NMN的作用原理

来自美国俄克拉荷马大学(University of Oklahoma)健康科学中心的Tamas Kiss 博士发现补充NMN提升脑星形胶质细胞线粒体功能,逆转老年小鼠“记忆减退”的现象6。南京农业大学的熊波教授发现补充NMN可以提高卵母细胞线粒体功能,促进有丝分裂过程,减弱有毒化学物质的生殖危害。

图1: NMN的分子机制
PRPP(5-磷酸核糖-1-焦磷酸)和NAM(烟酰胺)经NAMPT(烟酰胺磷酸核糖转移酶)催化后变为NMN(β-烟酰胺单核苷酸),再通过NMNAT(烟酰胺单核苷酸腺苷转移酶)催化形成NAD+,NAD+调节下游的PARP1(DNA修复酶)、Sirts(乙酰化酶,又称“长寿蛋白”)和CD38(特异性免疫抑制蛋白),从而改变线粒体功能,并影响DNA修复、干细胞增殖及氧化应激反应等,以此参与细胞的衰老机制。

图1: NMN的分子机制

  PRPP(5-磷酸核糖-1-焦磷酸)和NAM(烟酰胺)经NAMPT(烟酰胺磷酸核糖转移酶)催化后变为NMN(β-烟酰胺单核苷酸),再通过NMNAT(烟酰胺单核苷酸腺苷转移酶)催化形成NAD+,NAD+调节下游的PARP1(DNA修复酶)、Sirts(乙酰化酶,又称“长寿蛋白”)和CD38(特异性免疫抑制蛋白),从而改变线粒体功能,并影响DNA修复、干细胞增殖及氧化应激反应等,以此参与细胞的衰老机制。

  NMN(β-烟酰胺单核苷酸)在进入体内后可以直接转化为NAD+(烟酰胺腺嘌呤二核苷酸)分子1,而后者在400多种代谢反应中起着关键调节作用。其中就包括与细胞衰老机制密切相关的三类关键蛋白:PARP1(DNA修复酶)、Sirts(乙酰化酶,又称“长寿蛋白”)和CD38(特异性免疫抑制蛋白)。

  在小鼠、大鼠及人类中均发现,随着年龄增长,NAD+水平也会随之下降。在老年痴呆、心力衰竭等模型中亦发现NAD+水平下降2。NAD+分子耗竭会导致PARP1、Sirts和CD38等关键酶活性降低,从而引发诸如线粒体功能紊乱,DNA修复障碍等一系列连锁反应,成为衰老的一个重要原因。

  研究领域研究概述

NMN研究

  表1: 与NMN相关研究领域及成果汇总

  而多项研究表明(表1),补充NMN可以有效改善NAD+不足引起的上述反应。例如,来自哈佛医学院(Harvard Medical School)的David A Sinclair 教授发现,给老年小鼠的水中添加NMN,其运动耐力增加近一倍3。另有研究发现注射NMN可以抵抗伴随衰老而来的认知下降4。此外,美国华盛顿大学(Washington University School)Shin-ichiro Imai 教授发现,促进NMN合成能使老年小鼠的剩余寿命增加一倍以上,小鼠睡眠质量和皮肤、毛发等外貌状态都有显著提升5。

图2: 美国华盛顿大学研究发现,促进NMN合成能使老年小鼠的剩余寿命增加一倍以上,并显著改善小鼠睡眠质量和皮肤、毛发等外貌状态。

  图2: 美国华盛顿大学研究发现,促进NMN合成能使老年小鼠的剩余寿命增加一倍以上,并显著改善小鼠睡眠质量和皮肤、毛发等外貌状态。

  NMN能大幅提升线粒体功能

  线粒体是细胞中最主要的“能量发电站”,细胞内绝大多数的代谢活动必须使用储存于ATP 中的能量。线粒体可以将食物中的能量储存于 ATP 中,以供后续代谢活动利用。与年轻小鼠相比,年老小鼠线粒体功能下降,而补充NMN可以提高依赖NAD+的Sirts酶的活性,去除线粒体蛋白质过多的乙酰化修饰,调控下游代谢酶的活性,大幅提升线粒体提供能量的能力2,“滋养”多种组织和器官,抵抗衰老。

