编者按
       作为人体最重要的辅酶,NAD+的抗衰老作用被越来越多的研究发现,临床试验无疑是对其安全性和有效性最有力证明,本文将全球可以检索到的NAD+补充剂临床汇总起来供大家查阅。为加深理解,将先重点介绍几点,然后将相关临床罗列于后。

 

NAD+用药指南

       相比于NAD+补充剂,直接补充NAD+更为直接(注射形式)。NAD+早已作临床药用,国内主要有注射用辅酶I和复合辅酶(辅酶A+辅酶I),有意思是,复合辅酶的用法中有一条是“肿瘤病人要酌情加量”,这直接反驳了孤立地研究NAD+促癌的言论。

 

数据来源:CFDA网站

 

NAD+补充剂重要临床

       任何临床都需要有相应的适应症,目前世界上没有一国家的药品监管部门承认衰老是一种疾病,因此不会有关于NAD+治疗衰老的临床。最大的进步是2018年世界卫生组织在《国际疾病法典》中宣布,衰老是一种可以治疗的疾病。所幸的是我们可以从其他相关研究中窥伺一二,1965年~1985年美国进行了一项名为“Coronary Drug Project”长达20年的临床试验,本来这个实验是为了分析心肌梗死患者服用降脂药是否会降低5年内死亡率,但采用了烟酸这种NAD+补充剂的双盲试验,可谓搂草打兔子。

 

       在15年的临床试验中,1119人服用烟酸,2789人服用安慰剂,最后统计发现:实验组比安慰剂组的全因死亡率低11%,换个说法是烟酸延长了11%的寿命;更细的结果是:实验组比安慰剂组,心脏病和癌症的死亡率均降低,可以说是NAD+降低了癌症发生率。

 

数据来源:Fifteen Year Mortality in Coronary Drug Project Patients: Long-Term Benefit With Niacin

 

实验组和安慰剂组的全因死亡率

 

NMN临床

       披露的NMN临床有4例,日本有3例NMN临床试验美国有1例。广岛大学最近公布长期口服的NMN中期临床试验:NMN提升了Sirtuin1水平,有助于辅助癌症治疗;庆应大学在结束了I期临床的基础上,于2017年开启了II期临床;美国华盛顿大学则于2017年开启了针对的是对糖代谢的I期临床。除了披露的临床试验据报道,Sinclair Metrobio study的NMN临床已经结束了一期,在进行二期临床。

 

数据来源:日本大学医院信息网UMIN-CTR Clinical Trial和美国ClinicalTrials.go

 

NMN是在近几年才广受关注,动物实验相对更多,将各个研究的动物实验罗列如下。

数据来源:各个研究文献,请查阅后文

 

NAD+补充剂临床

       NAD+前体有长达60多年的安全用药史,有数十项临床到达III期、Ⅳ期,有的临床实验更是长达十几年,安全性无需顾虑。烟酰胺、烟酰胺核糖、烟酸、色氨酸是四类较差的NAD+补充剂,以下表格了检索了全球这四类NAD+补充剂的临床试验。其中烟酰胺和烟酰胺核糖有52项临床(考虑到语言问题,可能有遗漏;考虑到关键词,可能有重复),烟酸有52项临床(考虑到语言问题,可能有遗漏),色氨酸有20项临床(考虑到语言问题,可能有遗漏)。

 

 

参考文献:

[1] Revollo, J.R., Korner, A., Mills, K.F., Satoh, A., Wang, T., Garten, A., Dasgupta, B., Sasaki, Y., Wolberger, C., Townsend, R.R., et al. (2007). Nampt/PBEF/Visfatin regulates insulin secretion in beta cells as a systemic NAD biosynthetic enzyme. Cell Metab. 6, 363–375.

[2] Ramsey, K.M., Mills, K.F., Satoh, A., and Imai, S. (2008). Age-associated loss of Sirt1-mediated enhancement of glucose-stimulated insulin secretion in beta cell-specific Sirt1-overexpressing (BESTO) mice. Aging Cell 7, 78–88.

[3] Yoshino, J., Mills, K.F., Yoon, M.J., and Imai, S. (2011). Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 14, 528–536.

