Nicotinamide mononucleotide (NMN) is an intermediate of nicotinamide adenine dinucleotide (nad+) salvage synthesis pathway in mammals. In recent years, studies have found that artificial supplementation of NMN can repair brain injury, improve islet function, protect the heart from ischemia-reperfusion injury, repair brain mitochondrial respiratory defects, and has a certain therapeutic effect on senile degenerative diseases, retinal degenerative diseases, type 2 diabetes mellitus, cerebral hemorrhage, etc.
NMN(Nicotinamide mononucleotide）It is the product of nicotinamide phosphate ribose transferase (Nampt) reaction and one of the key precursors of nad+. In mammals, NMN is generated from nicotinamide (NAM) under the catalysis of Nampt, and then NMN is generated into nad+ under the catalysis of nicotinamide mononucleotide adenosine transferase (Nmnat). Extracellular NMN needs to be dephosphorylated and converted into nicotinamide riboside (NR) to enter the interior of hepatocytes. After entering the intracellular, NR is phosphorylated under the action of nicotinamide riboside kinase 1 (nrk1) to generate NMN, and then NMN and ATP combine to generate nad+. NMN exerts its physiological functions by converting into nad+ in human body, such as activating nad+ substrate dependent enzyme SIRT1 (histone deacetylase, also known as silent regulatory protein), regulating cell survival and death, and maintaining redox state. Recent studies have found that by regulating the level of NMN in the organism, it has a good treatment and repair effect on cardiovascular and cerebrovascular diseases, neurodegenerative diseases and aging degenerative diseases; In addition, NMN can also protect and repair pancreatic islet function, increase insulin secretion, and prevent metabolic diseases such as diabetes and obesity by participating in and regulating the body's endocrine.
The study found that NMN can protect brain nerves and promote blood vessel and nerve regeneration by activating Nampt NAD + defense system, and has a good protective effect on nerve injury caused by cerebral hemorrhage and transformation of cerebral hemorrhage, which is a potential anti stroke drug. By analyzing the metabolic process of NMN in brain tissue, Park et al found that NMN prevented cerebral ischemia induced neural apoptosis and promoted neural regeneration after cerebral ischemia by improving the bioenergetic metabolism of post ischemic tissue. Therefore, NMN has a strong protective effect on ischemic brain injury. . Further studies showed that NMN enhanced the expression of two cytoprotective proteins, namely nuclear factor E2 related factor 2 (Nrf2) and heme oxygenase (HO-1), activated the nrf2/ho-1signaling pathway, inhibited cerebral neuroinflammation and oxidative stress, and alleviated the injury after intracerebral hemorrhage.
Therapeutic effect of NMN on cardiac ischemia-reperfusion post ischemic reperfusion is a life-threatening ischemic injury, which is accompanied by inevitable cardiomyocyte death and severe organ dysfunction. Ischemic preconditioning (IPC) is an endogenous defense mechanism mediated by activating SIRT1, which can protect myocardial viability during transient ischemia-reperfusion. Yamamoto et al showed that NMN can protect the heart by mimicking the protective effect of IPC. The nad+ content in the heart decreased after ischemia. Exogenous NMN could increase the nad+ and NADH content in the heart and reduce the infarct size, and the data showed that the size of the infarct size reduced by NMN was positively correlated with the SIRT1 expression level. In addition, the expression level of Nampt in the heart will be down regulated under pathological conditions, such as ischemia, ischemia-reperfusion and pressure overload, which will further affect the biosynthesis of nad+ and disrupt the regulatory mechanism of SIRT1 activity, resulting in myocardial apoptosis and cardiac decompensation in pressure overload mice. Masamichi et al showed that in the model mice of heart failure, NMN treatment restored the nad+ level in cardiomyocytes and increased the deacetylase activity of SIRT1 and the gene expression level related to the function of mitomycin.
Biological activity of NMN
NMN alleviates and improves ischemic heart and brain tissue injury
The therapeutic effect of NMN on stroke stroke is an acute cerebrovascular disease caused by cerebral blood circulation disorder, with
It has a high mortality and disability rate, which seriously threatens human health.
NMN ameliorates oxidation related degenerative diseases and physical dysfunction
. The disease is a central nervous system disease, which is mainly characterized by cognitive dysfunction and memory impairment. The abnormality of mitochondrial structure and function is one of the pathogenesis factors of AD, and NMN promotes mitochondrial energy metabolism and plays an important role in improving cognitive function and memory function. Longaaron and other researchers found that when the level of NMN in the body was increased, the availability of nad+ immediately increased, which increased the mitochondrial oxygen consumption rate (OCR), promoted the fusion of mitochondria, reduced the fission trend, and made mitochondria produce longer mitochondria in the hippocampal subregion, thus improving the respiratory function of mitochondria. Amyloid β protein (a β) is considered to be the main nerve agent causing ad. Xiaonanwang et al found that NMN improved the cognitive and memory functions of Alzheimer's disease rats caused by a β 1-42 oligomers, restored the levels of nad+ and ATP, and reduced the accumulation of ROS (reactive oxygen species) in hippocampal slices of AD mice by improving energy metabolism and inhibiting oxidative stress. . The above experiments show that NMN can be used as a potential drug for the treatment of AD.
