June 27, 2022

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“Longevity factor” NMN: Metabolic mechanism and Application hazards

“Longevity factor” NMN: Metabolic mechanism and Application hazards

 

“Longevity factor” NMN: The metabolic mechanism and Application hazards.  NMN has become a hot topic in the medical market, and some businesses even claim that it is an “anti-aging drug” for “anti-aging, repairing DNA, and preventing Alzheimer’s.”

So what is NMN, and whether this eye-catching propaganda operation is collecting consumers’ “IQ tax”? This article gives a comprehensive introduction to NMN.

 

1. What is NMN?

Structural formula:

"Longevity factor" NMN: The metabolic mechanism and hidden dangers

 

  • CAS Number: 1094-61-7
  • English name: BETA-Nicotinamide Mononucleotide
  • Abbreviation: NMN
  • Molecular formula: C11H15N2O8P
  • Molecular weight: 334.22

 

NMN, also known as nicotinamide mononucleotide, is the precursor substance of the important coenzyme NAD+ in the human body. NMN is the most direct precursor of NAD+. It is a naturally occurring substance in the human body. It also exists in many foods. No side effects have been found. The NMN molecule easily penetrates the cell membrane. After entering the cell, the two NMN molecules will combine to form a NAD+ molecule. NMN can be quickly absorbed by the human body, especially through the sublingual mucosa. It can enter the blood circulation in 2-3 minutes, and can increase the content of NMN in the tissues in 15 minutes, thereby rapidly increasing the level of NAD+ in the body.

 

NAD+ is also called Coenzyme I, and its full name is nicotinamide adenine dinucleotide. It is an important coenzyme for the tricarboxylic acid cycle. It promotes the metabolism of sugars, fats, and amino acids, participates in energy synthesis, and participates in thousands of reactions in every cell. A large amount of experimental data shows that NAD+ is widely involved in a variety of basic physiological activities in the organism, thereby interfering with key cell functions such as energy metabolism, DNA repair, genetic modification, inflammation, biological rhythms, and stress resistance.

 

According to relevant studies, the NAD+ concentration in the human body will decrease with age (as shown in Figure 1). The decrease in NAD+ concentration may lead to neurological decline, decreased vision, obesity, and cardiac function decline, so how to increase it The concentration of NAD+ in the human body has always been a hot research topic in the biochemical medicine community. Although NMN is contained in many natural foods, it is too low to supplement sufficient NMN from natural food sources. If you want to consume 100mg of NMN, you need to consume about 8.9kg broccoli/11kg cabbage/23.8kg beef/45kg shrimp.

"Longevity factor" NMN: The metabolic mechanism and hidden dangers

Figure 1 The changing trend of NAD+ in human body

 

 

2. NAD+ metabolism mechanism

As one of the most important metabolites of the human body, NAD+ is in a metabolic steady state composed of synthesis, consumption, circulation and degradation for a long time in the body.

 

NAD+ consumption:

NAD+ in the organism will be used as a common substrate by a variety of key enzymes, participating in a large number of vital biological processes: Sirtuins protein family is a type of evolutionary highly conserved (from yeast to humans, this protein is Play the same function) deacetylases, they can adjust the oxidative metabolism and stress resistance of cells by binding and consuming NAD+.

 

NAD+ methylation:

NAD+ will be converted into nicotinamide (NAM) after being used by various key enzymes mentioned above. Some of these nicotinamide will enter the remedial pathway and be converted into NAD+ again, and the remaining part will be in NNMT and Methylation occurs under the action of the CYP2E1 enzyme, and is then excreted by the body through urine. Niacinamide inside the body will be preferentially methylated and eliminated from the body. In addition, increasing the expression levels of methylated nicotinamide and NNMT in the liver can stabilize Sirtuins protein and promote sugar and cholesterol metabolism.

 

NAD+ steady state:

NAD+ circulates between various tissues through the above process and forms a steady state. However, the level of distribution of NAD+ in each organization is significantly different. This is partly due to the tissue specificity of NAD+ synthetase expression. Take niacin as an example. This precursor can basically only be converted into NAD+ by organs such as the spleen, small intestine, and pancreas.

