Biological and potential therapeutic roles of sirtuin deacetylases

Cellular and Molecular Life Sciences

Volumn 65, Issue 24, 2008, Pages 4000-4018

  Taylor, D M ^a   Maxwell, M M ^b   Luthi Carter, R ^a   Kazantsev, A G ^b  

^a EPFL   (Switzerland)

^b MASSACHUSETTS GENERAL HOSPITAL   (United States)

Author keywords

Deacetylase; Human disease; Longevity; Sirtuin; Therapeutics

Indexed keywords

HISTONE DEACETYLASE 3; LIGAND; NICOTINAMIDE; NICOTINAMIDE ADENINE DINUCLEOTIDE; PROTEIN INHIBITOR; RESVERATROL; SILENT INFORMATION REGULATOR PROTEIN 2; SIRTINOL; SIRTUIN; SIRTUIN 1; SIRTUIN 2; SIRTUIN 3; SIRTUIN 4; SIRTUIN 5; SIRTUIN 6; SIRTUIN 7; UNCLASSIFIED DRUG;

AGING; AMINO ACID SEQUENCE; APOPTOSIS; BREAST CANCER; CELL DIVISION; CELL PROLIFERATION; CYTOLOGY; DEACETYLATION; DEGENERATIVE DISEASE; DNA RECOMBINATION; DROSOPHILA; DRUG EFFECT; ENZYME ACTIVATION; HEART DISEASE; HIPPOCAMPUS; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS; NEOPLASM; NONHUMAN; PANCREAS ISLET BETA CELL; PROTEIN DOMAIN; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN INTERACTION; PROTEIN LOCALIZATION; PROTEIN STRUCTURE; REVIEW; SACCHAROMYCES CEREVISIAE; SMOKING;

AMINO ACID SEQUENCE; ANIMALS; DISEASE; HISTONE DEACETYLASES; HUMANS; METABOLIC NETWORKS AND PATHWAYS; MOLECULAR SEQUENCE DATA; SEQUENCE HOMOLOGY, AMINO ACID; SIRTUINS; SUBSTRATE SPECIFICITY;

MAMMALIA;

EID: 58149140055     PISSN: 1420682X     EISSN: 15691632     Source Type: Journal    
DOI: 10.1007/s00018-008-8357-y     Document Type: Review

References (197)

