Vitality iSPPA-About NMN

VITALITY iSPPA（活力·18）-NMN

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~1972，Peter Duncan Goodearl Dean and David Barry Craven firstly clamed to obtain NMN from separation of enzymes.

NMN can be finitely obtained by digestion of natural foods.

NAD+ availability decreases with age and in certain disease conditions. Nicotinamide mononucleotide (NMN), a key NAD+ intermediate, has been shown to enhance NAD+ biosynthesis and ameliorate various pathologies in mouse disease models. In this study, we conducted a 12-month-long NMN administration to regular chow-fed wild-type C57BL/6N mice during their normal aging. Orally administered NMN was quickly utilized to synthesize NAD+ in tissues. Remarkably, NMN effectively mitigates age-associated physiological decline in mice. Without any obvious toxicity or deleterious effects, NMN suppressed age-associated body weight gain, enhanced energy metabolism, promoted physical activity, improved insulin sensitivity and plasma lipid profile, and ameliorated eye function and other pathophysiologies. Consistent with these phenotypes, NMN prevented age-associated gene expression changes in key metabolic organs and enhanced mitochondrial oxidative metabolism and mitonuclear protein imbalance in skeletal muscle. These effects of NMN highlight the preventive and therapeutic potential of NAD+ intermediates as effective anti-aging interventions in humans.

Mills K F, Yoshida S, Stein L R, et al. Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice[J]. Cell metabolism, 2016, 24(6): 795- 806.

What Is NMN?

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研究还证实多种食物中都含有有限量的NMN。一方面，研究充分证实NMN原本就是任何生物体内存在并流转的内源性物质，其与生物体不存在异源性；另一方面研究结果也显示，在没有足够量NMN类物质补充情况下，生物体会经历自然的变老和衰退进程，反言之，仅靠日常食物补给有限量的NMN，不可能达到逆转或减缓生物体活力衰减进程的目的。

NMN Mitigates Age-Associated Physiological Decline in Mice

NMN广泛存在于各种食物中

넳 넲

Nicotinamide adenine dinucleotide (NAD+) is an important coenzyme in living organism. It has been studied for many years by many researchers and its more and more functions have been discovered successively. There are 6 scientists won Nobel Prizes due to their significant research achievements about NAD+, therefore, it was also called NAD Revival (Noga Factor). 烟酰胺腺嘌呤二核苷酸 (Nicotinamide adenine dinucleotide，NAD+)是生命机体中的一种重要辅酶。围绕NAD+的研究先后诞生了6位诺贝尔奖得主，因此NAD+又有被称为诺加因子。

The discovery of nicotinamide adenine dinucleotide (NAD+) as a ‘‘cozymase’’ factor in fermentation has its 110th anniversary this year. Of the two billion people who were alive back in 1906, only 150 people remain. Interestingly, NAD+ itself may be the reason for their longevity.

In this issue, Eduardo Chini and colleagues address an open question in biogerontology: why do NAD+ levels fall as we age? They show that the major culprit is an NADase called CD38 whose levels rise during aging. Their results also add to the body of evidence indicating that loss of SIRT3 activity in mitochondria is a cause of age-related metabolic decline. Michael B S, and David A S. Why NAD+ Declines during Aging: It’s Destroyed[J]. Cell metabolism, 2016, 965- 966. David Sinclair博士的团队研究表明，NAD+含量下降的罪魁祸首其实正是蛋白酶CD38，它像剪刀一样剪碎NAD+分子。

NAD+ (NMN) is required not only for life but for a long life

不仅是长命所需，更是生命所需

More about NMN !

What Is NAD+?

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欲知更多关于NMN，且先了解NAD+

The fermentation of sugar into alcohol is the basis for bread as well as beer and wine. After Eduard Buchner discovered that fermentation is driven by chemical substances, enzymes formed by yeast fungi, details involved in the process still needed to be clarified. At first it was believed that fermentation was caused by a uniform enzyme, but when Arthur Harden filtered yeast extract through a very fine filter, he found two different substances, both of which were essential to the fermentation process: the real enzyme and a coenzyme.

