Cellular and molecular effects of sirtuins in health and disease

Clinical Science

Volumn 121, Issue 5, 2011, Pages 191-203

  Horio, Yoshiyuki ^a   Hayashi, Takashi ^a   Kuno, Atsushi ^a   Kunimoto, Risa ^a  

^a SAPPORO MEDICAL UNIVERSITY   (Japan)

Author keywords

Deacetylation; DNA repair; Inflammation; Metabolism; Mitochondrion; Sirtuin; Stress resistance

Indexed keywords

RESVERATROL; SIRTUIN; SIRTUIN 1;

ALZHEIMER DISEASE; BLOOD VESSEL; BRAIN; BREAST CANCER; CELL DIFFERENTIATION; CELL SURVIVAL; DNA REPAIR; ENERGY METABOLISM; ENZYME ACTIVITY; HEART FAILURE; HUMAN; INFLAMMATION; KIDNEY FIBROSIS; MITOCHONDRION; NEOPLASM; NONHUMAN; PRIORITY JOURNAL; PROTEIN FUNCTION; RETINA DEGENERATION; REVIEW;

ANIMALS; BLOOD GLUCOSE; CELL DEATH; CELL TRANSFORMATION, NEOPLASTIC; DNA REPAIR; ENERGY METABOLISM; HUMANS; INFLAMMATION; LIPID METABOLISM; MITOCHONDRIA; SIRTUINS;

EID: 79961162915     PISSN: 01435221     EISSN: None     Source Type: Journal    
DOI: 10.1042/CS20100587     Document Type: Review

References (134)