1. Huen, M. S. Y. and Chen, J. (2008) The DNA damage response pathways: at the crossroad of protein modifications. Cell Res. 18, 8-16.
2. Kouzarides, T. (2000) Acetylation: a regulatory modification to rival phosphorylation? EMBO J. 19, 1176-1179.
3. Butler, R. and Bates, G. P. (2006) Histone deacetylase inhibitors as therapeutics for polyglutamine disorders. Nat. Rev. Neurosci. 7, 784-96.
4. Yang, X. J. and Seto, E. (2007) HATs and HDACs: from structure, function and regulation to novel strategies for therapy and prevention. Oncogene. 26, 5310-5318.
5. Shore, D., Squire, M. and Nasmyth, K. A. (1984) Characterization of two genes required for the position-effect control of yeast mating-type genes. EMBO J. 3, 2817-2823.
6. Aparicio, O. M., Billington, B. L. and Gottschling, D. E. (1991) Modifiers of position effect are shared between telomeric and silent mating-type loci in S. cerevisiae. Cell. 66, 1279-1287.
7. Gottschling, D. E., Aparicio, O. M., Billington, B. L. and Zakian, V. A. (1990) Position effect at S. cerevisiae telomeres: reversible repression of Pol II transcription. Cell. 63, 751-762.
8. Rine, J. and Herskowitz, I. (1987) Four genes responsible for a position effect on expression from HML and HMR in Saccharomyces cerevisiae. Genetics. 116, 9-22.
9. Braunstein, M., Rose, A. B., Holmes, S. G., Allis, C. D. and Broach, J. R. (1993) Transcriptional silencing in yeast is associated with reduced nucleosome acetylation. Genes Dev. 7, 592-604.
10. Kennedy, B. K., Austriaco, N. R., Zhang, J. and Guarente, L. (1995) Mutation in the silencing gene SIR4 can delay aging in S. cerevisiae. Cell. 80, 485-496.
11. Kennedy, B. K., Austriaco, N. R. and Guarente, L. (1994) Daughter cells of Saccharomyces cerevisiae from old mothers display a reduced life span. J. Cell Biol. 127, 1985-1993.
12. Sinclair, D. A. and Guarente, L. (1997) Extrachromosomal rDNA circles-a cause of aging in yeast. Cell. 91, 1033-1042.
13. Kaeberlein, M., McVey, M. and Guarente, L. (1999) The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev. 13, 2570-2580.
14. Loeb, J. and Northrop, J. H. (1917) What Determines the Duration of Life in Metazoa? Proc. Natl. Acad. Sci. U. S. A. 3, 382-386.
15. Klass, M. R. (1977) Aging in the nematode Caenorhabditis elegans:major biological and environmental factors influencing life span. Mech. Ageing Dev. 6, 413-429.
16. McCay, C. M., Crowell, M. F. and Maynard, L. A. (1989) The effect of retarded growth upon the length of life span and upon the ultimate body size. 1935. Nutrition. 5, 155-171.
17. Lin, S. J., Defossez, P. A. and Guarente, L. (2000) Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science. 289, 2126-2128.
18. Brachmann, C. B., Sherman, J. M., Devine, S. E., Cameron, E. E., Pillus, L. and Boeke, J. D. (1995) The SIR2 gene family, conserved from bacteria to humans, functions in silencing, cell cycle progression, and chromosome stability. Genes Dev. 9, 2888-2902.
19. Frye, R. A. (2000) Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem. Biophys. Res. Commun. 273, 793-798.
20. Wood, J. G., Rogina, B., Lavu, S., Howitz, K., Helfand, S. L., Tatar, M. and Sinclair, D. (2004) Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature. 430, 686-689.
21. Tissenbaum, H. A. and Guarente, L. (2001) Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature. 410, 227-230.
22. Rogina, B. and Helfand, S. L. (2004) Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc. Natl. Acad. Sci. U. S. A. 101, 15998-16003.
23. Frye, R. A. (1999) Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity. Biochem. Biophys. Res. Commun. 260, 273-279.
24. Landry, J., Slama, J. T. and Sternglanz, R. (2000) Role of NAD(+) in the deacetylase activity of the SIR2-like proteins. Biochem. Biophys. Res. Commun. 278, 685-690.
25. Sauve, A. A., Celic, I., Avalos, J., Deng, H., Boeke, J. D. and Schramm, V. L. (2001) Chemistry of gene silencing: the mechanism of NAD+-dependent deacetylation reactions. Biochemistry. 40, 15456-15463.
26. Borra, M. T., O'Neill, F. J., Jackson, M. D., Marshall, B., Verdin, E., Foltz, K. R. and Denu, J. M. (2002) Conserved enzymatic production and biological effect of O-acetyl-ADP-ribose by silent information regulator 2-like NAD+-dependent deacetylases. J. Biol. Chem. 277, 12632-12641.
27. Kustatscher, G., Hothorn, M., Pugieux, C., Scheffzek, K. and Ladurner, A. G. (2005) Splicing regulates NAD metabolite binding to histone macroH2A. Nat. Struct. Mol. Biol. 12, 624-625.
28. Grubisha, O., Rafty, L. A., Takanishi, C. L., Xu, X., Tong, L., Perraud, A.-L., Scharenberg, A. M. and Denu, J. M. (2006) Metabolite of SIR2 reaction modulates TRPM2 ion channel. J. Biol. Chem. 281, 14057-14065.
29. Borra, M. T., Langer, M. R., Slama, J. T. and Denu, J. M. (2004) Substrate specificity and kinetic mechanism of the Sir2 family of NAD+-dependent histone/protein deacetylases. Biochemistry. 43, 9877-9887.
30. Denu, J. M. (2005) The Sir 2 family of protein deacetylases. Curr. Opin. Chem. Biol. 9, 431-440.
31. Ahuja, N., Schwer, B., Carobbio, S., Waltregny, D., North, B. J., Castronovo, V., Maechler, P. and Verdin, E. (2007) Regulation of insulin secretion by SIRT4, a mitochondrial ADP-ribosyltransferase. J. Biol. Chem. 282, 33583-33592.
32. Vaziri, H., Dessain, S. K., Ng Eaton, E., Imai, S. I., Frye, R. A., Pandita, T. K., Guarente, L. and Weinberg, R. A. (2001) hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell. 107, 149-159.
33. Luo, J., Nikolaev, A. Y., Imai, S., Chen, D., Su, F., Shiloh, A., Guarente, L. and Gu, W. (2001) Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell. 107, 137-148.
34. Onyango, P., Celic, I., McCaffery, J. M., Boeke, J. D. and Feinberg, A. P. (2002) SIRT3, a human SIR2 homologue, is an NAD-dependent deacetylase localized to mitochondria. Proc. Natl. Acad. Sci. U. S. A. 99, 13653-13658.
35. Vakhrusheva, O., Smolka, C., Gajawada, P., Kostin, S., Boettger, T., Kubin, T., Braun, T. and Bober, E. (2008) Sirt7 Increases Stress Resistance of Cardiomyocytes and Prevents Apoptosis and Inflammatory Cardiomyopathy in Mice. Circ. Res.
