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Immortality, longevity, treatment of Alzheimer’s disease Is the NMN deified so mysterious?

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why do adults believe the elixir of immortality that even children don’t believe?
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In ancient times, “Immortality” and “longevity” were the ultimate goals pursued by the “upper class”, so a variety of panacea came into being; today, with the improvement of living standards and the development of education, a variety of “anti-aging” and “anti age growth” claims of food and health products emerge in an endless stream; but it is a bit inconceivable that in the 21st century, there is still “longevity” “Medicine” is highly sought after by consumers:
In 2013, a research team at Harvard University discovered a substance called “β – nicotinamide mononucleotide (NMN)”, which claims to effectively prolong the life of mice, and manufacturers found business opportunities from it. Since then, all kinds of food products containing NMN have been sold well on foreign and domestic websites;
In 2017, Li Ka Shing, a rich man, said he “felt like he was 20 years old” after taking a supplement containing NMN from chromadex, an American company, and then invested $25 million;
In 2019, Pan Shiyi, a business tycoon, issued a personal certificate on Weibo. After eating a NMN product developed by MIT, his nails grew very fast;
In addition to the celebrities in the rich circle, there are also celebrities in the academic circle who also support NMN’s anti-aging concept, including Nobel laureates
With the certification of these authorities and the promotion of those top class people, NMN has quickly become a popular pastry in the market. Major media platforms are competing to report, and major and small enterprises are competing to produce. As a result, NMN is rolling like a snowball, and it is passed on like a magic ball!
Why do adults believe the elixir of immortality that even children don’t believe? Foodaily will unveil the legend of NMN today!

Who is NMN?
In fact, NMN, which has been deified, is just a derivative of vitamin B3 (also known as nicotinamide) which is very common in human body. Its scientific name is “nicotinamide adenine mononucleotide”. It exists in some fruits and vegetables (cauliflower, cabbage, avocado, tomato) and poultry (beef) in two forms – α and β, and the main component that plays a bioactive role is β – NMN.
When NMN is absorbed into the human body, it can directly cross the cell membrane and be transformed into NAD + (oxidized nicotinamide adenine dinucleotide) through mitochondria and other “energy processors”. This coenzyme participates in almost all physiological reactions in the body, such as energy generation, damage repair, metabolism, tissue regeneration and so on.
Photo source: NAD + synthesis pathway in the white paper on NMN category development
In addition, studies have shown that the amount of NAD + in the body will gradually decrease with the growth of age, and it is not easy to be absorbed by the human body to directly supplement this coenzyme. Therefore, NMN, as the precursor of NAD +, is both easy to absorb and can be synthesized in vitro, and it has become a well deserved star product.

