PMCID: PMC7238909 PMCID：PMC7238909 The Science Behind NMN–A Stable, Reliable NAD+Activator and Anti-Aging Molecule
NMN背后的科学——一种稳定、可靠的NAD+激活剂和抗衰老分子In June of 2018, the World Health Organization (WHO) released the 11th edition of its International Classification of Diseases, and for the first time added aging.1 The classification of aging as a disease paves the way for new research into novel therapeutics to delay or reverse age-related illnesses such as cancer, cardiovascular and metabolic disease, and neurodegeneration.2,3 Nutrient sensing systems have been an intense focus of investigation, including mTOR (the mammalian target of rapamycin) for regulating protein synthesis and cell growth; AMPK (activated protein kinase) for sensing low energy states; and sirtuins, a family of seven proteins critical to DNA expression and aging, which can only function in conjunction with NAD+ (nicotinamide adenine dinucleotide), a coenzyme present in all living cells.4
2018年6月，世界卫生组织（WHO）发布了第11版《国际疾病分类》，并首次增加了老龄化。 1 将衰老归类为一种疾病，为新疗法的新研究铺平了道路，以延缓或逆转与年龄相关的疾病，如癌症、心血管和代谢疾病以及神经退行性疾病。 2,3 营养传感系统一直是研究的重点，包括用于调节蛋白质合成和细胞生长的mTOR（雷帕霉素的哺乳动物靶标）;AMPK（活化蛋白激酶）用于感知低能量状态;和 sirtuins，一个对 DNA 表达和衰老至关重要的七种蛋白质家族，它只能与 NAD+（烟酰胺腺嘌呤二核苷酸）结合使用，NAD+ 是一种存在于所有活细胞中的辅酶。 4 Across the kingdom of life, an increase in intracellular levels of NAD+ triggers shifts that enhance survival, including boosting energy production and upregulating cellular repair.5 In fact, the slow, ineluctable process of aging has been described as a “cascade of robustness breakdown triggered by a decrease in systemic NAD+ biosynthesis and the resultant functional defects in susceptible organs and tissues.”6 Aging is marked by epigenetic shifts, genomic instability, altered nutrient sensing ability, telomere attrition, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and dysregulated intercellular communication.7,8
在整个生命王国中，NAD+细胞内水平的增加会引发提高生存率的转变，包括促进能量产生和上调细胞修复。 5 事实上，缓慢、不可避免的衰老过程被描述为“由全身性 NAD+ 生物合成减少以及由此产生的易感器官和组织功能缺陷引发的稳健性崩溃级联”。 6 衰老的特征是表观遗传变化、基因组不稳定、营养感知能力改变、端粒细胞损耗、线粒体功能障碍、细胞衰老、干细胞耗竭和细胞间通讯失调。 7,8 By middle age, our NAD+ levels have plummeted to half that of our youth.9 Numerous studies have demonstrated that boosting NAD+ levels increases insulin sensitivity, reverses mitochondrial dysfunction, and extends lifespan.10,11 NAD+ levels can be increased by activating enzymes that stimulate synthesis of NAD+, by inhibiting an enzyme (CD38) that degrades NAD+, and by supplementing with NAD precursors, including nicotinamide riboside(NR) and nicotinamide mononucleotide (NMN).12,13 A conceptual framework called NAD World, formulated over the last decade by developmental biologist Shin-ichiro Imai, MD, PhD, of Washington University School of Medicine, posits NMN as a critical, systemic signaling molecule that maintains biological robustness of the communication network supporting NAD+.6
