01 What is NMN?
NMN full name is nicotinamide mononucleotide, or nicotinamide mononucleotide, is a naturally occurring biologically active nucleotide, NMN exists in 2 irregular forms, α and β; the β isomer is the active form of NMN with a molecular weight of 334.221 g/mol.
NMN belongs to the category of vitamin B derivatives, which are widely involved in many biochemical reactions in the human body and are closely related to immunity and metabolism.
02 What are the sources of NMN?
NMN is found in a wide range of everyday foods, including vegetables such as cauliflower and cabbage, fruits such as avocados and tomatoes, and meat such as raw beef.
NMN can also be synthesised endogenously.
03 What are the roles of NMN?
NMN is an intermediate of the coenzyme NAD+, and its function is also manifested primarily through NAD+.Increased levels of NAD+ have the following benefits:
Activation of DNA repair pathways PARPs
PARPs, whose full name is poly ADP-ribose polymerase, are a class of proteins involved in cellular DNA repair, genome stability and programmed cell death.
PARPs consume a small portion of NAD+ in the normal state of the cell, and become the major NAD+ "consumers" in the cell when acute DNA damage occurs. In experimental models, if PARPs are over-activated, they may lead to cellular NAD+ depletion, triggering progressive ATP depletion and eventual cell death.
Other studies have found that high activity of PARPs appears to be associated with long lifespan. Lymphoblastoid cell lines from centenarians have more active PARPs than average, younger individuals (20-70 years old). These phenomena are reminiscent of the damage accumulation doctrine of aging theory, which suggests that the accumulation of DNA damage in the nucleus with age is the main cause of cellular and even organismal aging, and that whoever has a greater capacity for DNA repair is likely to have a longer lifespan.
Synthesis of NADP+ against oxidative damage
Normally, about one-tenth of NAD+ is catalytically converted to NADP+ and NADPH by NAD kinase and NADP+-dependent dehydrogenase, etc. The ratio of these two is important for maintaining the intracellular reducing environment.
The higher NADPH/NADP+ ratio in the cytoplasm and mitochondria of our cells helps to provide reducing equivalents for biosynthetic reactions, as well as maintain the level of glutathione (reduced form), which helps the cells to resist oxidative damage.
In addition, NADPH/NADP+ is involved in lipid synthesis, such as fatty acid chain elongation and cholesterol production. During the immune response, in order to kill pathogens, NADPH can be transformed into a substrate for NADPH oxidase, which is prompted to induce large amounts of ROS to attack the pathogen and fight infection.
Activation of histone deacetylases sirtuins
One of the most important health effects of increased NAD+ is its involvement in the activation of histone deacetylases sirtuins.
Sirtuins, also known as silencing regulator proteins, have the function of deacetylating chromatin histones and thus silencing genes. In addition to epitope modification of histones, more enzymatic activities of sirtuins have been discovered, and NAD+ is required as a substrate for all enzymatic catalytic effects exerted by sirtuins, so we often regard sirtuins as NAD+-dependent enzymes.
Sirtuins can respond to intracellular NAD+ levels, and thus convert the signal of "NAD+ increase" into several biological activities involving cell damage repair and metabolism regulation, which gives NAD+ enhancers great healthcare and therapeutic potential, including biological clock regulation, neuroprotection, skeletal muscle protection, anti-aging, cardiovascular protection, and anti-aging. anti-aging, cardiovascular protection, metabolic disorder improvement, liver and kidney function protection, etc.
04 Health Benefits of NAD+ Precursors
As we age, the body's NAD+ levels tend to decline, so the need for the major pathways that consume NAD+, sirtuins, PARPs, etc., may be stronger in the elderly.
In addition, metabolic syndrome, represented by obesity, and acute neurological, vascular, hepatic, and renal injuries caused by modern people's poor lifestyle habits may also result in NAD+ deficiency and insufficient sirtuins activity.
Therefore, supplementing NAD+ levels in the body through various precursors can prevent and alleviate many aging-related or acute pathophysiological processes.
Regulating the biological clock and slowing down biological aging
The activity of NAMPT, the key enzyme for NAD+ synthesis, is regulated by BMAL1:CLOCK, the core component of the biological clock, and sirtuins, which use NAD+ as a substrate, have a regulatory and modifying effect on BMAL1:CLOCK.