 

NAD+ synthesis:

NR and NMN are two precursors that can directly and significantly increase the level of NAD+ in cells. Due to its relatively small molecule, NR can penetrate directly into cells and be converted into NMN and then into NAD+. However, due to the large molecule of NMN, it has been questioned whether it can directly enter the cell. However, recent studies have pointed out that the Slc12a8 protein in the small intestine can directly transport NMN into the cell.

"Longevity factor" NMN: The metabolic mechanism and hidden dangers

Figure 2 Metabolic cycle diagram of NAD+ in organisms

 

Generally speaking, the current understanding of NAD+ steady-state in the academic community is still relatively rough. Although the model has been initially detailed, there are still a lot of key details missing. Probing and further completing the missing details in the current model should be the focus of future research.

 

 

 

3. The physiological functions of NAD+

Coenzyme NAD+ participates in a large number of key physiological processes in the organism, and its abnormal metabolism will seriously affect the health of cells and tissues. Generally speaking, depending on the type of tissue, the NAD+ level in the cell fluctuates between 0.2-0.5 millimolar. However, any physiological stimulus or cellular pressure will greatly affect the homeostasis of NAD+ and cause metabolic abnormalities.

 

1). NAD+ maintains oxidation-reduction steady state.

Maintaining the balance of intracellular oxides and antioxidants is the key to maintaining normal physiological functions of cells. However, adverse stimuli such as pollutants, nutritional fluctuations, and infections will cause the massive production of reactive oxygen species, disrupt redox homeostasis, cause damage to biological macromolecules such as DNA and proteins, and trigger abnormal cell death and inflammation. Studies have shown that insufficient NAD+ will aggravate the severity of oxidative stress in diseases, and supplementation of NAD+ can play a role in oxidative protection by increasing the level and activity of glutathione and a series of antioxidant enzymes. In addition, many NAD+-dependent enzymes, including SIRT3, can also regulate their activities to protect redox homeostasis in organisms.

 

2). NAD+ maintains genome stability.

In addition to mediating Sirtuins and PARPs to repair DNA damage, NAD+ is also an essential part of NHEJ (non-homologous end joining, an important DNA repair mechanism). Lack of NAD+ can cause serious DNA damage repair barriers, cause a large amount of DNA damage to accumulate, and cause genome instability.

 

3). NAD+ regulates immunity and inflammation levels.

In addition to the ability of NAD+ to slow down excessive inflammation by enhancing lysosomal function, the NAMPT enzyme necessary for its metabolism is also an important part of regulating immunity. The redox signal mediated by NADPH is also a key component of the cellular immune mechanism.

 

4). Decreased NAD+ causes mitochondrial dysfunction.

Abnormal mitochondrial function is one of the nine major signs of aging, and insufficient NAD+ is the main culprit for this phenomenon. The decrease of NAD+ in the nucleus will seriously affect the expression of mitochondrial-related genes, while NAD+ in the cytoplasm can protect mitochondria by regulating the activities of oxidase and reductase. Restoring NAD+ levels through NAD+ supplements and other methods can significantly improve mitochondrial function in a variety of aging models.

 

Given that the reduction of NAD+ is a sign of aging and many aging-related diseases, supplementation of NAD+ has become a promising strategy for anti-aging, longevity and disease treatment. The current strategies for increasing NAD+ levels are mainly divided into two categories. One is to use NAD+ precursors to supplement NAD+, and the other is to reduce NAD+ consumption by inhibiting key NAD+ consuming enzymes such as PARPs and CD38.

 

 

4.  NAD+ synthetic precursor substances

NAD+ has five major precursors in the human metabolic cycle: tryptophan (Trp), niacin (Na), nicotinamide (Nam), nicotinamide ribose (NR), nicotinamide mononucleotide (NMN), taking five All these monomers can increase the NAD+ concentration in the human body to some extent. In fact, niacin and niacinamide have been used clinically to treat pellagra. However, the consumption of these precursor substances has certain side effects, or the problem of poor absorption and conversion effects. Among them, NMN and NR are considered to have no toxic side effects, and NMN has a significant effect of increasing the content of NAD+.

