Cellular and Molecular Neurobiology

, Volume 29, Issue 8, pp 1093–1103 | Cite as

Sirt1’s Complex Roles in Neuroprotection

Commentary

Abstract

The nicotinamide adenine dinucleotide (NAD)-activated protein deacetylase Sir2p/Sirt1 has been strongly implicated in the modulation of replicative lifespan and promotion of longevity. Part of Sirt1’s capacity for lifespan extension in complex organisms may be attributed to its protective activity against neuronal degeneration. Manipulation of Sirt1’s activity or levels by pharmacological and genetic means in several models of neurodegenerative diseases demonstrated its neuroprotective credentials. However, recent data have indicated that under certain contexts, Sirt1 inhibition, rather than activation, is neuroprotective. These inconsistencies highlight the complex nature of Sirt1-mediated effects. The enzyme has both histone and nonhistone targets, and could potentially act in both nuclear and cytoplasmic compartments. These activities intertwine in a manner depending on the context of a system under investigation. One needs to be cautious in extrapolating results derived from short-term observations to a longer-term context, and in assessing efficacies of Sirt1-based therapeutic approaches in treating neurodegenerative diseases.

Keywords

Neuron Neuroprotection Resveratrol Sirt1 Sirtuin 

References

  1. Ahn BH, Kim HS, Song S, Lee IH, Liu J, Vassilopoulos A, Deng CX, Finkel T (2008) A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proc Natl Acad Sci USA 105:14447–14452. doi:10.1073/pnas.0803790105 PubMedGoogle Scholar
  2. Alvira D, Yeste-Velasco M, Folch J, Verdaguer E, Canudas AM, Pallàs M, Camins A (2007) Comparative analysis of the effects of resveratrol in two apoptotic models: inhibition of complex I and potassium deprivation in cerebellar neurons. Neuroscience 147:746–756. doi:10.1016/j.neuroscience.2007.04.029 PubMedGoogle Scholar
  3. Anastasiou D, Krek W (2006) SIRT1: linking adaptive cellular responses to aging-associated changes in organismal physiology. Physiology (Bethesda) 21:404–410. doi:10.1152/physiol.00031.2006 Google Scholar
  4. Anderson RM, Bitterman KJ, Wood JG, Medvedik O, Sinclair DA (2003) Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiae. Nature 423:181–185. doi:10.1038/nature01578 PubMedGoogle Scholar
  5. Anekonda TS (2006) Resveratrol—a boon for treating Alzheimer’s disease? Brain Res Brain Res Rev 52:316–326. doi:10.1016/j.brainresrev.2006.04.004 Google Scholar
  6. Anekonda TS, Reddy PH (2006) Neuronal protection by sirtuins in Alzheimer’s disease. J Neurochem 96:305–313. doi:10.1111/j.1471-4159.2005.03492.x PubMedGoogle Scholar
  7. Araki T, Sasaki Y, Milbrandt J (2004) Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration. Science 305:1010–1013. doi:10.1126/science.1098014 PubMedGoogle Scholar
  8. Avery MA, Sheehan AE, Kerr KS, Wang J, Freeman MR (2009) Wlds requires Nmnat1 enzymatic activity and N16-VCP interactions to suppress Wallerian degeneration. J Cell Biol 184:501–513. doi:10.1083/jcb.200808042 Google Scholar
  9. Banks AS, Kon N, Knight C, Matsumoto M, Gutiérrez-Juárez R, Rossetti L, Gu W, Accili D (2008) SirT1 gain of function increases energy efficiency and prevents diabetes in mice. Cell Metab 8:333–341. doi:10.1016/j.cmet.2008.08.014 PubMedGoogle Scholar
  10. Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, De Cabo R, Sinclair DA (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444:337–342. doi:10.1038/nature05354 PubMedGoogle Scholar
  11. Blander G, Guarente L (2004) The Sir2 family of protein deacetylases. Annu Rev Biochem 73:417–435. doi:10.1146/annurev.biochem.73.011303.073651 PubMedGoogle Scholar