1. Klar, A. J., Seymour, F. and Macleod, K. (1979) MAR1: a regulator of the HMa and HMα loci in Saccharomyces cerevisiae. Genetics 93, 37-50.
2. 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.
3. Smith, J. S. and Boeke, J. D. (1997) An unusual form of transcriptional silencing in yeast ribosomal DNA. Genes Dev. 15, 241-254.
4. Sinclair, D. A. and Guarente, L. (1997) Extrachromosomal rDNA circles: a cause of aging in yeast. Cell 91, 1033-1042.
5. 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.
6. Tissenbaum, H. A. and Guarente, L. (2001) Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 410, 227-230.
7. 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.
8. McCay, C. M., Crowell, M. F. and Maynard, L. A. (1935) The effect of retarded growth upon the length of life span and upon the ultimate body size. J. Nutr. 10, 63-79.
9. 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.
10. Rodriguez-Colman, M. J., Reverter-Branchat, G., Sorolla, M. A., Tamarit, J., Ros, J. and Cabiscol, E. (2010) The forkhead transcription factor hcm1 promotes mitochondrial biogenesis and stress resistance in yeast. J. Biol. Chem. 285, 37092-37101.
11. Martin, S. G., Laroche, T., Suka, N., Grunstein, M. and Gasser, S. M. (1999) Relocalization of telomeric Ku and SIR proteins in response to DNA strand breaks in yeast. Cell 97, 621-633.
12. Tsukamoto, Y., Kato, J. and Ikeda, H. (1997) Silencing factors participate in DNA repair and recombination in Saccharomyces cerevisiae. Nature 388, 900-903.
13. Liu, B., Larsson, L., Caballero, A., Hao, X., Oling, D., Grantham, J. and Nyström, T. (2010) The polarisome is required for segregation and retrograde transport of protein aggregates. Cell 140, 257-267.
14. Braunstein, M., Rose, A. B. and Holmes, S. G. (1993) Transcriptional silencing in yeast is associated with reduced nucleosome acetylation. Genes Dev. 7, 592-604.
15. 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.
16. Tanner, K. G., Landry, J., Sternglanz, R. and Denu, J. M. (2000) Silent information regulator 2 family of NAD-dependent histone/protein deacetylases generates a unique product, 1-O-acetyl-ADP-ribose. Proc. Natl. Acad. Sci. U.S.A. 97, 14178-14182.
17. Tong, L. and Denu, J. M. (2010) Function and metabolism of sirtuin metabolite O-acetyl-ADP-ribose. Biochim. Biophys. Acta 1804, 1617-1625.
18. 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.
19. Frye, R. A. (2000) Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem. Biophys. Res. Commun. 273, 793-798.
20. Tanno, M., Sakamoto, J., Miura, T., Shimamoto, K. and Horio, Y. (2007) Nucleocytoplasmic shuttling of the NAD+-dependent histone deacetylase SIRT1. J. Biol. Chem. 282, 6823-6832.
21. North, B. J. and Verdin, E. (2007) Interphase nucleo-cytoplasmic shuttling and localization of SIRT2 during mitosis. PLoS ONE 2, e784.
22. 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.
23. Sundaresan, N. R., Samant, S. A., Pillai, V. B., Rajamohan, S. B. and Gupta, M. P. (2008) SIRT3 is a stress-responsive deacetylase in cardiomyocytes that protects cells from stress-mediated cell death by deacetylation of Ku70. Mol. Cell Biol. 28, 6384-6401.
24. 32P-NAD. Biochemistry 48, 2878-2890.
25. Luo, J., Nikolaev, A. Y., Imai, S., Chen, D., Su, F., Shiloh, A. and Guarente, L. (2001) Negative control of p53 by Sir2α promotes cell survival under stress. Cell 107, 137-148.
26. Vaziri, H., Dessain, S. K., Ng Eaton, E., Imai, S., 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.
27. Kim, E. J., Kho, J. H., Kang, M. R. and Um, S. J. (2007) Active regulator of SIRT1 cooperates with SIRT1 and facilitates suppression of p53 activity. Mol. Cell 28, 277-290.
28. Hasegawa, K. and Yoshikawa, K. (2008) Necdin regulates p53 acetylation via Sirtuin1 to modulate DNA damage response in cortical neurons. J. Neurosci. 28, 8772-8784.
29. 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.
30. 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. 102, 703-710.
