Nicotinamide Mononucleotide (NMN)

Nicotinamide Mononucleotide (NMN and β-NMN) is a compound found naturally in the cells of our bodies and is integral to several cellular processes. NMN is a direct precursor to NAD+, a vital coenzyme essential for a myriad of cellular functions. The levels of NAD+ are known to decline as we age, and this decline is associated with aging and various age-related diseases. The has been shown in several clinical trials that by supplementing with NMN, we can boost the levels of NAD+ in the body, potentially counteracting age-related cellular decline and improving overall health. Preliminary studies, mainly in mice, suggest that NMN supplementation could offer a range of health benefits, such as enhanced energy metabolism and improved DNA repair, indicating its potential role in slowing the aging processes.

However, while NMN shows significant promise, comprehensive studies determining its long-term safety, effective dosage, and potential side effects in humans are still in progress. NMN is also present in several food sources, including broccoli, cabbage, cucumber, avocados, and edamame, but only in small quantities.

NMN and its impact on longevity are at the cutting edge of anti-aging research, with new discoveries and insights emerging regularly, deepening our understanding of the aging process and potential interventions to extend health and lifespan.

Sources of NMN in Food

NMN is naturally present in a variety of foods, albeit in relatively small quantities. Here is a list of some foods known to contain NMN, along with their respective NMN content.

Food Type	Name	NMN Content (mg/100g-Food)
Vegetable	Edamame	0.47–1.88
Vegetable	Broccoli	0.25–1.12
Vegetable	Cucumber Seed	0.56
Vegetable	Cucumber Peel	0.65
Vegetable	Cabbage	0.0–0.90
Fruit	Avocado	0.36–1.60
Fruit	Tomato	0.26–0.30
Other	Mushroom	0.0–1.01
Meat	Beef (raw)	0.06–0.42
Seafood	Shrimp	0.22

While these foods can contribute to NAD+ levels through the provision of NMN, the quantities present are relatively small, and it is currently unclear whether dietary intake alone can significantly impact NAD+ levels in the body. Therefore, research into NMN supplementation is ongoing to explore its potential in maintaining or elevating NAD+ levels and mitigating age-related decline.

Legal

European Union (EU)

In the European Union, the classification and regulation of substances are often determined by their intended use and the claims made by the manufacturer or distributor. As of the latest update, Nicotinamide Mononucleotide (NMN) is classified as a chemical in the EU and has not been approved for human consumption. This classification is due to the EU's stringent regulations surrounding novel foods and substances, emphasizing consumer safety.

While NMN is not approved for human consumption in the EU, consumers may come across NMN products online that appear to be marketed for human use. However, these are officially sold either as chemicals for research and laboratory purposes or as supplements for animals, including dogs and cats. It is important for consumers to recognize the legal status and potential risks of such unapproved substances.

United States (US)

In November 2022, the US Food and Drug Administration (FDA) issued a statement saying that NMN may not be sold as a supplement, citing its status as being under investigation as a drug. This development is a reversal of the FDA's previous decision to allow its sale as a new dietary supplement (NDI). The reason for the reversal is unknown, but in December 2021, Metro International Biotech, a startup pharmaceutical company that has developed the NMN formulation MIB-626, wrote to the FDA: "As a company that has instituted publicly available clinical trials on ß-NMN, we request that FDA take the preclusion provision … seriously to protect the rights of companies that have spent significant time and research to develop drug products from competition from dietary supplements". According to Insider, the FDA confirmed that it had considered Metro's request.

Different Forms of NMN

Nicotinamide Mononucleotide (NMN) exists in two stereoisomeric forms, α-NMN and β-NMN, which have the same molecular formula but differ in the spatial arrangement of atoms. Recent advancements in NMN supplementation have led to the development of various formulations aimed at enhancing the compound's bioavailability and efficacy.

β-NMN

β-NMN is the biologically active form of NMN, predominantly utilized in scientific studies and supplements. It is integral in the biosynthesis of Nicotinamide Adenine Dinucleotide (NAD+), a vital coenzyme involved in numerous cellular processes, including energy metabolism, DNA repair, and cellular aging. When references are made to NMN in the context of supplementation or scientific research, it typically pertains to β-NMN due to its biological significance and activity.