  12. Bordone L, Guarente L (2005) Calorie restriction, SIRT1 and metabolism: understanding longevity. Nat Rev Mol Cell Biol 6:298–305. doi:10.1038/nrm1616 PubMedGoogle Scholar
  13. Bordone L, Cohen D, Robinson A, Motta MC, van Veen E, Czopik A, Steele AD, Crowe H, Marmor S, Luo J, Gu W, Guarente L (2007) SIRT1 transgenic mice show phenotypes resembling calorie restriction. Aging Cell 6:759–767. doi:10.1111/j.1474-9726.2007.00335.x PubMedGoogle Scholar
  14. Borrell-Pages M, Zala D, Humbert S, Saudou F (2006) Huntington’s disease: from huntingtin function and dysfunction to therapeutic strategies. Cell Mol Life Sci 63:2642–2660. doi:10.1007/s00018-006-6242-0 PubMedGoogle Scholar
  15. Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y, Tran H, Ross SE, Mostoslavsky R, Cohen HY, Hu LS, Cheng HL, Jedrychowski MP, Gygi SP, Sinclair DA, Alt FW, Greenberg ME (2004) Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303:2011–2015. doi:10.1126/science.1094637 PubMedGoogle Scholar
  16. Chao J, Yu MS, Ho YS, Wang M, Chang RC (2008) Dietary oxyresveratrol prevents parkinsonian mimetic 6-hydroxydopamine neurotoxicity. Free Radic Biol Med 45:1019–1026. doi:10.1016/j.freeradbiomed.2008.07.002 PubMedGoogle Scholar
  17. Chen D, Steele AD, Lindquist S, Guarente L (2005a) Increase in activity during calorie restriction requires Sirt1. Science 310:1641. doi:10.1126/science.1118357 PubMedGoogle Scholar
  18. Chen J, Zhou Y, Mueller-Steiner S, Chen LF, Kwon H, Yi S, Mucke L, Gan L (2005b) SIRT1 protects against microglia-dependent amyloid-beta toxicity through inhibiting NF-κB signaling. J Biol Chem 280:40364–40374. doi:10.1074/jbc.M509329200 PubMedGoogle Scholar
  19. Chen WY, Wang DH, Yen RC, Luo J, Gu W, Baylin SB (2005c) Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses. Cell 123:437–448. doi:10.1016/j.cell.2005.08.011 PubMedGoogle Scholar
  20. Chen D, Bruno J, Easlon E, Lin SJ, Cheng HL, Alt FW, Guarente L (2008) Tissue-specific regulation of SIRT1 by calorie restriction. Genes Dev 22:1753–1757. doi:10.1101/gad.1650608 PubMedGoogle Scholar
  21. Cheng HL, Mostoslavsky R, Saito S, Manis JP, Gu Y, Patel P, Bronson R, Appella E, Alt FW, Chua KF (2003) Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice. Proc Natl Acad Sci USA 100:10794–10799. doi:10.1073/pnas.1934713100 PubMedGoogle Scholar
  22. Chong ZZ, Lin SH, Li F, 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. doi:10.2174/156720205774322584 PubMedGoogle Scholar
  23. Chua KF, Mostoslavsky R, Lombard DB, Pang WW, Saito S, Franco S, Kaushal D, Cheng HL, Fischer MR, Stokes N, Murphy MM, Appella E, Alt FW (2005) Mammalian SIRT1 limits replicative life span in response to chronic genotoxic stress. Cell Metab 2:67–76. doi:10.1016/j.cmet.2005.06.007 PubMedGoogle Scholar
  24. Cohen HY, Lavu S, Bitterman KJ, Hekking B, Imahiyerobo TA, Miller C, Frye R, Ploegh H, Kessler BM, Sinclair DA (2004a) Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis. Mol Cell 13:627–638. doi:10.1016/S1097-2765(04)00094-2 PubMedGoogle Scholar
  25. Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, Howitz KT, Gorospe M, de Cabo R, Sinclair DA (2004b) Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 305:390–392. doi:10.1126/science.1099196 PubMedGoogle Scholar
  26. Coleman MP, Perry VH (2002) Axon pathology in neurological disease: a neglected therapeutic target. Trends Neurosci 25:532–537. doi:10.1016/S0166-2236(02)02255-5 PubMedGoogle Scholar
  27. Conforti L, Fang G, Beirowski B, Wang MS, Sorci L, Asress S, Adalbert R, Silva A, Bridge K, Huang XP, Magni G, Glass JD, Coleman MP (2007) NAD+ and axon degeneration revisited: Nmnat1 cannot substitute for Wlds to delay Wallerian degeneration. Cell Death Differ 14:116–127. doi:10.1038/sj.cdd.4401944 PubMedGoogle Scholar