Where is the myth of NMN?
1. Support NAD + production and delay aging process
As early as 1904, NAD + was discovered in the process of wine making, and has been continuously explored for its key role in the metabolism of yeast cells – providing energy.
Nicotinic acid, nicotinamide, nicotinamide ribose, NMN and other NAD + precursors have been discovered in experiments, especially their anti-aging and life prolonging effects have become a hot topic.
In 1937, biochemist Conrad Elvehjem used nicotinic acid to treat dog’s pellagra. Since then, it has been used in disease treatment. After amidation, it can become nicotinamide, which has been active in various brands of skin care products.
In 1944, nicotinamide ribose was found to promote the growth of Haemophilus influenzae; 60 years later, it was used as a precursor of NAD + in anti-aging research.
In 2007, Charles Brenner, Professor of Biochemistry at the University of Iowa, discovered the anti-aging effect of NMN.
In 2013, David Professor Sinclair’s team took PBS and NMN to 6-month-old and 22 month old mice respectively. One week later, they found that the levels of NAD + and ATP in 22 month old mice increased significantly, and some other biochemical indicators of aging also reversed. [1]
Picture source: literature [1] Figure e: the changes of NAD + content in 6-month-old and 22 month old mice after using PBS and NMN respectively; figure I: the changes of ATP content in 6-month-old and 22 month old mice after using PBS and NMN respectively
The mechanism of the above four substances is to improve the activity of mitochondria, accelerate tissue repair and regeneration, assist the metabolism of the body, so as to improve human immunity and delay aging.
However, related studies have shown that nicotinic acid can cause skin flushing, liver toxicity and other adverse reactions. Nicotinamide stays in the body for a short time, and its efficacy is not fully exerted. Only nicotinamide ribose and NMN have less side effects and good oral bioavailability.
Therefore, NMN and nicotinamide ribose are more used in dietary supplements and other health products.
2. Sirtuins, a family of activating proteins, are involved in physiological reactions
There are seven proteins in sirtuins family, which exist in nucleus, cytoplasm and mitochondria respectively.
After Dr. Amar Klar, a geneticist, discovered the first Sir2 protein in the 1970s, other proteins such as Sir3, SIR4 and sir5 were discovered one after another.
With the in-depth study of these proteins, their functions and mechanisms gradually become clear. There are Sir2 involved in regulating caloric restriction, sir6 involved in accelerating cell repair and reducing the sensitivity of cells to oxidative damage, and sir7 involved in restricting the growth and development of tumor cells
Therefore, this family is called “anti-aging protein family”.
The activation of sirtuins depends on the catalysis of NAD +. It can also be said that one of the important ways of NAD + anti-aging is to activate sirtuins protein to regulate cell metabolism and gene repair stress.
In 2019, a team from the Department of science of University of Colorado carried out an experiment. Young and old mice were divided into control group and NMN group respectively. The results showed that the level of Sir1 protein in both young and old mice was significantly increased after supplementation with NMN.
In addition, by comparing the value of acetylated NF – κ B / total NF – κ B (the higher the ratio, the lower the Sir1 activity) in the aorta, it was found that NMN supplementation could effectively reduce this value in the aged mice group, that is, it could effectively restore the Sir1 activity in the aged aorta. [2]
Photo source: literature [2] YC: young mouse control group; OC: old mouse control group; ynnm: young mouse NMN group; onmn: old mouse NMN group: figure a: SIRT1 protein content; figure B: acetylated NF κ B / total NF κ B ratio change
3. Repair gene damage and prolong cell life
There was an article published in nature, which revealed the process and molecular mechanism of PARP enzyme repairing broken DNA, and provided a new idea for cancer cells to develop resistance to anticancer drugs.
NAD + is one of the important substrates for this enzyme to work. When NAD + level decreased, PARP enzyme was forced to bind with another factor and lost its DNA repair function; when NAD + level increased, PARP repair function would recover.
In 2017, Harvard Medical School published a study in the journal Science, in which 22 month old mice were divided into two groups and exposed to radiation at the same time. One group served as the control group without treatment, and the other group served as the experimental group with intraperitoneal injection of NMN One week later, the level of NAD + in mice injected with NMN was significantly increased, and the binding process of PARP with another factor was significantly interfered. [3]
Picture source: literature [3] Figure D: changes of NAD + content in 22 month old mice exposed to radiation after intraperitoneal injection of PBS and NMN; figure e: changes of NAD + concentration in 22 month old mice exposed to radiation after intraperitoneal injection of PBS and NMN
Therefore, intraperitoneal injection of NMN can repair gene damage indirectly.
4. Maintain metabolism and assist weight management
When it comes to the word “metabolism”, it must be familiar to everyone. It is involved in the process of weight loss, beauty, rehabilitation, acne, anti-aging and so on.
As the saying goes, the old will not go and the new will not come. Only by expelling the ineffective, Hypofunctional and aging things from the body can we promote the generation of new, functional and active substances. This continuous material exchange and metabolic balance is the key to maintaining life and the essence of maintaining weight.
In 2017, a team from the University of New South Wales took genetically obese mice as the research objects, and given NMN and exercise respectively. The results showed that both of them could reduce body weight, improve glucose tolerance and mitochondrial function; however, NMN was more effective than exercise in liver fat catabolism and anabolism. [4]
In 2019, the University of Maryland injected NMN into mice. It was found that NMN could promote the increase of mitochondrial NAD + level in the hippocampus of mice, promote the increase of energy molecule ATP in brain tissue, improve the activity of antioxidant enzymes in mitochondria, and improve the body’s energy metabolism. [5]
Picture source: literature [5] Figure C: changes of mitochondrial NAD + level in hippocampus of rats after NMN injection; figure e: changes of mitochondrial ATP level in hippocampus of rats after NMN injection
5. Improve the elasticity of blood vessels and promote the health of heart and brain vessels
With the popularity of sedentary work and Western style diet, obesity has become a symbol of a new generation of people. The terrible thing is that fat will not only accumulate in the subcutaneous and internal organs, but also deposit in the vascular wall, leading to a series of vascular diseases.
In addition, the growth of age will make blood vessels lose elasticity and softness gradually. Dry blood vessels can not effectively carry oxygen and carbon dioxide, nutrients and metabolic waste, which makes human tissues and organs like a pool of stagnant water and lose vitality.
The heart and brain, the two most important organs of the human body, have lost their blood supply, just like a fish without water, and the health of the human body has lost its guarantee.
In 2018, Professor David Sinclair of Harvard Medical School led a team to feed 18 month old mice with NMN for two months. It was found that the number and density of capillaries of these mice returned to the level of young mice, and the exercise endurance increased by 58-80%. [6]
Photo source: literature [6] changes in exercise tolerance of mice fed with NMN under low and high intensity exercise test
In addition, some studies have shown that intraperitoneal injection of NMN can not only prevent the decrease of NAD + in the heart during ischemia, but also protect the heart from ischemia / reperfusion injury (it can be understood that giving a hungry person big fish and big meat will increase the burden on the already fragile gastrointestinal tract); it can also reduce the oxidative stress of cerebral microvascular endothelial cells and protect the function of vascular endothelial cells. [7,8]
6. Improve insulin resistance
Generally speaking, insulin resistance means that the body’s sensitivity to insulin is low, and these insulin will lose its effect; when the body ingests glucose, there is not enough effective insulin to reduce blood sugar, which will lead to diabetes.
Dr. Kelly L. stromsdorfer of the University of Washington School of Medicine found that decreased NAD + levels in obese and elderly mice were associated with organ insulin resistance. They established a mouse model of insulin resistance and fed the mice with NMN in drinking water, and found that their blood glucose levels were significantly decreased. [9]
NMN can reverse insulin resistance.
Picture source: literature [9] Figure B: changes of NAD + content in mice after NMN feeding; figure C: changes of blood glucose level in mice after NMN injection with time
7. Prevent bone mineral density decline
With the growth of age, not only the appearance of the human body aging, the body’s organs will also decline.
Aging can never be absent, but can be late. Through artificial supplementary nutrition or good living habits, it can effectively reduce the accumulation of aging factors, so as to delay the process of aging.
In 2016, the University of Washington carried out a long-term experiment to compare the oral administration of NMN for 12 months with normal aging mice. It was found that the oral administration of NMN could effectively eliminate various physiological decline related to aging, such as weight gain, decreased metabolism, insufficient physical strength, decreased vision, low immunity, decreased bone mineral density, etc., without toxic and side effects. [10]
Image source: literature [10] red represents oral NMN group; figure F: bone mineral density