36. Michishita, E., McCord, R. A., Berber, E., Kioi, M., Padilla-Nash, H., Damian, M., Cheung, P., Kusumoto, R., Kawahara, T. L., Barrett, J. C., Chang, H. Y., Bohr, V. A., Ried, T., Gozani, O. and Chua, K. F. (2008) SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin. Nature. 452, 492-6.
37. North, B. J., Marshall, B. L., Borra, M. T., Denu, J. M. and Verdin, E. (2003) The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Mol. Cell. 11, 437-444.
38. Liszt, G., Ford, E., Kurtev, M. and Guarente, L. (2005) Mouse Sir2 homolog SIRT6 is a nuclear ADP-ribosyltransferase. J. Biol. Chem. 280, 21313-21320.
39. Haigis, M. C., Mostoslavsky, R., Haigis, K. M., Fahie, K., Christodoulou, D. C., Murphy, A. J., Valenzuela, D. M., Yancopoulos, G. D., Karow, M., Blander, G., Wolberger, C., Prolla, T. A., Weindruch, R., Alt, F. W. and Guarente, L. (2006) SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell. 126, 941-954.
40. Shi, T., Wang, F., Stieren, E. and Tong, Q. (2005) SIRT3, a mitochondrial sirtuin deacetylase, regulates mitochondrial function and thermogenesis in brown adipocytes. J. Biol. Chem. 280, 13560-13567.
41. Nemoto, S., Fergusson, M. M. and Finkel, T. (2005) SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1{alpha}. J. Biol Chem. 280, 16456-16460.
42. Anderson, R. M., Bitterman, K. J., Wood, J. G., Medvedik, O. and Sinclair, D. A. (2003) Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiae. Nature. 423, 181-185.
43. Araki, T., Sasaki, Y. and Milbrandt, J. (2004) Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration. Science. 305, 1010-1013.
44. Revollo, J. R., Grimm, A. A. and Imai, S.-i. (2004) The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltransferase regulates Sir2 activity in mammalian cells. J. Biol. Chem. 279, 50754-50763.
45. Fulco, M., Cen, Y., Zhao, P., Hoffman, E. P., McBurney, M. W., Sauve, A. A. and Sartorelli, V. (2008) Glucose restriction inhibits skeletal myoblast differentiation by activating SIRT1 through AMPK-mediated regulation of Nampt. Dev. Cell. 14, 661-73.
46. Busso, N., Karababa, M., Nobile, M., Rolaz, A., Van Gool, F., Galli, M., Leo, O., So, A. and De Smedt, T. (2008) Pharmacological inhibition of nicotinamide phosphoribosyltransferase/visfatin enzymatic activity identifies a new inflammatory pathway linked to NAD. PLoS. ONE. 3, e2267.
47. Murayama, A., Ohmori, K., Fujimura, A., Minami, H., Yasuzawa-Tanaka, K., Kuroda, T., Oie, S., Daitoku, H., Okuwaki, M., Nagata, K., Fukamizu, A., Kimura, K., Shimizu, T. and Yanagisawa, J. (2008) Epigenetic control of rDNA loci in response to intracellular energy status. Cell. 133, 627-39.
48. Yang, Y., Hou, H., Haller, E. M., Nicosia, S. V. and Bai, W. (2005) Suppression of FOXO1 activity by FHL2 through SIRT1-mediated deacetylation. EMBO J. 24, 1021-1032.
49. Motta, M. C., Divecha, N., Lemieux, M., Kamel, C., Chen, D., Gu, W., Bultsma, Y., McBurney, M. and Guarente, L. (2004) Mammalian SIRT1 represses forkhead transcription factors. Cell. 116, 551-563.
50. van der Horst, A., Tertoolen, L. G. J., de Vries-Smits, L. M. M., Frye, R. A., Medema, R. H. and Burgering, B. M. T. (2004) FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1). J. Biol. Chem. 279, 28873-28879.
51. Huang, H. and Tindall, D. J. (2007) Dynamic FoxO transcription factors. J. Cell. Sci. 120, 2479-2487.
52. Giannakou, M. E. and Partridge, L. (2004) The interaction between FOXO and SIRT1: tipping the balance towards survival. Trends Cell Biol. 14, 408-412.
53. Yeung, F., Hoberg, J. E., Ramsey, C. S., Keller, M. D., Jones, D. R., Frye, R. A. and Mayo, M. W. (2004) Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J. 23, 2369-2380.
54. Jeong, J., Juhn, K., Lee, H., Kim, S.-H., Min, B.-H., Lee, K.-M., Cho, M.-H., Park, G.-H. and Lee, K.-H. (2007) SIRT1 promotes DNA repair activity and deacetylation of Ku70. Exp. Mol. Med. 39, 8-13.
55. Aylon, Y. and Oren, M. (2007) Living with p53, dying of p53. Cell. 130, 597-600.
56. Mattagajasingh, I., Kim, C.-S., Naqvi, A., Yamamori, T., Hoffman, T. A., Jung, S.-B., DeRicco, J., Kasuno, K. and Irani, K. (2007) SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase. Proc. Natl. Acad. Sci. U. S. A. 104, 14855-14860.
57. Zhao, X., Sternsdorf, T., Bolger, T. A., Evans, R. M. and Yao, T. -P. (2005) Regulation of MEF2 by histone deacetylase 4-and SIRT1 deacetylase-mediated lysine modifications. Mol. Cell. Biol. 25, 8456-8464.
58. Pagans, S., Pedal, A., North, B. J., Kaehlcke, K., Marshall, B. L., Dorr, A., Hetzer-Egger, C., Henklein, P., Frye, R., McBurney, M. W., Hruby, H., Jung, M., Verdin, E. and Ott, M. (2005) SIRT1 regulates HIV transcription via Tat deacetylation. PLoS. Biol. 3.
59. Hallows, W. C., Lee, S. and Denu, J. M. (2006) Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases. Proc Natl Acad Sci U S A. 103, 10230-10235.
60. Rodgers, J. T., Lerin, C., Haas, W., Gygi, S. P., Spiegelman, B. M. and Puigserver, P. (2005) Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature. 434, 113-118.
61. Li, X., Zhang, S., Blander, G., Tse, J. G., Krieger, M. and Guarente, L. (2007) SIRT1 deacetylates and positively regulates the nuclear receptor LXR. Mol. Cell. 28, 91-9106.
62. 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. and Auwerx, J. (2006) Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell. 127, 1109-1122.
63. Lee, I. H., Cao, L., Mostoslavsky, R., Lombard, D. B., Liu, J., Bruns, N. E., Tsokos, M., Alt, F. W. and Finkel, T. (2008) A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proc. Natl. Acad. Sci. U. S. A. 105, 3374-3379.
64. Dryden, S. C., Nahhas, F. A., Nowak, J. E., Goustin, A.-S. and Tainsky, M. A. (2003) Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle. Mol. Cell. Biol. 23, 3173-3185.
65. Berdichevsky, A., Viswanathan, M., Horvitz, H. R. and Guarente, L. (2006) C. elegans SIR-2.1 interacts with 14-3-3 proteins to activate DAF-16 and extend life span. Cell. 125, 1165-77.
66. Picard, F., Kurtev, M., Chung, N., Topark-Ngarm, A., Senawong, T., Machado De Oliveira, R., Leid, M., McBurney, M. W. and Guarente, L. (2004) Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature. 429, 771-776.