  28. Conforti L, Wilbrey A, Morreale G, Janeckova L, Beirowski B, Adalbert R, Mazzola F, Di Stefano M, Hartley R, Babetto E, Smith T, Gilley J, Billington RA, Genazzani AA, Ribchester RR, Magni G, Coleman M (2009) WldS protein requires Nmnat activity and a short N-terminal sequence to protect axons in mice. J Cell Biol 184:491–500. doi:10.1083/jcb.200807175 PubMedGoogle Scholar
  29. Daitoku H, Hatta M, Matsuzaki H, Aratani S, Ohshima T, Miyagishi M, Nakajima T, Fukamizu A (2004) Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. Proc Natl Acad Sci USA 101:10042–10047. doi:10.1073/pnas.0400593101 PubMedGoogle Scholar
  30. Denu JM (2005) The Sir 2 family of protein deacetylases. Curr Opin Chem Biol 9:431–440. doi:10.1016/j.cbpa.2005.08.010 PubMedGoogle Scholar
  31. Fabrizio P, Gattazzo C, Battistella L, Wei M, Cheng C, McGrew K, Longo VD (2005) Sir2 blocks extreme life-span extension. Cell 123:655–667. doi:10.1016/j.cell.2005.08.042 PubMedGoogle Scholar
  32. Fainzilber M, Twiss JL (2006) Tracking in the Wlds-the hunting of the SIRT and the luring of the Draper. Neuron 50:819–821. doi:10.1016/j.neuron.2006.05.023 PubMedGoogle Scholar
  33. Fan E, Jiang S, Zhang L, Bai Y (2008) Molecular mechanism of apoptosis induction by resveratrol, a natural cancer chemopreventive agent. Int J Vitam Nutr Res 78:3–8. doi:10.1024/0300-9831.78.1.3 PubMedGoogle Scholar
  34. Filomeni G, Graziani I, Rotilio G, Ciriolo MR (2007) Trans-Resveratrol induces apoptosis in human breast cancer cells MCF-7 by the activation of MAP kinases pathways. Genes Nutr 2:295–305. doi:10.1007/s12263-007-0059-9 PubMedGoogle Scholar
  35. Firestein R, Blander G, Michan S, Oberdoerffer P, Ogino S, Campbell J, Bhimavarapu A, Luikenhuis S, de Cabo R, Fuchs C, Hahn WC, Guarente LP, Sinclair DA (2008) The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth. PLoS ONE 3:E2020. doi:10.1371/journal.pone.0002020 PubMedGoogle Scholar
  36. Fontana L, Weiss EP, Villareal DT, Klein S, Holloszy JO (2008) Long-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3 concentration in humans. Aging Cell 7:681–687. doi:10.1111/j.1474-9726.2008.00417.x PubMedGoogle Scholar
  37. Gan L, Mucke L (2008) Paths of convergence: sirtuins in aging and neurodegeneration. Neuron 58:10–14. doi:10.1016/j.neuron.2008.03.015 PubMedGoogle Scholar
  38. Giannakou ME, Partridge L (2004) The interaction between FOXO and SIRT1: tipping the balance towards survival. Trends Cell Biol 14:408–412. doi:10.1016/j.tcb.2004.07.006 PubMedGoogle Scholar
  39. Griswold AJ, Chang KT, Runko AP, Knight MA, Min KT (2008) Sir2 mediates apoptosis through JNK-dependent pathways in Drosophila. Proc Natl Acad Sci USA 105:8673–8678. doi:10.1073/pnas.0803837105 PubMedGoogle Scholar
  40. Guarente LP (2006) Sirtuins as potential targets for metabolic syndrome. Nature 444:868–874. doi:10.1038/nature05486 PubMedGoogle Scholar
  41. Haigis MC, Guarente LP (2006) Mammalian sirtuins—emerging roles in physiology, aging, and calorie restriction. Genes Dev 20:2913–2921. doi:10.1101/gad.1467506 PubMedGoogle Scholar
  42. Han MK, Song EK, Guo Y, Ou X, Mantel C, Broxmeyer HE (2008) SIRT1 regulates apoptosis and Nanog expression in mouse embryonic stem cells by controlling p53 subcellular localization. Cell Stem Cell 2:241–251. doi:10.1016/j.stem.2008.01.002 PubMedGoogle Scholar
  43. Hasegawa K, Yoshikawa K (2008) Necdin regulates p53 acetylation via Sirtuin1 to modulate DNA damage response in cortical neurons. J Neurosci 28:8772–8784. doi:10.1523/JNEUROSCI.3052-08.2008 PubMedGoogle Scholar
