清华大学最新发现：2大途径靶向NAD代谢，这些物质是改善认知关键_全球热讯

“真希望这个病是我得。其实，我也没准备好。”

影片《妈妈！》中，当得知女儿不幸患上阿尔茨海默症后，85岁的母亲呢喃着，而这也成为了此部荣获天坛奖最佳影片提名作品的经典台词。

人均寿命不断增加，神经退行性疾病已不再陌生，不少研究指出肠道菌的改变[1]、大脑老化[2]、自噬途径破坏[3]、线粒体功能障碍[4]等，都是可能的致病因素。

【资料图】

而这些因素似乎都指向了一个相同的对象——衰老。美国Salk研究所系统神经生物学家约翰·雷诺兹博士就曾表示：“衰老是神经退行疾病的最大风险因素”[5]。既如此，“抗衰方案”去“治病”，岂不是降维打击、“药”到病除？

近期，由清华大学药学院、新型高效NAD+合成激活剂研究者王戈林教授领导，团队首次系统评估了从热门抗衰方法——靶向NAD+代谢出发，改善年龄相关神经退行性疾病的可行性，并总结出多条有效干预措施[6]。

一、聊下NAD+与神经退行疾病

由于NAD+在新陈代谢的中枢作用，近年来它的物质合成与分解过程已相对清晰（见下图），而其横跨多物种、几乎无例外随衰老显著下降的属性，又让它与多种疾病紧密关联。

图注：NAD+的合成与消耗过程

在神经退行疾病中，阿尔茨海默病（AD）、帕金森病（PD）、肌萎缩侧索硬化症（ALS），称得上三大代表，臭名昭著的它们是人类健康老龄化路上的重大阻碍。

而想扫除这些“路障”也并非无从下手，研究发现，多数神经退行疾病的共性是：神经元死亡前的轴突损伤与丧失[7, 8]、线粒体功能与稳态失调[9]。而这些特征都与NAD+水平存在莫大关联。

例如，常见于AD与ALS病程中的“瓦勒式变性”（神经轴突断裂后的变性和退化过程），便与NAD+挽救途径中关键酶NMNAT2丢失有关[10, 11]。

而NAD+下降诱导的线粒体障碍也会通过降低生物能量供应与提升内环境氧化应激水平，加剧神经元变性、干扰神经细胞间的信号通讯[12]。

NAD+水平联结着细胞器、各种分子（蛋白质、活性氧等）、遗传物质，形成了复杂的网络，也为我们预防、延缓，甚至完全治愈神经退行疾病提供方向。

图注：NAD+在细胞水平上的变化与神经退行疾病的关联

二、开源：NAD+合成快跟上

想提升NAD+水平，促进其合成必不可少，好比账户的存款想增加，最有效的方法是增加收入。

综合目前研究证据已有了一些可行的方案：

1、 NAD+前体

“补充它=提升NAD+=健康长寿”，流传于坊间的言论足以说明近年NMN类物质的火热，而风头正盛的它，亮眼的研究结果也是一抓一把，其中不少就与神经退行疾病有关。

（1） NMN

在神经系统保护方面，补充NMN已被证实在多种生物模型中起到不错效果[13, 14]，并能调控年龄相关基因的表达、增加线粒体氧化代谢[15, 16]。

不仅如此，NMN脱颖而出还在于其安全性：从啮齿动物到人类（健康/超重），NMN的摄入都被证实安全、有效改善了代谢健康[15, 17, 18]。

（2） NR

另一被广泛研究的NAD+前体便是NR。

在正常衰老的小鼠上，NR被证明可延缓神经干细胞衰老并延长寿命[19]，并能加速AD小鼠和果蝇体内异常聚集蛋白质清除[20, 21]。而异常蛋白的聚集正是目前公认的AD最大患病因素。

（3） 色氨酸

色氨酸以从头合成途径产生NAD+，其代谢失调与多种神经退行疾病的生物标志物有关[22]，当抑制色氨酸关键分解酶时，生物体大脑组织如海马、脑室下区内神经元功能可被增强[23]。

（4） NAD+

直接补充NAD+也是提升NAD+水平的途径之一。向患有帕金森病的小鼠补充NAD+，能有效减轻线粒体功能障碍，减少神经元损伤[24]。

但同时，NAD+的利用效率也成为其发挥效果的掣肘之处——在延缓毒物诱导的神经轴突变性时，直接补充NAD+的效果相比其他前体要差不少[25]。

2、 天然成分

在促进NAD+合成上，天然成分如芹菜素、漆黄素、Embelin（一种从白花酸藤果植物中分离的天然对苯醌）得到了关注。

以研究较为充分的芹菜素与漆黄素为例，这两种黄酮类物质被发现可分别通过促进线粒体融合与自噬[26]以及激活细胞代谢中PI6K-Akt途径[27]，实现神经系统保护与延缓认知障碍发生。

图注：芹菜和草莓是两者的天然食物来源

三、节流：NAD+分解再慢一点

合成给力起来，但若是分解飞快，仿佛袋子底部始终有个大洞，NAD+稳态的维持也是难上加难。

如何通过调节如Sirtuins、PARP、CD38等消耗酶的活性，减少不必要的NAD+消耗，是当下学者们关心的热点话题，在此我们将选取重点内容与大家分享。

1、Sirtuins

在被称作“长寿蛋白”的Sirtuins家族中（人类有7种sirtuins亚型，称为SIRT1-7），激活SIRT1已被证明具有神经保护作用，是极具潜力的老年相关神经退行疾病的干预措施[28-30]。

其中，最明星、最具代表性的便是白藜芦醇[28]，也一度得到知名学者哈佛大学教授大卫.辛克莱的大力推荐。

此外，可用于治疗糖尿病的磺酰胺衍生物[28]（如甲磺酰脲、格列奈特）、NeuroHeal（AI设计的针对神经退行疾病的化合物）[31]也是SIRT1的活化剂。

2、CD38

衰老过程中，CD38酶活性的上调被认为是NAD+下降的主要原因[32]，抑制CD38活性能延缓NAD+的下降[33]，并减轻小鼠AD[34]、ALS[35]疾病进程。

在找寻CD38抑制剂的路上，芹菜素再次被选中。除了前文提到的“能促进NAD+合成”，芹菜素同样能降低CD38活性[36]，改善神经炎症和毒性及认知障碍[26, 37]。

（分割线）

除上述内容，在抑制NAD+消耗上，PARP酶抑制剂如奥拉帕尼[38]、SARM1酶抑制剂小檗碱氯化物[39]等，都逐渐被发掘与研究。

时光派点评（无序号一级标题）

当我们不可避免走入衰老的长夜，相比“患有什么特定疾病”，更多情况下“老年共病”则更普遍，治好了某个单病，其他疾病并不能解决，甚至还会出现治疗并发症。而如果能从多数慢病的根源去追溯，可能情况就会完全不同。

以今日分享的研究为例，看似仅是评估了靶向NAD+代谢对神经退行疾病的干预价值，实则却说明了一个问题：衰老作为疾病体现在更高层次的“涌现”，从衰老切入，很多当下的“不治之症”都或许会有更好的治疗方案。

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