  来自美国俄克拉荷马大学(University of Oklahoma)健康科学中心的Tamas Kiss 博士发现补充NMN提升脑星形胶质细胞线粒体功能,逆转老年小鼠“记忆减退”的现象6。南京农业大学的熊波教授发现补充NMN可以提高卵母细胞线粒体功能,促进有丝分裂过程,减弱有毒化学物质的生殖危害7。美国凯斯西储大学(Case Western Reserve University)的刘建仁教授发现,补充NMN可以提高心肌细胞线粒体功能,提高心肌细胞收缩能力,改善心力衰竭8。除了上述提到的三项研究,另有多项研究均证实NMN可以提高线粒体功能,抵抗衰老和多种疾病5,9,10。

  NMN能改善DNA修复功能

  如果人体是一部汽车,DNA 则是它的设计图。若设计图保持完整,理想状态下不论汽 车开了多久都可以恢复原状,因为磨损的零件可以按照设计图随时更新。DNA 的双螺旋结构使它具有极强的自我修复能力,若其中任何一条链遭到破坏,都可以另一条链作为模版迅速修复。在一些极端条件下,DNA的两条链同时断裂,失去模版后,细胞会紧急启动“精心修复”程序来挽救DNA 损伤。

  随着年龄的增长,DNA越来越容易断裂,且越来越无力于“精心修复”。这些损伤会随着年龄不断积累,是衰老的源动力之一。因此,修复DNA 损伤是逆转衰老的核心。来自欧洲、美国和澳大利亚的科学家组成的研究团队发现,补充 NMN等NAD+前体,可以提高NAD+依赖的PARP1酶的活性。 PARP1则是帮助修复双链断裂的DNA的关键酶,因此补充NMN可以逆转 DNA损伤9。

  NMN可促进多种干细胞增殖

  干细胞(stem cell,SC)的“干”,译自英文“stem”,意为“植物茎干”和“起源”,是一类具有自我更新能力和分化潜能的细胞。干细胞不断增殖,一部分保持干性,维持自我更新;另一部分分化补充各种组织和器官。体内绝大多数器官内都有干细胞的存在,比如神经干细胞,肌肉干细胞,肠道干细胞,骨髓造血干细胞等。NMN可以为多种干细胞提供补充能量,激活增殖相关通路,促进多种干细胞增殖。

  瑞士洛桑联邦理工学院(École Polytechnique Fédérale de Lausanne,EPFL)的研究人员发现补充 NMN可以显著提高老年小鼠肌肉干细胞的数目,缓解肌肉流失,提升运动能力 11。日本庆应大学(Keio University)Hidetsugu Saito教授发现补充NMN可以激活增殖相关信号通路,促进肠干细胞增殖12。瑞士研究人员发现NMN等NAD+前体可以提高自噬,提高造血干细胞补充血液的速度13。促进干细胞增殖是NMN抑制衰老的又一重要作用机制。

  NMN可减弱氧化应激反应

  很多与老化有关的健康问题,如老年痴呆、血糖和心脏功能受损等,都与体内氧化应激状态有关。氧化应激是指体内氧化与抗氧化作用失衡,产生大量有害的活性氧。人体几乎所有的器官都容易被氧化应激伤害。来自日本老年研究中心(National Center for Geriatrics and Gerontology, NCGG, Japan)和中国医科大学第一附属医院的研究人员合作发现补充NMN可以减弱老年痴呆症小鼠神经细胞内的氧化应激状态,提高认知功能1。美国凯斯西储大学(Case Western Reserve University)的许东教授发现NMN可以降低心肌细胞线粒体氧化应激水平,改善心肌收缩能力14。

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  文章来源:https://www.nmn.cn/what-does-nmn-do