到了中年，我们的NAD+水平已经下降到年轻人的一半。 9 大量研究表明，提高 NAD+ 水平可增加胰岛素敏感性、逆转线粒体功能障碍并延长寿命. 10,11 通过激活刺激 NAD+ 合成的酶、抑制降解 NAD+ 的酶 （CD38） 以及补充 NAD 前体（包括烟酰胺核苷 （NR） 和烟酰胺单核苷酸 （NMN））可以提高 NAD+ 水平。 12,13 华盛顿大学医学院的发育生物学家Shin-ichiro Imai医学博士在过去十年中制定了一个名为NAD World的概念框架，将NMN视为一种关键的系统性信号分子，可维持支持NAD+的通信网络的生物稳健性。 6 Taken orally, NMN is rapidly absorbed and converted to NAD+.14 In numerous studies, supplementation with NMN has increased NAD+ biosynthesis, suppressed age-related adipose tissue inflammation, enhanced insulin secretion and insulin action, improved mitochondrial function, improved neuronal function in the brain, and more. Here, we look at the science behind NMN, its stability, possible pharmacokinetics, transport, function, and ability to induce biosynthesis of NAD+.15 Supplementing NMN may be an effective nutraceutical anti-aging intervention, with beneficial effects on a wide array of physiological functions.16
口服，NMN被迅速吸收并转化为NAD+。 14 在许多研究中，补充 NMN 增加了 NAD+ 的生物合成，抑制了与年龄相关的脂肪组织炎症，增强了胰岛素分泌和胰岛素作用，改善了线粒体功能，改善了大脑中的神经元功能等等。在这里，我们研究了 NMN 背后的科学、其稳定性、可能的药代动力学、转运、功能和诱导 NAD+ 生物合成的能力。 15 补充NMN可能是一种有效的营养保健品抗衰老干预措施，对多种生理功能有益。 16 Pathways to NMN in the Human Body
人体内NMN的通路A veritable symphony of interlocking transformations allows NAD+ to be both synthesized and regulated in the body. It is well known that vitamin B3 is a building block for Nicotinamide adenine dinucleotide (NAD+). It is also widely recognized that NMN is a potent precursor for NAD+. Though NMN is naturally found in small amounts in fruits and vegetables such as avocados, broccoli, cabbage, edamame, and cucumbers17, in mammals most NMN is synthesized from vitamin B3 in the form of nicotinamide. At the center is nicotinamide phosphoribosyltransferase (NAMPT), an essential rate-limiting enzyme that catalyzes the conversion from nicotinamide to NMN, which exists in both an intracellular (iNAMPT) and extracellular form (eNAMPT).18 The extracellular form has higher enzymatic activity than the intracellular form and has been found in blood plasma, seminal plasma and cerebrospinal fluid in humans.19,20 In addition, eNAMPT appears to be produced by a wide array of cell types—including fat (adipocytes), liver (hepatocytes), white blood cells (leukocytes and monocytes), and heart and brain cells (cardiomyocytes and glia cells).21 Like NAD+ and NMN, eNAMPT declines with age. Both white and brown adipocytes actively secrete eNAMPT, suggesting that fatty tissue may be a modulator of NAD+ biosynthesis.6 Adipose tissue actively secretes extracellular vesicles (EVs) that are enriched with NMN, and can circulate through the plasma. EVs are membrane-derived particles surrounded by a phospholipid bilayer that are released by cells in the human body.22 These EVs not only protect their cargo, they can deposit their payload where needed.23
