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Immortality, longevity, treatment of Alzheimer's disease... Is the deified NMN really so mysterious?

March 1, 2021

latest company news about Immortality, longevity, treatment of Alzheimer's disease... Is the deified NMN really so mysterious?  0

 

Immortality, longevity, treatment of Alzheimer's disease... Is the deified NMN really so mysterious?

In ancient times, "immortality" and "longevity" were the ultimate goals pursued by the "upper class", so various panacea came into being. Nowadays, living standards have improved, education development has progressed, and various "anti-aging" and "reverse" Foods and health products claimed by "age growth" are emerging in endlessly; but it is a bit unbelievable that today in the 21st century, there are still "longevity medicines" that are highly sought after by consumers:
In 2013, a research team from Harvard University discovered a substance called "β-nicotinamide mononucleotide (NMN)", claiming to be able to effectively extend the lifespan of mice. Manufacturers discovered business opportunities from it. Since then, various Edible products containing NMN ingredients are selling well on foreign and domestic websites;
In 2017, tycoon Li Ka-shing said after taking a supplement containing NR (precursor of NMN) from the American company ChromaDex and said that he "feels back to 20 years old", and immediately invested 25 million US dollars;
In 2019, business tycoon Pan Shiyi sent a personal testimony on Weibo that after eating an NMN product developed by the Massachusetts Institute of Technology, his nails grew quickly;
In addition to the big names in the wealthy circle, there are also big names in the academic circle also expressing support for the concept of NMN anti-aging, and many of them have Nobel Prize winners...
Under the certification of these authoritative persons and the promotion of the top-class people, NMN has quickly become a popular sweet pastry in the market. Major media platforms have rushed to report, and various large and small enterprises are competing for production, so they are rolling like a snowball. The bigger the NMN is, it will be fascinating!
Why do adults believe in the "elixirs" that even children don't believe in? Today we will take you to unveil the legend of NMN!

 

Who is NMN?

The "deified" NMN is actually just a derivative of vitamin B3 (also known as nicotinamide) that is very common in the human body, and its scientific name is "nicotinamide adenine mononucleotide", in two forms-α and β-exists in some fruits and vegetables (broccoli, cabbage, avocado, tomato) and poultry (beef), and the main component that plays a biologically active role is β-NMN.
When NMN is absorbed into the human body, it can directly cross the cell membrane and be converted into the coenzyme NAD+ (oxidized nicotinamide adenine dinucleotide) through the "energy processor" such as mitochondria, and this coenzyme participates in almost all physiology in the body Reactions, such as energy production, damage repair, metabolism, tissue regeneration, etc.

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Image source: "NMN Category Development White Paper" NAD+ Synthetic Approach

In addition, studies have shown that NAD+ in the body will gradually decrease with age, and direct supplementation of this coenzyme is not easily absorbed by the body. Therefore, as the predecessor of NAD+-NMN can be absorbed and synthesized in vitro-has become Well-deserved star product.

 

Where is the "myth" of  NMN?

1. Support NAD+ generation and delay the body's aging process
As early as 1904, NAD+ was discovered during the brewing process, and it has been continuously explored for its key role in yeast cell metabolism-providing energy.
NAD+ precursors such as niacin, nicotinamide, nicotinamide ribose, and NMN have been unearthed in experiments, especially their anti-aging and life-prolonging effects have become an enduring hot topic.
In 1937, biochemist Conrad Elvehjem used niacin to treat pellagra in dogs. Since then, it has been used in disease treatment; and it can become niacinamide after amidation, and it has been active in whitening skin care products of major brands. in.
In 1944, nicotinamide ribose was discovered 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, a professor in the Department of Biochemistry at the University of Iowa, discovered the anti-aging effect of NMN. Since then, research on NMN has not stopped.
In 2013, the team of Professor David Sinclair of Harvard Medical School gave 6-month-old and 22-month-old mice PBS (phosphate buffered solution, which can be used as a placebo, which means no therapeutic effect) and NMN. One week later, they found The amount of NAD+ and ATP in the 22-month-old mice increased significantly, and some other biochemical indicators of aging were also reversed. [1]

