影片《媽媽！》斬獲天壇獎最佳影片提名，讓“85歲高齡母親陪伴不幸罹患老年癡呆女兒”的故事走入萬家。

當下，老年癡呆這類神經(jīng)退行疾病已不再罕見，不少研究指出腸道菌的改變[1]、大腦老化[2]、自噬途徑破壞[3]、線粒體功能障礙[4]等，都是潛在的致病因素。

而這些因素似乎都指向了一個相同的對象——衰老。

美國Salk研究所系統(tǒng)神經(jīng)生物學家約翰·雷諾茲博士就曾表示：“衰老是神經(jīng)退行疾病的最大風險因素”[5]。既如此，用“抗衰方案”去“治病”，豈不是降維打擊、“藥”到病除？

近日，由清華大學藥學院、新型高效NAD+合成激活劑研究者王戈林教授領導，團隊首次系統(tǒng)評估了從熱門抗衰方法——靶向NAD+代謝出發(fā)，改善年齡相關神經(jīng)退行性疾病的可行性，并總結(jié)出多條有效干預措施[6]。

由于NAD+在新陳代謝的中樞作用，近年來它的物質(zhì)合成與分解過程已相對清晰（見下圖），而其橫跨多物種、幾乎無例外隨衰老顯著下降的屬性，又讓它與多種疾病緊密關聯(lián)。

圖注：NAD+的合成與消耗過程

在神經(jīng)退行疾病中，阿爾茨海默病（AD）、帕金森?。≒D）、肌萎縮側(cè)索硬化癥（ALS），稱得上三大代表，臭名昭著的它們是人類健康老齡化路上的重大阻礙。

而想掃除這些“路障”也并非無從下手，研究發(fā)現(xiàn)，多數(shù)神經(jīng)退行疾病的共性是：神經(jīng)元死亡前的軸突損傷與喪失[7, 8]、線粒體功能與穩(wěn)態(tài)失調(diào)[9]。而這些特征都與NAD+水平存在莫大關聯(lián)。

例如，常見于AD與ALS病程中的“瓦勒式變性”（神經(jīng)軸突斷裂后的變性和退化過程），便與NAD+挽救途徑中關鍵酶NMNAT2丟失有關[10, 11]。

而NAD+下降誘導的線粒體障礙也會通過降低生物能量供應與提升內(nèi)環(huán)境氧化應激水平，加劇神經(jīng)元變性、干擾神經(jīng)細胞間的信號通訊[12]。

NAD+水平聯(lián)結(jié)著細胞器、各種分子（蛋白質(zhì)、活性氧等）、遺傳物質(zhì)，形成了復雜的網(wǎng)絡，也為我們預防、延緩，甚至完全治愈神經(jīng)退行疾病提供方向。

圖注：NAD+在細胞水平上的變化與神經(jīng)退行疾病的關聯(lián)

想提升NAD+水平，促進其合成必不可少，好比賬戶的存款想增加，最有效的方法是增加收入。

綜合目前研究證據(jù)已有了一些可行的方案：

No.1

NAD+前體

“補充它=提升NAD+=健康長壽”，流傳于坊間的言論足以說明近年NMN類物質(zhì)的火熱，而風頭正盛的它，亮眼的研究結(jié)果也是一抓一把，其中不少就與神經(jīng)退行疾病有關。

NMN

在神經(jīng)系統(tǒng)保護方面，補充NMN已被證實在多種生物模型中起到不錯效果[13, 14]，并能調(diào)控年齡相關基因的表達、增加線粒體氧化代謝[15, 16]。

不僅如此，NMN脫穎而出還在于其安全性：從嚙齒動物到人類（健康/超重），NMN的攝入都被證實安全、有效改善了代謝健康[15, 17, 18]。

NR

另一被廣泛研究的NAD+前體便是NR。

在正常衰老的小鼠上，NR被證明可延緩神經(jīng)干細胞衰老并延長壽命[19]，并能加速AD小鼠和果蠅體內(nèi)異常聚集蛋白質(zhì)清除[20, 21]。而異常蛋白的聚集正是目前公認的AD最大患病因素。