31. 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.
32. Sundaresan, N. R., Samant, S. A., Pillai, V. B., Rajamohan, S. B. and Gupta, M. P. (2008) SIRT3 is a stress-responsive deacetylase in cardiomyocytes that protects cells from stress-mediated cell death by deacetylation of Ku70. Mol. Cell. Biol. 28, 6384-6401.
33. Rajamohan, S. B., Pillai, V. B., Gupta, M., Sundaresan, N. R., Birukov, K. G., Samant, S., Hottiger, M. O. and Gupta, M. P. (2009) SIRT1 promotes cell survival under stress by deacetylation-dependent deactivation of poly(ADP-ribose) polymerase 1. Mol. Cell. Biol. 29, 4116-4129.
34. Westerheide, S. D., Anckar, J., Stevens, Jr, S. M., Sistonen, L. and Morimoto, R. I. (2009) Stress-inducible regulation of heat shock factor 1 by the deacetylase SIRT1. Science 323, 1063-1066.
35. Brunet, A., Sweeney, L. B., Sturgill, J. F., Chua, K. F., Greer, P. L., Lin, Y., Tran, H., Ross, S. E., Mostoslavsky, R., Cohen, H. Y. et al. (2004) Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303, 2011-2015.
36. Daitoku, H., Hatta, M., Matsuzaki, H., Aratani, S., Ohshima, T., Miyagishi, M., Nakajima, T. and Fukamizu, A. (2004) Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. Proc. Natl. Acad. Sci. U.S.A. 101, 10042-10047.
37. van der Horst, A., Tertoolen, L. G., de Vries-Smits, L. M., Frye, R. A., Medema, R. H. and Burgering, B. M. (2004) FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2 (SIRT1). J. Biol. Chem. 279, 28873-28879.
38. Kobayashi, Y., Furukawa-Hibi, Y., Chen, C., Horio, Y., Isobe, K., Ikeda, K. and Motoyama, N. (2005) SIRT1 is critical regulator of FOXO-mediated transcription in response to oxidative stress. Int. J. Mol. Med. 16, 237-243.
39. Tanno, M., Kuno, A., Yano, T., Miura, T., Hisahara, S., Ishikawa, S., Shimamoto, K. and Horio, Y. (2010) Induction of manganese superoxide dismutase by nuclear translocation and activation of SIRT1 promotes cell survival in chronic heart failure. J. Biol. Chem. 285, 8375-8382.
40. Shinmura, K., Tamaki, K. and Bolli, R. (2008) Impact of 6-mo caloric restriction on myocardial ischemic tolerance: possible involvement of nitric oxide-dependent increase in nuclear Sirt1. Am. J. Physiol. Heart Circ. Physiol. 295, H2348-H2355.
41. 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.
42. 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-1 and SIRT1. Nature 434, 113-118.
43. Nemoto, S., Fergusson, M. M. and Finkel, T. (2005) SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1α. J. Biol. Chem. 280, 16456-16460.
44. St-Pierre, J., Drori, S., Uldry, M., Silvaggi, J. M., Rhee, J., Jäger, S., Handschin, C., Zheng, K., Lin, J., Yang, W., Simon, D. K., Bachoo, R. and Spiegelman, B. M. (2006) Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell 127, 397-408.
45. Kume, S., Haneda, M., Kanasaki, K., Sugimoto, T., Araki, S., Isshiki, K., Isono, M., Uzu, T., Guarente, L., Kashiwagi, A. and Koya, D. (2007) SIRT1 inhibits transforming growth factor β-induced apoptosis in glomerular mesangial cells via Smad7 deacetylation. J. Biol. Chem. 282, 151-158.
46. Moynihan, K. A., Grimm, A. A., Plueger, M. M., Bernal-Mizrachi, E., Ford, E., Cras-Méneur, C., Permutt, M. A. and Imai, S. (2005) Increased dosage of mammalian Sir2 in pancreatic β cells enhances glucose-stimulated insulin secretion in mice. Cell Metab. 2, 105-117.
47. 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.
48. 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. et al. (2007) SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis. EMBO J. 26, 3169-3179.
49. 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-κB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J. 23, 2369-2380.
50. Chen, J., Zhou, Y., Mueller-Steiner, S., Chen, L. F., Kwon, H., Yi, S., Mucke, L. and Gan, L. (2005) SIRT1 protects against microglia-dependent amyloid-β toxicity through inhibiting NF-κB signaling. J. Biol. Chem. 280, 40364-40374.