In 1904, Arthur Harden, the Nobel Prize winner in chemistry, first discovered the presence of NAD+ in yeast fermentation. This is the first coenzyme found in human history, 53 years earlier than coenzyme Q10. 早在1904年，诺贝尔化学奖得主Arthur Harden首先在酵母发酵过程中发现NAD+ (Nicotinamide Adenine Dinucleotide, 烟酰胺腺嘌呤二核苷酸，又称辅酶Ⅰ)的存在，并将其命名。这是人类历史上首次发现的辅酶类物质，比辅酶Q10的发现足足早了53年。

NAD+ presents in any biological cell and plays an irreplaceable role in organism. Life organism will go to end in 30 seconds without NAD+. With the decrease of NAD+, organism will begin to grow old, and gradually appeared aging problems such as skin aging, decline of body function, decrease of muscle level, increase of inflammation. Simultaneously, various diseases appeared one after another. NAD+存在于每一个生物细胞中，参与上千项、多种细胞代谢相关的生化反应，为细胞保持活力起着不可替代的重要作用。没有它，机体将在30秒内死亡。少了它，机体开始慢慢变老，逐步出现皮肤衰老、身体机能下降、肌肉水平下降、炎症增多等衰老问题，同时各种疾病相继出现。

Declining tissue nicotinamide adenine dinucleotide (NAD) levels are linked to ageing and its associated diseases. However, the mechanism for this decline is unclear. Here, we show that pro-inflammatory M1- like macrophages, but not naive or M2 macrophages, accumulate in metabolic tissues, including visceral white adipose tissue and liver, during ageing and acute responses to inflammation. These M1-like macrophages express high levels of the NAD-consuming enzyme CD38 and have enhanced CD38-dependent NADase activity, thereby reducing tissue NAD levels. We also find that senescent cells progressively accumulate in visceral white adipose tissue and liver during ageing and that inflammatory cytokines secreted by senescent cells (the senescence-associated secretory phenotype, SASP) induce macrophages to proliferate and express CD38. These results uncover a new causal link among resident tissue macrophages, cellular senescence and tissue NAD decline during ageing and offer novel therapeutic opportunities to maintain NAD levels during ageing. Anthony J. Covarrubias, Abhijit Kale, Rosalba Perrone, etc., Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages[J] Nature Metabolism volume 2, pages1265–1283 (2020) 机体内的NAD+大约每20年减少一半，衰老过程中NAD的下降被认为是导致疾病和残疾的主要原因，如听力和视力丧失，认知和运动功能障碍，免疫缺陷，自身免疫炎症反应失调导致的关节炎、代谢障碍和心血管疾病。随着年龄增长，NAD+水平的降低导致DNA修复能力下降，DNA损伤积累，驱动衰老进程。

David A. Sinclair, A.O., Ph.D. is a Professor in the Department of Genetics and co-Director of the Paul F. Glenn Center for Biology of Aging Research at Harvard Medical School. He is best known for his work on understanding why we age and how to slow its effects. He obtained his Ph.D. in Molecular Genetics at the University of New South Wales, Sydney in 1995. He worked as a postdoctoral researcher at M.I.T. with Dr. Leonard Guarente where he co discovered a cause of aging for yeast as well as the role of Sir2 in epigenetic changes driven by genome instability. In 1999 he was recruited to Harvard Medical School where he has been teaching aging biology and translational medicine for aging for the past 16 years. His research has been primarily focused on the sirtuins, protein-modifying enzymes that respond to changing NAD+ levels and to caloric restriction (CR) with associated interests in chromatin, energy metabolism, mitochondria, learning and memory, neurodegeneration, and cancer. The Sinclair lab was the first one to identify a role for NAD+ biosynthesis in regulation of lifespan and first showed that sirtuins are involved in CR in mammals. They first identified small molecules that activate SIRT1 such as resveratrol and studied how they improve metabolic function using a combination of genetic, enzymological, biophysical and pharmacological approaches. They recently showed that natural and synthetic activators require SIRT1 to mediate the in vivo effects in muscle and identified a structured activation domain. They demonstrated that miscommunication between the mitochondrial and nuclear genomes is a cause of age-related physiological decline and that relocalization of chromatin factors in response to DNA breaks may be a cause of aging. Cell和Nature发表的大量研究证实，NAD+的作用非常广泛。而NMN就是NAD+最直接前体，可以给机体带来很多改善。哈佛医学院David Sinclair研究发现NMN可以逆转衰老，能让相当于60岁人体年龄的试验小鼠的机体&生命指标回到相当于20岁人体年龄的试验小鼠状态。因此，NMN开始被称为“长生不老药"Juliana C-P, Mariana G T, Claudia C S C, Joel M R, Antonio G, Eduardo N C. CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism [J]. Cell metabolism, 2016, 1127-1139.