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Image source: Literature [1] Figure E: The changes of NAD+ content in the body of 6-month and 22-month-old mice using PBS and NMN respectively; Figure I: 6-month and 22-month-old mice using PBS, respectively After NMN, the content of ATP in the body changes

The mechanism by which the above four substances work is to increase the activity of mitochondria, accelerate tissue repair and regeneration, and assist the body's metabolism after being converted into NAD+ in the cell, thereby improving human immunity and delaying aging.
However, related studies have shown that niacin can cause skin flushing, liver toxicity and other adverse reactions. Niacinamide stays in the body for a short time and its efficacy is insufficient. Only nicotinamide ribose and NMN not only have fewer side effects, but also have good oral organisms. Utilization.
Therefore, NMN and nicotinamide ribose are more used in health products such as dietary supplements.
2. Sirtuins, a family of activated proteins, participate in physiological responses
There are 7 proteins in the Sirtuins family, which are found in the nucleus, cytoplasm, and mitochondria, each performing its own functions.
Following the discovery of the first SIR2 protein by genetics expert Dr. Amar Klar in the 1970s, other proteins such as SIR3, SIR4, and SIR5 have been unearthed one after another.
With the in-depth study of these proteins by scientists, their functions and mechanisms have gradually become clear. There are SIR2, which is involved in regulating calorie restriction, SIR6, which accelerates cell repair and reduces the sensitivity of cells to oxidative damage, and SIR7, which limits the growth and development of tumor cells...
Therefore, this family is called the "anti-aging protein family".
The activation of the protein depends on the catalytic effect of NAD+. It can be said that one of the important ways for NAD+ to exert anti-aging is to activate the Sirtuins protein to regulate cell metabolism and gene repair stress and other processes.
In 2019, a team from the Department of Physiology of the University of Colorado carried out an experiment to divide young mice and old mice into a control group and an NMN group. The results showed that whether they are young or old mice, the SIR1 protein was supplemented with NMN. The level has been significantly improved.
In addition, by comparing the value of acetylated NFκB/total NFκB in the aorta (the higher the ratio, the lower the activity of SIR1), it is found that supplementation of NMN can effectively reduce this value in the elderly mouse group, that is, it can effectively restore aging SIR1 activity of the aorta. [2]

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Image 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 : Changes in the ratio of acetylated NFκB/total NFκB

3. Repair gene damage and extend cell lifespan
An article was published in the journal Nature, revealing the process and molecular mechanism of the repair of broken DNA by PARP enzymes, providing a new solution for cancer cells to develop resistance to anticancer drugs.
One of the important substrates for this enzyme to work is NAD+. When the level of NAD+ drops, the PARP enzyme is forced to combine with another factor and loses the function of repairing DNA; when the level of NAD+ rises, the repair function of PARP will be restored.
In 2017, Harvard University Medical School published a study in the journal Science. The 22-month-old mice were divided into two groups and exposed to radiation at the same time. One group was used as a control group-no treatment, and the other group was used as an experimental group. —— Intraperitoneal injection of NMN 500mg/kg/day, one week later, the NAD+ level of the mice in the NMN injection group increased significantly, and at the same time, the binding process of PARP and another factor was significantly disturbed. [3]

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Image source: Literature [3] Figure D: 22-month-old mice exposed to radiation, changes in NAD+ content after intraperitoneal injection of PBS and NMN; Figure E: 22-month-old mice exposed to radiation, combined after intraperitoneal injection of PBS and NMN Change in concentration

Therefore, intraperitoneal injection of NMN can indirectly repair gene damage.