Animal experiments have shown that NMN can quickly increase the level of NAD+ in cells, and is extremely safe. Although there is currently a large amount of evidence that NMN ingested into the body will be quickly absorbed by various organs, the actual mechanism still needs further research to confirm. On the other hand, the tissue specificity of NMN also needs to be solved urgently.

 

NR:

In the experiment, the systemic improvement effect of NR on NAD+ is very good. At present, this precursor is undergoing a large number of clinical tests in a planned way. More importantly, the transport mechanism of NR is relatively clear at present. It can be directly transferred into cells through ENTs, metabolized into NMN and then converted into NAD+.

 

NAM and NA:

Most of the oral intake of NAM (niacinamide) will be converted into NA (niacin) by intestinal bacteria. Although NAM has shown considerable efficacy in the treatment of metabolic diseases, several side effects of NAM severely limit its wider application. First, NAM has a strong inhibitory effect on SIRT1. Secondly, due to its special metabolic pathway, long-term intake of NAM will cause severe methylation loss. NA is excellent in the treatment of dyslipidemia, but due to the activation effect of this substance on the G protein-coupled receptor GPR109A, it will cause undesirable side effects such as skin flushing. In addition, it has strong tissue specificity and is also in use. Subject to many restrictions.

 

Other NAD+ enhancement methods:

exercise, fasting, glucose restriction and calorie restriction, etc., can effectively enhance the expression and activity of key NAD+ synthase in the organism, thereby increasing the body’s NAD+ level.

 

In recent years, clinical research on NMN has also continued to advance. Currently, global NMN clinical trials mainly include 3 cases in Japan and 1 case in the United States. Among them, three clinical trials in Japan are aimed at the effect of NMN on health, and the experiment at the University of Washington in the United States is on the effect of glucose metabolism. Regarding the positive effects of taking NMN, the Japanese company Xinxinghe once published an interim report on the “long-term (24-week) oral NMN benefit to the human body” clinical trial report, the world’s first clinical confirmation that the human body’s longevity protein expression increased after oral administration of NMN, and many types Hormone expression has also increased.

 

The current clinical data of NMN to comprehensively improve human functions still needs to be advanced, and the current progress is mainly concentrated in the animal research stage. Clinical evaluation shows that the effective oral dose of NMN is 200 mg/day, which is 6000 mg per month. Recent studies such as Cell have shown that the increase in NAD+ brought by NMN can extend the lifespan of experimental animals similar to humans by 31%. The physical strength and explosive power of elderly animals taking NMN are more than 60% higher than that of animals of the same age without taking NMN. Up to the level of youth.

 

 

5. Discovery of NMN activity and industrialization process

In 2005, Professor Shinichiro Imai from Washington University in St. Louis initiated continuous research on NMN;

In 2009, Professor Miao Chaoyu of Shanghai Second Military Medical University obtained the patent of NMN for the treatment of stroke (stroke);

In 2011, Professor Shinichiro Imai from Washington University in St. Louis jointly developed NMN with Japan’s OYC and successfully produced a sample;

In 2013, Harvard University professor David Sinclair published a paper in the world’s authoritative journal Cell, saying: After using NMN to boost NAD for one week, the lifespan of laboratory mice was extended by 30%. And established Metrobiotech company, planning to develop new NMN anti-aging drugs.

In 2016, Keio University in Japan and the University of Washington jointly launched a human clinical trial of NMN to discuss the potential of NMN as a functional food by evaluating metabolism-related parameters.

In 2016, Shinkowa of Japan commercialized NMN for the first time (brand Mirai Lab), but the cost of taking it was as high as 20,000 per month.