  44. Hisahara S, Chiba S, Matsumoto H, Tanno M, Yagi H, Shimohama S, Sato M, Horio Y (2008) Histone deacetylase SIRT1 modulates neuronal differentiation by its nuclear translocation. Proc Natl Acad Sci USA 105:15599–15604. doi:10.1073/pnas.0800612105 PubMedGoogle Scholar
  45. Holzenberger M, Dupont J, Ducos B, Leneuve P, Geloen A, Even PC, Cervera P, Le Bouc Y (2003) IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421:182–187. doi:10.1038/nature01298 PubMedGoogle Scholar
  46. Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA (2003) Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425:191–196. doi:10.1038/nature01960 PubMedGoogle Scholar
  47. Huffman DM, Grizzle WE, Bamman MM, Kim JS, Eltoum IA, Elgavish A, Nagy TR (2007) SIRT1 is significantly elevated in mouse and human prostate cancer. Cancer Res 67:6612–6618. doi:10.1158/0008-5472.CAN-07-0085 PubMedGoogle Scholar
  48. Hwang JT, Kwon DY, Park OJ, Kim MS (2008) Resveratrol protects ROS-induced cell death by activating AMPK in H9c2 cardiac muscle cells. Genes Nutr 2:323–326. doi:10.1007/s12263-007-0069-7 PubMedGoogle Scholar
  49. Jung-Hynes B, Nihal M, Zhong W, Ahmad N (2009) Role of sirtuin histone deacetylase Sirt1 in prostate cancer: a target for prostate cancer management via its inhibition? J Biol Chem (in press)Google Scholar
  50. 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 13:2570–2580. doi:10.1101/gad.13.19.2570 PubMedGoogle Scholar
  51. Kaeberlein M, Kirkland KT, Fields S, Kennedy BK (2004) Sir2-independent life span extension by calorie restriction in yeast. PLoS Biol 2:E296. doi:10.1371/journal.pbio.0020296 PubMedGoogle Scholar
  52. Kaeberlein M, Hu D, Kerr EO, Tsuchiya M, Westman EA, Dang N, Fields S, Kennedy BK (2005a) Increased life span due to calorie restriction in respiratory-deficient yeast. PLoS Genet 1:E69. doi:10.1371/journal.pgen.0010069 PubMedGoogle Scholar
  53. Kaeberlein M, Powers RW 3rd, Steffen KK, Westman EA, Hu D, Dang N, Kerr EO, Kirkland KT, Fields S, Kennedy BK (2005b) Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 310:1193–1196. doi:10.1126/science.1115535 PubMedGoogle Scholar
  54. Kaplan S, Bisleri G, Morgan JA, Cheema FH, Oz MC (2005) Resveratrol, a natural red wine polyphenol, reduces ischemia-reperfusion-induced spinal cord injury. Ann Thorac Surg 80:2242–2249. doi:10.1016/j.athoracsur.2005.05.016 PubMedGoogle Scholar
  55. Kim D, Nguyen MD, Dobbin MM, Fischer A, Sananbenesi F, Rodgers JT, Delalle I, Baur JA, Sui G, Armour SM, Puigserver P, Sinclair DA, Tsai LH (2007) SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer’s disease and amyotrophic lateral sclerosis. EMBO J 26:3169–3179. doi:10.1038/sj.emboj.7601758 PubMedGoogle Scholar
  56. Kimura KD, Tissenbaum HA, Liu Y, Ruvkun G (1997) daf-2, an insulin receptor like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 277:942–946. doi:10.1126/science.277.5328.942 PubMedGoogle Scholar
  57. Kiziltepe U, Turan NN, Han U, Ulus AT, Akar F (2004) Resveratrol, a red wine polyphenol, protects spinal cord from ischemia-reperfusion injury. J Vasc Surg 40:138–145. doi:10.1016/j.jvs.2004.03.032 PubMedGoogle Scholar
  58. Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P, Geny B, Laakso M, Puigserver P, Auwerx J (2006) Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell 127:1109–1122. doi:10.1016/j.cell.2006.11.013 PubMedGoogle Scholar
  59. Lam EW, Francis RE, Petkovic M (2006) FOXO transcription factors: key regulators of cell fate. Biochem Soc Trans 34:722–726. doi:10.1042/BST0340722 PubMedGoogle Scholar
  60. Lamming DW, Latorre-Esteves M, Medvedik O, Wong SN, Tsang FA, Wang C, Lin SJ, Sinclair DA (2005) HST2 mediates SIR2-independent life-span extension by calorie restriction. Science 309:1861–1864. doi:10.1126/science.1113611 PubMedGoogle Scholar