How to make such an enigmatic NMN?
How to present in front of the world?
1. Production method and quality assurance
With the development of science and technology, the production mode of NMN raw materials is constantly improving.
The most primitive method is fermentation, just like the process of wine making, which allows microorganisms to carry out the synthesis reaction slowly. However, this method has poor controllability, low efficiency and high cost, which is not conducive to industrial production.
Furthermore, chemical synthesis, in which different compounds react with various organic solvents, is a simple and low-cost method compared with fermentation. However, the pure compounds obtained by chemical synthesis are generally not approved in China.
The safest and most efficient method is enzyme catalysis, which makes use of the catalysis of enzyme to thoroughly carry out the biosynthesis reaction and improve the purity of raw materials. In addition, the directed evolution technology of enzyme accelerates the reaction and improves the efficiency. On the basis of this method, the scientists applied the directed evolution technology of enzyme, which greatly improved the production efficiency and product quality.
Considering the problem of food safety, in the production process, in addition to raw materials, processing aids such as excipients need to comply with the regulations and standards of usp-npo or EP or FDA guidelines for inactive ingredients. In addition, product packaging such as capsule shell must also ensure its safety and applicability.
Of course, different countries have different production requirements. The UK has the global food safety standard, the European Union has the registration of animal derived products, and the United States has the dynamic drug production management specification. When imported into China, it also needs to get the certification of the national food safety standard health food.
2. Product form of NMN in the market
At present, there are two kinds of NMN preparations on the market, one is single prescription preparation, the other is compound preparation.
Since its establishment in 1988, prohealth has been working hard to help people become healthy. According to the scientific research results over the years, prohealth longevity is committed to using the best raw materials to create NMN products that meet the quality standards and delay people’s aging.
The product usually comes in four forms: powder, sustained-release tablets, lozenges and capsules. Among them, the latest delayed release anti acid capsule has been patented, which can protect NMN from gastric acid and directly escort it to the small intestine for absorption.
Photo source: prohealthlongevity
Doublewood makes NMN into capsule form, and the recommended daily dose is 250-500mg.
The absorption rate of NMN is very fast and the half-life is short. If you want to maintain a high NAD + level as much as possible in a day, it is recommended to take one capsule in the morning and one in the afternoon. If you want to take a higher dose, you can take one 125 mg capsule in the morning, and then continue to take another capsule every 1-3 hours according to the total dose.
Photo source: Doublewood supplements
AliveByNature mainly consists of four forms: liposome sublingual gel, sublingual powder or tablet, percutaneous emulsion or essence, and intranasal spray.
Among them, liposome is composed of phospholipids, which can be fully combined with cell membrane to promote the absorption of nutrients; in addition, liposome has the characteristics of delaying the release, prolonging the bioavailability time of active substances, and it directly absorbs blood from sublingual lymphatic vessels and other ways, bypassing the gastrointestinal tract to give full play to its efficacy.
Intranasal spray is the most effective and rapid way to deliver NAD + directly to the brain, bypassing the blood-brain barrier to reduce systemic adverse reactions, and local medication can reduce the drug dose.
Photo source: alive by science

