NAD+缺乏加速衰老
现在人们普遍认为，在衰老过程中，NAD+水平会逐渐下降，NAD+消耗酶的活性受到NAD下降的影响，如sirtuins和PARPs，它们通过调节p53、NF-κB、PGC-1α和HIF-1α等信号通路，导致氧化损伤、代谢紊乱、昼夜节律异常和线粒体功能障碍[1-4]。因此，增强NAD水平是改善寿命和抗衰的一种新思路。
NAD+缺乏会加速衰老。NAD+水平在老蠕虫中稳步下降，导致寿命进一步缩短。同样，小鼠和大鼠在衰老过程中出现了各种组织中的NAD+下降，如肌肉、脂肪组织、大脑、皮肤、肝脏和胰腺[5]。在老年人的大脑和肝脏中也可以观察到NAD+的减少[6]。与此相一致的是，血浆中NAD+及其代谢物NADP+和NAAD的水平在衰老过程中也显著下降[7]。
NAD+的下降是生物功能障碍和年龄相关病理进展的主要驱动因素。一些相关研究发现，NAD+的基因和药理学补充改善了与年龄相关的生物学功能，并增加了蠕虫和小鼠的寿命[8,9]。
NAD下降的一个重要原因是NAMPT介导的NAD生物合成的减少。在年龄诱导的T2D模型中，肝脏、骨骼肌、WAT和胰腺等各种组织中NAD+水平和NAMPT的表达受到严重抑制。NAMPT下降可能是由于慢性炎症和生物钟受损所致[10,11]。
NAD+随着年龄的增长而下降的另一种解释是PARP或CD38导致的NAD+消耗量增加。CD38的蛋白水平和酶活性在衰老过程中都有所增强，导致哺乳动物与年龄相关的NAD+下降。CD38还通过调节SIRT3的活性来导致线粒体功能障碍[12]。CD38的表达可能是由慢性炎症引起的，这是衰老过程中的一个特征之一[12]。PARP1活性增加，可能是由于DNA损伤的积累，这种持续的PARP激活进一步耗尽NAD池，并导致SIRT1活性降低。
一个关于衰老的著名理论认为，线粒体的衰变是衰老的关键驱动因素。线粒体功能障碍是衰老的标志，NAD+在维持线粒体功能中起着至关重要的作用，与衰老相关的NAD+下降会导致线粒体功能障碍。
一组与抗衰老作用相关的蛋白质sirtuins，是依靠NAD+正常运作。Sirtuins在调节细胞和线粒体健康方面发挥作用。一些研究表明，Sirtuins有助于维持端粒酶的长度，而端粒酶的长度和寿命有关，sirtuin蛋白的激活有助于延长寿命。
越来越多的证据表明，NAD+依赖的SIR蛋白可以延长酵母、蠕虫、苍蝇和小鼠的寿命，并减轻许多与衰老相关的病理疾病。例如，大脑特异性或全身过表达sirt1的转基因小鼠都表现出了衰老速度减缓和寿命延长[8,13]。PARP抑制剂和NAD+前体能够调节NAD+可用性，通过SIR-2.1调节线粒体功能，延长寿命[8]。
老年小鼠肌肉和肝脏中的PAR化也显著增加，同时NAD+水平显著下降。由于CSB可以通过从受损DNA中置换PARP1来限制PARP1的活性，因此在CSB缺陷细胞和小鼠中，PAPRPs介导的PAR化增加，并占细胞NAD+消耗的大部分。PARP的这种异常激活抑制了SIRT1活性和线粒体功能障碍，这一过程可以通过PARP抑制剂和NAD+前体来挽救[14]。
衰老相关的核NAD+下降通过SIRT1-HIF-1α-c-Myc通路抑制线粒体编码基因，而提高NAD+水平则以SIRT1依赖的方式挽救老年小鼠的线粒体功能[15]。NAD+也通过改变SIRT3的活性来影响线粒体中氧化酶的乙酰化和活性[16]。
越来越多的人意识到，氧化损伤是与年龄相关的细胞功能恶化的一个重要驱动因素[17,18]。 老年人脑中的DNA氧化损伤和蛋白质氧化与抗氧化酶活性下降有关[19,20]。与年龄相关的氧化应激和细胞衰老的增加，会导致细胞更容易发生坏死性凋亡，从而释放DAMPs，触发炎症反应[21]。促炎细胞因子反过来增强线粒体和NOXs生成的ROS，促进氧化损伤的进一步积累[22-25]。
NAD+可改善衰老过程中的氧化损伤。NADH/NADPH是缓冲氧化应激的强大还原供体，保护细胞/组织在衰老过程中免受氧化应激。老年大鼠NAD+浓度和NAD+/NADH比值显著降低，同时氧化应激增强，抗氧化能力降低。在离体主动脉中添加NMN可提高NAD+和MnSOD水平，从而提高其抗氧化能力[26]。 Nmnat3的过表达有效地提高了多种小鼠组织中的NAD+，从而显著抑制ROS的生成，并防止与衰老相关的胰岛素抵抗[27]。NAD+还通过调节sirtuins和PARPs来调节细胞衰老过程中的氧化应激。NAD+依赖的SIRT1在氧化应激反应中显著上调，保护心脏免受氧化损伤，有助于延缓衰老[28]。
NAD+缺乏与衰老过程中的生物钟紊乱相关。除了减轻氧化损伤外，NAD+还可以通过驱动昼夜节律来延长寿命。生物钟是将代谢与外源性和内源性因素联系起来的内部计时器机制，它的失调与加速衰老有关[29]。在衰老过程中，昼夜节律蛋白将NAD+代谢与昼夜节律生物钟机制联系起来。SIRT1通过有节律地去乙酰化Bmal1或Per2诱导核心时钟基因（如Cry1、Per2、Rorγ和Bmal1）的昼夜节律转录[30,31]。SIRT1还调节昼夜节律启动子中H3 Lys9/Lys14的时钟介导的染色质重塑，以控制昼夜节律[31]。
在老年小鼠的中枢神经系统中，SIRT1水平显著降低，导致BMAL1等昼夜节律蛋白的降低[32]。自主肝时钟诱导NAD+挽救通路部分恢复NAD+振荡，即使没有其他时钟的输入，也能驱动肝脏中的SIRT1昼夜节律功能[33]。因此，NAD+依赖性SIRT1能够调节中枢昼夜节律功能随着衰老而下降。
衰老相关的核NAD下降通过SIRT1-HIF-1α-c-Myc通路抑制线粒体编码的基因，而提高NAD水平则以SIRT1依赖性方式挽救老年小鼠的线粒体功能[34]。
NAMPT在衰老人SMCs中的表达增加通过延缓衰老和增强对氧化应激的抵抗力来延长寿命[35]。
补充NAD前体NR和NMN，可提高NAD水平，通过激活小鼠体内的 SIRT1 来维持线粒体和代谢功能，从而延长小鼠的寿命[34,26,36]。
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