The role of NMN: regulate day and night, improve heart function, maintain neuronal health

The role of NMN: regulate day and night, improve heart function, maintain neuronal health
NMN is the precursor of NAD+, and its function is mainly reflected by NAD+, so we must first explain NAD+:</>

NAD+ is also known as Coenzyme I, the full name is nicotinamide adenine dinucleotide. It is widely distributed in all cells of the human body and participates in thousands of biocatalytic reactions. It is an indispensable coenzyme in the human body.

A. Circadian rhythm

Supplement NMN to increase the level of NAD+ in the body. The NAD+-dependent deacetylase SIRT1 connects the enzyme feedback loop that regulates the NAD+ salvage pathway and the circadian rhythm transcription-translation feedback loop to become a bridge between circadian rhythm and metabolism.
NAD+ regulates the biological clock through SIRT1. SIRT1 deacetylates BMAL1 and PER2, which is antagonistic to the acetylation function of CLOCK, so SIRT1 can inhibit the transcription of clock genes mediated by CLOCK-BMAL1. Therefore, NAD+ affects SIRT1 deacetylation activity at its own level, which in turn affects the expression of a series of biological clock-related proteins including NAMPT.

The regulation of the biological clock is related to many diseases, including but not limited to sleep disorders, diabetes, and tumors. Many pathological processes are triggered by circadian clock disorders, which may come from heredity or the environment. In short, keeping the circadian clock working properly plays an important role in maintaining health.

B. Nervous system

Sirtuins are a deacylase that relies on nicotinamide adenine dinucleotide (NAD+), which is traditionally believed to be related to calorie restriction and aging in mammals. These proteins also play an important role in maintaining the health of neurons during the aging process.

SIET1 During neuronal development

In the process of neural development, SIRT1 plays an important role in structure, promoting axonal growth, neurite growth and dendritic branching through the Akt-GSK3 pathway. The development of synapses and the regulation of synaptic strength are crucial to the formation of memory, and sirtuins proteins play an important role in this process, whether in physiology or after injury. SIRT1 can exist in the hippocampus as an inhibitory complex, which contains the transcription factor YY1 that can regulate 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.

In the development of neurological diseases, SIRT1 plays a protective role in a variety of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and motor neuron disease. These diseases may be related to SIRT1 in metabolism, anti-stress and genomics. Stability is related to the function. Drugs that activate SIRT1 may provide a promising method for the treatment of these diseases.

C. Cancer-inhibit tumor

Increasing NAD+ levels to treat cancer research shows: ① NMNAT3 overexpression increases mitochondrial NAD+ levels and inhibits the growth of glioblastoma cells; ② supplementation of NA or NAM can inhibit tumor growth and multi-organ tumor metastasis in SCID mice.
The principle is as follows: Excessive NAD+ will promote mitochondrial respiration, reduce glycolysis, and counteract the Warburg metabolism that cancer cells like (compared to oxidative phosphorylation, which is more dependent on the energy metabolism characteristics of glycolysis in cancer cells); increasing NAD+ will also increase SIRT1 The activity of SIRT6 and SIRT6 both inhibit tumors by down-regulating β-catenin signaling and down-regulating glycolysis.

However, there are also contradictions and concerns: NAD+ promotes DNA repair and angiogenesis, and may help cancer cells grow (existing long-term studies on wild-type mice have not provided any evidence for increasing tumors). After reducing tumor NAD+ levels, as the ability of PARPs to repair DNA damage decreases, the sensitivity of cancer cells/tissues to chemotherapeutic drugs will increase. It will be very important to further test the effects of NAD+ supplements in standard cancer models. To

D. Improve liver function

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

NAMPT plays a key regulatory role in the development of fatty liver induced by high-fat diet: inhibiting NAMPT will make the liver steatosis caused by high-fat diet more serious, and overexpression of NAMPT can significantly improve liver lipid accumulation; this regulatory effect is through ” Inhibition of NAMPT→decrease of NAD+→inhibition of SIRT1→decreased deacetylation of SREBP1→decrease of SREBP1 activity→up-regulation of 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 anti-oxidative stress; SIRT6 controls gluconeogenesis.

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, the level of NAMPT decreases and the level of CD38 increases, resulting in a two-fold decrease in steady-state NAD+ levels in middle age.

Increasing the level of NAD+ to a young level has significant effects in the prevention and treatment of obesity, alcoholic steatohepatitis and NASH. It can also improve glucose homeostasis and mitochondrial dysfunction, improve the health of the liver, enhance its regeneration ability, and protect the liver from Liver toxicity damage.

