Nicotinamide Mononucleotide (NMN) Uses & Dosage

Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice

Nicotinamide Mononucleotide (NMN) Uses & Dosage

NAD+ availability decreases with age and in certain disease conditions. Nicotinamide mononucleotide (NMN), a key NAD+ intermediate, has been shown to enhance NAD+ biosynthesis and ameliorate various pathologies in mouse disease models. In this study, we conducted a 12 month-long NMN administration to regular chow-fed wild-type C57BL/6N mice during their normal aging.

Orally administered NMN was quickly utilized to synthesize NAD+ in tissues. Remarkably, NMN effectively mitigates age-associated physiological decline in mice.

Without any obvious toxicity or deleterious effects, NMN suppressed age-associated body weight gain, enhanced energy metabolism, promoted physical activity, improved insulin sensitivity and plasma lipid profile, and ameliorated eye function and other pathophysiologies.

Consistent with these phenotypes, NMN prevented age-associated gene expression changes in key metabolic organs and enhanced mitochondrial oxidative metabolism and mitonuclear protein imbalance in skeletal muscle. These effects of NMN highlight the preventive and therapeutic potential of NAD+ intermediates as effective anti-aging interventions in humans.

Historically unprecedented worldwide trends in population aging are predicted to become an incessant burden on governmental healthcare finances (OECD, 2013).

To make the process of aging healthy and prevent expensive age-associated health problems, efforts to develop effective, affordable, anti-aging interventions have recently been intensified, leading to some promising compounds, such as metformin, rapamycin, and SIRT1 activators (Barzilai et al., 2016; Hubbard and Sinclair, 2014; Lamming et al., 2013).

Whereas these compounds were originally developed as pharmaceutical drugs, some endogenous compounds might also have the potential to achieve healthy and productive lives even at a very old age (Imai, 2010; Imai and Guarente, 2014).

Nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), key NAD+ intermediates in mammals, could be such candidates (Imai, 2010). NMN is synthesized from nicotinamide (Nic), an amide form of vitamin B3, and 5’-phosphoribosyl-pyrophosphate (PRPP) by nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in this particular NAD+ biosynthetic pathway (Canto et al.

, 2015; Imai and Guarente, 2014). NR is phosphorylated to NMN by nicotinamide riboside kinases (NRKs) (Belenky et al., 2007). Once NMN is synthesized, it is converted to NAD+ by three NMN adenylyltransferases, NMNAT1–3. The short-term administration of either NMN or NR has been reported to have remarkable therapeutic effects on metabolic complications and other disease conditions.

For example, we have shown that NMN ameliorates impairments in glucose-stimulated insulin secretion in aged wild-type mice and some genetic mouse models (Ramsey et al., 2008; Revollo et al., 2007). NMN treatment also significantly improves both insulin action and secretion in diet- and age-induced type 2 diabetic or obese mouse models (Caton et al., 2011; Yoshino et al., 2011).

Furthermore, NMN protects the heart from ischemia/reperfusion injury by preventing NAD+ decrease induced by ischemia (Yamamoto et al., 2014), maintains the neural stem/progenitor cell population and restores skeletal muscle mitochondrial function and arterial function in aged mice (de Picciotto et al., 2016; Gomes et al.

, 2013; Stein and Imai, 2014), ameliorates mitochondrial function, neural death, and cognitive function in Alzheimer’s disease rodent models (Long et al., 2015; Wang et al., 2016). NR is also able to ameliorate mitochondrial dysfunction in obese mouse models (Canto et al., 2012; Gariani et al., 2015; Lee et al., 2015) and various mitochondrial disease models (Cerutti et al., 2014; Khan et al.

, 2014), attenuate cognitive deterioration in Alzheimer’s disease model mice (Gong et al., 2013), prevent DNA damage and hepatocellular carcinoma formation (Tummala et al., 2014), improve noise-induced hearing loss (Brown et al., 2014), and maintain muscle stem cell function (Zhang et al., 2016).

Collectively, these findings strongly suggest that enhancing NAD+ biosynthesis by administering NMN or NR is an efficient therapeutic intervention against many disease conditions (Imai and Guarente, 2014).

Interestingly, it has been demonstrated that enhancing NAD+ biosynthesis extends lifespan in yeast, worms, and flies (Anderson et al., 2002; Balan et al., 2008; Mouchiroud et al., 2013).

