吃不起“长寿药”NMN,便宜大碗的烟酰胺NAM能成为平替吗?

虽说已是2021年,但“富商不老药”NMN家族仍是一番欣欣向荣之景,全新的积极研究结果也不断涌现。像是近期NAD +被发现能辅助癌症免疫治疗[1],为NMN癌症的关联再度画下浓墨重彩的一笔。

然而,不同于以往直接补充NMN,该项研究使用烟酰胺(NAM)作为前体物质来提升NAD +水平。既然NMN那么贵(动辄大几千),我能否用物美价廉的NAM作为替代品呢?看完NAM的科普,你定然会有答案。

图注:NAM分子结构及常用名称。图源[2]

是糙皮病的救星,也是肌肤年轻的秘密

1937年,正值糙皮病盛行之时,NAM如天降珍宝,成为众多患者的救命良药[3],其副作用小[4],易溶解于水、吸收较好[5],因此成为了治疗糙皮病的首选药物。

在帮助人类终结糙皮病后,NAM依旧扎根老本行,与困扰人类的多种皮肤健康问题斡旋,逐步奠定了在肌肤护理领域的王者地位。

例如,人体试验已经证实,仅需外用适宜浓度NAM,2周后就能显著降低皮脂排泄率[6],还能通过抑制痤疮杆菌诱导的Toll样受体2激活,降低体内促炎因子IL-8水平[7],消炎、抗氧化、加快血管新生促进伤口愈合[8]。

除此外,真正让NAM名声大噪,还是其偶然间被发掘,能通过阻断黑色素转移达到的美白功效[9-11]。进一步研究发现,NAM能促进表皮细胞胶原蛋白[12]及神经酰胺合成,改善肌肤屏障[13],再加上调控p53蛋白表达[14],共同对抗光老化。

人体试验更是表明,在接受12周5%烟酰胺的局部治疗后,中年女性的皮肤衰老(皱纹及色斑)问题得到肉眼可见的显著改善[15]。

图注:受试者在使用前与12周5%烟酰胺的局部治疗后

远不止“皮毛功夫”,

NAM体内代谢循环来咯

NAM延缓肌肤衰老确实好,但若是仅做些“表面功夫”,又好像不那么刺激。泡上一杯绿茶,派派继续外网遨游,终于探寻到作为一名抗衰达人该讲的东西。

2018年的一项研究发现,NAM能通过改善高脂饮食小鼠体内葡萄糖稳态肝脏脂肪情况延长小鼠的健康寿命,还参与了NAD +相关代谢过程[16]。这一发现,似乎在宣示NAM可能并不仅仅有消炎、除皱的功效

遍寻数据库与众多文献,派派终于找到NAM代谢“宝藏地图”,想先放出与大家共享。请各位往下看:

图注:NAM主要代谢途径。图源:[17]

看到这错综复杂的箭头线框,你是否:

别担忧看不懂,时光派独家整理、划重点型NAM主要代谢通路这就为各位奉上。

图注:时光派独家整理NAM主要生物学代谢通路

从上述代谢通路中,不难发现NAM与NAD +之间“千丝万缕的纠葛”。在身体各个组织中,NAM作为前体可在NAMPT催化下生成NMN,进而转化为NAD +;而NAM同时也是NAD +在众多消耗酶(如CD38、PARPs、SIRTs)作用下的产物

除此外,NAM还能通过去氨基反应生成NA(烟酸),借助NA的代谢通路,间接参与生物碱、柠檬酸、丙酮酸以及多种氨基酸代谢,甚至再次关联NAD +途径

从代谢通路上看,NAM几乎“打通了”NAD +关联的“任督二脉”,那么,这是否意味着,NAM真是提升NAD +水平的物美价廉好方法?

作为前体之一,

NAM却可能无法有效提升NAD +

虽然从代谢通路上分析,NAM确实是NAD +补救合成途径中的前体,但若真用它去补充NAD +,结果可能是“赔了夫人还折兵”。

在NAD +补救合成途径中,NAMPT是反应的限速酶[18, 19],这意味着即使你一个劲补充NAM,最后也只有很少部分会参与到合成NAD +中。甚至,先前小鼠体内研究发现,补充NAM根本无法有效提升NAD +水平[16]。

毫不夸张讲,NAM贡献的这点量,与NAD +因衰老而下降的幅度相比,实在是杯水车薪,难解燃眉之急。

用得不多、还不断生成,因此,NAM其实很容易过剩,而一旦其过量,就可能导致不少问题。

首先,从NAD +合成上讲,多余NAM可能抑制NAMPT活性[16],进一步限制了补救合成途径;其次,在负反馈机制的调控下,过量NAM会反过来抑制包括长寿蛋白Sirtuins[20]在内的多种NAD +消耗途径。

最后,过剩的NAM作为甲基受体,还可能显著影响细胞甲基代谢,干扰DNA和蛋白质的正常甲基化[21],造成如胰岛素抵抗、帕金森症肝脏毒性等不良影响[22, 23]。

最后,实锤NAM无效的证据是:我们的身体在日渐衰老中,压根就不缺NAM,老年人体内NAM的含量比年轻人还要高上不少[19]。

NAD +“日薄西山”,NAM纵然有心也无力,妄图依靠摄入它来提升NAD +,怕是还没延年益寿,就要先迎接副作用的狂风暴雨,听一句劝,别尝试了。

一点讨论:NAM究竟多少才算好?

“每一个硬币都有两面”,几乎不可能存在某一绝对“好”或“坏”的事物,NAM其实也是这么一回事,在生物体内含量不同,就可能造成完全不一样的结果。

前文提到,过量NAM会抑制SIRT1,影响机体NAD +过程。但不少实验甚至是临床研究也发现,低剂量NAM正是通过抑制SIRT1与PARP1,调控细胞周期代谢通路(如KRAS/AKT通路),以及关联基因(如Myc癌基因)的表达,进而预防或辅助多种癌症治疗[24-26]。

此外,还存在低剂量NAM可能治疗糖尿病、起到神经保护作用[27],高剂量又会导致胰岛素抵抗、帕金森症的矛盾现象。一条大大的“U”形曲线仿佛已呈现在眼前。

“成也萧何,败也萧何”,虽然可以肯定的是,从提升NAD +角度来说,NAM真的不是个好选择,但它是否真在其他领域有用武之地,或者应该怎么用、用多少,都值得再去思考。

—— TIMEPIE ——

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参考文献

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