Therapeutic effect of NMN on Parkinson's disease Parkinson's disease (PD) is a degenerative disease of the central nervous system, which mainly presents with motor symptoms such as bradykinesia, static tremor, rigidity, abnormal gait and posture, and non motor symptoms such as anosmia, anxiety, depression, constipation, etc. The pathogenesis of the disease is complex and still unclear, so there is almost no effective treatment. . Compared with Alzheimer's disease, the effect of NMN on Parkinson's disease is less studied, and more in vivo experimental data are needed to prove its effectiveness.
The therapeutic effect of NMN on vascular disorders another serious health-threatening disease related to aging is cardiovascular diseases (CVD), which has the characteristics of high incidence, high disability rate, wide harm population, etc. . Picciotto et al found that NMN supplementation can reduce vascular oxidative stress, improve aortic sclerosis and vascular dysfunction; NMN supplementation can reduce the accumulation of collagen in the whole blood vessels, increase the accumulation of arterial elastin, reduce arteriosclerosis, and delay arterial aging with age. NMN mainly increases nad+bioavailability in the vascular system, restores SIRT1 activity in arteries, and improves endothelial dysfunction and large elastic Arteriosclerosis Caused by aging. . In addition, NMN can also improve the lipid distribution in plasma and maintain blood glucose levels, thereby improving vascular function.
The therapeutic effect of NMN on acute kidney injury the incidence and mortality of acute kidney injury (AKI) are increasing year by year, which has attracted more and more attention. Yi Guan et al showed that the levels of SIRT1 and nad+ decreased with age; Decreased nad+ and SIRT1 in the kidneys of older organisms can lead to increased susceptibility to AKI; NMN supplementation can protect mice from cisplatin (which can be used to inhibit the replication of DNA) - induced AKI; The mechanism of nad+/sirt1 protecting kidney involves epigenetic regulation of JNK pathway; In vitro, SIRT1 attenuated the stress response by regulating the jnksignaling pathway. Endogenous nad+ is considered as a potential therapeutic target for AKI in the elderly, and NMN, an intermediate of nad+ supplementation, is a good therapeutic strategy.
Anti aging effect of NMN mills and other studies found that NMN can significantly improve age-related physiological decline in mice, such as inhibiting age-related weight gain, enhancing energy metabolism, improving insulin sensitivity and lipid distribution in plasma, and improving eye function; NMN prevents age-related gene expression changes in a tissue-specific manner, and enhances oxidative metabolism of mitochondria in skeletal muscle, at least partially mediating its anti-aging effect. . Because Nampt is inhibited by nad+, Nam is not converted to nad+ through the Nam → NMN → nad+ pathway, but nad+ is prepared through the Nam → nicotinic acid (NIA) → nicotinic acid mononucleotide (namn) → nicotinic acid adenine dinucleotide (naad) → nad+ pathway; On the other hand, nad+ synthesis from NMNS is not regulated by cellular nad+ levels, so the increase of nad+ is easier. According to the metabolic control mechanism and many reports on NMN, NMN may be more effective as a nad+ precursor than Nam. . SIRT1 can induce DNA silencing, contributing to anti-aging and prolonging life span. In addition to mammals, studies have also shown that enhancing nad+ biosynthesis can extend the lifespan of yeast, worms and flies.
. Photoreceptors constitute an important part of the neurosensory retina, which is one of the most metabolically active tissues in the body. Lin et al showed that several mouse models of retinal dysfunction (light induced degeneration, streptozotocin induced diabetic retinopathy, and age-related retinal dysfunction) showed early retinal nad+ deficiency, and nad+ not only performed coenzyme functions in all steps of the tricarboxylic acid cycle and glycolysis, but also maintained the optimal SIRT3 activity. SIRT3 and sirt5 play important roles in retinal homeostasis. The deficiency of nad+ causes a variety of metabolic dysfunction (such as glycolytic dysfunction and mitochondrial dysfunction), and cannot respond appropriately to metabolic stress, which ultimately leads to the death of photoreceptors and retinal degeneration. The researchers found that NMN supplementation could restore the normal basic glycolytic function, mitochondrial function and the ability to adapt to metabolic stress in mice, reduce photoreceptor cell death, and significantly improve dark vision and retinal function. . Since it can be implemented for a variety of diseases with multiple pathogenic mechanisms, once successfully implemented, the impact of this therapeutic strategy will be far-reaching.