51. Rajendrasozhan, S., Yang, S. R., Kinnula, V. L. and Rahman, I. (2008) SIRT1, an antiinflammatory and antiaging protein, is decreased in lungs of patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 177, 861-870.
52. Nakamaru, Y., Vuppusetty, C.,Wada, H., Milne, J. C., Ito, M., Rossios, C., Elliot, M., Hogg, J., Kharitonov, S., Goto, H. et al. (2010) A protein deacetylase SIRT1 is a negative regulator of metalloproteinase-9. J. Biol. Chem. 285, 7097-7110.
53. Kawahara, T. L., Michishita, E., Adler, A. S., Damian, M., Berber, E., Lin, M., McCord, R. A., Ongaigui, K. C., Boxer, L. D., Chang, H. Y. and Chua, K. F. (2009) SIRT6 links histone H3 lysine 9 deacetylation to NF-κBdependent gene expression and organismal life span. Cell 136, 62-74.
54. Sequeira, J., Boily, G., Bazinet, S., Saliba, S., He, X., Jardine, K., Kennedy, C., Staines, W., Rousseaux, C., Mueller, R. and McBurney, M.W. (2008) sirt1-null mice develop an autoimmune-like condition. Exp. Cell Res. 314, 3069-3074.
55. Zhang, J., Lee, S. M., Shannon, S., Gao, B., Chen, W., Chen, A., Divekar, R., McBurney, M. W., Braley-Mullen, H., Zaghouani, H. and Fang, D. (2009) The type III histone deacetylase Sirt1 is essential for maintenance of T cell tolerance in mice. J. Clin. Invest. 119, 3048-3058.
56. Zhang, R., Chen, H. Z., Liu, J. J., Jia, Y. Y., Zhang, Z. Q., Yang, R. F., Zhang, Y., Xu, J., Wei, Y. S., Liu, D. P. and Liang, C. C. (2010) SIRT1 suppresses activator protein-1 transcriptional activity and cyclooxygenase-2 expression in macrophages. J. Biol. Chem. 285, 7097-7110.
57. Yoshizaki, T., Schenk, S., Imamura, T., Babendure, J. L., Sonoda, N., Bae, E. J., Oh, D. Y., Lu, M., Milne, J. C. and Westphal, C. (2010) SIRT1 inhibits inflammatory pathways in macrophages and modulates insulin sensitivity. Am. J. Physiol. Endocrinol. Metab. 298, E419-E428.
58. Yang, Z., Kahn, B. B., Shi, H. and Xue, B. Z. (2010) Macrophage α1 AMP-activated protein kinase (α1AMPK) antagonizes fatty acid-induced inflammation through SIRT1. J. Biol. Chem. 285, 19051-19059.
59. Schug, T. T., Xu, Q., Gao, H., Peres-da-Silva, A., Draper, D. W., Fessler, M. B., Purushotham, A. and Li, X. (2010) Myeloid deletion of SIRT1 induces inflammatory signaling in response to environmental stress. Mol. Cell. Biol. 30, 4712-4721.
60. Li, J., Qu, X., Ricardo, S. D., Bertram, J. F. and Nikolic-Paterson, D. J. (2010) Resveratrol inhibits renal fibrosis in the obstructed kidney: potential role in deacetylation of Smad3. Am. J. Pathol. 177, 1065-1071.
61. Nie, Y., Erion, D. M., Yuan, Z., Dietrich, M., Shulman, G. I., Horvath, T. L. and Gao, Q. (2009) STAT3 inhibition of gluconeogenesis is downregulated by SirT1. Nat. Cell Biol. 11, 492-500.
62. Hou, X., Xu, S., Maitland-Toolan, K. A., Sato, K., Jiang, B., Ido, Y., Lan, F., Walsh, K., Wierzbicki, M., Verbeuren, T. J. et al. (2008) SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase. J. Biol. Chem. 283, 20015-20026.
63. Lan, F., Cacicedo, J. M., Ruderman, N. and 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, 27628-27635.
64. Pillai, V. B., Sundaresan, N. R., Kim, G., Gupta, M., Rajamohan, S. B., Pillai, J. B., Samant, S., Ravindra, P. V., Isbatan, A. and Gupta, M. P. (2010) Exogenous NAD blocks cardiac hypertrophic response via activation of the SIRT3-LKB1-AMP-activated kinase pathway. J. Biol. Chem. 285, 3133-3144.
65. 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.
66. Revollo, J. R., Grimm, A. A. and Imai, S. (2004) The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltransferase regulates Sir2 activity in mammalian cells. J. Biol. Chem. 279, 50754-50763.
67. + metabolism and SIRT1 activity. Nature 458, 1056-1060.
68. 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, 661-673.
69. + biosynthesis. Science 324, 651-654.
70. + salvage pathway by CLOCK-SIRT1. Science 324, 654-657.
71. Vaquero, A., Scher, M., Erdjument-Bromage, H., Tempst, P., Serrano, L. and Reinberg, D. (2007) SIRT1 regulates the histone methyl-transferase SUV39H1 during heterochromatin formation. Nature 450, 440-444.