名副其实的环环相扣的交响乐使 NAD+ 在体内得到合成和调节。众所周知，维生素B 3 是烟酰胺腺嘌呤二核苷酸（NAD+）的组成部分。人们还普遍认为，NMN是NAD+的有效前体。虽然 NMN 天然存在于水果和蔬菜中，如鳄梨、西兰花、卷心菜、毛豆和黄瓜 17 ，但在哺乳动物中，大多数 NMN 是由维生素 B 3 以烟酰胺的形式合成的。其中心是烟酰胺磷酸核糖基转移酶 （NAMPT），这是一种必需的限速酶，可催化从烟酰胺转化为 NMN，NMN 以细胞内 （iNAMPT） 和细胞外形式 （eNAMPT） 存在。 18 细胞外形式比细胞内形式具有更高的酶活性，并且已在人类的血浆、精浆和脑脊液中发现。 19,20 此外，eNAMPT似乎由多种细胞类型产生，包括脂肪（脂肪细胞）、肝脏（肝细胞）、白细胞（白细胞和单核细胞）以及心脏和脑细胞（心肌细胞和神经胶质细胞）。 21 与 NAD+ 和 NMN 一样，eNAMPT 会随着年龄的增长而下降。白色和棕色脂肪细胞都积极分泌 eNAMPT，表明脂肪组织可能是 NAD+ 生物合成的调节剂。 6 脂肪组织主动分泌富含 NMN 的细胞外囊泡 （EV），并可在血浆中循环。EV 是膜衍生的颗粒，被磷脂双层包围，由人体细胞释放。 22 这些电动汽车不仅可以保护货物，还可以将有效载荷存放在需要的地方。 23 NMN and NR dance together. NMN can be converted by the body to NR, which then enters cells, and is converted back to NMN by an enzyme called nicotinamide riboside kinase (NRK). More recently, an “elusive’ transporter was discovered, which can transport NMN directly into cells.24 NMN is transported across cell membranes directly into the cytoplasm of the cell, by an enzyme called Slc12a8. Uptake pathways of NMN vary with tissue types, and interestingly, Slc12a8 expression is about 100-fold times higher in the small intestine of mice than the brain or adipose tissue. Researchers speculate that the gut microbiome, and certain resident bacteria within it, may produce NMN.25
NMN 和 NR 一起跳舞。NMN 可以被人体转化为 NR，然后进入细胞，并通过一种称为烟酰胺核苷激酶 （NRK） 的酶转化回 NMN。最近，人们发现了一种“难以捉摸”的转运蛋白，它可以将NMN直接转运到细胞中。 24 NMN 通过一种称为 Slc12a8 的酶穿过细胞膜直接转运到细胞的细胞质中。NMN的摄取途径因组织类型而异，有趣的是，Slc12a8在小鼠小肠中的表达比大脑或脂肪组织高约100倍。研究人员推测，肠道微生物组和其中的某些常驻细菌可能会产生NMN。 25 NMN levels fall with age, and aging itself has also been shown to significantly compromise the body’s conversion of NMN to NAD+.26
NMN水平随着年龄的增长而下降，衰老本身也被证明会显着损害身体将NMN转化为NAD+。 26 Abundant Evidence for Anti-aging and Health-Enhancing Effects of NMN
NMN抗衰老和增强健康作用的丰富证据In numerous mouse models of disease and aging, NMN has demonstrated a wide array of remarkable effects, benefitting conditions ranging from diabetes to Alzheimer’s disease to ischemia.27 Orally
在众多疾病和衰老小鼠模型中，NMN已显示出广泛的显着效果，有益于从糖尿病到阿尔茨海默病再到缺血的各种疾病。 27 口头 administered NMN is quickly synthesized into NAD+ in tissues in mice. NMN has been able to suppress age-associated weight gain, enhance energy metabolism and physical activity, improve insulin sensitivity, improve eye function, improve mitochondrial metabolism and prevent age-linked changes in gene expression.28 In mice bred to be diabetic or obese, NMN improved both the action and secretion of insulin.29 NMN also protected the mouse heart from ischemia and/or reperfusion injury.30 It has restored skeletal muscle in aged mice31, and slowed cognitive decline in a mouse model of Alzheimer’s disease, by improving the survival of neurons, improving energy metabolism, and reducing reactive oxygen species.32 It may help maintain the integrity of the blood brain barrier.33 NMN is likely a good candidate to suppress inflammaging—the increase in inflammation associated with aging—since studies show it lowers adipose tissue inflammation associated with age. In fact, older mice appear to be more responsive to NMN, in comparison with young mice.