In rodents and humans, a number of studies have reported that NAD+ content declines with age in multiple organs, such as pancreas, adipose tissue, skeletal muscle, liver, skin, and brain (Gomes et al., 2013; Massudi et al., 2012; Mouchiroud et al.

, 2013; Stein and Imai, 2014; Yoshino et al., 2011; Zhu et al., 2015). Thus, enhancing NAD+ biosynthesis with NMN or NR is expected to provide significant preventive effects on various pathophysiological changes in the natural process of aging.

To address this critical question, long-term administration studies need to be performed under normal conditions in wild-type mice.

To examine whether long-term administration of NMN shows preventive effects on age-associated pathophysiological changes, we treated regular chow-fed wild-type mice for 12 months with two different doses of NMN in their drinking water.

We assessed a variety of functional traits, as well as long-term safety and toxicity, and found that NMN is remarkably capable of ameliorating age-associated physiological decline in mice.

Our findings from this long-term administration study provide a proof of concept to develop NMN as an effective anti-aging compound that prevents age-associated physiological decline, hoping to translate the results to humans.

In our previous study, we showed that a bolus intraperitoneal administration of NMN (500 mg/kg body weight) increased tissue NMN and NAD+ levels within 15 min in the liver, pancreas, and white adipose tissue (WAT) in regular chow-fed wild-type mice (Yoshino et al., 2011).

To make long-term NMN administration possible, we decided to test lower doses, which could potentially be translatable to humans, and add it to drinking water. We confirmed that 93–99% of NMN was maintained intact in drinking water at room temperature for 7–10 days (Figure S1A).

We next administered NMN at a dose of 300 mg/kg body weight to mice by oral gavage and measured plasma NMN and hepatic NAD+ levels over 30 min. Plasma NMN levels exhibited a steep increase at 2.5 min, further increases from 5 to 10 min, and then went back to original levels at 15 min (Figure 1A), implicating very fast absorption in the gut.

Consistent with this notion, hepatic NAD+ levels showed a steady increase from 15 to 30 min (Figure 1A). We also measured tissue NAD+ levels 60 min after oral gavage of NMN.

Although differences did not reach statistical significance at this particular dose, relatively small increases in NAD+ levels were observed in the liver, skeletal muscle, and cortex of the brain, but not in WAT or brown adipose tissue (BAT) (Figures 1B and S1B).

To further confirm whether orally administered NMN is utilized to synthesize NAD+ in tissues, we used doubly-labeled isotopic NMN (C13-D-NMN; Figure S1C) and traced these labels in NAD+ in the liver and soleus muscle by mass spectrometry.

Interestingly, in the liver, after administering C13-D-NMN by oral gavage, we clearly detected doubly-labeled NAD+ (C13-D-NAD+) at 10 min, and the level of C13-D-NAD+ further increased at 30 min (Figures 1C and S1D). In the soleus muscle, we detected C13-D-NAD+ at 30 min, but not at 10 min (Figures 1C and S1D). These results suggest that orally administered NMN is quickly absorbed, efficiently transported into blood circulation, and immediately converted to NAD+ in major metabolic tissues.

To determine the effects of long-term NMN administration on age-associated pathophysiologies, we performed a 12 month-long NMN administration study using regular chow-fed wild-type C57BL/6N mice (Figure 1D and S1E). We tested two doses of NMN, 100 and 300 mg/kg/day, from 5 months to 17 months of age.

During this period, we carefully monitored the tolerance of mice to NMN by measuring water intake in control and NMN-administered mice and found that NMN administration was well tolerated over 12 months (see below).

This long-term oral administration regimen could cause very small increases in the steady-state levels of plasma or tissue NMN and NAD+ when mice take a sip of NMN-containing water. However, it is technically very difficult to detect such small fluctuations of plasma or tissue NMN and NAD+ levels.

Nonetheless, we observed a tendency of dose-dependent NAD+ increase over time in the liver and BAT, but not in other tissues including skeletal muscle and WAT (Figure 1E).

We next assessed a variety of physiological, biochemical, and molecular parameters in control and NMN-administered mice. We found that NMN administration significantly and dose-dependently suppressed age-associated body weight gain (Figures 2A and 2B). There was a statistically highly significant interaction between time and group (P

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5668137/

Nicotinamide Mononucleotide (NMN) Uses & Dosage

Nicotinamide Mononucleotide (NMN) Uses & Dosage

Nicotinamide mononucleotide (NMN) is advertised as the fountain of youth, the anti-aging effect observed in preliminary research. However, there’s no clinical evidence to back up these claims. Is it a miracle drug or just another fad? Read on to learn and discover more.

