如何提高NAD+水平
NAD+的浓度和分布会随着不同的生理刺激和细胞应激而波动。NAD+稳态的改变与影响不同器官的多种疾病有关，包括大脑和神经系统、肝脏、心脏和肾脏。NAD+缺失是衰老和许多衰老相关疾病的标志[1-6]。人体NAD水平在40多岁到60多岁之间下降了50%，对健康的细胞产生和寿命有负面影响。因此，增强NAD水平有助于对抗衰老，增强对疾病的抵抗力，从而延长寿命。
NAD+水平主要可以通过三种方式来提高：第一，通过补充NAD的前体：如NR、NMN、烟酸、烟酰胺、色氨酸，它们都是NAD合成过程中的前体物质。
第二，抑制NAD消耗酶：包括PARP1和CD38。多种黄酮类化合物，包括芹菜素、槲皮素、木犀草素，对CD38活性具有抑制作用[7]。
第三，管理NAD+生物合成：控制NAD+生物合成酶，或通过运动、热量限制、间歇性禁食改善NAD的生物利用度，增加NAD的水平。
NAD+前体可作为一种营养补充剂，以改善生理功能和病理过程[8-13]。NAD+前体物质的治疗和预防效果，特别是可溶性和口服生物可利用的内源性分子NR、NAM和烟酸，已经在一系列人体临床试验中进行了评估。
NAD+前体：NMN
NMN可以有效、快速地增强NAD+在各种组织中的生物合成，甚至在大脑中，具有良好的安全性[14]。老年动物对NMN的治疗比年轻动物更敏感，因为NAD+可用性随着年龄下降。NMN治疗通过恢复NAD+的生物合成，对年龄和饮食诱导的糖尿病患者的胰岛素分泌和胰岛素敏感性产生有益影响。长期给药NMN可挽救与年龄相关的生理功能下降，包括线粒体功能、能量代谢、基因表达变化、胰岛素敏感性和血脂谱，从而改善身体活动，如骨密度和眼球功能[14]。NMN治疗改善了神经元功能，包括改善阿尔茨海默病动物模型中的记忆和认知，保护神经元免于脑出血或缺血后的细胞死亡，恢复视网膜变性，恢复与年龄相关的神经干细胞池的损失。此外，NMN给药对急性心力衰竭和肾损伤也有多效性作用[15-16]。
尽管NMN在骨骼肌、肾脏和肝脏等各种器官中的吸收速度快，但它进入细胞的运输模式仍然不清楚。NMN可能直接被特定的转运体吸收，因为NMN给药会立即增加肠道等外周器官中NAD+含量的增加[16]。
NAD+前体：NR
NR是另一种天然化合物，对全身NAD+代谢有着重要影响。一项NR的大型临床试验，包括感染、肿瘤、循环系统、泌尿生殖系统、神经系统和皮肤等相关的疾病，老年参与者口服NR补充可提高老年人肌肉NAD+代谢组，改善代谢功能障碍，抑制循环炎症细胞因子水平，增加抗炎分子脂联素[17-18]。NR可提高耐寒性、耐力和能量消耗。NR保护小鼠免受HFD诱导的体重增加，通过促进肝细胞复制和增加肝脏ATP含量来促进肝脏恢复[19]。NR通过改善心衰小鼠的线粒体功能和降低UPRmt，在几种肌肉疾病中表现出有益的作用。NR促进NAD+的生物合成，以防止DNA损伤和肿瘤的发生。在HFHS喂养的小鼠中，补充NAD+可以通过改善HFHS喂养的小鼠的线粒体功能来逆转NAFLD[20]。NR在神经系统中也有多种好处，包括改善阿尔茨海默病的认知功能和突触可塑性，以及防止噪声引起的听力损失。
NR可以通过ENTs直接转运到细胞中，并绕过NAMPT介导的挽救途径增强NAD+的生物合成。然而，NR在循环中的短稳定性和NRKs的表达限制了其利用率，限制了其临床应用。
NR是NAD生物合成途径中一个较远的前体，它使用ATP作为共底物，NR激酶将NR转化为NMN。研究表明，补充NR可增加NAD水平，增强氧化代谢，减少脂肪和肝脂肪变性[21-22]。多项实验表明，NR降解为烟酰胺和核糖的速度非常快，尤其是口服时[23,24]。因此，NR可以有效增加NAD的原因可能要归因于循环的烟酰胺或烟酰胺和核糖。
NAD+前体：NAM
NAM是一种不带电荷的分子，可以在血浆中快速扩散，支持在体内大多数组织中NAD+的生物合成[25]。口服NAM通过肠道微生物群的烟酰胺酶PncA转化为NA。肠道微生物介导的NAM脱酰胺化是必要的，并负责NAD+在各种器官中的生物合成，包括肾脏、肝脏和结肠[26]。NAM通过恢复胰岛细胞中NAD+的下降来预防链脲佐菌素（STZ）诱导的糖尿病。