色氨酸

色氨酸以從頭合成途徑產(chǎn)生NAD+，其代謝失調(diào)與多種神經(jīng)退行疾病的生物標志物有關[22]，當抑制色氨酸關鍵分解酶時，生物體大腦組織如海馬、腦室下區(qū)內(nèi)神經(jīng)元功能可被增強[23]。

NAD+

直接補充NAD+也是提升NAD+水平的途徑之一。向患有帕金森病的小鼠補充NAD+，能有效減輕線粒體功能障礙，減少神經(jīng)元損傷[24]。

但同時，NAD+的利用效率也成為其發(fā)揮效果的掣肘之處——在延緩毒物誘導的神經(jīng)軸突變性時，直接補充NAD+的效果相比其他前體要差不少[25]。

No.2

天然成分

在促進NAD+合成上，天然成分如芹菜素、漆黃素、Embelin（一種從白花酸藤果植物中分離的天然對苯醌）得到了關注。

以研究較為充分的芹菜素與漆黃素為例，這兩種黃酮類物質(zhì)被發(fā)現(xiàn)可分別通過促進線粒體融合與自噬[26]以及激活細胞代謝中PI6K-Akt途徑[27]，實現(xiàn)神經(jīng)系統(tǒng)保護與延緩認知障礙發(fā)生。

圖注：芹菜和草莓是兩者的天然食物來源

合成給力起來，但若是分解飛快，仿佛袋子底部始終有個大洞，NAD+穩(wěn)態(tài)的維持也是難上加難。

如何通過調(diào)節(jié)如Sirtuins、PARP、CD38等消耗酶的活性，減少不必要的NAD+消耗，是當下學者們關心的熱點話題，在此我們將選取重點內(nèi)容與大家分享。

No.1

Sirtuins

在被稱作“長壽蛋白”的Sirtuins家族中（人類有7種sirtuins亞型，稱為SIRT1-7），激活SIRT1已被證明具有神經(jīng)保護作用，是極具潛力的老年相關神經(jīng)退行疾病的干預措施[28-30]。

其中，最明星、最具代表性的便是白藜蘆醇[28]，也一度得到知名學者哈佛大學教授大衛(wèi).辛克萊的大力推薦。

此外，可用于治療糖尿病的磺酰胺衍生物[28]（如甲磺酰脲、格列奈特）、NeuroHeal（AI設計的針對神經(jīng)退行疾病的化合物）[31]也是SIRT1的活化劑。

No.2

CD38

衰老過程中，CD38酶活性的上調(diào)被認為是NAD+下降的主要原因[32]，抑制CD38活性能延緩NAD+的下降[33]，并減輕小鼠AD[34]、ALS[35]疾病進程。

在找尋CD38抑制劑的路上，芹菜素再次被選中。除了前文提到的“能促進NAD+合成”，芹菜素同樣能降低CD38活性[36]，改善神經(jīng)炎癥和毒性及認知障礙[26, 37]。

除上述內(nèi)容，在抑制NAD+消耗上，PARP酶抑制劑如奧拉帕尼[38]、SARM1酶抑制劑小檗堿氯化物[39]等，都逐漸被發(fā)掘與研究。

TIMEPIE點評

當我們不可避免走入衰老的長夜，相比“患有什么特定疾病”，更多情況下“老年共病”則更普遍，治好了某個單病，其他疾病并不能解決，甚至還會出現(xiàn)治療并發(fā)癥。而如果能從多數(shù)慢病的根源去追溯，可能情況就會完全不同。

以今日分享的研究為例，看似僅是評估了靶向NAD+代謝對神經(jīng)退行疾病的干預價值，實則卻說明了一個問題：衰老作為疾病體現(xiàn)在更高層次的“涌現(xiàn)”，從衰老切入，很多當下的“不治之癥”都或許會有更好的治療方案。

—— TIMEPIE ——

這里是只做硬核續(xù)命學研究的TIMEPIE，專注“長壽科技”科普。歡迎評論區(qū)留下你的觀點和我們一起討論。此外，【衰老干預大會】正在籌備中，通過這張”長壽船票“可與國內(nèi)外頂尖學者大咖面對面交流，獲得前沿科研信息和抗衰理念。同時開放招展，誠邀相關企業(yè)、機構(gòu)共同參加，感興趣歡迎來對話框交流。