E. Kidney function

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

① Activation of SIRT1 and SIRT3 by NMN supplementation protects high glucose-induced renal mesangial cell hypertrophy, while mice treated with NMN protect cisplatin-induced acute kidney injury (AKI) in a SIRT1-dependent manner.
②5-Aminoimidazole-4-carboxyamine nucleoside can stimulate AMPK activity, increase NAD+ level, and protect cisplatin-induced AKI in a sirt3-dependent manner.
③ Mice supplemented with NAM can stimulate the secretion of renal protective prostaglandin PGE2 and improve renal function after ischemia; NAM can also inhibit cisplatin-induced AKI by stimulating NAD+ synthesis.

F. Skeletal muscle-improve muscle function

Compared with young wild-type mice, the mice’s muscle atrophy and inflammation markers, as well as insulin signaling and insulin-stimulated glucose uptake capacity decreased. Treatment of 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 increase mitochondrial function, increase ATP production, reduce inflammation, and transform glycolytic type II muscle into oxidized fibrous muscle. Related harmful changes.

G. Improve heart function

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

①The OXPHOS enzyme in SIRT3 knockout mice is highly acetylated, ATP is reduced, and is highly sensitive to aortic contraction, which may be due to the activation of CypD, a regulator of mitochondrial permeability transition pore.

②SIRT3-KO mice will develop fibrosis and myocardial hypertrophy when they are 13 months old. As they age, their condition will further aggravate, and NMN treatment can reverse this decline.

③Whether it is repeated administration 30 minutes before ischemia (500 mg/kg, ip) or before reperfusion and during reperfusion, the use of NAMPT overexpression or NMN treatment can significantly prevent pressure overload and ischemia-reperfusion injury. Reduce the infarct size by about 44%.

④ Taking NMN also improved the heart function of elderly MDX cardiomyopathy mice.

⑤NMN improves the mitochondria and heart function in a mouse model of heart failure induced by iron deficiency.

⑥NMN can even protect and restore the heart function in a mouse model of Friedrich’s ataxia (FRDA) cardiomyopathy to a basic normal level by activating SIRT3.

H. Vascular endothelial cells

Endothelial cell (EC) senescence is a pathophysiological process of structural and functional changes, including vascular tone disorders, increased endothelial permeability, arteriosclerosis, impaired angiogenesis and vascular repair, and decreased EC mitochondrial biogenesis.

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

Because of the relationship between SIRTs and vascular aging, the supplement of NAD+precursor NMN has shown its effect in some studies:

①NMN treatment of elderly mice (300 mg/kg daily for 8 weeks) can restore the carotid artery endothelium-dependent expansion (a measurement method of endothelial function), while reducing aortic pulse wave velocity and elastic artery stiffness.

②NMN (500 mg/kg/day, water delivery, for 28 days) has achieved significant effects in the treatment of mice: by promoting the increase of sirt1-dependent capillary density, it improves the blood flow and endurance of elderly mice.

③NMN significantly improves the cognition of old mice by improving the vascular endothelial dysfunction and neurovascular coupling (NVC) response induced by age in old mice, and NMN reduces the mitochondrial ROS of the brain microvascular endothelial cells of old mice, and restores NAD+ and mitochondrial energy.

Increasing the level of NAD+ in the vascular endothelium may be a potential therapy to increase the mobility of the elderly, and can treat diseases that develop due to reduced blood flow such as: ischemia-reperfusion injury, slow wound healing, liver dysfunction, and Muscle myopathy, etc.

I. NMN and metabolic disorders

NMN can improve obesity caused by disorders of fat metabolism and glucose metabolism, type 2 diabetes, and reproductive inhibition, and can even improve the adverse effects of obese mothers on the reproduction of female offspring.


In 2016, Front Pharmacol’s article confirmed through animal models that NMN can significantly improve glucose tolerance, liver lipid metabolism, and mitochondrial function in female obese mice, and is even better than long-term exercise (6 weeks) in some indicators:

①After exercise, female obese mice increased their muscle NAD+ level and decreased NADH level, indicating that exercise has improved the ability of cell oxidative respiration to a certain extent.

② Obese mice that did not exercise but supplemented with NMN also showed a significant increase in muscle NAD+ levels, but at the same time NADH also maintained a higher level. It is said that NMN supplementation not only improves oxidative respiration, but also promotes rapid mutual conversion between NAD+ and NADH.

③Exercise did not significantly improve the contents of NAD+ and NADH in the liver of obese female mice.

④Non-exercise but supplementation of NMN has a significant effect on liver energy metabolism in obese mice, and the levels of NAD+ and NADH are greatly increased; and the liver weight and liver triglycerides of mice also significantly decrease.

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