What is the current situation of NMN in China?
1. Consumers: better mental state, various functions to be understood
At present, NMN has gradually entered the eyes of Chinese consumers and become a common nutritional supplement on China’s mainstream e-commerce platform. However, consumers are still generally lack of relevant professional knowledge, it is difficult to distinguish the advantages and disadvantages of NMN products, and their understanding of its efficacy is incomplete.
In October last year, iResearch conducted a survey of 1220 people who had daily habits of taking health care products, and found that 30.3% of them had taken NMN health care products.
Although NMN has a history of two centuries abroad, it is only in recent years that it has really opened up the domestic market. Among 369 people taking NMN health care products, nearly half of them have been exposed to NMN products in the past year.
Note: search popularity of “NMN” tmall from May to September 2020; data source: iResearch
In the vast majority of people’s cognition, the main effect of NMN is to enhance immunity and improve sleep. In fact, this is only the tip of the iceberg. It can be seen that the consumer group does not fully understand NMN, but 78.5% of consumers are willing to further understand it.
In addition, the respondents were very inclusive about the price of the product, with an average price acceptance value of 1511.9 yuan, which may be related to the efficacy they achieved after taking NMN products.
After taking the NMN health care products, the respondents felt that the most obvious effect was to improve their mental state and energy, followed by tight and shiny skin, and the improvement of sleep quality. Of course, a few people felt that their eyesight, memory and appetite had improved.
Note: the use effect of NMN health products in 2020; data source: iResearch
2. Mainly relying on cross-border e-commerce to enter the domestic market, the standard quality is uneven
Because NMN can not be used for food production in China, many brands of NMN products are mainly manufactured overseas and enter the domestic market to reach the consumer end through cross-border e-commerce.
Due to the different management systems of exporting countries, the management categories, definitions and product standards of NMN products vary greatly. For example, in Japan, it is common food, in the United States, it is dietary supplement, in Canada, it is natural health product, in the European Union, it is food supplement, and in Australia, it is supplementary drug.
However, the safety and quality of products depend on the quality of NMN raw materials. At present, China is the most important NMN raw material producer in the world, but there is no publicly released NMN raw material standard, and the raw material manufacturers implement their own enterprise standards, which will inevitably lead to the uneven key indicators and even safety indicators of NMN raw materials. Therefore, in order to promote the healthy development of NMN products industry, it is imperative to establish the industry standard of NMN raw materials.
To sum up, although the NMN market in China is in its infancy, there are still potential consumer groups and large sales space to be explored.