  61. Li W, Zhang B, Tang J, Cao Q, Wu Y, Wu C, Guo J, Ling EA, 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 α-tubulin. J Neurosci 27:2606–2616. doi:10.1523/JNEUROSCI.4181-06.2007 PubMedGoogle Scholar
  62. Li Y, Xu W, McBurney MW, Longo VD (2008) SirT1 inhibition reduces IGF-I/IRS-2/Ras/ERK1/2 signaling and protects neurons. Cell Metab 8:38–48. doi:10.1016/j.cmet.2008.05.004 PubMedGoogle Scholar
  63. Lin SJ, Defossez PA, Guarente L (2000) Requirement of NAD and SIR2 for life span extension by calorie restriction in Saccharomyces cerevisiae. Science 289:2126–2128. doi:10.1126/science.289.5487.2126 PubMedGoogle Scholar
  64. Longo VD (2009) Linking sirtuins, IGF-I signaling, and starvation. Exp Gerontol 44:70–74. doi:10.1016/j.exger.2008.06.005 PubMedGoogle Scholar
  65. Longo VD, Kennedy BK (2006) Sirtuins in aging and age-related disease. Cell 126:257–268. doi:10.1016/j.cell.2006.07.002 PubMedGoogle Scholar
  66. Luo J, Nikolaev AY, Imai S, Chen D, Su F, Shiloh A, Guarente L, Gu W (2001) Negative control of p53 by Sir2α promotes cell survival under stress. Cell 107:137–148. doi:10.1016/S0092-8674(01)00524-4 PubMedGoogle Scholar
  67. Markus MA, Morris BJ (2008) Resveratrol in prevention and treatment of common clinical conditions of aging. Clin Interv Aging 3:331–339PubMedGoogle Scholar
  68. Masoro EJ (2005) Overview of caloric restriction and ageing. Mech Ageing Dev 126:913–922. doi:10.1016/j.mad.2005.03.012 PubMedGoogle Scholar
  69. McBurney MW, Yang X, Jardine K, Hixon M, Boekelheide K, Webb JR, Lansdorp PM, Lemieux M (2003) The mammalian SIR2alpha protein has a role in embryogenesis and gametogenesis. Mol Cell Biol 23:38–54. doi:10.1128/MCB.23.1.38-54.2003 PubMedGoogle Scholar
  70. Michishita E, Park JY, Burneskis JM, Barrett JC, Horikawa I (2005) Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. Mol Biol Cell 16:4623–4635. doi:10.1091/mbc.E05-01-0033 PubMedGoogle Scholar
  71. Milne JC, Lambert PD, Schenk S, Carney DP, Smith JJ, Gagne DJ, Jin L, Boss O, Perni RB, Vu CB, Bemis JE, Xie R, Disch JS, Ng PY, Nunes JJ, Lynch AV, Yang H, Galonek H, Israelian K, Choy W, Iffland A, Lavu S, Medvedik O, Sinclair DA, Olefsky JM, Jirousek MR, Elliott PJ, Westphal CH (2007) Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 450:712–716. doi:10.1038/nature06261 PubMedGoogle Scholar
  72. Motta MC, Divecha N, Lemieux M, Kamel C, Chen D, Gu W, Bultsma Y, McBurney M, Guarente L (2004) Mammalian SIRT1 represses forkhead transcription factors. Cell 116:551–563. doi:10.1016/S0092-8674(04)00126-6 PubMedGoogle Scholar
  73. Nemoto S, Fergusson MM, Finkel T (2005) SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1α. J Biol Chem 280:16456–16460. doi:10.1074/jbc.M501485200 PubMedGoogle Scholar
  74. North BJ, Marshall BL, Borra MT, Denu JM, Verdin E (2003) The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Mol Cell 11:437–444. doi:10.1016/S1097-2765(03)00038-8 PubMedGoogle Scholar
  75. Oberdoerffer P, Michan S, McVay M, Mostoslavsky R, Vann J, Park SK, Hartlerode A, Stegmuller J, Hafner A, Loerch P, Wright SM, Mills KD, Bonni A, Yankner BA, Scully R, Prolla TA, Alt FW, Sinclair DA (2008) SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell 135:907–918. doi:10.1016/j.cell.2008.10.025 PubMedGoogle Scholar
  76. Okawara M, Katsuki H, Kurimoto E, Shibata H, Kume T, Akaike A (2007) Resveratrol protects dopaminergic neurons in midbrain slice culture from multiple insults. Biochem Pharmacol 73:550–560. doi:10.1016/j.bcp.2006.11.003 PubMedGoogle Scholar
  77. Ota H, Tokunaga E, Chang K, Hikasa M, Iijima K, Eto M, Kozaki K, Akishita M, Ouchi Y, Kaneki M (2006) Sirt1 inhibitor, Sirtinol, induces senescence-like growth arrest with attenuated Ras-MAPK signaling in human cancer cells. Oncogene 25:176–185PubMedGoogle Scholar