4. Maintain metabolism and assist weight management
When it comes to the term "metabolism", everyone is familiar with it, and it will be involved in various processes such as weight loss, beauty, rehabilitation, acne removal, and anti-aging.
As the saying goes, the old does not go away, and the new does not come. Only by expelling the ineffective, diminished, and aging things from the body can new, functional and active substances be generated. Material exchange and metabolic balance are the key to maintaining life and the essence of maintaining weight.
In 2017, a team from the University of New South Wales used genetically obese mice as research subjects. They were given NMN and exercise respectively. The results showed that both can reduce body weight, improve glucose tolerance and mitochondrial function; however, NMN is in Fat catabolism and anabolism of the liver are more effective than exercise. [4]
In 2019, the University of Maryland injected NMN into mice and found that it can promote the increase of mitochondrial NAD+ levels in the hippocampus of the rat's brain, promote the increase of the energy molecule ATP in the brain tissue, increase the activity of antioxidant enzymes in the mitochondria, and increase the body's energy metabolism. [5]

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Image source: Literature [5] Figure C: Changes in mitochondrial NAD+ levels in the hippocampus of the mouse brain after injection of NMN; Figure E: Changes in mitochondrial ATP levels in the hippocampus of the mouse brain after NMN injection

5. Improve blood vessel elasticity and promote cardiovascular and cerebrovascular health
With the popularity of sedentary work and western food, obesity has become a symbol of the new generation of people. The frightening thing is that fat will not only accumulate in the subcutaneous and internal organs, but also in the blood vessel wall, resulting in a series of blood vessels. disease.
In addition, aging will cause the blood vessels to gradually lose their elasticity and flexibility. Dry blood vessels cannot effectively carry oxygen and carbon dioxide, nutrients and metabolic wastes, etc., making the body's tissues and organs lose their vitality like stagnant water.
The two most important organs of the human body-the heart and the brain-have lost their blood supply, just like a fish leaving the water, the human body's health has lost its protection.
In 2018, Professor David Sinclair of Harvard Medical School led a team to feed NMN to 18-month-old mice for 2 months. It was found that the number and density of capillaries in these mice returned to the level of young mice, and exercise endurance was improved. 58-80%. [6]

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Picture source: Literature [6] Changes in exercise endurance of mice fed with NMN under low-intensity and high-intensity exercise tests

In addition, studies have shown that intraperitoneal injection of NMN can not only prevent the reduction of NAD+ in the heart during ischemia, but also protect the heart from ischemia/reperfusion injury (it can be understood as giving a very hungry person eating big fish and meat, but it will It puts a greater burden on the already fragile gastrointestinal tract); it can also reduce the oxidative stress of brain microvascular endothelial cells and protect the function of vascular endothelium. [7,8]
6. Improve insulin resistance
Generally speaking, insulin resistance means that the body's sensitivity to insulin is low, and these insulins have no effect; when the body takes in glucose, there is not enough effective insulin to lower blood sugar, which will lead to diabetes.
Dr. Kelly L. Stromsdorfer of the University of Washington School of Medicine found that the decrease in NAD+ levels in obese and elderly mice is related to insulin resistance in the organs. They established a mouse model of insulin resistance and fed the mice by injecting NMN into their drinking water, and found that their blood sugar levels decreased significantly. [9]
It can be seen that NMN has a reversal effect on insulin resistance.

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Image source: Literature [9] Figure B: Changes in NAD+ content in mice after NMN feeding; Figure C: Changes in blood glucose levels in mice after NMN injection over time

7. Prevent the decrease of bone density
As we age, not only the appearance of the human body will become aging, but the organs in the body will also decline in function.
Aging will never be absent, but it can be late. Artificial nutrition or good living habits can effectively reduce the accumulation of aging factors, thereby delaying the aging process.
In 2016, the University of Washington conducted a long-term trial-comparing oral administration of NMN for 12 months with normal aging mice, and found that the oral group can effectively eliminate various aging-related physiological declines, such as weight gain, decreased metabolism, and physical strength Insufficiency, impaired vision, low immunity, decreased bone density, etc., and no toxic side effects. [10]

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Image source: Literature [10] Red represents the oral NMN group; Figure F: Bone mineral density

 

How is such an unpredictable NMN made?
How to present it to the world?