In 2017, Fumiko Higashikawa of Hiroshima University in Japan and others conducted clinical trials to study the safety of long-term oral NMN and its effects on human health.

In 2018, under the cooperation of scientists from the world’s top scientific research institutions such as the US Herbalmax Company, California Institute of Technology and the University of Pennsylvania, after safety assessment and clinical feedback, the use of advanced enzymatic catalysis has reduced the cost of NMN by more than 95%. It is a breakthrough that reduces the price of food-grade high-purity NMN products (branded Ruiweituo) that exceed the effective dose to less than US$500.

In July 2019, Buffett’s global supply chain giant McLane (McLane) and Herbalmax reached a strategic cooperation, which further promoted the global popularity of Revista. Subsequently, Ruiweituo launched a more universally priced “basic version”, further reducing the price to 250 US dollars (NMN basic version Jingdong priced at 1,980 yuan).

In 2019, GeneHarbor in Hong Kong used the all-enzyme method to industrially produce NMN. The current product, Ai Mu Yin NMN9000, is priced at 1,500 yuan on the official website.

Japan: In 2020, the Ministry of Health, Labour and Welfare of Japan included NMN on the “Non-Medical List”, allowing it to be used in food production.

 

 

 

6.  the status quo of China’s NMN market

Most of the current mainstream NMN products in China are cross-border e-commerce products from the United States, Japan, Australia, New Zealand, Germany, Hong Kong and other countries and regions. In addition to Hong Kong Gene Harbor, other companies in some countries are still catching up in the NMN field. Situation, the main enterprises involve Jindawei, Yaben Chemical, Fengyuan Pharmaceutical, etc.

 

On January 29, a reporter from the Beijing News searched on Alibaba’s cross-border e-commerce platform Tmall Global. NMN product NMN product preparations are divided into two types: single preparations and compound preparations. The dosage forms are mainly tablets and capsules. Powder and sublingual lozenge.

 

The number one monthly sales volume is the American brand Puerfons NMN capsule, which is 10,000+, and the single bottle is priced at 1,690 yuan. The merchant stated that the product was produced in a factory approved by the U.S. Food and Drug Administration (FDA), and was inspected and certified by the National Sanitation Foundation (NSF). The monthly sales volume of NMN products in the flagship store of the Canadian brand Real House is 1000+, ranking sixth, with a price of 2,980 yuan per bottle. Although there is no excessive publicity in the product’s promotional pictures, the customer service said in a message to consumers that NMN is known as the industry’s “oral medicine”, which can restore people’s weight to a young state; Delay the physiological decline and aging of various organs caused by aging; enhance the body’s energy metabolism, improve the body function in many aspects, etc. The six Nobel Prize winners theoretically confirmed that long-term use can reduce the risk of disease and extend healthy life.

 

In the official flagship store of Kingway Doctor’s Best, the monthly sales of NMN products also exceed 1,000, ranking ninth, with a single bottle price of 1799 yuan. Since it failed to take the top spot in the automatic sales ranking, it marked “Business Staff Market Ranking (November 1, 2020-December 31, 2020) data: Jindawei NMN in the sky Cat International Beauty ranks No. 1 in overseas category sales. Judging from the certificates displayed, the product has obtained the US Dietary Supplement Certification and Sports Nutrition Supplement Certification.

 

Subsequently, reporters from the Beijing News searched Taobao with “NMN” as a keyword. In addition to NMN products sold by Tmall international cross-border e-commerce, there are also NMN products sold by individual merchants through overseas agents, or even directly sold. NMN raw material powder in bags, etc. The store with the highest monthly sales volume of original powder is the shop named “NMN Bio-Black Technology”. The promotional map says “Enzymatic original powder, longevity gene, special for export.” However, the name of the unit on the inspection report is marked with mosaics. The bottle price is 390 yuan. There are not a few merchants selling raw powder in this way, although some will say “prohibited to take” and “prohibited to purchase by individuals” in their propaganda, but in fact there is no means to restrict individual purchases. In the WeChat Moments, some WeChat merchants are even more unscrupulously promoting the effectiveness of NMN.