[4] Caton, P.W., Kieswich, J., Yaqoob, M.M., Holness, M.J., and Sugden, M.C. (2011). Nicotinamide mononucleotide protects against pro-inflammatory cytokine-mediated impairment of mouse islet function. Diabetologia 54, 3083–3092.

[5] Gomes, A.P., Price, N.L., Ling, A.J., Moslehi, J.J., Montgomery, M.K., Rajman, L., White, J.P., Teodoro, J.S., Wrann, C.D., Hubbard, B.P., et al. (2013). Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell 155, 1624–1638.

[6] Peek, C.B., Affinati, A.H., Ramsey, K.M., Kuo, H.Y., Yu, W., Sena, L.A., Ilkayeva, O., Marcheva, B., Kobayashi, Y., Omura, C., et al. (2013). Circadian clock NAD+ cycle drives mitochondrial oxidative metabolism in mice. Science 342, 1243417.

[7] Karamanlidis, G., Lee, C.F., Garcia-Menendez, L., Kolwicz, S.C., Jr., Suthammarak, W., Gong, G., Sedensky, M.M., Morgan, P.G., Wang, W., and Tian, R.(2013). Mitochondrial complex I deficiency increases protein acetylation and accelerates heart failure. Cell Metab. 18, 239–250.

[8] Choi, S.E., Fu, T., Seok, S., Kim, D.H., Yu, E., Lee, K.W., Kang, Y., Li, X., Kemper, B., and Kemper, J.K. (2013). Elevated microRNA-34a in obesity reduces NAD+ levels and SIRT1 activity by directly targeting NAMPT. Aging Cell 12, 1062–1072.

[9] Stein, L.R., and Imai, S. (2014). Specific ablation of Nampt in adult neural stem cells recapitulates their functional defects during aging. EMBO J. 33, 1321–1340.

[10] Yamamoto, T., Byun, J., Zhai, P., Ikeda, Y., Oka, S., and Sadoshima, J. (2014). Nicotinamide mononucleotide, an intermediate of NAD+ synthesis, protects the heart from ischemia and reperfusion. PLoS One 9, e98972.

[11] Picciotto N D , Gano L , Johnson L , et al. Nicotinamide mononucleotide supplementation reverses vascular endothelial dysfunction and large elastic artery stiffness in old mice (698.10)[J]. Faseb Journal, 2014.

[12] Long, A.N., Owens, K., Schlappal, A.E., Kristian, T., Fishman, P.S., and Schuh, R.A. (2015). Effect of nicotinamide mononucleotide on brain mitochondrial respiratory deficits in an Alzheimer’s disease-relevant murine model. BMC Neurol. 15, 19.

[13] Yoon, M.J., Yoshida, M., Johnson, S., Takikawa, A., Usui, I., Tobe, K., Nakagawa, T., Yoshino, J., and Imai, S. (2015). SIRT1-mediated eNAMPT secretion from adipose tissue regulates hypothalamic NAD(+) and function in mice. Cell Metab. 21, 706–717.

[14] Zhao Y , Guan Y F , Zhou X M , et al. Regenerative Neurogenesis After Ischemic Stroke Promoted by Nicotinamide Phosphoribosyltransferase-Nicotinamide Adenine Dinucleotide Cascade.[J]. Stroke; a journal of cerebral circulation, 2015, 46(7):1966.

[15] Park, J.H., Long, A., Owens, K., and Kristian, T. (2016). Nicotinamide mononucleotide inhibits post-ischemic NAD(+) degradation and dramatically ameliorates brain damage following global cerebral ischemia. Neurobiol. Dis. 95, 102–110.

[16] de Picciotto, N.E., Gano, L.B., Johnson, L.C., Martens, C.R., Sindler, A.L., Mills, K.F., Imai, S., and Seals, D.R. (2016). Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice. Aging Cell 15, 522–530.

[17] Lin, J.B., Kubota, S., Ban, N., Yoshida, M., Santeford, A., Sene, A., Nakamura, R., Zapata, N., Kubota, M., Tsubota, K., et al. (2016). NAMPT-mediated NAD(+) biosynthesis is essential for vision in mice. Cell Rep. 17, 69–85.