67. Michishita, E., Park, J. Y., Burneskis, J. M., Barrett, J. C. and Horikawa, I. (2005) Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. Mol. Biol. Cell. 16, 4623-4635.
68. North, B. J. and Verdin, E. (2007) Interphase nucleocytoplasmic shuttling and localization of SIRT2 during mitosis. PLoS. ONE. 2.
69. Pandithage, R., Lilischkis, R., Harting, K., Wolf, A., Jedamzik, B., Luscher-Firzlaff, J., Vervoorts, J., Lasonder, E., Kremmer, E., Knoll, B. and Luscher, B. (2008) The regulation of SIRT2 function by cyclin-dependent kinases affects cell motility. J. Cell Biol. 180, 915-929.
70. Suzuki, K. and Koike, T. (2007) Resveratrol abolishes resistance to axonal degeneration in slow Wallerian degeneration (WldS) mice: activation of SIRT2, an NAD-dependent tubulin deacetylase. Biochem. Biophys. Res. Commun. 359, 665-671.
71. Nakamura, Y., Ogura, M., Tanaka, D. and Inagaki, N. (2008) Localization of mouse mitochondrial SIRT proteins: shift of SIRT3 to nucleus by co-expression with SIRT5. Biochem. Biophys. Res. Commun. 366, 174-179.
72. Schwer, B., North, B. J., Frye, R. A., Ott, M. and Verdin, E. (2002) The human silent information regulator (Sir)2 homologue hSIRT3 is a mitochondrial nicotinamide adenine dinucleotide-dependent deacetylase. J. Cell Biol. 158, 647-657.
73. Lombard, D. B., Alt, F. W., Cheng, H.-L., Bunkenborg, J., Streeper, R. S., Mostoslavsky, R., Kim, J., Yancopoulos, G., Valenzuela, D., Murphy, A., Yang, Y., Chen, Y., Hirschey, M. D., Bronson, R. T., Haigis, M., Guarente, L. P., Farese, R. V., Weissman, S., Verdin, E. and Schwer, B. (2007) Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation. Mol. Cell. Biol. 27, 8807-8814.
74. Scher, M. B., Vaquero, A. and Reinberg, D. (2007) SirT3 is a nuclear NAD+-dependent histone deacetylase that translocates to the mitochondria upon cellular stress. Genes Dev. 21, 920-928.
75. Gotta, M., Strahl-Bolsinger, S., Renauld, H., Laroche, T., Kennedy, B. K., Grunstein, M. and Gasser, S. M. (1997) Localization of Sir2p: the nucleolus as a compartment for silent information regulators. EMBO J. 16, 3243-3255.
76. Cohen, H. Y., Miller, C., Bitterman, K. J., Wall, N. R., Hekking, B., Kessler, B., Howitz, K. T., Gorospe, M., de Cabo, R. and Sinclair, D. A. (2004) Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science. 305, 390-392.
77. Nemoto, S., Fergusson, M. M. and Finkel, T. (2004) Nutrient availability regulates SIRT1 through a forkhead-dependent pathway. Science. 306, 2105-2108.
78. Qin, W., Yang, T., Ho, L., Zhao, Z., Wang, J., Chen, L., Zhao, W., Thiyagarajan, M., MacGrogan, D., Rodgers, J. T., Puigserver, P., Sadoshima, J., Deng, H., Pedrini, S., Gandy, S., Sauve, A. A. and Pasinetti, G. M. (2006) Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction. J. Biol. Chem. 281, 21745-21754.
79. Kanfi, Y., Peshti, V., Gozlan, Y. M., Rathaus, M., Gil, R. and Cohen, H. Y. (2008) Regulation of SIRT1 protein levels by nutrient availability. FEBS Lett.
80. Rodgers, J. T. and Puigserver, P. (2007) Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1. Proc. Natl. Acad. Sci. U. S. A. 104, 12861-12866.
81. Gerhart-Hines, Z., Rodgers, J. T., Bare, O., Lerin, C., Kim, S.-H., Mostoslavsky, R., Alt, F. W., Wu, Z. and Puigserver, P. (2007) Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha. EMBO J. 26, 1913-1923.
82. Bordone, L., Cohen, D., Robinson, A., Motta, M. C., van Veen, E., Czopik, A., Steele, A. D., Crowe, H., Marmor, S., Luo, J., Gu, W. and Guarente, L. (2007) SIRT1 transgenic mice show phenotypes resembling calorie restriction. Aging Cell. 6, 759-767.
83. Milne, J. C., Lambert, P. D., Schenk, S., Carney, D. P., Smith, J. J., Gagne, D. J., Jin, L., Boss, O., Perni, R. B., Vu, C. B., Bemis, J. E., Xie, R., Disch, J. S., Ng, P. Y., Nunes, J. J., Lynch, A. V., Yang, H., Galonek, H., Israelian, K., Choy, W., Iffland, A., Lavu, S., Medvedik, O., Sinclair, D. A., Olefsky, J. M., Jirousek, M. R., Elliott, P. J. and Westphal, C. H. (2007) Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature. 450, 712-716.
84. Moynihan, K. A., Grimm, A. A., Plueger, M. M., Bernal-Mizrachi, E., Ford, E., Cras-Meneur, C., Permutt, M. A. and Imai, S.-I. (2005) Increased dosage of mammalian Sir2 in pancreatic beta cells enhances glucose-stimulated insulin secretion in mice. Cell Metab. 2, 105-117.
85. Bordone, L., Motta, M. C., Picard, F., Robinson, A., Jhala, U. S., Apfeld, J., McDonagh, T., Lemieux, M., McBurney, M., Szilvasi, A., Easlon, E. J., Lin, S.-J. and Guarente, L. (2006) Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells. PLoS. Biol. 4.
86. Ogg, S., Paradis, S., Gottlieb, S., Patterson, G. I., Lee, L., Tissenbaum, H. A. and Ruvkun, G. (1997) The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature. 389, 994-999.
87. Nakae, J., Cao, Y., Daitoku, H., Fukamizu, A., Ogawa, W., Yano, Y. and Hayashi, Y. (2006) The LXXLL motif of murine forkhead transcription factor FoxO1 mediates Sirt1-dependent transcriptional activity. J. Clin. Invest. 116, 2473-2483.
88. Subauste, A. R. and Burant, C. F. (2007) Role of FoxO1 in FFA-induced oxidative stress in adipocytes. Am. J. Physiol. Endocrinol. Metab. 293, 159-164.
89. Qiao, L. and Shao, J. (2006) SIRT1 regulates adiponectin gene expression through Foxo1-C/enhancer-binding protein alpha transcriptional complex. J. Biol. Chem. 281, 39915-39924.
90. Zhu, M., Miura, J., Lu, L. X., Bernier, M., DeCabo, R., Lane, M. A., Roth, G. S. and Ingram, D. K. (2004) Circulating adiponectin levels increase in rats on caloric restriction: the potential for insulin sensitization. Exp. Gerontol. 39, 1049-1059.
91. Jing, E., Gesta, S. and Kahn, C. R. (2007) SIRT2 regulates adipocyte differentiation through FoxO1 acetylation/deacetylation. Cell Metab. 6, 105-114.
92. Turdi, S., Li, Q., Lopez, F. L. and Ren, J. (2007) Catalase alleviates cardiomyocyte dysfunction in diabetes: role of Akt, Forkhead transcriptional factor and silent information regulator 2. Life Sci. 81, 895-905.