 

In fact, some countries’s health food (non-nutrients) allows the 27 types of health functions to be claimed, but does not have the “anti-aging” function claimed by NMN. If NMN wants to become a legal health food in China for production and sales, it should also be produced and sold in accordance with Chinese regulations. Laws and regulations, what kind of function the human body can perform on the function evaluation test. At present, a large number of NMN products use words such as “anti-aging” and “regulating blood sugar and blood pressure” in their advertisements, which are suspected of exaggerating publicity.

 

According to the Regulations for the Implementation of the Food Safety Law, foods other than health foods are prohibited from claiming to have health functions. NMN is only exported as a non-food raw material in some countries. The raw material is neither a new food resource, nor does the final product have a corresponding food standard. From the perspective of academic research, the research of NMN is in its infancy, and its effectiveness and safety are also subject to academic controversy. Online sales of NMN products are chaotic, with different standards, and the phenomenon of claiming randomness. Consumers’ personal choices need to be more rational. “

 

On January 13, 2021, the Food Operation Department of the State Administration of Market Supervision issued a “Letter on Investigating Illegal Operation of’Anti-aging Drugs'” to provincial market supervision departments, pointing out that NMN (Nicotinamide Mononucleotide) is currently in some countries. Without the approval of medicines, health foods, food additives and new food raw materials, that is, NMN cannot be produced and operated as food in some countries.

 

 

7. Application hazards

Although NAD+ has shown good prospects in the treatment of aging-related diseases. In the past two years, NMN users in the United States, Japan, Hong Kong, and China have generally responded well, but these results cannot replace the clinical effects. At present, there are still several key gaps in the research of the entire NAD+ field:

 

1) At present, the most exogenous supplementary NAD+ experimental data are based on animal experiments. Since the mechanism of action in animals is different from that in humans, previous data shows that half of the products that pass animal experiments are in humans The experiment will fail.

 

2) What specific mechanisms are used to achieve the therapeutic effects of NAD+ on various diseases and the overall health benefits? There are still a lot of key information missing in the NAD+ metabolic process.

 

3) The optimal concentration of NAD+ and its precursors varies with species and tissues, and supplementation with high concentrations of NAD+ and its precursors has adverse effects on cells or the body. At present, the mutual transformation efficiency of NAD+ and its precursor substances in the body is not clear. Future research should not only continue to focus on exploring the target and regulation mechanism of NAD+ in the organism, but also clarify the pharmacokinetics of NAD+ and its precursor substances. Kinetics, clarify its best use plan in the key process and area of ​​body aging.

 

4) Purity and safety issues. Among the current two main types of synthesis methods, chemical synthesis has the problem of high cost and production of chiral compounds. There are many reaction steps, low NMN yield, low product purity, and a large amount of organic solvents are used, which is serious to the environment; Among them, phosphorus oxychloride is still a more dangerous reagent. The bioenzyme catalysis method does not contain organic solvent residues and does not have chirality problems, and the prepared NMN is of the same type as in the body, so it is a relatively green and environmentally friendly preparation method. At present, biocatalysis generally uses nicotinamide and phosphoribosyl pyrophosphate as substrates to generate NMN under the catalysis of nicotinamide phosphoribosyl transferase. However, the phosphate in NMN is mainly derived from energy substances such as ATP or PRPP. The high market prices of these two precursors also lead to the high production cost of the biocatalysis method, which severely restricts its application and development.

 

5) Continue in-depth research on the mechanism of action and metabolism. Although oral NMN can alleviate the problems caused by the attenuation of NAD+ concentration, human aging is not only due to the decrease in NAD+ content, but also may include a variety of currently known and unknown complex factors. Human health, life span and the process of aging involve many factors It will not be determined by a single factor, nor can it change the aging process by taking a certain product. Unscrupulous publicity combining NMN with the concept of “immortality” is bound to be unsuitable for the long-term development of this product in the future.

 

 

(source:internet, reference only)


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