72. Murayama, A., Ohmori, K., Fujimura, A., Minami, H., Yasuzawa-Tanaka, K., Kuroda, T., Oie, S., Daitoku, H., Okuwaki, M., Nagata, K. et al. (2008) Epigenetic control of rDNA loci in response to intracellular energy status. Cell 133, 627-639.
73. 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.
74. 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.
75. Frescas, D., Valenti, L. and Accili, D. (2005) Nuclear trapping of the forkhead transcription factor FoxO1 via Sirt-dependent deacetylation promotes expression of glucogenetic genes. J. Biol. Chem. 280, 20589-20595.
76. Kelly, T. J., Lerin, C., Haas,W., Gygi, S. P. and Puigserver, P. (2009) GCN5-mediated transcriptional control of the metabolic coactivator PGC-1β through lysine acetylation. J. Biol. Chem. 284, 19945-19952.
77. Sun, C., Zhang, F., Ge, X., Yan, T., Chen, X., Shi, X. and Zhai, Q. (2007) SIRT1 improves insulin sensitivity under insulin-resistant conditions by repressing PTP1B. Cell Metab. 6, 307-319.
78. Lim, J. H., Lee, Y. M., Chun, Y. S., Chen, J., Kim, J. E. and Park, J.W. (2010) Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1α. Mol. Cell 38, 864-878.
79. Zhong, L., D'Urso, A., Toiber, D., Sebastian, C., Henry, R. E., Vadysirisack, D. D., Guimaraes, A., Marinelli, B., Wikstrom, J. D., Nir, T. et al. (2010) The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1α. Cell 140, 280-293.
80. Dioum, E. M., Chen, R., Alexander, M. S., Zhang, Q., Hogg, R. T., Gerard, R. D. and Garcia, J. A. (2009) Regulation of hypoxia-inducible factor 2α signaling by the stress-responsive deacetylase sirtuin 1. Science 324, 1289-1293.
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-1α. EMBO J. 26, 1913-1923.
82. 2+ and AMPK/SIRT1. Nature 464, 1313-1319.
83. Chau, M. D., Gao, J., Yang, Q., Wu, Z. and Gromada, J. (2010) Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK-SIRT1-PGC-1α pathway. Proc. Natl. Acad. Sci. U.S.A. 107, 12553-12558.
84. 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.
85. 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.
86. Ahn, B. H., Kim, H. S., Song, S., Lee, I. H., Liu, J., Vassilopoulos, A., Deng, C. X. and Finkel, T. (2008) A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proc. Natl. Acad. Sci. U.S.A. 105, 14447-14452.
87. Cimen, H., Han, M. J., Yang, Y., Tong, Q., Koc, H. and Koc, E. C. (2010) Regulation of succinate dehydrogenase activity by SIRT3 in mammalian mitochondria. Biochemistry 49, 304-311.
88. 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. et al. (2006) SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic β cells. Cell 126, 941-954.
89. Nakagawa, T., Lomb, D. J., Haigis, M. C. and Guarente, L. (2009) SIRT5 Deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle. Cell 137, 560-570.
90. 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-γ. Nature 429, 771-776.
91. Purushotham, A., Schug, T. T., Xu, Q., Surapureddi, S., Guo, X. and Li, X. (2009) Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metab. 9, 327-338.
92. 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, 91-106.
93. Kemper, J. K., Xiao, Z., Ponugoti, B., Miao, J., Fang, S., Kanamaluru, D., Tsang, S., Wu, S. Y., Chiang, C. M. and Veenstra, T. D. (2009) FXR acetylation is normally dynamically regulated by p300 and SIRT1 but constitutively elevated in metabolic disease states. Cell Metab. 10, 392-404.
94. Walker, A. K., Yang, F., Jiang, K., Ji, J. Y., Watts, J. L., Purushotham, A., Boss, O., Hirsch, M. L., Ribich, S., Smith, J. J. et al. (2010) Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP. Genes Dev. 24, 1403-1417.
95. Hirschey, M. D., Shimazu, T., Goetzman, E., Jing, E., Schwer, B., Lombard, D. B., Grueter, C. A., Harris, C., Biddinger, S., Ilkayeva, O. R. et al. (2010) SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 464, 121-125.