UGN使用的NAD合成补充剂中，使用专利成分RiaGev®，它将烟酰胺与核糖结合在一起。这种专利核糖复合物的优势在于它可以直接进入NAD+生物合成途径，有效地增加身体的NAD+水平。
简而言之，虽然还有其他NAD前体可以促进NAD的产生，烟酰胺和D-核糖的组合更有效率。它可以更快地增加 NAD 水平，因为它直接进入通路，产生NAD所需的步骤更少。NR促进NAD水平增加，因为NR降解为烟酰胺和核糖的速度非常快，主要归因于循环的烟酰胺或烟酰胺和核糖。RiaGev®直接略过了NR降解的步骤，促进NAD的合成。
一项随机、三盲、安慰剂对照、交叉试验研究评估了NAM和D-核糖（RiaGev®）组合在健康成人中的疗效和安全性。补充RiaGev®有效地增加了循环血液中NAD代谢组的浓度，特别是NADP水平。它还增强了血液中的高能磷酸盐和谷胱甘肽水平。RiaGev®组餐后血糖水平显着改善，而没有过量的胰岛素分泌，表明葡萄糖耐量有所改善。问卷评估表明，RiaGev可以减轻身体疲劳、提高注意力、提高动机，改善受试者的整体健康状况[27]。
PARPs或CD38的过度激活会导致NAD+的消耗，从而导致ATP下降、能量损失和细胞死亡。因此，通过抑制PARPs或CD38来减少NAD+的消耗，也是提高NAD+的一种策略[28,29]。
越来越多的证据表明，DNA损伤引起的异常PARPs激活会导致NAD+耗竭，从而导致肿瘤发生和神经退行性疾病的进展[30-32]。PARPs介导的ADP核糖基化占细胞内NAD+消耗的90%，导致sirtuins的NAD+可用性降低。因此，PARP- 1的基因消融或药理抑制通过恢复NAD+含量来增强Sirt1的活性，为肝脏、肌肉和棕色脂肪组织等多种组织提供保护作用[33-34]。
芹菜素、槲皮素、木犀草素、毛地黄、黄黄素等黄酮对CD38活性均有抑制作用[7]。
提高NAD+生物合成是通过增加NAD+生物合成途径中酶的活性或抑制侧支途径中酶的活性来提高NAD+浓度的另一种方法[35]。
NAPRT在不同健康组织中的不同表达水平决定了NAD+生物合成途径的选择。NAPRT水平高的组织的癌症表达完全不可逆地依赖于NAPRT调控的从头途径，NAPRT水平低的组织的癌症主要依赖于NAMPT介导的NAD+挽救途径。这种不同的依赖性使癌症细胞对其他NAD+合成对NAMPT的抑制具有抗性。
药物P7C3或SBI-797812可增强NAMPT的酶促能力。P7C3是一种具有良好的生物利用度和无毒性的NAMPT增强剂。已经证明，P7C3及其类似物在广泛的依赖于NAMPT激活的临床前啮齿动物和非人灵长类动物模型中具有神经保护作用[36-39]。因此，P7C3的神经保护活性为治疗年龄相关性肌萎缩性侧索硬化症、阿尔茨海默病和帕金森病提供了一种新的药物治疗方法[36,38,39]。SBI- 797812通过稳定NAMPT在His247位点的磷酸化来激活NAMPT，提高了NMN的生成效率，为提高NAD+提供了另一种选择[40]。
细胞内的NAD+水平也可以通过能量应激而增加，包括禁食、血糖限制、热量限制（CR）和运动[41]。
CR介导的NAD+增强依赖于NAD+的挽救生物合成，而不是通过提高NAMPT表达的从头途径[42-46]。CR通过增强对NAD+代谢的昼夜节律控制和NAD+/sirt1调节的表观遗传修饰，恢复与年龄相关的昼夜节律衰退[47–50]。研究表明，长期和短期的CR均能挽救大弹性动脉硬化和内皮功能障碍[51,52]。同样的，CR增强的NAD+水平通过降低质膜脂质过氧化和氧化应激来保护大脑免受衰老和疾病的侵袭[53]。
除了CR之外，由于NAMPT的增加，运动也可以增加NAD+水平和SIRT1活性[54]。
肠道微环境，特别是宿主-细菌的相互作用也有助于NAD+的代谢。肠道微生物群来源的脱氨基化途径促进了利用NAM或NR进行肝脏NAD+的合成，这表明微生物群可能是调控NAD+代谢的一种新选择[26]。
总的来说，健康的生活方式和锻炼通过非药物方式提高NAD+水平来提高身体的恢复力和延长寿命。NAD+补充剂可应用于NAD+缺乏症相关的病理学，如感染、癌症、代谢性疾病、急性损伤、衰老和与衰老相关的神经退行性疾病。
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