1. Production methods and quality assurance
With the development of science and technology, the production methods of NMN raw materials are constantly improving.
The most primitive is the fermentation method, which is like the process of wine making, allowing microorganisms to slowly carry out the synthesis reaction, but this method has poor controllability, low efficiency, and high cost, which is not conducive to industrial production.
Further is the chemical synthesis method, in which different compounds are reacted with various organic solvents as a medium. Compared with the fermentation method, this method is simpler and lower in cost, but in China, pure compounds obtained by chemical synthesis processes are generally not approved.
The safest and most efficient method is the biological enzyme catalysis method, which uses the catalysis of enzymes to thoroughly carry out the biosynthesis reaction and improve the purity of raw materials. In addition, the directed evolution technology of enzymes accelerates the reaction and improves efficiency. On the basis of this method, the scientists applied the enzyme directed evolution technology, which greatly improved the production efficiency and product quality.
Taking into account the issue 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 the United States Pharmacopoeia-National Prescription Bureau or European Pharmacopoeia or FDA inactive ingredient guidelines. In addition, product packaging such as capsule shells must also ensure its safety and applicability.
Of course, the production requirements of different countries are also different. The United Kingdom has "Global Food Safety Standards", Europe has EU animal-derived product registrations, and the United States has "Dynamic Pharmaceutical Production Management Regulations" and other certifications. Imports into the country also need to obtain "Food Safety". National Standard Health Food" certification.
2. The product form of NMN in the market
The NMN preparations currently on the market are divided into two types: single preparations and compound preparations. The dosage forms are mainly tablets and capsules, as well as powder and sublingual lozenges.
The product usually comes in four forms: powder, sustained-release tablets, lozenges and capsules. Among them, the latest delayed-release antacid capsule has been patented, which can protect NMN from gastric acid and be directly escorted to the small intestine for absorption.

NMN is made 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 the day, it is recommended to take one capsule in the morning and the afternoon; if you want to take a higher dose, you can take one capsule of 125 mg in the morning Capsules, and then continue to take an additional capsule every 1-3 hours based on the total dose.

There are mainly four forms of liposome sublingual gel, sublingual powder or tablet, transdermal lotion or essence, and intranasal spray.
Among them, liposomes are composed of phospholipids, which can be fully combined with cell membranes to promote the absorption of nutrients; in addition, liposomes also have the characteristics of delaying release, prolonging the bioavailability of active substances, and it directly releases from the tongue. The lower lymphatic vessels and other channels are directly absorbed into the blood, bypassing the gastrointestinal tract to give full play to the efficacy of the medicine.
Intranasal spray is the most effective and fastest way to deliver NAD+ directly to the brain, bypassing the blood-brain barrier to reduce systemic adverse reactions, and topical medication can reduce the drug dose.

 

What is the current status of NMN in the Chinese market?

1. Consumers: the mental state is getting better, and various functions need to be understood
Nowadays, NMN has gradually entered the attention of Chinese consumers and has become a common nutritional supplement on mainstream e-commerce platforms in China. However, consumers still generally lack relevant professional knowledge, it is difficult to distinguish the advantages and disadvantages of NMN products, and their efficacy is not fully understood. .
In October last year, iResearch conducted a survey of 1,220 people who have the habit of taking health care products on a daily basis, and found that 30.3% of them had taken NMN health care products.
Although NMN has a history of as long as two centuries abroad, it has really opened up the domestic market in recent years. Among the 369 people taking NMN health products, nearly half have been exposed to NMN products within the past year.

In the cognition of most people, 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 take further steps. To understanding.
In addition, the respondents are very tolerant of the price of the product. The average price acceptance value is 1511.9 yuan, which may be related to the effect they achieved after taking NMN products.
After taking NMN supplements, the respondents felt that the most obvious effect was improved mental state and energetic energy, followed by firmer and shiny skin, and improved sleep quality. Of course, a few people felt that their eyesight , Memory and appetite have all improved
.

