What
is
Nicotinamide
Mononucleotide
(NMN Supplement | NAD+ Precursor)? NMN Nicotinamide Mononucleotide is a safe and naturally occurring vitamin B3 metabolite already found in our bodies. NMN can also be found in tiny amounts (less than 2mg/100g-food) in various foods sources such as edamame, broccoli, cabbage, cucumber, avocados, mushrooms, tomatoes, raw-beef and shrimp. Nicotinamide mononucleotide (NMN) is one of the intermediates in NAD+ biosynthesis. In mammalian cells, NAD+ is synthetized, predominantly through NMN, to replenish the consumption by NAD+ participating in physiologic processes including DNA repair, metabolism, and cell death. Recent preclinical studies have demonstrated that the administration of NMN could compensate for the deficiency of NAD+, and NMN supplementation was able to effect diverse pharmacological activities in various diseases.
What is Nicotinamide adenine dinucleotide (NAD+)? Why do we need it? NAD is a coenzyme found in all living cells. The compound is a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base and the other nicotinamide. Nicotinamide adenine dinucleotide exists in two forms: an oxidized and reduced form abbreviated as NAD+ and NADH respectively. Nicotinamide adenine dinucleotide (NAD) is a vital metabolic redox co-enzyme found in eukaryotic cells and is necessary for over 500 enzymatic reactions. It plays a crucial role in various biological processes, including metabolism, aging, cell death, DNA repair, and gene expression. The deficiency of NAD+ is closely associated with diverse pathophysiologies, including type 2 diabetes (T2D), obesity, heart failure, Alzheimer's disease (AD), and cerebral ischemia. The NAD+ levels decline in multiple organs with age, and this contributes to the development of various
age-related diseases. Therefore, NAD+ supplementation could be an effective therapy for the treatment of the conditions mentioned above.
Why is NAD+ so critical? There are three fundamental functions that require NAD+ which are critical for the normal operation of all living cells. First, NAD+ is responsible for the production of ATP, the chemical energy necessary to sustain life. For example, turning food into energy requires the NAD+/NADH redox cycle which drives mitochondrial oxidative phosphorylation. Secondly, SIRTUINS, the so-called "longevity-genes" that regulate or silence other genes, do not work without an adequate supply of NAD+. Thirdly, NAD+ is a facilitator and a substrate that is used for the repair of broken DNA strands. This maintains the integrity of the genetic code by protecting against various mutations. NMN Nicotinamide Mononucleotide is a direct NAD+ precursor supplement that helps to replenish the NAD+ supply. It has been established in principle, by treating old mice with NMN, that at least some biometric markers used to measure the aging process can be reversed.
What causes NAD+ levels to fall? As we age, NAD+ levels fall. In simple terms, this is the core concept that is behind the science, a clear link between falling NAD levels and aging. This rate of decline is greater than the body’s own natural ability to maintain an adequate supply of NAD+. NAD levels decline over time because NAD+ is used and CONSUMED as a substrate by SIRTUINS, DNA-Repair enzymes and aggressively by another enzyme called CD38 for calcium balancing and immune function response. Inflammatory cytokines released by the immune system causes the production of CD38. The problem is further exacerbated, at least in theory by senescent cells, cells that can no longer divide but increasingly causes the release of even more inflammatory cytokines and more CD38 expression. Eventually, more NAD gets consumed than the ability to replenish the supply, leading to the over-all decline that is experienced with aging. It is now evident that supporting the NAD pool is vital for promoting good health & wellness, especially as we age.
Nicotinamide
Mononucleotide
Benefits
and Uses
NMN boosts Energy Metabolism - NAD+ helps to breakdown food like sugars into energy. NMN promotes Healthy Brain and Cardiovascular Function. Anti-Aging DNA Repair - NAD+ is used to repair broken DNA strands. SIRTUIN Activator - NAD+ is required for our longevity genes to work.
Why supplement with NMN? As we have shown, NMN plays a crucial role in creating NAD+. When we have high levels of NAD+ in our bodies, cellular energy increases which becomes the fuel of life—powering every organ and cell in our bodies and protecting us from DNA damage. NAD+ also activates Sirtuins which are essential in increasing our life expectancy and slowing down the aging process. Supplementing with NMN directly increases the levels of NAD+ in our bodies, which counteracts the natural decline that occurs as we age. Research has shown that by supplementing with NMN, the NAD+ levels in older people can be raised to that of a 20-year-old!
How are NMN Supplements Absorbed and Distributed Throughout the Body? NMN has some very interesting absorption mechanisms, which leaves a lot of room for improving NMN bioavailability. In fact, there are even some rumors that NMN itself does not absorb at all, and has to be converted into Nicotinamide Riboside (NR) first. However, this rumor is false. Newly discovered NMN transporter gene SLC12A8 shows NMN enters cells directly putting an end to the assertion that NMN must turn into NR before entering cells. In fact, NMN has a rapid transport system that is specific to NMN, one that does NOT transport NR. It is now fair to say NMN is the most powerful NAD supplement and is superior to NR. The study found that when cells are low in NAD+, they respond by expressing more of the SLC12A8 transporters, allowing for the efficient absorption of NMN from the bloodstream. The SLC12A8 transporter gene is found expressed in many tissues and is abundant in the gut, where NMN is rapidly absorbed from the small intestine
within 2-3 minutes, turning into NAD+ in 10-30 min (mice study). NMN appears to be absorbed into cells through a molecular transporter embedded in the cell surface. Being smaller than NAD+, the NMN molecule may be absorbed more efficiently into cells. NAD+ cannot easily enter the body because of the barrier presented by the cell membrane. The membrane has a waterless space which prevents ions, polar molecules, and large molecules from entering without the use of transporters. Furthermore, injections of NMN result in increased NAD+ in many regions in the body including the pancreas, fat tissue, the heart, skeletal muscle, kidneys, testes, eyes, and blood vessels. Oral administration of NMN in mice increases NAD+ in the liver within 15 minutes.