96. Li, K., Casta, A., Wang, R., Lozada, E., Fan, W., Kane, S., Ge, Q., Gu, W., Orren, D. and Luo, J. (2008) Regulation of WRN protein cellular localization and enzymatic activities by SIRT1-mediated deacetylation. J. Biol. Chem. 283, 7590-7598.
97. 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. et al. (2006) Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 124, 315-329.
98. Michishita, E., McCord, R. A., Berber, E., Kioi, M., Padilla-Nash, H., Damian, M., Cheung, P., Kusumoto, R., Kawahara, T. L., Barrett, J. C. et al. (2008) SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin. Nature 452, 492-496.
99. Yuan, Z., Zhang, X., Sengupta, N., Lane, W. S. and Seto, E. (2007) SIRT1 regulates the function of the Nijmegen breakage syndrome protein. Mol. Cell 27, 149-162.
100. Kaidi, A.,Weinert, B. T., Choudhary, C. and Jackson, S. P. (2010) Human SIRT6 promotes DNA end resection through CtIP deacetylation. Science 329, 1348-1353.
101. Firestein, R., Blander, G., Michan, S., Oberdoerffer, P., Ogino, S., Campbell, J., Bhimavarapu, A., Luikenhuis, S., de Cabo, R., Fuchs, C. et al. (2008) The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth. PLoS ONE 3, e2020.
102. Wang, R. H., Zheng, Y., Kim, H. S.,Xu, X.,Cao, L., Luhasen, T., Lee, M. H., Xiao, C., Vassilopoulos, A., Chen, W. et al. (2008) Interplay among BRCA1, SIRT1, and Survivin during BRCA1-associated tumorigenesis. Mol. Cell 32, 11-20.
103. Ford, J., Jiang, M. and Milner, J. (2005) Cancer-specific functions of SIRT1 enable human epithelial cancer cell growth and survival. Cancer Res. 65, 10457-10463.
104. Ota, H., Tokunaga, E., Chang, K., Hikasa, M., Iijima, K., Eto, M., Kozaki, K., Akishita, M., Ouchi, Y. and Kaneki, M. (2006) Sirt1 inhibitor, Sirtinol, induces senescence-like growth arrest with attenuated Ras-MAPK signaling in human cancer cells. Oncogene 25, 176-185.
105. Chen, W. Y., Wang, D. H., Yen, R. C., Luo, J., Gu, W. and Baylin, S. B. (2005) Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNAdamage responses. Cell 123, 437-448.
106. 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.
107. McBurney, M.W., Yang, X., Jardine, K., Hixon, M., Boekelheide, K., Webb, J. R., Lansdorp, P. M. and Lemieux, M. (2003) The mammalian SIR2α protein has a role in embryogenesis and gametogenesis. Mol. Cell. Biol. 23, 38-54.
108. 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. U.S.A. 100, 10794-10799.
109. Sakamoto, J., Miura, T., Shimamoto, K. and Horio, Y. (2004) Predominant expression of Sir2α, an NAD-dependent histone deacetylase, in the embryonic mouse heart and brain. FEBS Lett. 556, 281-286.
110. Hisahara, S., Chiba, S., Matsumoto, H., Tanno, M., Yagi, H., Shimohama, S., Sato, M. and Horio, Y. (2008) Histone deacetylase SIRT1 modulates neuronal differentiation by its nuclear translocation. Proc. Natl. Acad. Sci. U.S.A. 105, 15599-15604.
111. Fortini, M. E. (2009) Notch signaling: the core pathway and its posttranslational regulation. Dev. Cell 16, 633-647.
112. Prozorovski, T., Schulze-Topphoff, U., Glumm, R., Baumgart, J., Schröter, F., Ninnemann, O., Siegert, E., Bendix, I., Brüstle, O. and Nitsch, R. et al. (2008) Sirt1 contributes critically to the redox-dependent fate of neural progenitors. Nat. Cell Biol. 10, 385-394.
113. Ramadori, G., Lee, C. E., Bookout, A. L., Lee, S., Williams, K. W., Anderson, J., Elmquist, J. K. and Coppari, R. (2008) Brain SIRT1: anatomical distribution and regulation by energy availability. J. Neurosci. 28, 9989-9996.
114. Qin, W., Yang, T., Ho, L., Zhao, Z.,Wang, J., Chen, L., Zhao, W., Thiyagarajan, M., MacGrogan, D., Rodgers, J. T. 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, 21745-21754.
115. Donmez, G., Wang, D., Cohen, D. E. and Guarente, L. (2010) SIRT1 suppresses β-amyloid production by activating the α-secretase gene ADAM10. Cell 142, 320-332.
116. Mich́an, S., Li, Y., Chou, M. M., Parrella, E., Ge, H., Long, J. M., Allard, J. S., Lewis, K., Miller, M., Xu, W. et al. (2010) SIRT1 is essential for normal cognitive function and synaptic plasticity. J. Neurosci. 30, 9695-9707.