2. Mainly rely on cross-border e-commerce to enter the domestic market, with uneven standard quality
Because NMN is not yet available for food production in China, in the current domestic market, many brands of NMN products are mainly manufactured overseas and enter the domestic market through cross-border e-commerce to reach the consumer end.
Due to the different relevant management systems of various exporting countries, the management categories, definitions and product standards of NMN products are very different. For example, it is a general food in Japan, a dietary supplement in the United States, a natural health product in Canada, and a natural health product in the European Union. It is a food supplement, and in Australia it is a supplementary medicine.
However, the safety and quality of products is first determined by the quality of NMN raw materials. At present, China is the world's most important producer of NMN raw materials, but there is no publicly released NMN raw material standard. The raw material manufacturers implement their own corporate standards. This will inevitably cause the key indicators and even the safety indicators of NMN raw materials to vary. Qi's status quo. It can be seen that in order to promote the healthy development of the NMN product industry, it is imperative to establish industry standards for NMN raw materials.
In summary, although NMN's market in China is in its infancy, there are still potential consumer groups and a larger sales space to be explored.

2. Mainly rely on cross-border e-commerce to enter the domestic market, with uneven standard quality
Because NMN is not yet available for food production in China, in the current domestic market, many brands of NMN products are mainly manufactured overseas and enter the domestic market through cross-border e-commerce to reach the consumer end.
Due to the different relevant management systems of various exporting countries, the management categories, definitions and product standards of NMN products are very different. For example, it is a general food in Japan, a dietary supplement in the United States, a natural health product in Canada, and a natural health product in the European Union. It is a food supplement, and in Australia it is a supplementary medicine.
However, the safety and quality of products is first determined by the quality of NMN raw materials. At present, China is the world's most important producer of NMN raw materials, but there is no publicly released NMN raw material standard. The raw material manufacturers implement their own corporate standards. This will inevitably cause the key indicators and even the safety indicators of NMN raw materials to vary. Qi's status quo. It can be seen that in order to promote the healthy development of the NMN product industry, it is imperative to establish industry standards for NMN raw materials.
In summary, although NMN's market in China is in its infancy, there are still potential consumer groups and a larger sales space to be explored.

 

Summary

After decades of scientific research, NMN is related to promoting metabolism, improving vascular function, preventing bone density decline, etc., but these are all based on animal experiments and cannot be copied to the human body. Efficacy, appropriate dosage, adverse reactions, treatment courses, etc. An unknown number.
Currently, there is only one human clinical trial. It is a non-randomized trial conducted by Keio University in Japan in 2019. It recruited 10 healthy people to give 100mg, 250mg and 500mg of NMN respectively. The concentration of NMN in the body after 5 minutes each time was taken as End goal.
The results showed that NMN was quickly metabolized in the body without causing any adverse reactions. [11]
Although the results are very good, the sample size is too small, and there is no other clinical trials to support it. In the future, more energy will be needed to carry out related human trials.
According to reports, Guangzhou Institute of Physical Education has established a national key special project on the effect of exercise combined with NMN nutrition on middle-aged and elderly patients with prediabetes, which is currently being vigorously carried out. It is believed that in the near future, NMN health care products will have a more rigorous scientific basis to fight for the protection of consumers' personal safety rights.
In addition, the market demand for NMN has skyrocketed, and many small companies, even if they do not have any basic nutritional supplement business, are rushing to invest in capital in order to reap considerable benefits.
Coupled with the publicity of media traffic, consumers' lack of product awareness, lack of administrative management, domestic NMN products have large price differences and uneven quality, and there is a certain risk of market confusion and consumer safety risks.
To sum up, even if there is a lot of room for the development of NMN, if you want to quickly and steadily gain a foothold in the market, you must strictly regulate the production conditions, such as toxicological evaluation and safety evaluation of raw materials, and strictly prohibit the use of ingredients that are banned by the state; still need Establish norms, whether it is importing, putting on the shelves, propaganda, sales, etc.