93. Schwer, B., Bunkenborg, J., Verdin, R. O., Andersen, J. S. and Verdin, E. (2006) Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2. Proc. Natl. Acad. Sci. U S A. 103, 10224-10229.
94. Huang, J., Gan, Q., Han, L., Li, J., Zhang, H., Sun, Y., Zhang, Z. and Tong, T. (2008) SIRT1 Overexpression Antagonizes Cellular Senescence with Activated ERK/S6k1 Signaling in Human Diploid Fibroblasts. PLoS. ONE. 3.
95. Sasaki, T., Maier, B., Bartke, A. and Scrable, H. (2006) Progressive loss of SIRT1 with cell cycle withdrawal. Aging Cell. 5, 413-422.
96. Martin-Gronert, M. S., Tarry-Adkins, J. L., Cripps, R. L., Chen, J.-H. and Ozanne, S. E. (2008) Maternal protein restriction leads to early life alterations in the expression of key molecules involved in the aging process in rat offspring. Am. J .Physiol. Regul. Integr. Comp. Physiol. 294, 494-500.
97. Melendez, A., Talloczy, Z., Seaman, M., Eskelinen, E.-L., Hall, D. H. and Levine, B. (2003) Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science. 301, 1387-1391.
98. Hansen, M., Chandra, A., Mitic, L. L., Onken, B., Driscoll, M. and Kenyon, C. (2008) A Role for Autophagy in the Extension of Lifespan by Dietary Restriction in C. elegans. PLoS. Genet. 4.
99. Kaeberlein, M., Powers, R. W., 3rd, Steffen, K. K., Westman, E. A., Hu, D., Dang, N., Kerr, E. O., Kirkland, K. T., Fields, S. and Kennedy, B. K. (2005) Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science. 310, 1193-6.
100. Wang, F., Nguyen, M., Qin, F. X.-F. and Tong, Q. (2007) SIRT2 deacetylates FOXO3a in response to oxidative stress and caloric restriction. Aging Cell. 6, 505-514.
101. Outeiro, T. F., Kontopoulos, E., Altmann, S. M., Kufareva, I., Strathearn, K. E., Amore, A. M., Volk, C. B., Maxwell, M. M., Rochet, J.-C., McLean, P. J., Young, A. B., Abagyan, R., Feany, M. B., Hyman, B. T. and Kazantsev, A. G. (2007) Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson's disease. Science. 317, 516-519.
102. Sibille, E., Su, J., Leman, S., Le Guisquet, A. M., Ibarguen-Vargas, Y., Joeyen-Waldorf, J., Glorioso, C., Tseng, G. C., Pezzone, M., Hen, R. and Belzung, C. (2007) 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.
103. Bellizzi, D., Rose, G., Cavalcante, P., Covello, G., Dato, S., De Rango, F., Greco, V., Maggiolini, M., Feraco, E., Mari, V., Franceschi, C., Passarino, G. and De Benedictis, G. (2005) A novel VNTR enhancer within the SIRT3 gene, a human homologue of SIR2, is associated with survival at oldest ages. Genomics. 85, 258-263.
104. Kuningas, M., Putters, M., Westendorp, R. G. J., Slagboom, P. E. and van Heemst, D. (2007) SIRT1 gene, age-related diseases, and mortality: the Leiden 85-plus study. J. Gerontol. A. Biol. Sci. Med. Sci. 62, 960-965.
105. Flachsbart, F., Croucher, P. J. P., Nikolaus, S., Hampe, J., Cordes, C., Schreiber, S. and Nebel, A. (2006) Sirtuin 1 (SIRT1) sequence variation is not associated with exceptional human longevity. Exp. Gerontol. 41, 98-9102.
106. Yang, H., Yang, T., Baur, J. A., Perez, E., Matsui, T., Carmona, J. J., Lamming, D. W., Souza-Pinto, N. C., Bohr, V. A., Rosenzweig, A., de Cabo, R., Sauve, A. A. and Sinclair, D. A. (2007) Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival. Cell. 130, 1095-1107.
107. Mostoslavsky, R., Chua, K. F., Lombard, D. B., Pang, W. W., Fischer, M. R., Gellon, L., Liu, P., Mostoslavsky, G., Franco, S., Murphy, M. M., Mills, K. D., Patel, P., Hsu, J. T., Hong, A. L., Ford, E., Cheng, H.-L., Kennedy, C., Nunez, N., Bronson, R., Frendewey, D., Auerbach, W., Valenzuela, D., Karow, M., Hottiger, M. O., Hursting, S., Barrett, J. C., Guarente, L., Mulligan, R., Demple, B., Yancopoulos, G. D. and Alt, F. W. (2006) Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell. 124, 315-329.
108. Kanfi, Y., Shalman, R., Peshti, V., Pilosof, S. N., Gozlan, Y. M., Pearson, K. J., Lerrer, B., Moazed, D., Marine, J.-C., de Cabo, R. and Cohen, H. Y. (2008) Regulation of SIRT6 protein levels by nutrient availability. FEBS Lett. 582, 543-548.
109. Ford, E., Voit, R., Liszt, G., Magin, C., Grummt, I. and Guarente, L. (2006) Mammalian Sir2 homolog SIRT7 is an activator of RNA polymerase I transcription. Genes Dev. 20, 1075-1080.
110. Yang, H., Lavu, S. and Sinclair, D. A. (2006) Nampt/PBEF/Visfatin: a regulator of mammalian health and longevity? Exp. Gerontol. 41, 718-726.
111. van der Veer, E., Ho, C., O'Neil, C., Barbosa, N., Scott, R., Cregan, S. P. and Pickering, J. G. (2007) Extension of human cell lifespan by nicotinamide phosphoribosyltransferase. J. Biol. Chem. 282, 10841-10845.
112. Revollo, J. R., Korner, A., Mills, K. F., Satoh, A., Wang, T., Garten, A., Dasgupta, B., Sasaki, Y., Wolberger, C., Townsend, R. R., Milbrandt, J., Kiess, W. and Imai, S. (2007) Nampt/PBEF/Visfatin regulates insulin secretion in beta cells as a systemic NAD biosynthetic enzyme. Cell Metab. 6, 363-75.
113. Wu, A., Ying, Z. and Gomez-Pinilla, F. (2006) Oxidative stress modulates Sir2alpha in rat hippocampus and cerebral cortex. Eur. J. Neurosci. 23, 2573-2580.
114. Virgili, M. and Contestabile, A. (2000) Partial neuroprotection of in vivo excitotoxic brain damage by chronic administration of the red wine antioxidant agent, trans-resveratrol in rats. Neurosci. Lett. 281, 123-126.
115. Dong, W., Zhang, X., Gao, D. and Li, N. (2007) Cerebral angiogenesis induced by resveratrol contributes to relieve cerebral ischemic-reperfusion injury. Med. Hypotheses. 69, 226-227.
116. Sharma, M. and Gupta, Y. K. (2002) Chronic treatment with trans resveratrol prevents intracerebroventricular streptozotocin induced cognitive impairment and oxidative stress in rats. Life Sci. 71, 2489-2498.
117. Bi, X. L., Yang, J. Y., Dong, Y. X., Wang, J. M., Cui, Y. H., Ikeshima, T., Zhao, Y. Q. and Wu, C. F. (2005) Resveratrol inhibits nitric oxide and TNF-alpha production by lipopolysaccharide-activated microglia. Int. Immunopharmacol. 5, 185-193.
118. Marambaud, P., Zhao, H. and Davies, P. (2005) Resveratrol promotes clearance of Alzheimer's disease amyloid-beta peptides. J. Biol. Chem. 280, 37377-37382.