What is Nicotinamide Mononucleotide (NMN)?

NMN belongs to the family of nucleotides, organic molecules found in most of the foods we eat.

As with all nucleotides, NMN is composed of 3 parts: a nitrogenous base, a sugar, and a phosphate group.

While most nucleotides are used to build DNA, NMN is used to make nicotinamide adenine dinucleotide (NAD) and fine-tune energy balance [1].

The body creates NMN as an intermediate step or “precursor” to NAD. Put simply: higher NMN levels mean higher NAD levels [1].

NAD increases the body’s main energy currency (ATP), balances the circadian rhythm, and enables hundreds of enzymatic reactions – many of which delay aging. Levels of NAD, especially its NAD+ form, naturally decrease with age in many tissues [1].

Proponents:

  • Slows aging in animals
  • May improve diabetes & metabolic syndrome
  • May support kidney and heart health
  • More stable than nicotinamide riboside (NR)
  • No observed side effects

Skeptics:

  • Not studied in humans
  • Expensive
  • Oral form may not be bioavailable
  • Long-term safety unknown

Food Sources

Because most human cells cannot directly import NAD, they have to create it from the inside. NMN, on the other hand, can quickly enter cells in the small intestine, liver, pancreas, and fatty tissue. Mice absorb NMN from the small intestine into the bloodstream within 3-5 minutes. Within 15 minutes, NMN is distributed to tissues and converted to NAD [2].

A small amount of NMN is present in some food sources, including [3, 4]:

  • Edamame (immature soybeans)
  • Broccoli
  • Cucumbers
  • Cabbage
  • Avocados
  • Tomatoes

While NMN can be found in trace amounts in these vegetables, it would be difficult to eat enough of them to effectively boost NAD levels [4].

Potential Benefits of NMN

NAD levels naturally decline with aging; as they do, cells and organs start to function less efficiently. Low NAD levels have been associated with multiple age-related diseases. That said, the research behind the health effects of NMN, in particular, is scarce [1].

So, is NMN the fountain of youth or just another anti-aging fad?

Animal and Cellular Research (Lacking Evidence)

No clinical evidence supports the use of NMN for any of the conditions listed in this section. Below is a summary of the existing animal and cell-based research, which should guide further investigational efforts. However, the studies listed below should not be interpreted as supportive of any health benefit.

1) Anti-Aging

Harvard geneticist David Sinclair proposed that increasing NAD will slow down aging and delay age-related disease in humans. Sinclair’s group leads NMN research under the assumption that it can boost NAD levels [1].

Sinclair even patented an NAD booster, which is currently marketed by Elysium Health. The company was founded in 2014 by Sinclair’s former mentor, MIT biologist Leonard Guarente. They sell products claimed to boost NAD levels.

The figure below depicts the mechanisms by which Sinclair believes NAD levels can be increased in the human body alongside corresponding health benefits [1].

Telomere Length

Telomeres are long “tails” of repeating DNA code at the ends of chromosomes. Every time a chromosome duplicates itself, it loses some of its telomere; thus, as an organism ages, telomeres shorten, eventually leading to cell death [5].

NMN increased telomere length in mouse liver cells [5].

Sirtuins

In mice, NMN increases the activity of a family of molecules called the sirtuins, which are involved in a complex anti-aging mechanism that scientists are only beginning to understand. NMN specifically increases SIRT1 (sirtuin 1) gene activity [6].

Sirtuins combat oxidative stress, DNA damage, and cellular aging. Low sirtuins levels have been linked to aging and aging-related diseases, while high sirtuins enhance fertility in women [7, 8].

2) Diabetes

NMN oral supplementation in mice helped with age- and diet-related diabetes. After a single dose of NMN, mice had increased insulin secretion in response to glucose as well as increased sensitivity to insulin [3, 9].

In a mouse study, oral NMN improved several health markers, including weight gain, energy metabolism, physical activity, fat profile, and eyesight [10].

This was a long-term study: lab mice typically only live for 2 years, and the mice were followed for 1 year. At a high NMN dose (300 mg per kg of body weight per day) mice lost 18% of their body weight with no added exercise [10].

Interestingly, younger mice did not benefit; older mice were simply restored to a “younger” health profile, which might support the claims about the anti-aging effects of NMN.