  78. Outeiro TF, Kontopoulos E, Altmann SM, Kufareva I, Strathearn KE, Amore AM, Volk CB, Maxwell MM, Rochet JC, McLean PJ, Young AB, Abagyan R, Feany MB, Hyman BT, Kazantsev AG (2007) Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson’s disease. Science 317:516–519. doi:10.1126/science.1143780 PubMedGoogle Scholar
  79. Outeiro TF, Marques O, Kazantsev A (2008) Therapeutic role of sirtuins in neurodegenerative disease. Biochim Biophys Acta 1782:363–369PubMedGoogle Scholar
  80. Pallos J, Bodai L, Lukacsovich T, Purcell JM, Steffan JS, Thompson LM, Marsh JL (2008) Inhibition of specific HDACs and sirtuins suppresses pathogenesis in a Drosophila model of Huntington’s disease. Hum Mol Genet 17:3767–3775. doi:10.1093/hmg/ddn273 PubMedGoogle Scholar
  81. Pandithage R, Lilischkis R, Harting K, Wolf A, Jedamzik B, Lüscher-Firzlaff J, Vervoorts J, Lasonder E, Kremmer E, Knöll B, Lüscher B (2008) The regulation of SIRT2 function by cyclin-dependent kinases affects cell motility. J Cell Biol 180:915–929. doi:10.1083/jcb.200707126 PubMedGoogle Scholar
  82. Patel NV, Gordon MN, Connor KE, Good RA, Engelman RW, Mason J, Morgan DG, Morgan TE, Finch CE (2005) Caloric restriction attenuates Aβ-deposition in Alzheimer transgenic models. Neurobiol Aging 26:995–1000. doi:10.1016/j.neurobiolaging.2004.09.014 PubMedGoogle Scholar
  83. Pedrini S, Carter TL, Prendergast G, Petanceska S, Ehrlich ME, Gandy S (2005) Modulation of statin-activated shedding of Alzheimer APP ectodomain by ROCK. PLoS Med 2:E18. doi:10.1371/journal.pmed.0020018 PubMedGoogle Scholar
  84. Perry VH, Lunn ER, Brown MC, Cahusac S, Gordon S (1990) Evidence that the rate of Wallerian degeneration is controlled by a single autosomal dominant gene. Eur J NeuroSci 2:408–413. doi:10.1111/j.1460-9568.1990.tb00433.x PubMedGoogle Scholar
  85. Pfister JA, Ma C, Morrison BE, D’Mello SR (2008) Opposing effects of sirtuins on neuronal survival: SIRT1-mediated neuroprotection is independent of its deacetylase activity. PLoS ONE 3:E4090. doi:10.1371/journal.pone.0004090 PubMedGoogle Scholar
  86. Picard F, Kurtev M, Chung N, Topark-Ngarm A, Senawong T, Machado De Oliveira R, Leid M, McBurney MW, Guarente L (2004) Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-γ. Nature 429:771–776. doi:10.1038/nature02583 PubMedGoogle Scholar
  87. Prozorovski T, Schulze-Topphoff U, Glumm R, Baumgart J, Schröter F, Ninnemann O, Siegert E, Bendix I, Brüstle O, Nitsch R, Zipp F, Aktas O (2008) Sirt1 contributes critically to the redox-dependent fate of neural progenitors. Nat Cell Biol 10:385–394. doi:10.1038/ncb1700 PubMedGoogle Scholar
  88. Qin W, Chachich M, Lane M, Roth G, Bryant M, De Cabo R, Ottinger MA, Mattison J, Ingram D, Gandy S, Pasinetti GM (2006a) Calorie restriction attenuates Alzheimer’s disease type brain amyloidosis in Squirrel monkeys (Saimiri sciureus). J Alzheimers Dis 10:417–422PubMedGoogle Scholar
  89. Qin W, Yang T, Ho L, Zhao Z, Wang J, Chen L, Zhao W, Thiyagarajan M, MacGrogan D, Rodgers JT, Puigserver P, Sadoshima J, Deng H, Pedrini S, Gandy S, Sauve AA, Pasinetti GM (2006b) Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction. J Biol Chem 281:21745–21754. doi:10.1074/jbc.M602909200 PubMedGoogle Scholar
  90. Qin W, Zhao W, Ho L, Wang J, Walsh K, Gandy S, Pasinetti GM (2008) Regulation of forkhead transcription factor FoxO3a contributes to calorie restriction-induced prevention of Alzheimer’s disease-type amyloid neuropathology and spatial memory deterioration. Ann N Y Acad Sci 1147:335–347PubMedCrossRefGoogle Scholar
