Department of Pharmacology, School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.
PLoS One. 2012;7(7):e42357. doi: 10.1371/journal.pone.0042357. Epub 2012 Jul 27.
Nicotinamide adenine dinucleotide (NAD(+)) is an essential electron transporter in mitochondrial respiration and oxidative phosphorylation. In genomic DNA, NAD(+) also represents the sole substrate for the nuclear repair enzyme, poly(ADP-ribose) polymerase (PARP) and the sirtuin family of NAD-dependent histone deacetylases. Age associated increases in oxidative nuclear damage have been associated with PARP-mediated NAD(+) depletion and loss of SIRT1 activity in rodents. In this study, we further investigated whether these same associations were present in aging human tissue. Human pelvic skin samples were obtained from consenting patients aged between 15-77 and newborn babies (0-1 year old) (n = 49) previously scheduled for an unrelated surgical procedure. DNA damage correlated strongly with age in both males (p = 0.029; r = 0.490) and females (p = 0.003; r = 0.600) whereas lipid oxidation (MDA) levels increased with age in males (p = 0.004; r = 0.623) but not females (p = 0.3734; r = 0.200). PARP activity significantly increased with age in males (p<0.0001; r = 0.768) and inversely correlated with tissue NAD(+) levels (p = 0.0003; r = -0.639). These associations were less evident in females. A strong negative correlation was observed between NAD(+) levels and age in both males (p = 0.001; r = -0.706) and females (p = 0.01; r = -0.537). SIRT1 activity also negatively correlated with age in males (p = 0.007; r = -0.612) but not in females. Strong positive correlations were also observed between lipid peroxidation and DNA damage (p<0.0001; r = 0.4962), and PARP activity and NAD(+) levels (p = 0.0213; r = 0.5241) in post pubescent males. This study provides quantitative evidence in support of the hypothesis that hyperactivation of PARP due to an accumulation of oxidative damage to DNA during aging may be responsible for increased NAD(+) catabolism in human tissue. The resulting NAD(+) depletion may play a major role in the aging process, by limiting energy production, DNA repair and genomic signalling.
烟酰胺腺嘌呤二核苷酸（NAD(+)）是线粒体呼吸和氧化磷酸化中重要的电子转运体。在基因组 DNA 中，NAD(+)也是核修复酶聚（ADP-核糖）聚合酶（PARP）和依赖 NAD 的组蛋白去乙酰化酶 Sirtuin 家族的唯一底物。与年龄相关的氧化核损伤增加与 PARP 介导的 NAD(+)耗竭和 SIRT1 活性丧失有关在啮齿动物中。在这项研究中，我们进一步研究了这些相同的关联是否存在于衰老的人体组织中。从年龄在 15-77 岁之间的同意患者和新生儿（0-1 岁）（n=49）获得人体骨盆皮肤样本，这些患者之前计划进行无关的手术。DNA 损伤与男性（p=0.029；r=0.490）和女性（p=0.003；r=0.600）的年龄密切相关，而脂质氧化（MDA）水平在男性中随年龄增长而增加（p=0.004；r=0.623），但在女性中则不然（p=0.3734；r=0.200）。PARP 活性在男性中随年龄显著增加（p<0.0001；r=0.768），并且与组织 NAD(+)水平呈负相关（p=0.0003；r=-0.639）。这些关联在女性中不太明显。在男性（p=0.001；r=-0.706）和女性（p=0.01；r=-0.537）中均观察到 NAD(+)水平与年龄之间的强烈负相关。SIRT1 活性也与男性（p=0.007；r=-0.612）但不是女性的年龄呈负相关。在青春期后的男性中，脂质过氧化和 DNA 损伤之间也存在强烈的正相关（p<0.0001；r=0.4962），PARP 活性和 NAD(+)水平之间也存在强烈的正相关（p=0.0213；r=0.5241）。这项研究提供了定量证据支持这样的假设，即由于 DNA 氧化损伤的积累导致 PARP 的过度激活，可能导致人类组织中 NAD(+)分解代谢增加。由此产生的 NAD(+)耗竭可能通过限制能量产生、DNA 修复和基因组信号转导，在衰老过程中发挥主要作用。
