Department of Pharmacology, School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia.
PLoS One. 2011 Apr 26;6(4):e19194. doi: 10.1371/journal.pone.0019194.
The cofactor nicotinamide adenine dinucleotide (NAD+) has emerged as a key regulator of metabolism, stress resistance and longevity. Apart from its role as an important redox carrier, NAD+ also serves as the sole substrate for NAD-dependent enzymes, including poly(ADP-ribose) polymerase (PARP), an important DNA nick sensor, and NAD-dependent histone deacetylases, Sirtuins which play an important role in a wide variety of processes, including senescence, apoptosis, differentiation, and aging. We examined the effect of aging on intracellular NAD+ metabolism in the whole heart, lung, liver and kidney of female wistar rats. Our results are the first to show a significant decline in intracellular NAD+ levels and NAD:NADH ratio in all organs by middle age (i.e.12 months) compared to young (i.e. 3 month old) rats. These changes in [NAD(H)] occurred in parallel with an increase in lipid peroxidation and protein carbonyls (o- and m- tyrosine) formation and decline in total antioxidant capacity in these organs. An age dependent increase in DNA damage (phosphorylated H2AX) was also observed in these same organs. Decreased Sirt1 activity and increased acetylated p53 were observed in organ tissues in parallel with the drop in NAD+ and moderate over-expression of Sirt1 protein. Reduced mitochondrial activity of complex I-IV was also observed in aging animals, impacting both redox status and ATP production. The strong positive correlation observed between DNA damage associated NAD+ depletion and Sirt1 activity suggests that adequate NAD+ concentrations may be an important longevity assurance factor.
辅酶烟酰胺腺嘌呤二核苷酸（NAD+）已成为代谢、应激抵抗和长寿的关键调节因子。除了作为重要的氧化还原载体的作用外，NAD+还是 NAD 依赖性酶的唯一底物，包括聚（ADP-核糖）聚合酶（PARP），一种重要的 DNA 缺口传感器，以及 NAD 依赖性组蛋白去乙酰化酶 Sirtuins，它们在多种过程中发挥重要作用，包括衰老、凋亡、分化和老化。我们研究了衰老对雌性 Wistar 大鼠整个心脏、肺、肝和肾细胞内 NAD+代谢的影响。我们的结果首次表明，与年轻（即 3 个月大）大鼠相比，中年（即 12 个月）大鼠所有器官的细胞内 NAD+水平和 NAD:NADH 比值均显著下降。这些 [NAD(H)] 的变化与脂质过氧化、蛋白质羰基（o-和 m-酪氨酸）形成的增加以及这些器官总抗氧化能力的下降同时发生。在这些相同的器官中还观察到 DNA 损伤（磷酸化 H2AX）随年龄的增加而增加。在器官组织中还观察到 Sirt1 活性降低和乙酰化 p53 增加，这与 NAD+下降和 Sirt1 蛋白适度过表达平行。还观察到衰老动物中线粒体复合物 I-IV 的活性降低，这影响了氧化还原状态和 ATP 产生。与 DNA 损伤相关的 NAD+耗竭和 Sirt1 活性之间观察到的强正相关表明，足够的 NAD+浓度可能是一个重要的长寿保证因素。