4) Kidney Damage

In another study, oral NMN improved kidney function and prevented kidney damage in aging mice. These effects are probably due to increased NAD and SIRT1, which activate anti-aging and anti-inflammatory pathways [6].

5) Heart Health

In elderly mice, oral NMN restored the elasticity of capillary walls and reversed blood vessel damage caused by age (through SIRT1). These mice had improved blood flow and capillary repair compared to mice that did not receive NMN [11].

New blood vessels actually sprouted within the elderly mice’s skeletal muscles. After the experiment, their vascular system and endurance were similar to that of young mice [11].

In a similar and more recent study, elderly mice that received NMN had drastically improved blood flow to their brains. Given that blood flow to the brain is impaired in hypertension, Alzheimer’s disease, and stroke, this result bodes well for NMN’s impact on these diseases [12].

Friedreich’s Ataxia

One study investigated a mouse model of Friedreich’s Ataxia, a rare genetic heart disease that emerges during childhood. High dose NMN (500 mg per kg of body weight) twice a week for six weeks improved heart muscle strength and function compared to controls [13].

6) Alzheimer’s Disease

NAD levels are decreased in Alzheimer’s Disease. In two mouse studies of Alzheimer’s Disease, both NMN and nicotinamide riboside (NR) decreased neuroinflammation and improved memory, learning, and motor control. SIRT3 gene activity, the loss of which may be correlated with brain tissue degeneration, also increased [14, 15, 16].

NMN also reduced β-amyloid plaque levels in the brains of diseased mice; NR did not [15].

The superior performance of NMN may be due to its ability to cross the blood-brain barrier. Note, however, that NMN was injected under the skin, whereas NR was administered by mouth [17].

Limitations and Caveats

Regardless of Dr. Sinclair’s claims and the general hype around anti-aging supplements, current NMN research is limited to animal studies.

Sinclair’s motives are also questionable: his research helped spur the resveratrol anti-aging fad of the early 2000’s, and he has financial interests in over two dozen companies.

In 2004, Sinclair founded a company called Sirtris Pharmaceuticals to promote resveratrol supplements. Four years later, Sirtris was sold to GlaxoSmithKline for $720 million dollars.

However, in 2010, Glaxo halted the research on resveratrol (SRT501) after discouraging results and even some side effects in humans [18, 19].

Finally, the higher manufacturing cost of NMN vs NR presents a potential drawback to customers [17].

Nicotinamide Riboside vs. Nicotinamide Mononucleotide

Nicotinamide riboside (NR) is another intermediate in the biosynthesis of NAD. Un NAD, NR is highly available in diet, predominantly in cow’s milk, and is more readily taken up by cells than NMN [17, 20].

Chemically, NR is an NMN molecule lacking a phosphate group.

Clinical Studies & Known Effects in Humans

In contrast to NMN, human studies have been completed on NR. NR is currently marketed as a supplement by various companies including Elysium Health, alone or in combination with the antioxidant pterostilbene, a polyphenol found in blueberries. Pterostilbene is closely related to resveratrol, though it is more bioavailable [21, 22].

Completed studies have confirmed that NR is safe and increases NAD+ in humans [23, 24].

More than 20 clinical studies are underway evaluating specific health benefits of NR across a spectrum of health conditions [25].

Tissue & Cell Penetration

NR is not stable in the bloodstream – that is, it breaks down quickly into other compounds – and is not detected in blood plasma in either mice or humans, even after very high doses. NR alone or in combination with pterostilbene increases NAD in the blood, however [23, 21].

NMN is absorbed and detected in the blood in animals for a short time; it then penetrates into cells and tissues. As such, it might be distributed throughout the body more effectively than NR [2].

Which One is Better?

It is difficult to determine whether NMN or NR is more effective: they have overlapping roles in boosting NAD and activating sirtuins, but human studies for NMN are lacking. However, several mouse studies have shown clear advantages of NMN over NR.

Safety & Side Effects

Keep in mind that the safety profile of NMN is relatively unknown, given the lack of well-designed clinical studies. The list of side effects below is not a definite one, and you should consult your doctor about other potential side effects, your health condition and possible drug or supplement interactions.

Safety

NR is generally recognized as safe by the FDA. NMN hasn’t been evaluated yet, although it is already on the market [26].

