsky A, Guarente L. 2005. A role for SIR-2.1 regulation of ER stress response genes in determining C. elegans life span. Dev. Cell 9:605-15
74. Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, et al. 2004. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 430:686-89
75. Bauer JH, Goupil S, Garber GB, Helfand SL. 2004. An accelerated assay for the identification of lifespanextending interventions in Drosophila melanogaster. Proc. Natl. Acad. Sci. USA 101:12980-85
76. Bauer JH, Morris SN, Chang C, Flatt T, Wood JG, Helfand SL. 2009. dSir2 and Dmp53 interact to mediate aspects of CR-dependent lifespan extension in D. melanogaster. Aging 1:38-48
77. Wang C, Wheeler CT, Alberico T, Sun X, Seeberger J, et al. 2013. The effect of resveratrol on lifespan depends on both gender and dietary nutrient composition in Drosophila melanogaster. Age 35:69-81
78. Valenzano DR, Terzibasi E, Genade T, Cattaneo A, Domenici L, Cellerino A. 2006. Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate. Curr. Biol. 16:296-300
79. Rascon B, Hubbard BP, Sinclair DA, Amdam GV. 2012. The lifespan extension effects of resveratrol are conserved in the honey bee and may be driven by a mechanism related to caloric restriction. Aging 4:499-508
80. Milne JC, Lambert PD, Schenk S, Carney DP, Smith JJ, et al. 2007. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 450:712-16
81. Hubbard BP, Gomes AP, Dai H, Li J, Case AW, et al. 2013. Evidence for a common mechanism of SIRT1 regulation by allosteric activators. Science 339:1216-19
82. Dai H, Kustigian L, Carney D, Case A, Considine T, et al. 2010. SIRT1 activation by small molecules: kinetic and biophysical evidence for direct interaction of enzyme and activator. J. Biol. Chem. 285:32695-703
83. Bemis JE, Vu CB, Xie R, Nunes JJ, Ng PY, et al. 2009. Discovery of oxazolo[4,5-b]pyridines and related heterocyclic analogs as novel SIRT1 activators. Bioorg. Med. Chem. Lett. 19:2350-53
84. Szczepankiewicz BG, Ng PY. 2008. Sirtuin modulators: targets for metabolic diseases and beyond. Curr. Top. Med. Chem. 8:1533-44
85. Minor RK, Baur JA, Gomes AP, Ward TM, Csiszar A, et al. 2011. SRT1720 improves survival and healthspan of obese mice. Sci. Rep. 1:70
86. Yamazaki Y, Usui I, Kanatani Y, Matsuya Y, Tsuneyama K, et al. 2009. Treatment with SRT1720, a SIRT1 activator, ameliorates fatty liver with reduced expression of lipogenic enzymes in MSG mice. Am. J. Physiol. Endocrinol. Metab. 297:E1179-86
87. Liu Y, Dentin R, Chen D, Hedrick S, Ravnskjaer K, et al. 2008. A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange. Nature 456:269-73
88. Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, et al. 2006. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444:337-42
89. Pearson KJ, Baur JA, Lewis KN, Peshkin L, Price NL, et al. 2008. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab. 8:157-68
90. Price NL, Gomes AP, Ling AJ, Duarte FV, Martin-Montalvo A, et al. 2012. SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab. 15:675-90
91. Smith JJ, Kenney RD, Gagne DJ, Frushour BP, Ladd W, et al. 2009. Small molecule activators of SIRT1 replicate signaling pathways triggered by calorie restriction in vivo. BMC Syst. Biol. 3:31
92. Barger JL, Kayo T, Pugh TD, Prolla TA, Weindruch R. 2008. Short-term consumption of a resveratrolcontaining nutraceutical mixturemimics gene expression of long-term caloric restriction inmouse heart. Exp. Gerontol. 43:859-66
93. Barger JL, Kayo T, Vann JM, Arias EB, Wang J, et al. 2008. A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS ONE 3:e2264
94. Lamming DW, Sabatini DM, Baur JA. 2012. Pharmacologic means of extending lifespan. J. Clin. Exp. Pathol. S4:002
95. Boily G, He XH, Pearce B, Jardine K, McBurney MW. 2009. SirT1-null mice develop tumors at normal rates but are poorly protected by resveratrol. Oncogene 28:2882-93
96. Magyar K, Halmosi R, Palfi A, Feher G, Czopf L, et al. 2012. Cardioprotection by resveratrol: a human clinical trial in patients with stable coronary artery disease. Clin. Hemorheol. Microcirc. 50:179-87
97. Tome-Carneiro J, Larrosa M, Gonzalez-Sarrias A, Tomas-Barberan FA, Garcia-Conesa MT, Espin JC. 2013. Resveratrol and clinical trials: the crossroad from in vitro studies to human evidence. Curr. Pharm. Des. 19:6064-93
98. Bhatt JK, Thomas S, Nanjan MJ. 2012. Resveratrol supplementation improves glycemic control in type 2 diabetes mellitus. Nutr. Res. 32:537-41
99. Wong RH, Howe PR, Buckley JD, Coates AM, Kunz I, Berry NM. 2011. Acute resveratrol supplementation improves flow-mediated dilatation in overweight/obese individuals with mildly elevated blood pressure. Nutr. Metab. Cardiovasc. Dis. 21:851-56
