negative regulator of yeast sir2 and human SIRT1. J Biol Chem 277: 45099–45107. 59. Lin SJ, Guarente L (2003) Nicotinamide adenine dinucleotide, a metabolic regulator of transcription, longevity and disease. Curr Opin Cell Biol 15: 241–246. 60. Borra MT, Denu JM (2004) Quantitative assays for characterization of the Sir2 family of NAD(+)-dependent deacetylases. Methods Enzymol 376: 171–187. 61. Marmorstein R (2004) Structure and chemistry of the Sir2 family of NAD+- dependent histone/protein deactylases. Biochem Soc Trans 32: 904–909. 62. Masoro EJ (2004) Role of sirtuin proteins in life extension by caloric restriction. Mech Ageing Dev 125: 591–594. 63. Borra MT, Smith BC, Denu JM (2005) Mechanism of human SIRT1 activation by resveratrol. J Biol Chem 280: 17187–17195. 64. Koltai E, Szabo Z, Atalay M, Bolodogh I, Naito H, et al. (2010) Exercise alters SIRT1, SIRT6, NAD and NAMPT levels in skeletal muscle of aged rats. Mech Ageing Dev 131: 21–28. 65. Radak Z, Atalay M, Jakus J, Boldogh I, Davies K, et al. (2009) Exercise improves import of 8-oxoguanine DNA glycosylase into the mitochondrial matrix of skeletal muscle and enhances the relative activity. Free Radic Biol Med 46: 153–159. 66. He W, Wang Y, Zhang MZ, You L, Davis L, et al. (2010) Sirt1 activation protectes the mouse renal medulla from oxidative injury. J Clin Invest 120: 1056–1068. 67. Alcendor R, Gao S, Zhai P, Zablocki D, Holle E, et al. (2007) Sirt1 regulates aging and resistance to oxidative stress in the heart. Circ Res 100: 1512–1521. 68. Arraki T, Sasaki A, Milbrandt J (2004) Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration. Science 305: 1010–1013. Age Related Changes in NAD+ Metabolism 69. Rajendrasozhan S, Yang SR, Kinnula V, 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. 70. Deng XQ, Chen LL, Li NX (2007) The expression of SIRT1 in nonalcoholic fatty liver disease induced by high-fat diet in rats. Liver International doi: 10.1111/j.1478-3231.2007.01497.x. 71. Chen D, Bruno J, Easlon E, Lin SJ, Cheng HL, et al. (2008) Tissue-specific regulation of SIRT1 by calorie restriction. Genes & Dev 22: 1753–1757. 72. Malanga M, Pleschke J, Kleczkowska H, Althaus F (1998) Poly(ADP-ribose) binds to specific domains of p53 and alters its DNA binding functions. J Biol Chem 273: 11839–11848. 73. Yamakuchi M, Ferlito M, Lowenstein C (2008) miR-34a repression of SIRT1 regulates apoptosis. Proc Natl Acad Sci USA 105: 13421–13426. 74. Beal MF (1995) Aging, energy, and oxidative stress in neurodegenerative diseases. Ann Neurol 38: 357–366. 75. Starkov A, Fiskum G (2003) Regulation of brain mitochondrial H2O2 production by membrane potential and NAD(P)H redox state. J Neurochem 86: 1101–1107. 76. Sipos I, Tretter L, Adam-Vizi V (2003) Quantitative relationship between inhibition of respiratory complexes and formation of reactive oxygen species in isolated nerve terminals. J Neurochem 84: 112–118. 77. Tretter L, Adam-Vizi V (2004) Generation of reactive oxygen species in the reaction catalysed by a-Ketoglutarate dehydrogenase. J Neurosci 24: 7771–7778. 78. Kukielka E, Cederbaum A (1989) NADH-dependent microsomal interaction with ferric complexes and production of reactive oxygen intermediates. Arch Biochem Biophys 275: 540. PLoS ONE | www.plosone.org 18 April 2011 | Volume 6 | Issue 4 | e19194