參考文獻

[1] Zhu, X., Li, B., Lou, P., Dai, T., Chen, Y., & Zhuge, A. et al. (2021). The Relationship Between the Gut Microbiome and Neurodegenerative Diseases. Neuroscience Bulletin, 37(10), 1510-1522. doi: 10.1007/s12264-021-00730-8

[2] Wyss-Coray, T. (2016). Ageing, neurodegeneration and brain rejuvenation. Nature, 539(7628), 180-186. doi: 10.1038/nature20411

[3] Amin, S., Liu, B., & Gan, L. (2023). Autophagy prevents microglial senescence. Nature Cell Biology. doi: 10.1038/s41556-023-01168-y

[4] Johri, A., & Beal, M. (2012). Mitochondrial Dysfunction in Neurodegenerative Diseases. Journal Of Pharmacology And Experimental Therapeutics, 342(3), 619-630. doi: 10.1124/jpet.112.192138

[5] Glavis-Bloom, C., Vanderlip, C., Weiser Novak, S., Kuwajima, M., Kirk, L., & Harris, K. et al. (2023). Violation of the ultrastructural size principle in the dorsolateral prefrontal cortex underlies working memory impairment in the aged common marmoset (Callithrix jacchus). Frontiers In Aging Neuroscience, 15. doi: 10.3389/fnagi.2023.1146245

[6] Li, F., Wu, C., & Wang, G. (2023). Targeting NAD Metabolism for the Therapy of Age-Related Neurodegenerative Diseases. Neuroscience Bulletin. doi: 10.1007/s12264-023-01072-3

[7] Loreto, A., Angeletti, C., Gu, W., Osborne, A., Nieuwenhuis, B., Gilley, J., Merlini, E., Arthur-Farraj, P., Amici, A., Luo, Z., Hartley-Tassell, L., Ve, T., Desrochers, L. M., Wang, Q., Kobe, B., Orsomando, G., & Coleman, M. P. (2021). Neurotoxin-mediated potent activation of the axon degeneration regulator SARM1. eLife, 10, e72823. https://doi.org/10.7554/eLife.72823

[8] Conforti, L., Gilley, J., & Coleman, M. P. (2014). Wallerian degeneration: an emerging axon death pathway linking injury and disease. Nature reviews. Neuroscience, 15(6), 394–409. https://doi.org/10.1038/nrn3680

[9] Fang, E. F., Scheibye-Knudsen, M., Brace, L. E., Kassahun, H., SenGupta, T., Nilsen, H., Mitchell, J. R., Croteau, D. L., & Bohr, V. A. (2014). Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction. Cell, 157(4), 882–896. https://doi.org/10.1016/j.cell.2014.03.026

[10] Figley, M. D., Gu, W., Nanson, J. D., Shi, Y., Sasaki, Y., Cunnea, K., Malde, A. K., Jia, X., Luo, Z., Saikot, F. K., Mosaiab, T., Masic, V., Holt, S., Hartley-Tassell, L., McGuinness, H. Y., Manik, M. K., Bosanac, T., Landsberg, M. J., Kerry, P. S., Mobli, M., … Ve, T. (2021). SARM1 is a metabolic sensor activated by an increased NMN/NAD+ ratio to trigger axon degeneration. Neuron, 109(7), 1118–1136.e11. https://doi.org/10.1016/j.neuron.2021.02.009

[11] Figley, M. D., & DiAntonio, A. (2020). The SARM1 axon degeneration pathway: control of the NAD+ metabolome regulates axon survival in health and disease. Current opinion in neurobiology, 63, 59–66. https://doi.org/10.1016/j.conb.2020.02.012

[12] Bhat, A. H., Dar, K. B., Anees, S., Zargar, M. A., Masood, A., Sofi, M. A., & Ganie, S. A. (2015). Oxidative stress, mitochondrial dysfunction and neurodegenerative diseases; a mechanistic insight. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 74, 101–110. https://doi.org/10.1016/j.biopha.2015.07.025