Several studies are underway to determine the safety of NMN as a nutraceutical in humans. The first Phase I study began in 2016 to assess the safety of NMN and its and time course in the blood. Another large study is evaluating the supplement in a group of 50 older women with high blood glucose, BMI, and blood triglycerides [27, 28].

In a long-term study in mice, oral NMN was administered for 1 year at 100 and 300 mg per kg of body weight per day – much higher than the dosage advertised for humans. There were no adverse effects or signs of toxicity [10].

Cancer Risks

One concern is that, because NMN promotes the growth of new blood vessels, it could also promote angiogenesis and increase blood flow to tumors. In theory, this could cause tumors to grow and resist treatment.

Additionally, certain brain cancers depend on NAD to grow. Therefore, increasing NAD through NMN supplementation could be dangerous in people at risk of these cancers [11, 29].

However, in Sinclair’s study, NMN’s effect on angiogenesis – the growth of new blood vessels – only restored the elderly mice’s vascular health to that of normal young mice. There were no signs of increased cancer risk in this or other long-term NMN animal studies. More studies should look into its effects on cancer risk, though [11].

Side Effects

NR and NMN have fewer unfavorable side effects than other NAD precursors. For example, niacin (vitamin B3), the most widely used NAD precursor, causes an array of side effects including niacin flush when taken at high doses [1, 30].

Dosage

Because NMN is not approved by the FDA for any condition, there is no official dose. Users and supplement manufacturers have established unofficial doses trial and error. Discuss with your doctor if NMN may be useful as a complementary approach in your case and which dose you should take.

In mouse studies, NMN was given through a feeding tube or added directly to the animals’ water at dosages of several hundred mg per kg of body weight per day. This dosage would be impractical for humans: using a common conversion factor, a corresponding dose in a 60 kg adult would easily be greater than 2 grams per day (2,000 mg per day) [31].

Doses in human supplements vary around a few hundred mg per day. For example, in a study of 50 women, the dosage being tested is 125 mg NMN twice daily over 8 weeks [27].

David Sinclair, who publicly attributes his own youthfulness and good health to the benefits of NMN, reportedly takes 1 gram of NMN daily in combination with 0.5 grams of resveratrol, but his claims should be taken with a grain of salt.

Supplement Forms

NMN supplements have not been approved by the FDA for medical use. In general, regulatory bodies aren’t assuring the quality, safety, and efficacy of supplements. Speak with your doctor before supplementing.

NMN is currently marketed as a pill and in powder form.

Companies selling NMN as a supplement claim that taking it orally is effective in boosting NAD. This claim is the discovery of Slc12a8, the protein which helps absorb NMN in the gut [2].

The company ALIVE BY NATURE markets a sublingual (under the tongue) formulation of NMN that they claim is more ly to be absorbed into the bloodstream.

It’s worth mentioning that a one-time purchase of 10 g of NMN from RevGenetics comes with a hefty price-tag of $195.

Source: https://selfhacked.com/blog/nicotinamide-mononucleotide/

NADH

Nicotinamide Mononucleotide (NMN) Uses & Dosage
Vitamins & Supplements

  • Overview
  • Uses
  • Side Effects
  • Interactions
  • Dosing

Overview NADH stands for “nicotinamide adenine dinucleotide (NAD) + hydrogen (H).” This chemical occurs naturally in the body and plays a role in the chemical process that generates energy.

People use NADH supplements as medicine.

NADH is used for improving mental clarity, alertness, concentration, and memory; as well as for treating Alzheimer’s disease and dementia.

Because of its role in energy production, NADH is also used for improving athletic performance and treating chronic fatigue syndrome (CFS).

Some people use NADH for treating high blood pressure, high cholesterol, jet lag, depression, and Parkinson’s disease; opposing alcohol’s effects on the liver; reducing signs of aging; and protecting against the side effects of an AIDS drug called zidovudine (AZT).

Healthcare providers sometimes give NADH by intramuscular (IM) or intravenous (IV) injection for Parkinson's disease and depression.