As a result, "NAD+ concentration → sirtuins → biological clock → NAD+ synthesis" forms a feedback loop, in which the concentration of NAD+ and the activity of sirtuins oscillate diurnally with the biological clock; in turn, intervention in the concentration of these two substances will have an effect on the core component of the biological clock, BMAL1:CLOCK. CLOCK.
A 2014 study found that SIRT1, a member of the sirtuins protein family, is a major player in central biological clock aging (i.e., master clock aging). Insufficient levels of NAD+ in the SCN of aged mice, and consequently decreased SIRT1 activity, predispose them to metabolic syndrome, and their sleep, exercise, and eating behaviours become disturbed.
By supplementing NAD+ precursors and increasing SIRT1 activity, it can theoretically enhance the body's circadian rhythm, improve sleep and boost energy.
Protecting the central nervous system
SIRT1 has an important regulatory role in normal neuronal development and formation. It promotes neurite growth through inhibition of mTOR, neural axon growth via the Akt-GSK3 pathway, and dendrite formation through inhibition of ROCK kinase.
The concentration of NAD+, a common substrate of the SIRTs family SIRT1~SIRT7, decreases significantly with age, and the addition of NAD+ precursors to the diet may be beneficial in the prevention and treatment of neurodegenerative disorders, and there are countless animal and cellular tests of this type, a few of which are briefly listed below:
-Cognitive performance and synaptic plasticity in a mouse model of Alzheimer's disease can be improved by the NAD+ precursors NMN, NR.
-The NAD+ precursor nicotinamide improves somatic cell survival in a Drosophila model of Parkinson's disease (PD).
-Several human studies have shown that a dietary regimen rich in the NAD+ synthetic ingredient niacin reduces the risk of Parkinson's disease in the elderly or improves physical functioning in Parkinson's patients.
-A potential activator of NAMPTase, P7C3, improves neurological function in animal models of PD, ALS.
-NAD+ precursors were able to prevent or even reverse neuronal damage, degeneration associated with hearing loss, retinal injury, traumatic brain injury (TBI), and peripheral neuropathy under certain experimental conditions, demonstrating potent and broad neuronal protective functions.
In 2016, Front Pharmacol's article confirmed through animal models that NMN significantly improved glucose tolerance, hepatic lipid metabolism, and mitochondrial function in female obese mice, and in some indexes was even better than the effect of long-term exercise (6 weeks):
① Muscle NAD+ levels rebounded and NADH levels fell after exercise in female obese mice, indicating that exercise improved cellular oxidative respiratory capacity to a certain extent.
② Obese mice without exercise but supplemented with NMN also showed a significant increase in muscle NAD+ levels, but at the same time NADH also maintained a high level, suggesting that NMN supplementation not only improves oxidative respiration, but also promotes rapid interconversion between NAD+ and NADH.
(iii) Exercise did not significantly improve the liver NAD+ and NADH content in obese female mice.
(iv) No exercise but NMN supplementation had a significant effect on hepatic energy metabolism in obese mice, with a substantial increase in the levels of NAD+ and NADH; and there was also a significant decrease in liver weight and hepatic triglycerides in the mice.
Reversing Vascular Aging
Increasing NAD+ levels in the endothelium of aging blood vessels would be a potential therapy that holds promise for the treatment of diseases that develop as a result of reduced blood flow such as ischemia-reperfusion injury, slow wound healing, and liver dysfunction.
Because of the relationship between SIRTs and vascular aging, NMN has already demonstrated effects in several studies:
① NMN treatment of aged mice (300 mg/kg administered daily for 8 weeks) restored endothelium-dependent dilation of carotid arteries (a measure of endothelial function), increased arterial elasticity, and reduced the level of oxidative stress in aging vessels.
(ii) NMN (500 mg/kg/day in water for 28 days) achieved significant efficacy in mice: it improved blood flow and endurance in aged mice by promoting sirt1-dependent increases in capillary density.
(iii) NMN significantly improved cognition in aged mice by ameliorating age-induced vascular endothelial dysfunction as well as neurovascular coupling (NVC) responses, and NMN reduced mitochondrial ROS and restored NAD+, mitochondrial energy in cerebral microvascular endothelial cells of aged mice.