[13] Chen, X., Amorim, J. A., Moustafa, G. A., Lee, J. J., Yu, Z., Ishihara, K., Iesato, Y., Barbisan, P., Ueta, T., Togka, K. A., Lu, L., Sinclair, D. A., & Vavvas, D. G. (2020). Neuroprotective effects and mechanisms of action of nicotinamide mononucleotide (NMN) in a photoreceptor degenerative model of retinal detachment. Aging, 12(24), 24504–24521. https://doi.org/10.18632/aging.202453

[14] Lee, D., Tomita, Y., Miwa, Y., Shinojima, A., Ban, N., Yamaguchi, S., Nishioka, K., Negishi, K., Yoshino, J., & Kurihara, T. (2022). Nicotinamide Mononucleotide Prevents Retinal Dysfunction in a Mouse Model of Retinal Ischemia/Reperfusion Injury. International journal of molecular sciences, 23(19), 11228. https://doi.org/10.3390/ijms231911228

Kiss, T., Nyúl-Tóth, á., Balasubramanian, P., Tarantini, S., Ahire, C., Yabluchanskiy, A., Csipo, T., [15] Farkas, E., Wren, J. D., Garman, L., Csiszar, A., & Ungvari, Z. (2020). Nicotinamide mononucleotide (NMN) supplementation promotes neurovascular rejuvenation in aged mice: transcriptional footprint of SIRT1 activation, mitochondrial protection, anti-inflammatory, and anti-apoptotic effects. GeroScience, 42(2), 527–546. https://doi.org/10.1007/s11357-020-00165-5

[16] Mills, K. F., Yoshida, S., Stein, L. R., Grozio, A., Kubota, S., Sasaki, Y., Redpath, P., Migaud, M. E., Apte, R. S., Uchida, K., Yoshino, J., & Imai, S. I. (2016). Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice. Cell metabolism, 24(6), 795–806. https://doi.org/10.1016/j.cmet.2016.09.013

[17] Zheng, S. L., Wang, D. S., Dong, X., Guan, Y. F., Qi, Q., Hu, W. J., Hong, C., Zhang, C., & Miao, C. Y. (2023). Distribution of Nicotinamide Mononucleotide after Intravenous Injection in Normal and Ischemic Stroke Mice. Current pharmaceutical biotechnology, 24(2), 299–309. https://doi.org/10.2174/1389201023666220518113219

[18] Pencina, K. M., Lavu, S., Dos Santos, M., Beleva, Y. M., Cheng, M., Livingston, D., & Bhasin, S. (2023). MIB-626, an Oral Formulation of a Microcrystalline Unique Polymorph of β-Nicotinamide Mononucleotide, Increases Circulating Nicotinamide Adenine Dinucleotide and its Metabolome in Middle-Aged and Older Adults. The journals of gerontology. Series A, Biological sciences and medical sciences, 78(1), 90–96. https://doi.org/10.1093/gerona/glac049

[19] Zhang, H., Ryu, D., Wu, Y., Gariani, K., Wang, X., Luan, P., D'Amico, D., Ropelle, E. R., Lutolf, M. P., Aebersold, R., Schoonjans, K., Menzies, K. J., & Auwerx, J. (2016). NAD? repletion improves mitochondrial and stem cell function and enhances life span in mice. Science (New York, N.Y.), 352(6292), 1436–1443. https://doi.org/10.1126/science.aaf2693

[20] Hou, Y., Wei, Y., Lautrup, S., Yang, B., Wang, Y., Cordonnier, S., Mattson, M. P., Croteau, D. L., & Bohr, V. A. (2021). NAD+ supplementation reduces neuroinflammation and cell senescence in a transgenic mouse model of Alzheimer's disease via cGAS-STING. Proceedings of the National Academy of Sciences of the United States of America, 118(37), e2011226118. https://doi.org/10.1073/pnas.2011226118

[21] Sch?ndorf, D. C., Ivanyuk, D., Baden, P., Sanchez-Martinez, A., De Cicco, S., Yu, C., Giunta, I., Schwarz, L. K., Di Napoli, G., Panagiotakopoulou, V., Nestel, S., Keatinge, M., Pruszak, J., Bandmann, O., Heimrich, B., Gasser, T., Whitworth, A. J., & Deleidi, M. (2018). The NAD+ Precursor Nicotinamide Riboside Rescues Mitochondrial Defects and Neuronal Loss in iPSC and Fly Models of Parkinson's Disease. Cell reports, 23(10), 2976–2988. https://doi.org/10.1016/j.celrep.2018.05.009