Therapeutic effects of NMN on metabolic diseases
Therapeutic effect of NMN on type 2 diabetes chronic inflammation is an important factor causing islet β - cell failure in type 2 diabetes mellitus (T2DM). Exposure to proinflammatory cytokines such as interleukin 1 β (IL1 β); . Because the pancreas lacks inampt (intracellular Nampt), pancreatic islets rely on circulating enampt (extracellular Nampt) to stimulate insulin secretion. NMN can restore the level of enampt, reverse the impaired state of insulin secretion, and protect pancreatic islets from the negative effects of pro-inflammatory factors. Caton et al found that NMN can improve islet dysfunction in high fructose group (FRD) mice, reverse FRD and proinflammatory cytokine mediated changes in the expression of genes encoding islet markers, reduce the expression of proinflammatory factors, restore insulin secretion, and improve cytokine Nampt mediated islet dysfunction. Taken together, NMN improves islet function in FRD mice, which is associated with beneficial changes in the expression of genes involved in glucose metabolism, anti-inflammatory and apoptotic processes.
Therapeutic effect of NMN on obesity obesity is closely related to the development of type 2 diabetes. Type 2 diabetes is mainly due to the failure of pancreatic islets to produce enough insulin and the reduced sensitivity of glucose metabolism tissues to insulin. Obesity leads to dysfunction of adipose tissue, increased release of pro-inflammatory cytokines, and increased secretion of fat synthase, which all promote pancreatic beta cell damage. NMN can improve islet dysfunction and restore insulin secretion by catalyzing the biosynthesis of mammalian nad+. Spinnler et al found that Nampt and NMN had no direct effect on the viability of human islet β cells, nor did they cause apoptosis, but they could strengthen glucose stimulated insulin secretion and improve the level of nad+. Exercise is an effective means to fight obesity, which is due to the increase of nad+ level caused by exercise and the enhancement of mitochondrial energy metabolism. NMN can also increase the level of nad+, so in theory, NMN can achieve the same weight loss effect as exercise. Stromsdorfer et al compared NMN mice injected intraperitoneally with exercise mice. The results showed that NMN supplementation increased fat catabolism and increased nad+ levels in liver, while exercise mainly increased nad+ levels in muscle, suggesting the possibility of using NMN, a nad+ precursor, to treat obesity related liver diseases such as nonalcoholic fatty liver disease.
Application status of NMN
Application of NMN in medical health care
In view of the above biological activities of NMN, the development of drugs with NMN as the active ingredient has become a medical hotspot. Huizenga from the United States invented a group of compositions containing nad+, NMN, NR and other active ingredients, which can be used for anti-aging and antioxidant treatment. Akihiro from Yoshida University and others invented drugs based on NMN, NR and their salts, which can be used to treat corneal disorders. . Douglas et al invented a method for evaluating and treating vascular endothelial disorders and a drug with NMN as the active ingredient. Michael et al developed NMN modulators, a neuroprotective drug, which can be used to treat neurodegenerative diseases.
Application of NMN in food
NMN is widely found in natural foods, such as vegetables, fungi, meat and shrimp. Ummarino et al also found NMN in human milk and donkey milk through a new enzyme coupling technology, and the content in human milk is relatively high. The processing characteristics of NMN showed that the activity of NMN was stable when it was treated in water or milk at 75 ℃ for 5 min; After treatment at 95 ℃ for 5 min, the activity loss was about 20%, which indicated that adding NMN into pasteurized milk was theoretically feasible. . In addition, during the intervention period lasting for 12 months, NMN did not show any obvious toxicity and lethality, nor serious side effects, so it has high food safety. Currently, Megumi in Japan has developed a food composition of NMN with resveratrol. Resveratrol is a natural polyphenol compound, which can act as estrogen. It has the effects of antioxidation, antibacterial, inhibition of tyrosinase activity, improvement of metabolic syndrome, and extension of life. Experiments have proved that the food composition can reduce the total cholesterol content in blood and reduce the incidence of myocardial infarction; Reduce the content of low density lipoprotein; Reduce uric acid content and neutral fat such as triglyceride content in blood. . In terms of health food, with NMN as the active ingredient, furongzhao invented health care products that can be used to improve arteriosclerosis and cardiovascular disease, Parkinson's disease and anti-aging.
At present, the application of NMN in China is still concentrated in medicine, and the application in food is still in the blank stage. With the further disclosure of the safety of NMN, it is believed that more foods or health products added with NMN will benefit human life in the future.
expectation
As an intermediate in the nad+ salvage pathway, nicotinamide mononucleotide has the effect of antioxidation and reducing oxidative stress, and it also has good performance in the treatment of some specific diseases, such as stroke, cardiac ischemia-reperfusion, Alzheimer's disease, Parkinson's disease, acute kidney injury, retinal degenerative disease, type 2 diabetes, etc. Especially in the aspect of anti-aging, NMN can slow down the physiological decline of organisms, enhance energy metabolism, and extend life span. As NMN is an endogenous substance in human body, with high safety and good thermal stability, NMN has broad prospects in the development of functional food as an active substance. However, the synthesis of NMN is difficult, time-consuming, high cost, low yield, and difficult to achieve large-scale industrial production, which limits the application of NMN. In addition, most of the functional studies on NMN remain in animal experiments, and there are few data on human experiments. The safety of adding NMN health care products cannot be fully guaranteed, especially the safety of long-term human intake needs more experiments to prove.