NMN full name nicotinamide mononucleotide

NMN's food sources
NMN is widely distributed in daily food, with vegetables such as cauliflower (0.25-1.12mg NMN/100 gm) and Chinese cabbage (0.0-0.90 mg NMN/100 gm), fruits such as avocados (0.36-1.60 mg NMN/100 gm), tomatoes (0.26-0.30 mg NMN/100 gm), and meat such as raw beef (0.06-0.42 mg NMN/100 gm) all containing abundant NMN [1].

Endogenous synthesis of NMN

One molecule of nicotinamide and one molecule of 5-phosphoribosyl-1-phosphate (PRPP) are catalyzed by nicotinamide phosphoribosyltransferase (NAMPT or NAMPRT) to generate one molecule of NMN and one molecule of pyrophosphate (PPi). Except for nicotinamide, which can generate NMN, 1 molecule of nicotinamide nucleoside (NR) is phosphorylated under the catalysis of nicotinamide nucleoside kinase (NRK) to generate 1 molecule of NMN.

Tissue specificity of NMN synthase and consumer enzymes
(1) NAMPT is ubiquitous in the body, but there are significant differences in expression levels between tissues. In the brain and heart, the NAMPT dependent salvage pathway is the preferred mode of NAD+production; In skeletal muscle, the NRK dependent remedial pathway is the preferred mode of NAD+production.

(2) NMNATs (NMN consuming enzymes): The metabolic profile of mouse tissues shows that the activity of NMNAT subtypes is much higher than that of NAMPT, and the activity of NMNAT subtypes is not restricted in most tissues except for blood.

(3) The expression analysis of NRKs: NRK subtypes shows that NRK1 is ubiquitous, while NRK2 mainly exists in skeletal muscle. Consistent with this, chronic NR supplementation causes an increase in NAD+levels in muscles, but has little effect in the brain or white adipose tissue [2].

Intake of NMN

Different pathways of NMN entering cells
NMN has membrane transporters on the surface of certain cells that can directly transport NMN into the cell, so there are two ways for NMN to enter the cell:

① Directly entering cells through transporters: In early 2019, a paper on nature metabolism confirmed this idea by discovering the presence of NMN specific transporters in the small intestine of mice, called Slc12a8. This is an amino acid and polyamine transporter that has high selectivity for NMN and does not transport NaMN, which is structurally similar to NMN [3].

② Dephosphorylation of CD73 on the cell membrane surface to NR (via the balanced nucleoside transporter ENT) enters the cell, and then is catalyzed by the cytoplasmic NRK enzyme to NMN, which is utilized in mitochondria (mitochondria without NRK) [4].

NAM is both a precursor of NMN and a product of NAD+hydrolysis via the NADase activity pathway CD38. Therefore, the synthesis, utilization, and regeneration of NAD+involve a cycle of intracellular and extracellular NMN/NR → NAD+→ NAM → NMN.

Oral NMN promotes NAD+
NMN is a precursor of NAD+, and its function is mainly manifested through NAD+(nicotinamide adenine dinucleotide).

In the salvage synthesis pathway, nicotinamide ribose (NR) or nicotinamide (NAM) synthesizes nicotinamide mononucleotide (NMN) through NRK (nicotinamide nucleoside kinase) or NAMPT, NMNAT, and NMN synthesizes NAD+through NMNAT1-3 enzyme.

PNP： Purine nucleoside phosphorylase; NRK： Nicotinamide nucleoside kinase; QPRT： Quinoline acid phosphoribosyltransferase NAPRT: Nicotinic acid phosphoribosyltransferase; NAMPT： Nicotinamide phosphoribosyltransferase; NMNAT： Nicotinamide mononucleotide adenyltransferase
Although the complete structure of NMN cannot be detected in serum, oral administration of NMN can still quickly (15 minutes) increase NAD+levels in female and male mice [5]:

NMN and NAD+levels in liver, pancreas, and white adipose tissue
The role of NMN
NMN mainly functions by converting to NAD+, also known as coenzyme I or nicotinamide adenine dinucleotide. It is widely distributed in all cells of the human body and participates in thousands of biocatalytic reactions. It is an essential coenzyme in the human body.

The decrease of NAD+during the aging process is considered to be the main cause of diseases and disabilities, such as hearing and vision loss, cognitive and motor dysfunction, immune deficiency, arthritis caused by autoimmune inflammatory response disorders, metabolic disorders, and cardiovascular diseases.

Therefore, supplementing NMN increases the NAD+content in the body, thereby delaying, improving, and preventing various phenotypes related to aging, or age-related metabolic disorders and age-related diseases.