NADH produced by our bodies is involved in making energy in the body. While there is some evidence that suggests NADH supplements might reduce blood pressure, lower cholesterol, help chronic fatigue syndrome by providing energy, and increase nerve signals for people with Parkinson's disease, there isn't enough information to know for sure how or if these supplements work. Uses

  • Chronic fatigue syndrome (CFS). Some research shows that NADH might reduce symptoms of CFS. It has shown benefit on fatigue when used alone, in combination with coenzyme Q10, or as an adjunct to traditional medications.
  • Mental decline (dementia) related to Alzheimer's disease and other conditions. Taking NADH does not seem to improve memory or mental function in people with dementia.
  • Parkinson's disease. So far, study results don’t agree about the effectiveness of NADH in treating Parkinson’s disease.
  • Depression.
  • Jet lag.
  • High blood pressure.
  • Improving athletic performance.
  • Improving memory and concentration.
  • Reducing signs of aging.
  • Lowering cholesterol levels.
  • Opposing alcohol's effects on the liver.
  • Protecting against side effects of the drug zidovudine (AZT) used to treat AIDS.
  • Other conditions.

More evidence is needed to rate the effectiveness of NADH for these uses. Side Effects NADH seems safe for most people when used appropriately and short-term, up to 12 weeks. Most people do not experience any side effects when taking the recommended amount each day, which is 10 mg. Pregnancy and breast-feeding: Not enough is known about the use of NADH during pregnancy and breast-feeding. Stay on the safe side and avoid use. Interactions Dosing

The following doses have been studied in scientific research:

ADULTS

BY MOUTH:

  • For chronic fatigue syndrome (CFS): 5-10 mg of NADH has been used daily for up to 24 weeks. A specific product containing 10 mg of NADH and 100 mg of coenzyme Q10 has been taken twice daily for 8 weeks.

View References

  • Birkmayer JG, Vrecko C, Volc D, Birkmayer W. Nicotinamide adenine dinucleotide (NADH) – a new therapeutic approach to Parkinson's disease. Comparison of oral and parenteral application. Acta Neurol Scand Suppl 1993;146:32-5. View abstract.
  • Budavari S, ed. The Merck Index. 12th ed. Whitehouse Station, NJ: Merck & Co., Inc., 1996.
  • Bushehri N, Jarrell ST, Lieberman S, et al. Oral reduced B-nicotinamide adenine dinucleotide (NADH) affects blood pressure, lipid peroxidation, and lipid profile in hypertensive rats (SHR). Geriatr Nephrol Urol 1998;8:95-100. View abstract.
  • Bushehri N, Jarrell ST, Lieberman S, et al. Oral reduced B-nicotinamide adenine dinucleotide (NADH) affects blood pressure, lipid peroxidation, and lipid profile in hypertensive rats (SHR). Geriatr Nephrol Urol 1998;8:95-100. View abstract.
  • Castro-Marrero J, Cordero MD, Segundo MJ, et al. Does oral coenzyme Q10 plus NADH supplementation improve fatigue and biochemical parameters in chronic fatigue syndrome? Antioxid Redox Signal 2015;22(8):679-85. View abstract.
  • Dizdar N, Kagedal B, Lindvall B. Treatment of Parkinson's disease with NADH. Acta Neurol Scand 1994;90:345-7. View abstract.
  • Forsyth LM, Preuss HG, MacDowell AL, et al. Therapeutic effects of oral NADH on the symptoms of patients with chronic fatigue syndrome. Ann Allergy Asthma Immunol 1999;82:185-91. View abstract.
  • Hawkins EB. NADH: Advanced supplementation for more energy and slower aging. Natural Pharmacy 1998;2:10.
  • Kuhn W, Muller T, Winkel R, et al. Parenteral application of NADH in Parkinson's disease: clinical improvement partially due to stimulation of endogenous levodopa biosynthesis. J Neural Transmiss (Budapest) 1996;103:1187-93. View abstract.
  • Rainer M, Kraxberger E, Haushofer M, et al. No evidence for cognitive improvement from oral nicotinamide adenine dinucleotide (NADH) in dementia. J Neural Transm 2000;107:1475-81. View abstract.
  • Santaella ML, Font I, Disdier OM. Comparison of oral nicotinamide adenine dinucleotide (NADH) versus conventional therapy for chronic fatigue syndrome. P R Health Sci J 2004;23(2):89-93. View abstract.
  • Swerdlow RH. Is NADH effective in the treatment of Parkinson's disease? Drugs Aging 1998;13:263-8. View abstract.
  • Vrecko K, Birkmayer JG, Krainz J. Stimulation of dopamine biosynthesis in cultured PC 12 phaeochromocytoma cells by the coenzyme nicotinamide adeninedinucleotide (NADH). J Neural Transm Park Dis Dement Sect 1993;5:147-56. View abstract.
  • Vrecko K, Storga D, Birkmayer JG, et al. NADH stimulates endogenous dopamine biosynthesis by enhancing the recycling of tetrahydrobiopterin in rat phaeochromocytoma cells. Biochim Biophys Acta 1997;1361:59-65. View abstract.