  91. Ramadori G, Lee CE, Bookout AL, Lee S, Williams KW, Anderson J, Elmquist JK, Coppari R (2008) Brain SIRT1: anatomical distribution and regulation by energy availability. J Neurosci 28:9989–9996. doi:10.1523/JNEUROSCI.3257-08.2008 PubMedGoogle Scholar
  92. Raval AP, Dave KR, Perez-Pinzon MA (2006) Resveratrol mimics ischemic preconditioning in the brain. J Cereb Blood Flow Metab 26:1141–1147PubMedGoogle Scholar
  93. Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P (2005) Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature 434:113–118. doi:10.1038/nature03354 PubMedGoogle Scholar
  94. Rogina B, Helfand SL (2004) Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc Natl Acad Sci USA 101:15998–16003. doi:10.1073/pnas.0404184101 PubMedGoogle Scholar
  95. Sakamoto J, Miura T, Shimamoto K, Horio Y (2004) Predominant expression of Sir2alpha, an NAD-dependent histone deacetylase, in the embryonic mouse heart and brain. FEBS Lett 556:281–286. doi:10.1016/S0014-5793(03)01444-3 PubMedGoogle Scholar
  96. Sasaki Y, Araki T, Milbrandt J (2006) Stimulation of nicotinamide adenine dinucleotide biosynthetic pathways delays axonal degeneration after axotomy. J Neurosci 26:8484–8491. doi:10.1523/JNEUROSCI.2320-06.2006 PubMedGoogle Scholar
  97. Saunders LR, Verdin E (2007) Sirtuins: critical regulators at the crossroads between cancer and aging. Oncogene 26:5489–5504. doi:10.1038/sj.onc.1210616 PubMedGoogle Scholar
  98. Sawada M, Sun W, Hayes P, Leskov K, Boothman DA, Matsuyama S (2003) Ku70 suppresses the apoptotic translocation of Bax to mitochondria. Nat Cell Biol 5:320–329. doi:10.1038/ncb950 PubMedGoogle Scholar
  99. Shindler KS, Ventura E, Rex TS, Elliott P, Rostami A (2007) SIRT1 activation confers neuroprotection in experimental optic neuritis. Invest Ophthalmol Vis Sci 48:3602–3609. doi:10.1167/iovs.07-0131 PubMedGoogle Scholar
  100. Sinclair DA, Guarente L (1997) Extrachromosomal rDNA circles-a cause of aging in yeast. Cell 91:1033–1042. doi:10.1016/S0092-8674(00)80493-6 PubMedGoogle Scholar
  101. Sinclair DA, Lin SJ, Guarente L (2006) Life-span extension in yeast. Science 312:195–197. doi:10.1126/science.312.5771.195d PubMedGoogle Scholar
  102. Steinkraus KA, Smith ED, Davis C, Carr D, Pendergrass WR, Sutphin GL, Kennedy BK, Kaeberlein M (2008) Dietary restriction suppresses proteotoxicity and enhances longevity by an hsf-1-dependent mechanism in Caenorhabditis elegans. Aging Cell 7:394–404. doi:10.1111/j.1474-9726.2008.00385.x PubMedGoogle Scholar
  103. Suzuki K, Koike T (2007a) 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. doi:10.1016/j.neuroscience.2007.04.059 PubMedGoogle Scholar
  104. Suzuki K, Koike T (2007b) 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. doi:10.1016/j.bbrc.2007.05.164 PubMedGoogle Scholar
  105. Tang BL (2005) Alzheimer’s disease: channeling APP to nonamyloidogenic processing. Biochem Biophys Res Commun 331:375–378. doi:10.1016/j.bbrc.2005.03.074 PubMedGoogle Scholar
  106. Tang BL (2006) SIRT1, neuronal cell survival and the insulin/IGF-1 aging paradox. Neurobiol Aging 27:501–505. doi:10.1016/j.neurobiolaging.2005.02.001 PubMedGoogle Scholar
  107. Tanno M, Sakamoto J, Miura T, Shimamoto K, Horio Y (2007) Nucleocytoplasmic shuttling of the NAD+-dependent histone deacetylase SIRT1. J Biol Chem 282:6823–6832. doi:10.1074/jbc.M609554200 PubMedGoogle Scholar
  108. Tatar M, Kopelman A, Epstein D, Tu M-P, Yin C-M, Garofalo RS (2001) A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function. Science 292:107–110. doi:10.1126/science.1057987 PubMedGoogle Scholar
  109. Tissenbaum HA, Guarente L (2001) Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 410:227–230. doi:10.1038/35065638 PubMedGoogle Scholar