[22] Maddison, D. C., & Giorgini, F. (2015). The kynurenine pathway and neurodegenerative disease. Seminars in cell & developmental biology, 40, 134–141. https://doi.org/10.1016/j.semcdb.2015.03.002

[23] Kanai, M., Funakoshi, H., Takahashi, H., Hayakawa, T., Mizuno, S., Matsumoto, K., & Nakamura, T. (2009). Tryptophan 2,3-dioxygenase is a key modulator of physiological neurogenesis and anxiety-related behavior in mice. Molecular brain, 2, 8. https://doi.org/10.1186/1756-6606-2-8

[24] Shan, C., Gong, Y. L., Zhuang, Q. Q., Hou, Y. F., Wang, S. M., Zhu, Q., Huang, G. R., Tao, B., Sun, L. H., Zhao, H. Y., Li, S. T., & Liu, J. M. (2019). Protective effects of β- nicotinamide adenine dinucleotide against motor deficits and dopaminergic neuronal damage in a mouse model of Parkinson's disease. Progress in neuro-psychopharmacology & biological psychiatry, 94, 109670. https://doi.org/10.1016/j.pnpbp.2019.109670

[25] Vaur, P., Brugg, B., Mericskay, M., Li, Z., Schmidt, M. S., Vivien, D., Orset, C., Jacotot, E., Brenner, C., & Duplus, E. (2017). Nicotinamide riboside, a form of vitamin B3, protects against excitotoxicity-induced axonal degeneration. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 31(12), 5440–5452. https://doi.org/10.1096/fj.201700221RR

[26] Ahmedy, O. A., Abdelghany, T. M., El-Shamarka, M. E. A., Khattab, M. A., & El-Tanbouly, D. M. (2022). Apigenin attenuates LPS-induced neurotoxicity and cognitive impairment in mice via promoting mitochondrial fusion/mitophagy: role of SIRT3/PINK1/Parkin pathway. Psychopharmacology, 239(12), 3903–3917. https://doi.org/10.1007/s00213-022-06262-x

[27] Watanabe, R., Kurose, T., Morishige, Y., & Fujimori, K. (2018). Protective Effects of Fisetin Against 6-OHDA-Induced Apoptosis by Activation of PI3K-Akt Signaling in Human Neuroblastoma SH-SY5Y Cells. Neurochemical research, 43(2), 488–499. https://doi.org/10.1007/s11064-017-2445-z

[28] Apiraksattayakul, S., Pingaew, R., Prachayasittikul, V., Ruankham, W., Jongwachirachai, P., Songtawee, N., Suwanjang, W., Tantimongcolwat, T., Prachayasittikul, S., Prachayasittikul, V., & Phopin, K. (2022). Neuroprotective Properties of Bis-Sulfonamide Derivatives Against 6-OHDA-Induced Parkinson's Model via Sirtuin 1 Activity and in silico Pharmacokinetic Properties. Frontiers in molecular neuroscience, 15, 890838. https://doi.org/10.3389/fnmol.2022.890838

[29] Chandrasekaran, K., Salimian, M., Konduru, S. R., Choi, J., Kumar, P., Long, A., Klimova, N., Ho, C. Y., Kristian, T., & Russell, J. W. (2019). Overexpression of Sirtuin 1 protein in neurons prevents and reverses experimental diabetic neuropathy. Brain : a journal of neurology, 142(12), 3737–3752. https://doi.org/10.1093/brain/awz324

[30] Ross, A. G., Chaqour, B., McDougald, D. S., Dine, K. E., Duong, T. T., Shindler, R. E., Yue, J., Liu, T., & Shindler, K. S. (2022). Selective Upregulation of SIRT1 Expression in Retinal Ganglion Cells by AAV-Mediated Gene Delivery Increases Neuronal Cell Survival and Alleviates Axon Demyelination Associated with Optic Neuritis. Biomolecules, 12(6), 830. https://doi.org/10.3390/biom12060830