A. NAD+and circadian rhythm
The NAD+- dependent deacetylase SIRT1 serves as a bridge between circadian rhythm and metabolism by connecting the enzyme feedback loop that regulates the NAD+salvage pathway and the circadian transcription translation feedback loop.

NAD+regulates the biological clock through SIRT1. SIRT1 deacetylates BMAL1 and PER2, which is antagonistic to the acetylation function of CLOCK. Therefore, SIRT1 can inhibit the transcription of clock genes mediated by CLOCK-BMAL1. Therefore, NAD+affects the deacetylation activity of SIRT1 at its own level, which in turn affects the expression of a series of clock related proteins, including NAMPT [6].

Biological clock regulation is associated with many diseases, including but not limited to sleep disorders, diabetes, and tumors. Many pathological processes are triggered by disruptions in the biological clock, which may come from genetics or the environment. In summary, maintaining the normal functioning of the biological clock plays an important role in maintaining health.

B. NAD+and the nervous system
Sirtuins is a deacetylase that relies on nicotinamide adenine dinucleotide (NAD+) and is traditionally associated with calorie restriction and aging in mammals. These proteins also play an important role in maintaining the health of neurons during the aging process.

During the process of neural development, SIRT1 plays an important role in structure, promoting axonal growth, neurite outgrowth, and dendritic branching through the Akt-GGSK3 pathway. The development of synapses and the regulation of synaptic strength are crucial for the formation of memory, and sirtuins proteins play an important regulatory role in this process, both physiologically and after injury. SIRT1 can exist in the hippocampus in the form of an inhibitory complex, which contains the transcription factor YY1 that regulates microRNA-134. The distribution of microRNA-134 is brain specific and can regulate the expression of cAMP response binding protein (CREB) and brain-derived neurotrophic factor (BDNF). This is important for the formation and long-term enhancement of synapses [7].

In the occurrence and development of neurological diseases, SIRT1 plays a protective role in various neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and motor neuron disease [8], which may be related to the functions of SIRT1 in metabolism, stress resistance, and genomic stability. Drugs that activate SIRT1 may provide a promising approach for treating these diseases.

C. NAD+and Cancer
Research on increasing NAD+levels for cancer treatment shows: ① Overexpression of NMNAT3 increases mitochondrial NAD+levels and inhibits the growth of glioblastoma cells Supplementing with NA or NAM can inhibit tumor growth and multi organ tumor metastasis in SCID mice.

The principle is that excessive NAD+promotes mitochondrial respiration, reduces glycolysis, and counteracts the Warburg metabolism favored by cancer cells (which is more dependent on glycolysis than oxidative phosphorylation); Increasing NAD+also increases the activity of SIRT1 and SIRT6, both of which inhibit tumors by downregulating β - catenin signaling and downregulating glycolysis [9].

However, there are also contradictions and concerns involved: NAD+promotes DNA repair and angiogenesis, which may help cancer cell growth (existing long-term studies on wild-type mice have not provided any evidence of tumor growth) [10]. After reducing tumor NAD+levels, as the ability of PARPs to repair DNA damage decreases, the sensitivity of cancer cells/tissues to chemotherapy drugs will increase. Further testing the effectiveness of NAD+supplements in the standard cancer model will be crucial.

D. NAD+and liver function
It is known that enzymes in the NAD+signaling pathway can protect the liver from the effects of fat accumulation, fibrosis, and insulin resistance, all of which are associated with the occurrence of fatty liver disease.

NAMPT plays a key regulatory role in the development of high-fat diet induced fatty liver: inhibition of NAMPT will exacerbate liver steatosis caused by high-fat diet, while overexpression of NAMPT significantly improves liver lipid accumulation; This regulatory effect is generated by "inhibiting NAMPT → reducing NAD+→ inhibiting SIRT1 → reducing deacetylation of SREBP1 → decreasing SREBP1 activity → upregulating FASN and ACC expression".

SIRT1 and its downstream targets PGC-1a, PSK9, and SREBP1 maintain mitochondrial function, cholesterol transport, and fatty acid homeostasis. SIRT2 controls gluconeogenesis by deacetylating phosphoenolpyruvate carboxykinase; SIRT3 regulates OXPHOS, fatty acid oxidation, ketone production, and antioxidant stress; SIRT6 controls gluconeogenesis [11].

Due to the importance of these pathways in the liver, maintaining NAD+levels is essential for maintaining good organ function. Under normal circumstances, due to obesity and aging, NAMPT levels decrease and CD38 levels increase, leading to a two-fold decrease in steady-state NAD+levels by middle age.

Raising NAD+levels to younger levels has significant effects in preventing and treating obesity, alcoholic steatohepatitis, and NASH, while also improving glucose homeostasis and mitochondrial dysfunction, improving liver health, enhancing its regenerative capacity, and protecting the liver from liver toxicity damage.