  110. Van Ham TJ, Thijssen KL, Breitling R, Hofstra RM, Plasterk RH, Nollen EA (2008) C. elegans model identifies genetic modifiers of α-synuclein inclusion formation during aging. PLoS Genet 4:E1000027. doi:10.1371/journal.pgen.1000027
  111. Vaziri H, Dessain SK, Ng EE, Imai SI, Frye RA, Pandita TK, Guarente L, Weinberg RA (2001) hSIR2 (SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 107:149–159. doi:10.1016/S0092-8674(01)00527-X PubMedGoogle Scholar
  112. 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 9:605–615. doi:10.1016/j.devcel.2005.09.017 Google Scholar
  113. Wang J, Ho L, Qin W, Rocher AB, Seror I, Humala N, Maniar K, Dolios G, Wang R, Hof PR, Pasinetti GM (2005a) Caloric restriction attenuates β-amyloid neuropathology in a mouse model of Alzheimer’s disease. FASEB J 19:659–661. doi:10.1096/fj.04-2370com PubMedGoogle Scholar
  114. Wang J, Zhai Q, Chen Y, Lin E, Gu W, McBurney MW, He Z (2005b) A local mechanism mediates NAD-dependent protection of axon degeneration. J Cell Biol 170:349–355. doi:10.1083/jcb.200504028 PubMedGoogle Scholar
  115. Wang C, Chen L, Hou X, Li Z, Kabra N, Ma Y, Nemoto S, Finkel T, Gu W, Cress WD, Chen J (2006) Interactions between E2F1 and SirT1 regulate apoptotic response to DNA damage. Nat Cell Biol 8:1025–1031. doi:10.1038/ncb1468 PubMedGoogle Scholar
  116. Wang F, Nguyen M, Qin FX, Tong Q (2007) SIRT2 deacetylates FOXO3a in response to oxidative stress and caloric restriction. Aging Cell 6:505–514. doi:10.1111/j.1474-9726.2007.00304.x PubMedGoogle Scholar
  117. Wang RH, Sengupta K, Li C, Kim HS, Cao L, Xiao C, Kim S, Xu X, Zheng Y, Chilton B, Jia R, Zheng ZM, Appella E, Wang XW, Ried T, Deng CX (2008a) Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice. Cancer Cell 14:312–323. doi:10.1016/j.ccr.2008.09.001 PubMedGoogle Scholar
  118. Wang RH, Zheng Y, Kim HS, Xu X, Cao L, Luhasen T, Lee MH, Xiao C, Vassilopoulos A, Chen W, Gardner K, Man YG, Hung MC, Finkel T, Deng CX (2008b) Interplay among BRCA1, SIRT1, and Survivin during BRCA1-associated tumorigenesis. Mol Cell 32:11–20. doi:10.1016/j.molcel.2008.09.011 PubMedGoogle Scholar
  119. Wolkow C, Kimura KD, Lee M, Ruvkun G (2000) Regulation of C. elegans life span by insulin-like signaling in the nervous system. Science 290:147–150. doi:10.1126/science.290.5489.147 PubMedGoogle Scholar
  120. Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M, Sinclair D (2004) Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 430:686–689. doi:10.1038/nature02789 PubMedGoogle Scholar
  121. Yeung F, Hoberg JE, Ramsey CS, Keller MD, Jones DR, Frye RA, Mayo MW (2004) Modulation of NF-κB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J 23:2369–2380. doi:10.1038/sj.emboj.7600244 PubMedGoogle Scholar
  122. Zhai Q, Wang J, Kim A, Liu Q, Watts R, Hoopfer E, Mitchison T, Luo L, He Z (2003) Involvement of the ubiquitin-proteasome system in the early stages of Wallerian degeneration. Neuron 39:217–225. doi:10.1016/S0896-6273(03)00429-X PubMedGoogle Scholar
  123. Zhang QJ, Wang Z, Chen HZ, Zhou S, Zheng W, Liu G, Wei YS, Cai H, Liu DP, Liang CC (2008) Endothelium-specific overexpression of class III deacetylase SIRT1 decreases atherosclerosis in apolipoprotein E-deficient mice. Cardiovasc Res 80:191–199. doi:10.1093/cvr/cvn224 PubMedGoogle Scholar
  124. Zhou Y, Su Y, Li B, Liu F, Ryder JW, Wu X, Gonzalez-DeWhitt PA, Gelfanova V, Hale JE, May PC, Paul SM, Ni B (2003) Nonsteroidal anti-inflammatory drugs can lower amyloidogenic Aβ42 by inhibiting Rho. Science 302:1215–1217. doi:10.1126/science.1090154 PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of Biochemistry, Yong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore

Personalised recommendations