119. Maswood, N., Young, J., Tilmont, E., Zhang, Z., Gash, D. M., Gerhardt, G. A., Grondin, R., Roth, G. S., Mattison, J., Lane, M. A., Carson, R. E., Cohen, R. M., Mouton, P. R., Quigley, C., Mattson, M. P. and Ingram, D. K. (2004) Caloric restriction increases neurotrophic factor levels and attenuates neurochemical and behavioral deficits in a primate model of Parkinson's disease. Proc. Natl. Acad. Sci. U. S. A. 101, 18171-18176.
120. Baur, J. A. and Sinclair, D. A. (2006) Therapeutic potential of resveratrol: the in vivo evidence. Nat. Rev. Drug. Discov. 5, 493-506.
121. Csiszar, A., Labinskyy, N., Podlutsky, A., Kaminski, P. M., Wolin, M. S., Zhang, C., Mukhopadhyay, P., Pacher, P., Hu, F., de Cabo, R., Ballabh, P. and Ungvari, Z. (2008) Vasoprotective effects of resveratrol and SIRT1: attenuation of cigarette smoke-induced oxidative stress and proinflammatory phenotypic alterations. Am. J. Physiol. Heart Circ. Physiol. 294, H2721-35.
122. Howitz, K. T., Bitterman, K. J., Cohen, H. Y., Lamming, D. W., Lavu, S., Wood, J. G., Zipkin, R. E., Chung, P., Kisielewski, A., Zhang, L.-L., Scherer, B. and Sinclair, D. A. (2003) Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 425, 191-196.
123. Kim, D., Nguyen, M. D., Dobbin, M. M., Fischer, A., Sananbenesi, F., Rodgers, J. T., Delalle, I., Baur, J. A., Sui, G., Armour, S. M., Puigserver, P., Sinclair, D. A. and Tsai, L.-H. (2007) SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis. EMBO J. 26, 3169-3179.
124. Parker, J. A., Arango, M., Abderrahmane, S., Lambert, E., Tourette, C., Catoire, H. and Neri, C. (2005) Resveratrol rescues mutant polyglutamine cytotoxicity in nematode and mammalian neurons. Nat. Genet. 37, 349-350.
125. Prozorovski, T., Schulze-Topphoff, U., Glumm, R., Baumgart, J., Schroter, F., Ninnemann, O., Siegert, E., Bendix, I., Brustle, O., Nitsch, R., Zipp, F. and Aktas, O. (2008) Sirt1 contributes critically to the redox-dependent fate of neural progenitors. Nat. Cell. Biol. 10, 385-394.
126. Chong, Z.-Z., Lin, S.-H., Li, F. and Maiese, K. (2005) The sirtuin inhibitor nicotinamide enhances neuronal cell survival during acute anoxic injury through AKT, BAD, PARP, and mitochondrial associated "anti- apoptotic" pathways. Curr. Neurovasc. Res. 2, 271-285.
127. Suzuki, K. and Koike, T. (2007) Mammalian Sir2-related protein (SIRT) 2-mediated modulation of resistance to axonal degeneration in slow Wallerian degeneration mice: a crucial role of tubulin deacetylation. Neuroscience. 147, 599-612.
128. Dompierre, J. P., Godin, J. D., Charrin, B. C., Cordelieres, F. P., King, S. J., Humbert, S. and Saudou, F. (2007) Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington's disease by increasing tubulin acetylation. J. Neurosci. 27, 3571-3583.
129. Steffan, J. S., Bodai, L., Pallos, J., Poelman, M., McCampbell, A., Apostol, B. L., Kazantsev, A., Schmidt, E., Zhu, Y. Z., Greenwald, M., Kurokawa, R., Housman, D. E., Jackson, G. R., Marsh, J. L. and Thompson, L. M. (2001) Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature. 413, 739-743.
130. Garske, A. L., Smith, B. C. and Denu, J. M. (2007) Linking SIRT2 to Parkinson's disease. ACS Chem. Biol. 2, 529-532.
131. Dillin, A. and Kelly, J. W. (2007) Medicine. The yin-yang of sirtuins. Science. 317, 461-462.
132. Li, W., Zhang, B., Tang, J., Cao, Q., Wu, Y., Wu, C., Guo, J., Ling, E.-A. and Liang, F. (2007) Sirtuin 2, a mammalian homolog of yeast silent information regulator-2 longevity regulator, is an oligodendroglial protein that decelerates cell differentiation through deacetylating alpha-tubulin. J. Neurosci. 27, 2606-2616.
133. Werner, H. B., Kuhlmann, K., Shen, S., Uecker, M., Schardt, A., Dimova, K., Orfaniotou, F., Dhaunchak, A., Brinkmann, B. G., Mobius, W., Guarente, L., Casaccia-Bonnefil, P., Jahn, O. and Nave, K.-A. (2007) Proteolipid protein is required for transport of sirtuin 2 into CNS myelin. J. Neurosci. 27, 7717-7730.
134. Huffman, D. M., Grizzle, W. E., Bamman, M. M., Kim, J.-s., Eltoum, I. A., Elgavish, A. and Nagy, T. R. (2007) SIRT1 is significantly elevated in mouse and human prostate cancer. Cancer Res. 67, 6612-6618.
135. Dai, Y., Ngo, D., Forman, L. W., Qin, D. C., Jacob, J. and Faller, D. V. (2007) Sirtuin 1 is required for antagonist-induced transcriptional repression of androgen-responsive genes by the androgen receptor. Mol. Endocrinol. 21, 1807-1821.
136. Stankovic-Valentin, N., Deltour, S., Seeler, J., Pinte, S., Vergoten, G., Guerardel, C., Dejean, A. and Leprince, D. (2007) An acetylation/deacetylation- SUMOylation switch through a phylogenetically conserved psiKXEP motif in the tumor suppressor HIC1 regulates transcriptional repression activity. Mol. Cell. Biol. 27, 2661-2675.
137. Zhao, W., Kruse, J.-P., Tang, Y., Jung, S. Y., Qin, J. and Gu, W. (2008) Negative regulation of the deacetylase SIRT1 by DBC1. Nature. 451, 587-590.
138. Bereshchenko, O. R., Gu, W. and Dalla-Favera, R. (2002) Acetylation inactivates the transcriptional repressor BCL6. Nat. Genet. 32, 606-13.
139. Heltweg, B., Gatbonton, T., Schuler, A. D., Posakony, J., Li, H., Goehle, S., Kollipara, R., Depinho, R. A., Gu, Y., Simon, J. A. and Bedalov, A. (2006) Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes. Cancer Res. 66, 4368-4377.
140. Sun, Y., Sun, D., Li, F., Tian, L., Li, C., Li, L., Lin, R. and Wang, S. (2007) Downregulation of Sirt1 by antisense oligonucleotides induces apoptosis and enhances radiation sensitization in A549 lung cancer cells. Lung Cancer. 58, 21-29.
141. Wong, S. and Weber, J. D. (2007) Deacetylation of the retinoblastoma tumour suppressor protein by SIRT1. Biochem. J. 407, 451-460.
142. Hiratsuka, M., Inoue, T., Toda, T., Kimura, N., Shirayoshi, Y., Kamitani, H., Watanabe, T., Ohama, E., Tahimic, C. G. T., Kurimasa, A. and Oshimura, M. (2003) Proteomics-based identification of differentially expressed genes in human gliomas: down-regulation of SIRT2 gene. Biochem. Biophys. Res. Commun. 309, 558-566.
143. Jin, Y.-H., Kim, Y.-J., Kim, D.-W., Baek, K.-H., Kang, B. Y., Yeo, C.-Y. and Lee, K.-Y. (2008) Sirt2 interacts with 14-3-3 beta/gamma and down-regulates the activity of p53. Biochem. Biophys. Res. Commun. 368, 690-695.
