烟酰胺腺嘌呤二核苷酸(NAD)是调节各种生物过程的重要辅助因子,包括代谢和基因表达。作为一种辅酶,NAD通过三羧酸(TCA)循环的酶控制线粒体呼吸,β-氧化,和氧化磷酸化,也作为翻译后蛋白质修饰的底物,例如通过去乙酰化酶和聚(ADP-核糖)聚合酶(PARP)进行的脱乙酰和ADP-核糖基化,分别。许多研究表明,NAD水平随着衰老而降低,并且这些下降导致各种与衰老相关的疾病。相比之下,NAD代谢的激活可防止衰老过程中NAD水平的下降。特别是,饮食补充NAD前体与预防年龄相关的胰岛素抵抗相关。然而,尚不清楚哪种NAD合成途径在体内增加NAD水平方面是重要的和/或有效的。在这项研究中,小鼠中的Nmnat3过表达有效地增加了各种组织中的NAD水平,并防止了NAD水平的衰老相关下降。我们还证明了Nmnat3过表达(Nmnat3Tg)小鼠可以抵抗饮食诱导的和衰老相关的胰岛素抵抗。此外,在Nmnat3Tg小鼠的骨骼肌中,TCA循环活性显著增强,氧化磷酸化的能量来源转向脂肪酸氧化。此外,在老年Nmmat3Tg小鼠中,活性氧(ROS)的产生受到显着抑制。有趣的是,我们还发现,在Nmnat3Tg小鼠中,NAD类似物烟酰胺鸟嘌呤二核苷酸(NGD)的浓度显著增加。这些结果表明,Nmnat3过表达改善代谢健康,并且Nmnat3是由衰老引起的代谢紊乱的有吸引力的治疗靶标。
Nicotinamide adenine dinucleotide (NAD) is an important cofactor that regulates various biological processes, including metabolism and gene expression. As a coenzyme, NAD controls mitochondrial respiration through enzymes of the tricarboxylic acid (TCA) cycle, β-oxidation, and oxidative phosphorylation and also serves as a substrate for posttranslational protein modifications, such as deacetylation and ADP-ribosylation by sirtuins and poly(ADP-ribose) polymerase (PARP), respectively. Many studies have demonstrated that NAD levels decrease with aging and that these declines cause various aging-associated diseases. In contrast, activation of NAD metabolism prevents declines in NAD levels during aging. In particular, dietary supplementation with NAD precursors has been associated with protection against age-associated insulin resistance. However, it remains unclear which NAD synthesis pathway is important and/or efficient at increasing NAD levels in vivo. In this study, Nmnat3 overexpression in mice efficiently increased NAD levels in various tissues and prevented aging-related declines in NAD levels. We also demonstrated that Nmnat3-overexpressing (Nmnat3 Tg) mice were protected against diet-induced and aging-associated insulin resistance. Moreover, in skeletal muscles of Nmnat3 Tg mice, TCA cycle activity was significantly enhanced, and the energy source for oxidative phosphorylation was shifted toward fatty acid oxidation. Furthermore, reactive oxygen species (ROS) generation was significantly suppressed in aged Nmnat3 Tg mice. Interestingly, we also found that concentrations of the NAD analog nicotinamide guanine dinucleotide (
NGD) were dramatically increased in Nmnat3 Tg mice. These results suggest that Nmnat3 overexpression improves metabolic health and that Nmnat3 is an attractive therapeutic target for metabolic disorders that are caused by aging.