[18] Stromsdorfer, K.L., Yamaguchi, S., Yoon, M.J., Moseley, A.C., Franczyk, M.P., Kelly, S.C., Qi, N., Imai, S., and Yoshino, J. (2016). NAMPT-mediated NAD(+) biosynthesis in adipocytes regulates adipose tissue function and multi-organ insulin sensitivity in mice. Cell Rep. 16, 1851–1860.

[19] Lee, C.F., Chavez, J.D., Garcia-Menendez, L., Choi, Y., Roe, N.D., Chiao, Y.A., Edgar, J.S., Goo, Y.A., Goodlett, D.R., Bruce, J.E., et al. (2016). Normalization of NAD+ redox balance as a therapy for heart failure. Circulation 134, 883–894.

[20] Wang, X., Hu, X., Yang, Y., Takata, T., and Sakurai, T. (2016). Nicotinamide mononucleotide protects against beta-amyloid oligomer-induced cognitive impairment and neuronal death. Brain Res. 1643, 1–9.

[21] Mills KF, Yoshida S, Stein LR, Grozio A, Kubota S, Sasaki Y, Redpath P, Migaud ME, Apte RS, Uchida K, Yoshino J, Imai SI (2016) Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metab 24:795–806

[22] Uddin, G. M. , Youngson, N. A. , Sinclair, D. A. , & Morris, M. J. . (2016). Head to head comparison of short-term treatment with the nad+ precursor nicotinamide mononucleotide (nmn) and 6 weeks of exercise in obese female mice. Frontiers in Pharmacology, 7.

[23] Yao, Z., Yang, W., Gao, Z., and Jia, P. (2017). Nicotinamide mononucleotide inhibits JNK activation to reverse Alzheimer disease. Neurosci. Lett. 647, 133–140.

[24] Wei, C.C., Kong, Y.Y., Li, G.Q., Guan, Y.F., Wang, P., and Miao, C.Y. (2017a). Nicotinamide mononucleotide attenuates brain injury after intracerebral hemorrhage by activating Nrf2/HO-1 signaling pathway. Sci. Rep. 7, 717.

[25] Li, J., Bonkowski, M.S., Moniot, S., Zhang, D., Hubbard, B.P., Ling, A.J., Rajman, L.A., Qin, B., Lou, Z., Gorbunova, V., et al. (2017). A conserved NAD+ binding pocket that regulates protein-protein interactions during aging. Science 355, 1312–1317.

[26] Guan, Y., Wang, S.R., Huang, X.Z., Xie, Q.H., Xu, Y.Y., Shang, D., and Hao, C.M. (2017). Nicotinamide mononucleotide, an NAD+ precursor, rescues age-associated susceptibility to AKI in a sirtuin 1-dependent manner. J. Am. Soc. Nephrol. 28, 2337–2352.

[27] Martin AS, Abraham DM, Hershberger KA, Bhatt DP, Mao L, Cui H, Liu J, Liu X, Muehlbauer MJ, Grimsrud PA, Locasale JW, Payne RM, Hirschey MD (2017) Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich’s ataxia cardiomyopathy model. JCI Insight 2:93885

[28] Wei, C.C., Kong, Y.Y., Xia, H., Li, G.Q., Zheng, S.L., Cheng, M.H., Wang, P., and Miao, C.Y. (2017b). NAD replenishment with nicotinamide mononucleotide protects blood-brain barrier integrity and attenuates delayed tPA-induced haemorrhagic transformation after cerebral ischemia. Br. J. Pharmacol. 174, 3823–3836.

[29] Zhang, R. , Shen, Y. , Zhou, L. , Sangwung, P. , Fujioka, H. , & Zhang, L. , et al. (2017). Short-term administration of nicotinamide mononucleotide preserves cardiac mitochondrial homeostasis and prevents heart failure. Journal of Molecular and Cellular Cardiology, 112, 64-73.

[30] Uddin, G. M. , Youngson, N. A. , Doyle, B. M. , Sinclair, D. A. , & Morris, M. J. . (2017). Nicotinamide mononucleotide (nmn) supplementation ameliorates the impact of maternal obesity in mice: comparison with exercise. Scientific Reports, 7(1).

[31] Nadtochiy SM, Wang YT, Nehrke K, Munger J, Brookes PS (2018) Cardioprotection by nicotinamide mononucleotide (NMN): involvement of glycolysis and acidic pH. J Mol Cell Cardiol 121:155–162