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Deru Xu Dec 20, 2020
How to treat the relationship between "NMN" and anti-aging, and supplement the relevant knowledge of "NDA+".
Image credit: Picture from Rod Long
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The full name of "NMN" is β-nicotinamide mononucleotide, which is the first step in the synthesis of NAD+ in the human body, and enters the body by converting it into NAD+ to play a role.
NAD+ is called Coenzyme I. It is the coenzyme of hundreds of oxidoreductases, responsible for generating more than 95% of the energy in the body and regulating hundreds of metabolic reactions in the body. It is the key to maintaining Sirtuins protein, repairing DNA and maintaining the normal function of the immune system. NDA+ in the human body is ubiquitous. When it is a coenzyme, it can be repeatedly used hundreds of thousands of times, such as NAD+/NADH in the tricarboxylic acid cycle. NAD+ is a one-time consumable when it participates in DNA repair. With age, the amount of NAD+ in the human body decreases drastically, only one-tenth of that when young, and NAD+ cannot be directly supplemented by oral administration.
The functions of NDA+ are as follows:
- Repair DNA
- Regulate the circadian rhythm
- Protect nerves
- Improve cognitive function
- Inhibit inflammation
- Improve liver, kidney, skeletal muscle, cardiovascular function and metabolic disorders related diseases.
Therefore, NAD+ has anti-aging effects, and can improve aging-related diseases and prolong healthy survival . What are its current researches?
[1]Okabe, K., Yaku, K., Tobe, K., & Nakagawa, T. (2019). Implications of altered NAD metabolism in metabolic disorders. J Biomed Sci, 26(1), 34. doi:10.1186/s12929-019-0527-8
[2]Yang, Y., & Sauve, A. A. (2016). NAD(+) metabolism: Bioenergetics, signaling and manipulation for therapy. Biochim Biophys Acta, 1864(12), 1787-1800. doi:10.1016/j.bbapap.2016.06.014
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Creative contributions
NAD+ and 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 significantly improves liver lipid accumulation; this regulatory effect is achieved through " Inhibit NAMPT→reduce NAD+→inhibit SIRT1→decrease the deacetylation of SREBP1→decrease SREBP1 activity→up-regulate 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 is effective in preventing and treating obesity, alcoholic steatohepatitis and NASH. It can also improve glucose homeostasis and mitochondrial dysfunction, improve liver health, enhance its regeneration ability, and protect the liver from Liver toxicity damage.
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The relationship between NAD+ and circadian rhythm
The NAD+-dependent deacetylase SIRT1 becomes a bridge between circadian rhythm and metabolism by connecting the enzyme feedback loop that regulates the NAD+ salvage pathway and the circadian rhythm 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, 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.
American geneticists Jeffrey C. Hall, Michael Rosbash, and Michael W. Young won the 2017 Nobel Prize in Physiology or Medicine for discovering the molecular mechanism that regulates the circadian rhythm. The biological clock of mammals is controlled by the "hypothalamic suprachiasmatic nucleus" (SCN), which is a pair of cell clusters located above the optic nerve chiasm.
There are three circuits that are jointly responsible for regulating the circadian rhythm:
Circuit 1: Start and express biological clock genes. The specific process is that CLOCK and BMAL1 form a dimer (CLOCK:BMAL1) and transcribe clock genes.
Circuit 2: Block and inhibit the biological clock gene. The specific process is that when PER and CRY proteins accumulate to a certain amount, they inhibit the transcription activity of CLOCK:BMAL1 and inhibit their own transcription.
Circuit 3: Play the role of activating or inhibiting the BMAL1 gene.
Summarized as follows: forming a loop of "NAD+——SIRT1——CLOC: BMAL1——NAMPT——NAD+"
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NAD+ and 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.
①Activation of SIRT1 and SIRT3 by NAD+ 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.
③Mice supplemented with NAM can stimulate the secretion of the renal protective prostaglandin PGE2 and improve renal function after ischemia; NAM can also inhibit cisplatin-induced AKI by stimulating NAD+ synthesis.
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NAD+ and skeletal muscle
Compared with young wild-type mice, the mice's muscle atrophy and inflammation markers, as well as insulin signaling and insulin-stimulated glucose uptake ability 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.
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NAD+ and 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 it 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 worsen. 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, NAMPT overexpression or NMN treatment can significantly prevent pressure overload and ischemia-reperfusion injury. Reduce the infarct size by about 44%.
④The use of NAD+precursor therapy also improved the cardiac function of elderly MDX cardiomyopathy mice.
⑤ NAD+ precursor improves the mitochondria and heart function in a mouse model of heart failure induced by iron deficiency.
⑥NAD+ precursor can even protect and restore the heart function of the mouse model of Friedrich's ataxia (FRDA) cardiomyopathy to a basically normal level by activating SIRT3.