144. Neugebauer, R., Uchiechowska, U., Meier, R., Hruby, H., Valkov, V., Verdin, E., Sippl, W. and Jung, M. (2008) Structure-Activity Studies on Splitomicin Derivatives as Sirtuin Inhibitors and Computational Prediction of Binding Mode. J. Med. Chem. 51, 1203-1213.
145. Ashraf, N., Zino, S., Macintyre, A., Kingsmore, D., Payne, A. P., George, W. D. and Shiels, P. G. (2006) Altered sirtuin expression is associated with node-positive breast cancer. Br. J. Cancer. 95, 1056-1061.
146. De Nigris, F., Cerutti, J., Morelli, C., Califano, D., Chiariotti, L., Viglietto, G., Santelli, G. and Fusco, A. (2002) Isolation of a SIR-like gene, SIR-T8, that is overexpressed in thyroid carcinoma cell lines and tissues. Br. J. Cancer. 87, 1479-1479.
147. Allison, S. J. and Milner, J. (2007) SIRT3 is pro-apoptotic and participates in distinct basal apoptotic pathways. Cell Cycle. 6, 2669-2677.
148. Ma, W., Stafford, L. J., Li, D., Luo, J., Li, X., Ning, G. and Liu, M. (2007) GCIP/CCNDBP1, a helix-loop-helix protein, suppresses tumorigenesis. J. Cell Biochem. 100, 1376-1386.
149. Bradbury, C. A., Khanim, F. L., Hayden, R., Bunce, C. M., White, D. A., Drayson, M. T., Craddock, C. and Turner, B. M. (2005) Histone deacetylases in acute myeloid leukaemia show a distinctive pattern of expression that changes selectively in response to deacetylase inhibitors. Leukemia. 19, 1751-1759.
150. Alcendor, R. R., Gao, S., Zhai, P., Zablocki, D., Holle, E., Yu, X., Tian, B., Wagner, T., Vatner, S. F. and Sadoshima, J. (2007) Sirt1 regulates aging and resistance to oxidative stress in the heart. Circ. Res. 100, 1512-1521.
151. Potente, M., Ghaeni, L., Baldessari, D., Mostoslavsky, R., Rossig, L., Dequiedt, F., Haendeler, J., Mione, M., Dejana, E., Alt, F. W., Zeiher, A. M.
152. Nisoli, E., Tonello, C., Cardile, A., Cozzi, V., Bracale, R., Tedesco, L., Falcone, S., Valerio, A., Cantoni, O., Clementi, E., Moncada, S. and Carruba, M. O. (2005) Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science. 310, 314-317.
153. Ferrara, N., Rinaldi, B., Corbi, G., Conti, V., Stiuso, P., Boccuti, S., Rengo, G., Rossi, F. and Filippelli, A. (2008) Exercise Training Promotes SIRT1 Activity in Aged Rats. Rejuvenation Res. 11, 139-150.
154. Blazek, D. and Peterlin, B. M. (2008) Tat-SIRT1 Tango. Mol Cell. 29, 539-540.
155. Kwon, H.-S., Brent, M. M., Getachew, R., Jayakumar, P., Chen, L.-F., Schnolzer, M., McBurney, M. W., Marmorstein, R., Greene, W. C. and Ott, M. (2008) Human Immunodeficiency Virus Type 1 Tat Protein Inhibits the SIRT1 Deacetylase and Induces T Cell Hyperactivation. Cell Host Microbe. 3, 158-167.
156. Rajendrasozhan, S., Yang, S.-R., Kinnula, V. L. and Rahman, I. (2008) SIRT1, an Anti-Inflammatory and Anti-Aging Protein, is Decreased in Lungs of Patients with COPD. Am. J. Respir. Crit. Care Med.
157. Kume, S., Haneda, M., Kanasaki, K., Sugimoto, T., Araki, S.-i., Isono, M., Isshiki, K., Uzu, T., Kashiwagi, A. and Koya, D. (2006) Silent information regulator 2 (SIRT1) attenuates oxidative stress-induced mesangial cell apoptosis via p53 deacetylation. Free Radic. Biol. Med. 40, 2175-2182.
158. Hasegawa, K., Wakino, S., Yoshioka, K., Tatematsu, S., Hara, Y., Minakuchi, H., Washida, N., Tokuyama, H., Hayashi, K. and Itoh, H. (2008) Sirt1 protects against oxidative stress-induced renal tubular cell apoptosis by the bidirectional regulation of catalase expression. Biochem. Biophys. Res. Commun. 372, 51-6.
159. Fauconneau, B., Waffo-Teguo, P., Huguet, F., Barrier, L., Decendit, A. and Merillon, J. M. (1997) Comparative study of radical scavenger and antioxidant properties of phenolic compounds from Vitis vinifera cell cultures using in vitro tests. Life Sci. 61, 2103-10.
160. Jang, M., Cai, L., Udeani, G. O., Slowing, K. V., Thomas, C. F., Beecher, C. W., Fong, H. H., Farnsworth, N. R., Kinghorn, A. D., Mehta, R. G., Moon, R. C. and Pezzuto, J. M. (1997) Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science. 275, 218-20.
161. Baur, J. A., Pearson, K. J., Price, N. L., Jamieson, H. A., Lerin, C., Kalra, A., Prabhu, V. V., Allard, J. S., Lopez-Lluch, G., Lewis, K., Pistell, P. J., Poosala, S., Becker, K. G., Boss, O., Gwinn, D., Wang, M., Ramaswamy, S., Fishbein, K. W., Spencer, R. G., Lakatta, E. G., Le Couteur, D., Shaw, R. J., Navas, P., Puigserver, P., Ingram, D. K., de Cabo, R. and Sinclair, D. A. (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 444, 337-42.
162. Pearson, K. J., Baur, J. A., Lewis, K. N., Peshkin, L., Price, N. L., Labinskyy, N., Swindell, W. R., Kamara, D., Minor, R. K., Perez, E., Jamieson, H. A., Zhang, Y., Dunn, S. R., Sharma, K., Pleshko, N., Woollett, L. A., Csiszar, A., Ikeno, Y., Le Couteur, D., Elliott, P. J., Becker, K. G., Navas, P., Ingram, D. K., Wolf, N. S., Ungvari, Z., Sinclair, D. A. and de Cabo, R. (2008) Resveratrol Delays Age-Related Deterioration and Mimics Transcriptional Aspects of Dietary Restriction without Extending Life Span. Cell Metab.
163. Bickenbach, K. A., Veerapong, J., Shao, M. Y., Mauceri, H. J., Posner, M. C., Kron, S. J. and Weichselbaum, R. R. (2008) Resveratrol is an effective inducer of CArG-driven TNF-alpha gene therapy. Cancer Gene Ther. 15, 133-139.
164. Kaeberlein, M. and Kennedy, B. K. (2007) Does resveratrol activate yeast Sir2 in vivo? Aging Cell. 6, 415-416.
165. de Boer, V. C. J., de Goffau, M. C., Arts, I. C. W., Hollman, P. C. H. and Keijer, J. (2006) SIRT1 stimulation by polyphenols is affected by their stability and metabolism. Mech. Ageing Dev. 127, 618-627.
166. Yang, H., Baur, J. A., Chen, A., Miller, C., Adams, J. K., Kisielewski, A., Howitz, K. T., Zipkin, R. E. and Sinclair, D. A. (2007) Design and synthesis of compounds that extend yeast replicative lifespan. Aging Cell. 6, 35-43.
167. Olaharski, A. J., Rine, J., Marshall, B. L., Babiarz, J., Zhang, L., Verdin, E. and Smith, M. T. (2005) The flavoring agent dihydrocoumarin reverses epigenetic silencing and inhibits sirtuin deacetylases. PLoS. Genet. 1.
168. Jackson, M. D., Schmidt, M. T., Oppenheimer, N. J. and Denu, J. M. (2003) Mechanism of nicotinamide inhibition and transglycosidation by Sir2 histone/protein deacetylases. J. Biol. Chem. 278, 50985-50998.