Summary
After decades of scientific research, NMN is related to promoting metabolism, improving vascular function, and preventing the decline of bone mineral density. However, these are based on animal experiments, which can not be copied to the human body. The efficacy, appropriate dose, adverse reactions, and course of treatment of NMN are unknown.
At present, there is only one open human clinical trial, which is a non randomized trial carried out by Keio University in 2019. Ten healthy people were recruited and given NMN of 100mg, 250mg and 500mg respectively, with the concentration of NMN in the body 5min after each administration as the end point.
The results showed that NMN was metabolized quickly in vivo without any adverse reactions. [11]
Although the results are very good, but the sample size is too small, and there is no other clinical trials to prove it. In the future, we need to invest more energy in human trials.
According to reports, Guangzhou Institute of physical education has set up a national key special project on the effect of exercise combined with NMN nutrition on the middle-aged and elderly patients with pre diabetes, which is being vigorously carried out. It is believed that in the near future, NMN health care products will have more rigorous and scientific basis to protect the personal safety rights of consumers.
In addition, the market demand for NMN has soared, and many small enterprises, even if they do not have any basic business of nutritional supplements, are scrambling to invest in order to make considerable profits.
In addition, due to the hype of media traffic, the lack of consumer awareness of products, the lack of administrative management, the large price difference and uneven quality of domestic NMN products, there is a certain risk of market confusion and consumer safety.
To sum up, even though NMN has a large space for development, in order to quickly and stably base on the market, it is necessary to strictly regulate the production conditions, such as toxicological evaluation and safety evaluation of raw materials, strictly forbidding the use of ingredients that are prohibited by the state, etc.; it is also necessary to establish norms, whether it is import, shelf, or publicity, sales, etc.

reference:

[1]Gomes A P, PriceN L, Ling A J,et al. Declining NAD(+) induces a pseudohypoxic state disruptingnuclear-mitochondrial communication during aging[J]. Cell,2013,155(7):1624-1638.

[2]de Picciotto N E, Gano L B,Johnson L C, et al. Nicotinamide mononucleotide supplementation reversesvascular dysfunction and oxidative stress with aging in mice[J]. Aging Cell, 2016,15(3):522-530.

[3]Li J, Bonkowski M S, Moniot S,et al. A conserved NAD(+) binding pocket that regulates protein-proteininteractions during aging[J]. Science, 2017,355(6331):1312-1317.

[4]Uddin G M, Youngson N A, DoyleB M, et al. Nicotinamide mononucleotide (NMN) supplementation ameliorates theimpact of maternal obesity in mice: comparison with exercise[J]. Sci Rep,2017,7(1):15063.

[5]Klimova N, Long A, Kristian T.Nicotinamide mononucleotide alters mitochondrial dynamics by SIRT3-dependent mechanismin male mice[J]. J Neurosci Res, 2019,97(8):975-990.

[6]Das A, Huang G X, Bonkowski MS, et al. Impairment of an Endothelial NAD(+)-H2S Signaling Network Is aReversible Cause of Vascular Aging[J]. Cell, 2019,176(4):944-945.

[7]Tarantini S, Valcarcel-Ares MN, Toth P, et al. Nicotinamide mononucleotide (NMN) supplementation rescuescerebromicrovascular endothelial function and neurovascular coupling responsesand improves cognitive  function in agedmice[J]. Redox Biol, 2019,24:101192.

[8]Kiss T, Nyul-Toth A,Balasubramanian P, et al. Nicotinamide mononucleotide (NMN) supplementationpromotes neurovascular rejuvenation in aged mice: transcriptional footprint ofSIRT1 activation, mitochondrial protection, anti-inflammatory, andanti-apoptotic effects[J]. Geroscience, 2020,42(2):527-546.

[9]Stromsdorfer K L, Yamaguchi S,Yoon M J, et al. NAMPT-Mediated NAD(+) Biosynthesis in Adipocytes RegulatesAdipose Tissue Function and Multi-organ Insulin Sensitivity in Mice[J]. CellRep, 2016,16(7):1851-1860.

[10]Mills K F, Yoshida S, Stein LR, et al. Long-Term Administration of Nicotinamide Mononucleotide MitigatesAge-Associated  Physiological Decline inMice[J]. Cell Metab, 2016,24(6):795-806.

[11]Irie J, Inagaki E, Fujita M, etal. Effect of oral administration of nicotinamide mononucleotide on clinicalparameters and nicotinamide metabolite levels in healthy Japanese men[J].Endocr J, 2020,67(2):153-160.

[12] NMN category development white paper, Suzheng KANGXUN x tmall global, November 2020

 
Source: tru niagen
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