Why Is NMN？

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● NAD+ biosynthesis, degradation and salvage

Beyond its role as a coenzyme in redox reactions, NAD+ is an important cosubstrate for three classes of enzymes: (i) the sirtuins(SIRTs), (ii) the adenosine diphosphate (ADP)-ribose transferases (ARTs) and poly (ADP-ribose) polymerases (PARPs), and (iii) the cyclic ADP-ribose (CADPR) synthases (CD38 and CD157). NAD+ is consumed by these enzymes and continuously degraded. To maintain stable cellular concentrations of NAD+ organisms primarily use a nicotinamide salvage pathway but also rely on several biosynthetic pathways. NAD+分子较大，无法被人体直接吸收利用，直接口服摄入的 NAD+主要在小肠内被刷状缘细胞水解。从思路上来说，补充NAD+的确还有另一种方法，就是想办法补充某种物质，使其在人体内自主合成NAD+。人体中合成NAD+的途径有3种：Preiss-Handler途径、从头合成途径和补救合成途径。虽说三种途径都能合成NAD+，但也有个主次之分。其中，前两种合成途径产生的NAD+只占人体NAD+总量的15%左右，剩下85%都是通过补救合成的NMN途径来实现。也就是说，补救合成途径才是人体补充NAD+的关键。

● NAD+ biosynthetic pathways

Nicotinamide adenine dinucleotide can be synthesized from diverse dietary sources, including nicotinic acid and nicotinamide, tryptophan and nicotinamide riboside (NR).The major dietary source of NAD+ is nicotinic acidaform of niacin (i.e., vitamin B3) that can be transformed into NAD+ through three steps in the Preiss-Handler pathway. A key enzyme in this pathway is nicotinamide mononucleotide adenylyltransferase (NMNAT) which transforms nicotinic acid mononucleotide (NAMN) into nicotinic acid adenine dinucleotide (NAAD) in the presence of adenosine triphosphate (ATP). Three forms of the enzyme have distinct subcellular localizations: NMNAT1 in the nucleus, NMNAT2 in the cytosol and Golgi, and NMNAT3 in the cytosol and mitochondria (2-4).This enzyme is also important in the NAD+ salvage pathway.

Synthesis of NAD+ from tryptophan occurs in the kinurenine pathway. The first step is conversion of tryptophan to N-formylkinurenine by indoleamine 2,3-dioxygenase (IDO) or tryptophan 2,3-dioxygenase (TDO). IDO and TDO activities lead to metabolites in the kinurenine pathway that modulate the activity of the mammalian immune, reproductive, and central nervous systems. This is a rate-limiting step in the pathway, and both enzymes are frequently overexpressed in cancer and maycontribute to immune tolerance to cancer cells through their immunomodulatory activities. Another key step is transformation of 2-amino-3-carboxymuconate semialdehyde (ACMS). This compound spontaneously condenses and rearranges into quinolinate, which serves as a precursor to NAD+ synthesis. However, under most circumstances, ACMS is decarboxylated by ACMS decarboxylase into 2-amino-3-muconatesemialdehyde (AMS), leading to its oxidation into acetyl-coenzyme A (CoA) via the tricarboxvlic acid (TCA) cycle. If the ACMS decarboxylase enzymatic capacity is exceeded by an excess of tryptophan (6) quinolinate is transformed into NAMN, thus linking with the Preiss-Handler pathway.

● NAD+ salvage pathway

NAD+ salvage pathway is the key pathway for maintaining cellular NAD+ levels. The NAD+-consuming enzymes-the SIRTs, ARTs, and PARPs-all generate nicotinamide as a by-product of their enzymatic activities. Nicotinamide regulates their activities as an inhibitory factor by binding in a conserved NAD+ pocket and also as a biosynthetic precursor to NAD+ via activity of nicotinamide phosphoribosyltransferase (NAMPT). This enzyme recycles nicotinamide into nicotinamide mononucleotide (NMN), which is converted into NAD+ by the various NMNATs. This pathway leads to recycling of nicotinamide into NAD+ and relieves nicotinamide inhibition of NAD+-consuming enzymes. NAMPT is expressed in low amounts in pancreatic β cells and neurons, which might allow it to become more rapidly limiting in these cells. NAMPT can be either intracellular(iNAMPT) or extracellular(eNAMPT).

Verdin E. NAD+ in aging, metabolism, and neurodegeneration[J]. Science, 2015, 350 (6265): 1208-1213.