More Resources for NADH

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CONDITIONS OF USE AND IMPORTANT INFORMATION: This information is meant to supplement, not replace advice from your doctor or healthcare provider and is not meant to cover all possible uses, precautions, interactions or adverse effects. This information may not fit your specific health circumstances.

Never delay or disregard seeking professional medical advice from your doctor or other qualified health care provider because of something you have read on WebMD.

You should always speak with your doctor or health care professional before you start, stop, or change any prescribed part of your health care plan or treatment and to determine what course of therapy is right for you.

This copyrighted material is provided by Natural Medicines Comprehensive Database Consumer Version. Information from this source is evidence-based and objective, and without commercial influence. For professional medical information on natural medicines, see Natural Medicines Comprehensive Database Professional Version.
© Therapeutic Research Faculty 2018.

Source: https://www.webmd.com/vitamins/ai/ingredientmono-1016/nadh

Poor Results from an Initial Human Trial of Nicotinamide Mononucleotide

Nicotinamide Mononucleotide (NMN) Uses & Dosage

Mitochondria are the power plants of the cell, responsible for packaging energy store molecules that power cellular processes. NAD+ is an essential metabolite for mitochondrial function, but levels decline with age.

The proximate causes of this decline are fairly well mapped, and involve insufficient resources in a variety of pathways for synthesis or recycling of NAD+.

The deeper reasons are poorly understood, however, meaning how these pathway issues emerge from the underlying molecular damage to cells and tissues that causes aging.

Ways to force an increase in NAD+ levels have been shown to improve mitochondrial function in old animals, reversing some of the losses that occur with age. Loss of mitochondrial function is implicated in age-related diseases, particularly those in energy-hungry tissues such as the brain and muscles.

There are a number of ways to raise NAD+ levels: delivery of sizable amounts of NAD+ directly via infusion, of which a tiny fraction makes it into cells where it is needed; delivery of various precursor molecules that are used to manufacture NAD+; or delivery of factors known to improve recycling of NAD+. Most present effort is focused on the second of those options, via supplements such as nicotinamide riboside or nicotinamide mononucleotide, though groups Nuchido are trying to produce better means of raising NAD+ levels that target multiple mechanisms at once.

Nicotinamide riboside has been trialed in humans, in a small number of people, with data showing reductions in age-related increases in blood pressure through improvement in the function of vascular smooth muscle.

A similarly small trial of nicotinamide mononucleotide took place in Japan, and in today's open access paper, the researchers involved report on the results. As you can see from their summary, this approach achieved none of the benefits noted in the trial of nicotinamide riboside.

At least some of the patients were old enough to expect some positive outcome on blood pressure, but none was observed.

Recent studies have revealed that decline in cellular nicotinamide adenine dinucleotide (NAD+) levels causes aging-related disorders and therapeutic approaches increasing cellular NAD+ prevent these disorders in animal models.

The administration of nicotinamide mononucleotide (NMN) has been shown to mitigate aging-related dysfunctions. However, the safety of NMN in humans have remained unclear.

We, therefore, conducted a clinical trial to investigate the safety of single NMN administration in 10 healthy men of 40 to 60 years of age.

A single-arm non-randomized intervention was conducted by single oral administration of 100, 250, and 500 mg NMN. Clinical findings and parameters, and the pharmacokinetics of NMN metabolites were investigated for 5 hours after each intervention. Ophthalmic examination and sleep quality assessment were also conducted before and after the intervention.

The single oral administrations of NMN did not cause any significant clinical symptoms or changes in heart rate, blood pressure, oxygen saturation, and body temperature.

Laboratory analysis results did not show significant changes, except for increases in serum bilirubin levels and decreases in serum creatinine, chloride, and blood glucose levels within the normal ranges, independent of the dose of NMN.

Results of ophthalmic examination and sleep quality score showed no differences before and after the intervention. Plasma concentrations of N-methyl-2-pyridone-5-carboxamide and N-methyl-4-pyridone-5-carboxamide were significantly increased dose-dependently by NMN administration.

The single oral administration of NMN was safe and effectively metabolized in healthy men without causing any significant deleterious effects. Thus, the oral administration of NMN was found to be feasible, implicating a potential therapeutic strategy to mitigate aging-related disorders in humans.