施用的NMN在小鼠组织中迅速合成为NAD +。NMN已经能够抑制与年龄相关的体重增加，增强能量代谢和身体活动，提高胰岛素敏感性，改善眼睛功能，改善线粒体代谢并防止与年龄相关的基因表达变化。 28 在培育为糖尿病或肥胖的小鼠中，NMN改善了胰岛素的作用和分泌。 29 NMN还可以保护小鼠心脏免受缺血和/或再灌注损伤。 30 它通过提高神经元的存活率、改善能量代谢和减少活性氧，恢复了老年小鼠 31 的骨骼肌，并减缓了阿尔茨海默病小鼠模型的认知能力下降。 32 它可能有助于维持血脑屏障的完整性。 33 NMN可能是抑制炎症（与衰老相关的炎症增加）的良好候选者，因为研究表明它可以降低与年龄相关的脂肪组织炎症。事实上，与年轻小鼠相比，老年小鼠似乎对NMN反应更灵敏。 NMN appears to be stable in water; in one study 93%–99% of NMN was maintained intact in drinking water at room temperature for 7–10 days. NMN also appears to be rapidly absorbed. When given to mice by oral gavage, there was a steep increase of plasma NMN in a mere two and a half minutes, with further increases at 5-10 minutes. Plasma levels then declined to baseline, suggesting rapid absorption in the gut.29 Long-term (1-year) NMN given orally, in doses of up to 300 mg/kg, was found to be safe and well tolerated in normal mice.29
NMN在水中似乎很稳定;在一项研究中，93%-99% 的 NMN 在室温下在饮用水中保持完整 7-10 天.NMN似乎也被迅速吸收。当通过口服强饲法给予小鼠时，血浆NMN在短短两分半钟内急剧增加，并在5-10分钟进一步增加。血浆水平随后下降到基线水平，表明肠道吸收迅速。 29 长期（1 年）口服 NMN，剂量高达 300 mg/kg，在正常小鼠中被发现是安全的且耐受性良好。 29 Looking Forward: NMN and Human Health
展望未来：NMN与人类健康NMN is clearly a murine fountain of youth. But what about humans? Shin-ichiro Imai has said that NMN may improve adult human metabolism, rendering it more like that of someone ten or twenty years younger.34 His team is now studying NMN in humans. David Sinclair, Harvard University’s noted anti-aging researcher, whose research on resveratrol, NAD+ and sirtuins is world renowned, is also conducting human trials. He is taking NMN himself; he has said his lipid profile has improved dramatically and he feels more energetic and that his blood markers, at nearly 60 years old, are closer to those of a 31-year-old.35,36
NMN显然是青春的喷泉。但是人类呢？今井真一郎曾说过，NMN可以改善成年人的新陈代谢，使其更像年轻十岁或二十岁的人。 34 他的团队现在正在研究人类的NMN。哈佛大学著名的抗衰老研究员大卫·辛克莱（David Sinclair）对白藜芦醇、NAD+和sirtuins的研究享誉世界，他也在进行人体试验。他自己正在服用 NMN;他说他的血脂状况有了显着改善，他感觉更有活力，他的血液标志物在近60岁时更接近31岁的血液标志物。 35,36 An interesting question is the delivery system for oral NMN: the EVs that transport the molecule through plasma in the body are liposomes. A liposomal version of NMN may well mimic the body’s own transport system, enhancing uptake and delivery, as science advances its understanding of the holy grail of reversing aging.
一个有趣的问题是口服NMN的递送系统：通过体内血浆运输分子的EV是脂质体。NMN的脂质体版本可以很好地模仿人体自身的运输系统，增强摄取和输送，因为科学对逆转衰老的圣杯的理解不断加深。 Biography 传记· Christopher Shade, PhD, founder and CEO of Quicksilver Scientific, continues to be the driving force of development and innovation. Dr. Shade’s vast depth and breadth of knowledge, passion for healing, and intuitive understanding of chemistry and biology are reflected in Quicksilver Scientific’s well-designed detoxification protocols, unique supplement delivery systems, and patented mercury speciation test. Dr. Shade earned his PhD from the University of Illinois Urbana-Champaign and his undergraduate degree in Environmental Chemistry is from Lehigh University.
Quicksilver Scientific 的创始人兼首席执行官 Christopher Shade 博士继续成为发展和创新的驱动力。Shade 博士渊博的知识深度和广度、对治疗的热情以及对化学和生物学的直观理解都反映在 Quicksilver Scientific 精心设计的排毒方案、独特的补充剂输送系统和获得专利的汞形态测试中。Shade 博士在伊利诺伊大学厄巴纳-香槟分校获得博士学位，并在利哈伊大学获得环境化学本科学位。 Dr. Shade is a recognized expert on mercury and liposomal delivery systems. He has lectured and trained doctors in the United States and internationally on the subject of mercury, heavy metals, and the human detoxification system. Dr. Shade’s current focus is on the development of cutting-edge, lipid-based delivery systems for nutraceuticals, such as liposomes and micro-emulsion systems, to address the growing need of high-quality, affordable detoxification solutions.
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