117. Sugino, T., Maruyama, M., Tanno, M., Kuno, A., Houkin, K. and Horio, Y. (2010) Protein deacetylase SIRT1 in the cytoplasm promotes nerve growth factor-induced neurite outgrowth in PC12 cells. FEBS Lett. 584, 2821-2826.
118. Gao, J., Wang,W. Y., Mao, Y. W.,Gräff, J., Guan, J. S., Pan, L., Mak, G., Kim, D., Su, S. C. and Tsai, L. H. (2010) A novel pathway regulates memory and plasticity via SIRT1 and miR-134. Nature 466, 1105-1109.
119. Cakir, I., Perello, M., Lansari, O.,Messier, N. J., Vaslet, C. A. and Nillni, E. A. (2009) Hypothalamic Sirt1 regulates food intake in a rodent model system. PLoS ONE 4, e8322.
120. Dietrich, M. O., Antunes, C., Geliang, G., Liu, Z. W., Borok, E., Nie, Y., Xu, A. W., Souza, D. O., Gao, Q., Diano, S. et al. (2010) Agrp neurons mediate Sirt1's action on the melanocortin system and energy balance: roles for Sirt1 in neuronal firing and synaptic plasticity. J. Neurosci. 30, 11815-11825.
121. Pandithage, R., Lilischkis, R., Harting, K., Wolf, A., Jedamzik, B., Lüscher-Firzlaff, J., Vervoorts, J., Lasonder, E., Kremmer, E., Knöll, B. and Lüscher, B. (2008) The regulation of SIRT2 function by cyclindependent kinases affects cell motility. J. Cell Biol. 180, 915-929.
122. Potente, M., Ghaeni, L., Baldessari, D., Mostoslavsky, R., Rossig, L., Dequiedt, F., Haendeler, J., Mione, M., Dejana, E., Alt, F. W. et al. (2007) SIRT1 controls endothelial angiogenic functions during vascular growth. Genes Dev 21, 2644-2658.
123. Zhang, Y., Zhang, M., Dong, H., Yong, S., Li, X., Olashaw, N., Kruk, P. A., Cheng, J. Q., Bai, W. and Chen, J. et al. (2009) Deacetylation of cortactin by SIRT1 promotes cell migration. Oncogene 28, 445-460.
124. Renaud, S. and de Lorgeril, M. (1992)Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet 339, 1523-1526.
125. 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. et al. (1997) Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275, 218-220.
126. Pacholec, M., Bleasdale, J. E., Chrunyk, B., Cunningham, D., Flynn, D., Garofalo, R. S., Griffith, D., Griffor, M., Loulakis, P., Pabst, B. et al. (2010) SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1. J. Biol. Chem. 285, 8340-8351.
127. 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. et al. (2003) Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425, 191-196.
128. Su, H. C., Hung, L. M. and Chen, J. K. (2006) Resveratrol, a red wine antioxidant, possesses an insulin-like effect in streptozotocin-induced diabetic rats. Am. J. Physiol. Endocrinol. Metab. 290, E1339-E1346.
129. Lagouge, M., Argmann, C., Gerhart-Hines, Z., Meziane, H., Lerin, C., Daussin, F., Messadeq, N., Milne, J., Lambert, P., Elliott, P. et al. (2006) Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell 127, 1109-1122.
130. 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. et al. (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444, 337-342.
131. 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. et al. (2008) Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab. 8, 157-168.
132. Wang, R. H., Zheng, Y., Kim, H. S.,Xu, X.,Cao, L., Luhasen, T., Lee, M. H., Xiao, C., Vassilopoulos, A., Chen, W. et al. (2008) Interplay among BRCA1, SIRT1, and Survivin during BRCA1-associated tumorigenesis. Mol. Cell 32, 11-20.
133. Kubota, S., Kurihara, T., Ebinuma, M., Kubota, M., Yuki, K., Sasaki, M., Noda, K., Ozawa, Y., Oike, Y., Ishida, S. and Tsubota, K. (2010) Resveratrol prevents light-induced retinal degeneration via suppressing activator protein-1 activation. Am. J. Pathol. 177, 1725-1731.
134. Dai, H., Kustigian, L., Carney, D., Case, A., Considine, T., Hubbard, B. P., Perni, R. B., Riera, T. V., Szczepankiewicz, B., Vlasuk, G. P. and Stein, R. L. (2010) SIRT1 activation by small molecules: kinetic and biophysical evidence for direct interaction of enzyme and activator. J. Biol. Chem. 285, 32695-326703.