Link: https://doi.org/10.1507/endocrj.EJ19-0313

Source: https://www.fightaging.org/archives/2019/11/poor-results-from-an-initial-human-trial-of-nicotinamide-mononucleotide/

Human Safety Trial of NMN Concludes

Nicotinamide Mononucleotide (NMN) Uses & Dosage

A human trial of NMN has recently concluded, and the results are not impressive at all; however, this is perfectly fine because that was not the purpose of the study, and, despite the lackluster results, the study was a success!

This might sound strange, but perhaps the words of the study authors may make it a bit clearer why this is absolutely no cause for alarm.

We, therefore, conducted a clinical trial to investigate the safety of single NMN administration in 10 healthy men.

The reason we should not be concerned with the results of this small human trial of NMN is because it achieved what it set out to establish: to demonstrate that the drug is safe and well tolerated at the dosage used.

The trial did not set out to demonstrate efficacy of NMN, and given the small number of trial participants, the single dose, and the short study time, it was never going to do more than establish that the drug is safe for human use.

The study at the Clinical Trial Unit, Keio University School of Medicine, Japan included a total of 10 healthy men aged between 40 and 60 years old and observed them to ensure that there were no adverse side effects.

During the study, the researchers observed various biomarkers, and no significant changes were evident following the single dose of NMN. This is hardly surprising, as the dosage range used of 100, 250, and 500 mg is also fairly low.

The only notable result was that bilirubin levels rose by 51.3% and glucose fell by 11.7% following dosage.

However, those two changes are most ly associated with the overnight fast prior to taking NMN and the five-hour fast following dosage.

The researchers also could not detect NMN in the blood samples taken in the study, but this is ly due to them being frozen before extraction, which degraded the NMN. This is unfortunate, but it serves as a useful cautionary tale for future studies to hopefully learn from.

Recent studies have revealed that decline in cellular nicotinamide adenine dinucleotide (NAD+) levels causes aging-related disorders and therapeutic approaches increasing cellular NAD+ prevent these disorders in animal models. The administration of nicotinamide mononucleotide (NMN) has been shown to mitigate aging-related dysfunctions.

However, the safety of NMN in humans have remained unclear. We, therefore, conducted a clinical trial to investigate the safety of single NMN administration in 10 healthy men. A single-arm non-randomized intervention was conducted by single oral administration of 100, 250, and 500 mg NMN.

Clinical findings and parameters, and the pharmacokinetics of NMN metabolites were investigated for 5 h after each intervention. Ophthalmic examination and sleep quality assessment were also conducted before and after the intervention.

The single oral administrations of NMN did not cause any significant clinical symptoms or changes in heart rate, blood pressure, oxygen saturation, and body temperature.

Laboratory analysis results did not show significant changes, except for increases in serum bilirubin levels and decreases in serum creatinine, chloride, and blood glucose levels within the normal ranges, independent of the dose of NMN. Results of ophthalmic examination and sleep quality score showed no differences before and after the intervention.

Plasma concentrations of N-methyl-2-pyridone-5-carboxamide and N-methyl-4-pyridone-5-carboxamide were significantly increased dose-dependently by NMN administration. The single oral administration of NMN was safe and effectively metabolized in healthy men without causing any significant deleterious effects. Thus, the oral administration of NMN was found to be feasible, implicating a potential therapeutic strategy to mitigate aging-related disorders in humans.

Conclusion

There have been a plethora of mouse studies; however, the safety and efficacy of NMN in humans was unclear, and this trial helps to confirm that, in general, the drug is safe and well tolerated; to that end, the trial can be considered a success.

The next step for researchers will be to investigate the efficacy of NMN, and a suitable dosage and frequency would then be established as part of that process. Of course, it is certainly possible that NMN may fail during efficacy testing in humans, but this initial safety study has no bearing on that potential outcome whatsoever.

There is currently an ongoing human trial for NMN at Brigham and Women’s Hospital in Boston from which efficacy data should be forthcoming, and until that data is in, no conclusion beyond NMN being safe can really be drawn.

Literature

Irie, J., Inagaki, E., Fujita, M., Nakaya, H., Mitsuishi, M., Yamaguchi, S., … & Okano, H. (2019). Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men. Endocrine journal, EJ19-0313.

Source: https://www.lifespan.io/news/human-safety-trial-of-nmn-concludes/

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