[31] Romeo-Guitart, D., Marcos-DeJuana, C., Marmolejo-Martínez-Artesero, S., Navarro, X., & Casas, C. (2020). Novel neuroprotective therapy with NeuroHeal by autophagy induction for damaged neonatal motoneurons. Theranostics, 10(11), 5154–5168. https://doi.org/10.7150/thno.43765

[32] Camacho-Pereira, J., Tarragó, M. G., Chini, C. C. S., Nin, V., Escande, C., Warner, G. M., Puranik, A. S., Schoon, R. A., Reid, J. M., Galina, A., & Chini, E. N. (2016). CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism. Cell metabolism, 23(6), 1127–1139. https://doi.org/10.1016/j.cmet.2016.05.006

[33] Tarragó, M. G., Chini, C. C. S., Kanamori, K. S., Warner, G. M., Caride, A., de Oliveira, G. C., Rud, M., Samani, A., Hein, K. Z., Huang, R., Jurk, D., Cho, D. S., Boslett, J. J., Miller, J. D., Zweier, J. L., Passos, J. F., Doles, J. D., Becherer, D. J., & Chini, E. N. (2018). A Potent and Specific CD38 Inhibitor Ameliorates Age-Related Metabolic Dysfunction by Reversing Tissue NAD+ Decline. Cell metabolism, 27(5), 1081–1095.e10. https://doi.org/10.1016/j.cmet.2018.03.016

[34] Blacher, E., Dadali, T., Bespalko, A., Haupenthal, V. J., Grimm, M. O., Hartmann, T., Lund, F. E., Stein, R., & Levy, A. (2015). Alzheimer's disease pathology is attenuated in a CD38-deficient mouse model. Annals of neurology, 78(1), 88–103. https://doi.org/10.1002/ana.24425

[35] Harlan, B. A., Killoy, K. M., Pehar, M., Liu, L., Auwerx, J., & Vargas, M. R. (2020). Evaluation of the NAD+ biosynthetic pathway in ALS patients and effect of modulating NAD+ levels in hSOD1-linked ALS mouse models. Experimental neurology, 327, 113219. https://doi.org/10.1016/j.expneurol.2020.113219

[36] Escande, C., Nin, V., Price, N. L., Capellini, V., Gomes, A. P., Barbosa, M. T., O'Neil, L., White, T. A., Sinclair, D. A., & Chini, E. N. (2013). Flavonoid apigenin is an inhibitor of the NAD+ ase CD38: implications for cellular NAD+ metabolism, protein acetylation, and treatment of metabolic syndrome. Diabetes, 62(4), 1084–1093. https://doi.org/10.2337/db12-1139

[37] Roboon, J., Hattori, T., Ishii, H., Takarada-Iemata, M., Nguyen, D. T., Heer, C. D., O'Meally, D., Brenner, C., Yamamoto, Y., Okamoto, H., Higashida, H., & Hori, O. (2021). Inhibition of CD38 and supplementation of nicotinamide riboside ameliorate lipopolysaccharide-induced microglial and astrocytic neuroinflammation by increasing NAD. Journal of neurochemistry, 158(2), 311–327. https://doi.org/10.1111/jnc.15367

[38] Banfi, F., Rubio, A., Zaghi, M., Massimino, L., Fagnocchi, G., Bellini, E., Luoni, M., Cancellieri, C., Bagliani, A., Di Resta, C., Maffezzini, C., Ianielli, A., Ferrari, M., Piazza, R., Mologni, L., Broccoli, V., & Sessa, A. (2021). SETBP1 accumulation induces P53 inhibition and genotoxic stress in neural progenitors underlying neurodegeneration in Schinzel-Giedion syndrome. Nature communications, 12(1), 4050. https://doi.org/10.1038/s41467-021-24391-3

[39] Wang, S., Zhang, Y., Lou, J., Yong, H., Shan, S., Liu, Z., Song, M., Zhang, C., Kou, R., Liu, Z., Yu, W., Zhao, X., & Song, F. (2023). The therapeutic potential of berberine chloride against SARM1-dependent axon degeneration in acrylamide-induced neuropathy. Phytotherapy research : PTR, 37(1), 77–88. https://doi.org/10.1002/ptr.7594