169. Bitterman, K. J., Anderson, R. M., Cohen, H. Y., Latorre-Esteves, M. and Sinclair, D. A. (2002) Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1. J. Biol. Chem. 277, 45099-45107.
170. Grozinger, C. M., Chao, E. D., Blackwell, H. E., Moazed, D. and Schreiber, S. L. (2001) Identification of a class of small molecule inhibitors of the sirtuin family of NAD-dependent deacetylases by phenotypic screening. J. Biol. Chem. 276, 38837-38843.
171. Bedalov, A., Gatbonton, T., Irvine, W. P., Gottschling, D. E. and Simon, J. A. (2001) Identification of a small molecule inhibitor of Sir2p. Proc. Natl. Acad. Sci. U. S. A. 98, 15113-15118.
172. Finnin, M. S., Donigian, J. R. and Pavletich, N. P. (2001) Structure of the histone deacetylase SIRT2. Nat. Struct. Biol. 8, 621-625.
173. Min, J., Landry, J., Sternglanz, R. and Xu, R. M. (2001) Crystal structure of a SIR2 homolog-NAD complex. Cell. 105, 269-79.
174. Zhao, K., Chai, X. and Marmorstein, R. (2003) Structure of the yeast Hst2 protein deacetylase in ternary complex with 2′-O-acetyl ADP ribose and histone peptide. Structure. 11, 1403-11.
175. Chang, J. H., Kim, H. C., Hwang, K. Y., Lee, J. W., Jackson, S. P., Bell, S. D. and Cho, Y. (2002) Structural basis for the NAD-dependent deacetylase mechanism of Sir2. J. Biol. Chem. 277, 34489-98.
176. Avalos, J. L., Celic, I., Muhammad, S., Cosgrove, M. S., Boeke, J. D. and Wolberger, C. (2002) Structure of a Sir2 enzyme bound to an acetylated p53 peptide. Mol. Cell. 10, 523-535.
177. Hoff, K. G., Avalos, J. L., Sens, K. and Wolberger, C. (2006) Insights into the sirtuin mechanism from ternary complexes containing NAD+ and acetylated peptide. Structure. 14, 1231-40.
178. Tervo, A. J., Kyrylenko, S., Niskanen, P., Salminen, A., Leppanen, J., Nyronen, T. H., Jarvinen, T. and Poso, A. (2004) Anin silico approach to discovering novel inhibitors of human sirtuin type 2. J. Med. Chem. 47, 6292-6298.
179. Schuetz, A., Min, J., Antoshenko, T., Wang, C.-L., Allali-Hassani, A., Dong, A., Loppnau, P., Vedadi, M., Bochkarev, A., Sternglanz, R. and Plotnikov, A. N. (2007) Structural basis of inhibition of the human NAD+-dependent deacetylase SIRT5 by suramin. Structure. 15, 377-389.
180. Lain, S., Hollick, J. J., Campbell, J., Staples, O. D., Higgins, M., Aoubala, M., McCarthy, A., Appleyard, V., Murray, K. E., Baker, L., Thompson, A., Mathers, J., Holland, S. J., Stark, M. J., Pass, G., Woods, J., Lane, D. P. and Westwood, N. J. (2008) Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator. Cancer Cell. 13, 454-63.
181. Imai, S., Armstrong, C. M., Kaeberlein, M. and Guarente, L. (2000) Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature. 403, 795-800.
182. Landry, J., Sutton, A., Tafrov, S. T., Heller, R. C., Stebbins, J., Pillus, L. and Sternglanz, R. (2000) The silencing protein SIR2 and its homologs are NAD-dependent protein deacetylases. Proc. Natl. Acad. Sci. U. S. A. 97, 5807-5811.
183. Xu, F., Zhang, Q., Zhang, K., Xie, W. and Grunstein, M. (2007) Sir2 deacetylates histone H3 lysine 56 to regulate telomeric heterochromatin structure in yeast. Mol. Cell. 27, 890-900.
184. Parsons, X. H., Garcia, S. N., Pillus, L. and Kadonaga, J. T. (2003) Histone deacetylation by Sir2 generates a transcriptionally repressed nucleoprotein complex. Proc. Natl. Acad. Sci. U. S. A. 100, 1609-14.
185. Vaquero, A., Scher, M., Lee, D., Erdjument-Bromage, H., Tempst, P. and Reinberg, D. (2004) Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin. Mol. Cell. 16, 93-9105.
186. Pruitt, K., Zinn, R. L., Ohm, J. E., McGarvey, K. M., Kang, S.-H. L., Watkins, D. N., Herman, J. G. and Baylin, S. B. (2006) Inhibition of SIRT1 reactivates silenced cancer genes without loss of promoter DNA hypermethylation. PLoS. Genet. 2.
187. Chen, B., Nelson, D. M. and Sadovsky, Y. (2006) N-myc down-regulated gene 1 modulates the response of term human trophoblasts to hypoxic injury. J. Biol. Chem. 281, 2764-2772.
188. Dai, J. M., Wang, Z. Y., Sun, D. C., Lin, R. X. and Wang, S. Q. (2007) SIRT1 interacts with p73 and suppresses p73-dependent transcriptional activity. J. Cell Physiol. 210, 161-166.
189. Takata, T. and Ishikawa, F. (2003) Human Sir2-related protein SIRT1 associates with the bHLH repressors HES1 and HEY2 and is involved in HES1- and HEY2-mediated transcriptional repression. Biochem. Biophys. Res. Commun. 301, 250-257.
190. Fulco, M., Schiltz, R. L., Iezzi, S., King, M. T., Zhao, P., Kashiwaya, Y., Hoffman, E., Veech, R. L. and Sartorelli, V. (2003) Sir2 regulates skeletal muscle differentiation as a potential sensor of the redox state. Mol. Cell. 12, 51-62.
191. Muth, V., Nadaud, S., Grummt, I. and Voit, R. (2001) Acetylation of TAF(I)68, a subunit of TIF-IB/SL1, activates RNA polymerase I transcription. EMBO J. 20, 1353-62.
192. Vaquero, A., Sternglanz, R. and Reinberg, D. (2007) NAD+-dependent deacetylation of H4 lysine 16 by class III HDACs. Oncogene. 26, 5505-5520.
193. Solomon, J. M., Pasupuleti, R., Xu, L., McDonagh, T., Curtis, R., DiStefano, P. S. and Huber, L. J. (2006) Inhibition of SIRT1 catalytic activity increases p53 acetylation but does not alter cell survival following DNA damage. Mol. Cell. Biol. 26, 28-38.
194. Howitz, K.a.Z., Robert (2006) in: U. S. Patent Application.
195. Firestein, R., Blander, G., Michan, S., Oberdoerffer, P., Ogino, S., Campbell, J., Bhimavarapu, A., Luikenhuis, S., de Cabo, R., Fuchs, C., Hahn, W. C., Guarente, L. P. and Sinclair, D. A. (2008) The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth. PLoS. ONE. 3, e2020.
196. Cheng, H. L., Mostoslavsky, R., Saito, S., Manis, J. P., Gu, Y., Patel, P., Bronson, R., Appella, E., Alt, F. W. and Chua, K. F. (2003) Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice. Proc. Natl. Acad. Sci. USA. 100, 10794-10799.
197. McBurney, M. W., Yang, X., Jardine, K., Hixon, M., Boekelheide, K., Webb, J. R., Lansdorp, P. M. and Lemieux, M. (2003) The mammalian SIR2alpha protein has a role in embryogenesis and gametogenesis. Mol. Cell Biol. 23, 38-54.