Does Nmn help lose weight? As people age, they gain weight. In a 2016 study, it was found that subjects given NMN saw their fat mass decrease and lean mass increase. By supplementing with NMN, you can lose weight and build muscle—two powerful ways to improve muscle health and look and feel younger.
Nicotinamide
Mononucleotide
(NMN)
research is still in its infancy NMN has gained a lot of attention lately, especially after the release of David Sinclair’s book Lifespan. In his book, the Ph.D. and longevity scientist discusses his research examining NMN, particularly in mice. He has been very open about taking NMN, but has also made it clear that he has no opinion on whether anyone else should take the supplement. Similar to NR, the research in animal studies looks promising, but the first study in humans was only published this year. Phase I of this study merely assessed the safety of NMN supplementation, and therefore NAD+ levels were not even measured. Ten healthy Japanese men received a single dose of 100mg, 250mg, and 500mg of NMN on separate occasions. All quantities were tolerated without adverse side effects. The authors concluded that up to 500mg of NMN is safe in healthy men. For phase II, researchers will reportedly examine the efficacy of NMN, as well as appropriate dosage and frequency; however, it remains unclear if this study has started. Other ongoing human trials (like this one) will examine the safety and effects of NMN in older adults, while this one will investigate NMN’s impact on cardiovascular and metabolic functions.
But, similar to NR, research is preliminary and more studies are needed to draw further conclusions.
Long-term NMN study A 12-month long study carried out by the University of Washington St Louis (as published in Cell Metabolism), found that oral supplementation of NMN in mice was safe and effective at improving NAD+ levels. Mice, supplemented with NMN vs. a control group, showed remarkable age-associated differences in body weight gain, energy metabolism, blood sugar, lipid metabolism, gene expression changes, mitochondrial oxygen use, eye function, bone density and immune function with no apparent toxic effects. The study showed that oral administration of NMN was quick to action, effectively raising NAD+ levels in minutes. NMN showed a sharp increase in the blood measurement after only 2.5 minutes. It increased NAD+ levels in the liver in just 10 minutes and muscle tissue by 30 minutes.
Sum up Given that NMN has shown high efficacy and benefits in various mouse models of human disease, several clinical trials of NMN have been conducted to investigate its clinical applicability. This has led to some capsule formulations of NMN being approved and put on the market as health supplements. The first phase I human clinical study for NMN is to examine the safety and bioavailability of NMN in human bodies. Recently, it was reported that a single oral administration of NMN up to 500 mg was safe and effectively metabolized in healthy subjects without causing severe adverse events. The major final metabolites of NMN were significantly increased in a dose-dependent manner by NMN administration. A phase II study is also underway to assess the safety of long-term NMN in healthy subjects, the kinetics of NMN and metabolites of NAM, and the effect of daily administration of NMN on glucose metabolism. Other clinical trials of NMN are ongoing to examine the effect of NMN on insulin sensitivity, endothelial function, blood lipids, body fat and liver fat, and fat tissue and muscle tissue markers of cardiovascular and metabolic health. Additionally, a study has been initiated to evaluate the effect of long-term oral administration of NMN on various hormones in healthy volunteers. Recently, a new clinical study was initiated to evaluate the effect of NMN oral administration on the body composition in elderly persons. In summary, despite the tremendous research efforts aimed at exploiting the therapeutic
potential of NMN to treat metabolic and aging-related diseases, the clinical and toxicological evidence to support its utility is currently insufficient. Thus, further research is needed to increase the prospects of developing drugs based on NMN.
Reference: [1] NAD(+) Intermediates: The Biology and Therapeutic Potential of NMN and NR. Yoshino J, Baur JA, Imai SI. Cell Metab. 2018 Mar 6;27(3):513-528. doi: 10.1016/j.cmet.2017.11.002. Epub 2017 Dec 14. [2] Nicotinamide mononucleotide (NMN) supplementation rescues cerebromicrovascular endothelial function and neurovascular coupling responses and improves cognitive function in aged mice. Tarantini S, Valcarcel-Ares MN, Toth P, Yabluchanskiy A, Tucsek Z, Kiss T, Hertelendy P, Kinter M, Ballabh P, Süle Z, Farkas E, Baur JA, Sinclair DA, Csiszar A, Ungvari Z. [3] Nicotinamide mononucleotide (NMN) supplementation ameliorates the impact of maternal obesity in mice: comparison with exercise. Uddin GM, Youngson NA, Doyle BM, Sinclair DA, Morris MJ. [4] The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cantó C, Houtkooper RH, Pirinen E, Youn DY, Oosterveer MH, Cen Y, Fernandez-Marcos PJ, Yamamoto H, Andreux PA, Cettour-Rose P, Gademann K, Rinsch C, Schoonjans K, Sauve AA, Auwerx J. [5] Nicotinamide mononucleotide (NMN) supplementation promotes neurovascular rejuvenation in aged mice: transcriptional footprint of SIRT1 activation, mitochondrial protection, anti-inflammatory, and anti-apoptotic effects. Kiss T, Nyúl-Tóth Á, Balasubramanian P, Tarantini S, Ahire C, Yabluchanskiy A, Csipo T, Farkas E, Wren JD, Garman L, Csiszar A, Ungvari Z. [6] NAD+ in aging, metabolism, and neurodegeneration. Verdin E. Science. 2015 Dec 4;350(6265):1208-13. doi: 10.1126/science.aac4854.