E. NAD+and renal function
The decrease in NAD+levels and the corresponding decrease in sirtuin activity in elderly kidneys are largely responsible for the decline in renal function and compliance with age.

① Supplementing with NAD+activates SIRT1 and SIRT3 to protect against high glucose induced mesangial cell hypertrophy, while treating mice with NMN protects against cisplatin induced acute kidney injury (AKI) in a SIRT1 dependent manner [12].

② 5-aminoimidazole-4-carboxamine nucleoside can stimulate AMPK activity, increase NAD+levels, and protect cisplatin induced AKI in a sirt3 dependent manner.

③ Supplementing mice with NAM can stimulate the secretion of renal protective prostaglandin PGE2 and enhance renal function after ischemia; NAM can also inhibit cisplatin induced AKI by stimulating NAD+synthesis.

F. NAD+and Skeletal Muscle
Compared with young wild-type mice, mice showed decreased muscle atrophy and inflammatory markers, as well as decreased insulin signaling and insulin stimulated glucose uptake ability. Treating elderly mice with NAD+precursors can significantly improve muscle function.

Treating elderly mice with NMN (500 mg/kg/day ip for 7 consecutive days) can reverse age-related harmful changes by increasing mitochondrial function, increasing ATP production, reducing inflammation, and transforming glycolytic type II muscles into oxidized fiber type muscles.

G. NAD+and cardiac function
NAD+levels are crucial for normal cardiac function and recovery after injury. Among all NAD+- dependent signaling proteins, SIRT3 seems to be the most important:

① The OXPHOS enzyme in SIRT3 knockout mice is highly acetylated, ATP is reduced, and highly sensitive to aortic constriction, possibly due to the activation of CypD, a regulatory factor of mitochondrial permeability transition pore.

② SIRT3-KO mice develop fibrosis and myocardial hypertrophy at 13 months of age, and the condition worsens with age. NMN treatment can reverse this decline.

③ Whether administered repeatedly 30 minutes before ischemia (500 mg/kg, i.p.) or before and during reperfusion, overexpression of NAMPT or treatment with NMN can significantly prevent pressure overload and ischemia-reperfusion injury, reducing infarct size by approximately 44%.

④ The use of NAD+precursor therapy also improved cardiac function in elderly MDX cardiomyopathy mice.

⑤ NAD+precursor improved mitochondrial and cardiac function in a mouse model of iron deficiency induced heart failure.

⑥ The NAD+precursor can even protect and restore the heart function of a mouse model of Friedel's ataxia (FRDA) cardiomyopathy to basic normal levels by activating SIRT3.

H. NAD+and vascular endothelial cells
Endothelial cell (EC) aging is a pathophysiological process characterized by structural and functional changes, including dysregulation of vascular tone, increased endothelial permeability, arteriosclerosis, impaired angiogenesis and vascular repair, and reduced EC mitochondrial biogenesis.

Cell cycle dysregulation, oxidative stress, changes in calcium signaling, hyperuricemia, and vascular inflammation are closely related to the occurrence and development of EC aging and vascular diseases. Many abnormal molecular pathways are associated with these potential pathophysiological changes, including SIRT1 Klotho、 Activation of fibroblast growth factor-21 and renin angiotensin aldosterone system.

Due to the relationship between SIRTs and vascular aging, the supplementation of NAD+precursor NMN has been shown to be effective in some studies

① NMN treatment in elderly mice (administered daily at 300 mg/kg for 8 weeks) can restore carotid artery endothelial dependent dilation (a measure of endothelial function), while reducing aortic pulse velocity and elastic arterial stiffness.

② NMN (500 mg/kg/day, administered in water for 8 days) achieved significant therapeutic effects on mice: by promoting an increase in Sirt1 dependent capillary density, it improved blood flow and endurance in elderly mice.

③ NMN significantly improves cognition in elderly mice by improving age-related endothelial dysfunction and neurovascular coupling (NVC) response. Additionally, NMN reduces mitochondrial ROS in brain microvascular endothelial cells and restores NAD+and mitochondrial energy.

Increasing NAD+levels in the endothelium of blood vessels may become a potential therapy to enhance the mobility of the elderly and treat diseases that develop due to reduced blood flow, such as ischemia-reperfusion injury, slow wound healing, liver dysfunction, and muscle disease.

I. NAD+and metabolic disorders
NMN can improve fat metabolism, obesity caused by glucose metabolism disorder, type II diabetes, reproductive depression, and even can improve the adverse effects of obese mothers on female offspring reproduction.

The therapeutic effect of NAD+precursor on metabolic disorders in animal experiments