100. Crandall JP, Oram V, Trandafirescu G, Reid M, Kishore P, et al. 2012. Pilot study of resveratrol in older adults with impaired glucose tolerance. J. Gerontol. A Biol. Sci. Med. Sci. 67:1307-12
101. Timmers S, Konings E, Bilet L, Houtkooper RH, van de Weijer T, et al. 2011. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab. 14:612-22
102. Yoshino J, Conte C, Fontana L, Mittendorfer B, Imai S, et al. 2012. Resveratrol supplementation does not improve metabolic function in nonobese women with normal glucose tolerance. Cell Metab. 16:658-64
103. Poulsen MM, Vestergaard PF, Clasen BF, Radko Y, Christensen LP, et al. 2012. High-dose resveratrol supplementation in obese men: an investigator-initiated, randomized, placebo-controlled clinical trial of substrate metabolism, insulin sensitivity, and body composition. Diabetes 62:1186-95
104. Kaeberlein M, McDonagh T, Heltweg B, Hixon J, Westman EA, et al. 2005. Substrate-specific activation of sirtuins by resveratrol. J. Biol. Chem. 280:17038-45
105. Borra MT, Langer MR, Slama JT, Denu JM. 2004. Substrate specificity and kinetic mechanism of the Sir2 family of NAD+-dependent histone/protein deacetylases. Biochemistry 43:9877-87
106. Pacholec M, Bleasdale JE, Chrunyk B, Cunningham D, Flynn D, et al. 2010. SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1. J. Biol. Chem. 285:8340-51
107. Dasgupta B, Milbrandt J. 2007. Resveratrol stimulates AMP kinase activity in neurons. Proc. Natl. Acad. Sci. USA 104:7217-22
108. Hou X, Xu S, Maitland-Toolan KA, Sato K, Jiang B, et al. 2008. SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase. J. Biol. Chem. 283:20015-26
109. Fulco M, Cen Y, Zhao P, Hoffman EP, McBurney MW, et al. 2008. Glucose restriction inhibits skeletal myoblast differentiation by activating SIRT1 through AMPK-mediated regulation of Nampt. Dev. Cell 14:661-73
110. Lan F, Cacicedo JM, Ruderman N, Ido Y. 2008. SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1: possible role in AMP-activated protein kinase activation. J. Biol. Chem. 283:27628-35
111. Suchankova G, Nelson LE, Gerhart-Hines Z, Kelly M, Gauthier MS, et al. 2009. Concurrent regulation of AMP-activated protein kinase and SIRT1 inmammalian cells. Biochem. Biophys. Res. Commun. 378:836-41
112. Gerhart-Hines Z, Dominy JE Jr, Blattler SM, Jedrychowski MP, Banks AS, et al. 2011. The cAMP/PKA pathway rapidly activates SIRT1 to promote fatty acid oxidation independently of changes in NAD+. Mol. Cell 44:851-63
113. Um JH, Park SJ, Kang H, Yang S, Foretz M, et al. 2010. AMP-activated protein kinase-deficient mice are resistant to the metabolic effects of resveratrol. Diabetes 59:554-63
114. Park SJ, Ahmad F, Philp A, Baar K, Williams T, et al. 2012. Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell 148:421-33
115. Kugel S, Mostoslavsky R. 2013. SIRT1 activators: The evidence STACks up. Aging 5:142-43
116. Lakshminarasimhan M, Rauh D, Schutkowski M, Steegborn C. 2013. Sirt1 activation by resveratrol is substrate sequence-selective. Aging 5:1-4
117. Tanny JC, Kirkpatrick DS, Gerber SA, Gygi SP, Moazed D. 2004. Budding yeast silencing complexes and regulation of Sir2 activity by protein-protein interactions. Mol. Cell. Biol. 16:6931-46
118. Hsu HC, Wang CL, Wang M, Yang N, Chen Z, et al. 2013. Structural basis for allosteric stimulation of Sir2 activity by Sir4 binding. Genes Dev. 27:64-73
119. Cuperus G, Shafaatian R, Shore D. 2000. Locus specificity determinants in the multifunctional yeast silencing protein Sir2. EMBO J. 19:2641-51
120. Kim EJ, Kho JH, Kang MR, Um SJ. 2007. Active regulator of SIRT1 cooperates with SIRT1 and facilitates suppression of p53 activity. Mol. Cell 28:277-90
121. Liu B, Ghosh S, Yang X, Zheng H, Liu X, et al. 2012. Resveratrol rescues SIRT1-dependent adult stem cell decline and alleviates progeroid features in laminopathy-based progeria. Cell Metab. D16:738-50
122. Sauve AA. 2009. Pharmaceutical strategies for activating sirtuins. Curr. Pharm. Des. 15:45-56
123. Pan M, Yuan H, Brent M, Ding EC, Marmorstein R. 2012. SIRT1 contains N- and C-terminal regions that potentiate deacetylase activity. J. Biol. Chem. 287:2468-76
124. Kang H, Suh JY, Jung YS, Jung JW, Kim MK, Chung JH. 2011. Peptide switch is essential for Sirt1 deacetylase activity. Mol. Cell 44:203-13
125. Hall JA, Dominy JE, Lee Y, Puigserver P. 2013. The sirtuin family's role in aging and age-associated pathologies. J. Clin. Investig. 123:973-79
126. Sebastian C, Zwaans BM, Silberman DM, Gymrek M, Goren A, et al. 2012. The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism. Cell 151:1185-99