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What are the ways to supplement NAD+?
The main way to synthesize NAD+:
The synthesis of NAD+ is divided into salvage pathway, de novo synthesis pathway and Preiss-handler pathway according to different synthesis materials.
① De novo synthesis pathway: tryptophan (Trp) is converted to quinolinic acid (QA), and then converted to NAMN by quinolinic acid-phosphoribosyl transferase (QPRT). NAMN is converted to NAAD, and finally NAD+ is catalyzed by NAD+ synthetase (NADS).
②P-H synthesis pathway (also called NA salvage pathway): Niacin (NA) synthesizes NAD+ through NAPRT, NMNAT, NADS (NAD synthetase).
③Remedial synthesis pathway (also called NR remedial pathway): Nicotinamide ribose (NR) or nicotinamide (NAM) is synthesized through NRK (nicotinamide riboside kinase) or NAMPT, NMNAT to synthesize nicotinamide mononucleotide (NMN), NMN NAD+ is synthesized by NMNAT1-3 enzyme.
In addition, nicotinic acid nucleoside (NAR) can also produce NAMN through NRK catalysis, and then NAD+ can be synthesized by the enzymatic reaction in 1.
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NAD+ and the nervous system
Sir2 is a conserved protein involved in regulating the lifespan of yeast. Under yeastdietary restriction conditions, Sir2 can induce a phenotype with extended lifespan. Sir2 related proteins are collectively referred to as sirtuins, which usually use theaction of their deacylase to remove the acyl groups on the lysine residues of the targetprotein, including acetyl, succinyl and malonyl. Sirtuins are deacylases that rely on NAD+ and are 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 aging.
In the process of neural development, SIRT1 plays an important role instructure,
promoting axonal growth, neurite growth and dendritic branchingthrough the Akt-GSK3 pathway. The development of synapses and the regulationof synaptic strength are crucial to the formation of memory, and sirtuins proteinsplay an important role in this process, whether in physiology or after injury.SIRT1 regulates the expression of brain-derived neurotrophic factor (BDNF). SIRT1 can exist in the hippocampus as an inhibitory complex, which contains thetranscription factor YY1 that can regulate microRNA-134. The distribution of microRNA-134 is brain-specific and can regulate the expression of cAMP responsebinding 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 avariety of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and motor neuron disease.These diseases may interact with SIRT1 in metabolism, anti-stress and genomics. Stability is related to the function.Drugs that activate SIRT1 may provide a promising way to treat these diseases.
[1]Campisi, J., Kapahi, P., Lithgow, G.J. et al. From discoveries in ageing research to therapeutics for healthy ageing. Nature 571, 183–192 (2019).
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NAD+ and cancer
Increasing NAD+ levels to treat cancer research shows: ① NMNAT3 overexpression increases mitochondrial NAD+ levels and inhibits the growth of glioblastoma cells; ②supplementation 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 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. 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. It will be very important to further test the effects of NAD+ supplements in standard cancer models.
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 to promote tumor growth).
Related studies have found that the level of extracellular nicotinamide phosphoribosyl transferase (eNAMPT) decreases with age. Increasing eNAMPT can promote the increase of NAD +, resist aging and extend healthy life.In mammals, nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the main NAD+ biosynthetic pathway, which converts nicotinamide and 50-phosphoribose pyrophosphate (PRPP) into NMN. However, exactly how eNAMPT regulates hypothalamic NAD+ levels remains unclear. The hypothalamus is the high-order control center of mammalian aging. The study hypothesized that eNAMPT secreted by adipose tissue plays a key role in affecting the aging process and ultimate life span. In this study, adipose tissue-specific Nampt knock-in protein (ANKI) mice were constructed and their aging phenotypes were characterized. The results showed that elderly ANKI mice maintained young levels of circulating eNAMPT and increased NAD + levels in a variety of tissues (including hypothalamus, hippocampus, pancreas and retina), showing improved physical activity, sleep quality, cognitive function, and glucose metabolism And the photoreceptor function is significantly improved. Surprisingly, injection of eNAMPT-containing EVs purified from young mice or cultured adipocytes can enhance the mobility of older mice and extend their lifespan. These findings prove that this new physiological system mediated by EV-eNAMPT plays a key role in maintaining systemic NAD + biosynthesis and counteracting age-related physiological decline, implying that the eNAMPT contained in EVs may serve as a potential human antidote.
[1]Mitsukuni Yoshida,Akiko Satoh,Jonathan B. Lin,Kathryn F. Mills,Yo Sasaki,Nicholas Rensing,Michael Wong,Rajendra S. Apte,Shin-ichiro Imai. Extracellular Vesicle-Contained eNAMPT Delays Aging and Extends Lifespan in Mice[J]. Cell Metabolism,2019,30(2).