α-NMN

α-NMN, on the other hand, does not participate in NAD+ biosynthesis and lacks the biological activity and associated health benefits of β-NMN. It is not the focus of NMN-related research or supplementation.

Liposomal NMN

Liposomal NMN is a form of NMN that is encapsulated within liposomes to enhance stability and bioavailability. This dietary supplement is available on the market and is being explored for its potential to increase the effectiveness of NMN supplementation. However, as of the latest updates, there are no published clinical studies specifically validating the benefits and efficacy of liposomal NMN, which means that while the theoretical advantages are promising, they have not yet been confirmed by scientific research.

MIB-626

MIB-626, developed by MetroBiotech, is a microcrystalline form of NMN. This formulation may offer enhanced stability, solubility, or bioavailability compared to the regular crystalline form of NMN, potentially optimizing the efficacy of NMN supplementation.

Reduced NMN (NMNH)

Reduced Nicotinamide Mononucleotide (NMNH) is a novel, potentially more effective NAD+ precursor.

Bioavailability of NMN

Bioavailability is a crucial factor in the effectiveness of any dietary supplement, including Nicotinamide Mononucleotide (NMN). It refers to the proportion of a substance that enters the circulation when introduced into the body and is thus able to have an active effect. In the case of NMN, bioavailability determines how much of the compound reaches the bloodstream and subsequently contributes to NAD+ biosynthesis.

One of the main challenges with NMN bioavailability is its absorption and transportation within the body. When taken orally, NMN needs to be absorbed through the gastrointestinal tract, which can present barriers to its effective uptake.

• Molecular Size: NMN's relatively large molecular size compared to other NAD+ precursors (like NR, or nicotinamide riboside) poses a challenge for its absorption in the gut.
• Enzymatic Degradation: NMN can be subject to degradation by enzymes in the digestive tract, potentially reducing the amount that actually enters the bloodstream.

To address these challenges, various strategies and formulations have been developed:

• Liposomal Encapsulation: Liposomal NMN involves wrapping NMN molecules in a lipid layer, which can help protect them from degradation in the digestive system and enhance absorption.
• Sublingual Administration: Taking NMN sublingually (under the tongue) is proposed to increase its bioavailability by allowing direct absorption into the bloodstream, bypassing the digestive system.
• Microcrystalline Formulation: MIB-626, a microcrystalline form of NMN developed by MetroBiotech, is believed to offer enhanced stability and bioavailability.

While various methods to enhance NMN’s bioavailability are being explored, conclusive evidence on the most effective form or administration method is still emerging. Current research is focused on understanding how different formulations affect NMN's absorption and utilization in the body. Future studies are expected to provide more insights and possibly lead to more effective NMN supplementation strategies.

Potential Benefits

NMN supplementation has been associated with several potential benefits, primarily due to its role as a precursor to NAD+, a crucial coenzyme involved in various cellular processes. Here are some potential benefits based on preliminary research:

• Cellular Energy and Metabolism: By increasing NAD+ levels, NMN supplementation can potentially enhance cellular energy production and metabolism, leading to improved physiological functions and reduced age-related metabolic decline.
• Longevity and Aging: Preliminary studies, particularly in animal models, have suggested that NMN can potentially extend lifespan and slow the aging process by improving cellular health and function, although more research is needed to confirm these effects in humans.
• Cognitive Function: Some research indicates that NMN may have neuroprotective effects, potentially improving cognitive function and reducing the risk of neurodegenerative diseases by maintaining neuronal health and resilience.
• Cardiovascular Health: NMN supplementation may offer cardiovascular benefits by improving blood flow and reducing the risk of age-related cardiovascular diseases, contributing to heart health and longevity.
• DNA Repair: Enhanced NAD+ levels through NMN supplementation can support DNA repair mechanisms, potentially reducing DNA damage and the risk of mutation, which are associated with aging and cancer.
• Insulin Sensitivity: NMN has been shown to improve insulin sensitivity, potentially reducing the risk of type 2 diabetes and metabolic syndrome, contributing to overall metabolic health.

Considerations for NMN Supplementation

When considering NMN supplementation, it is crucial to understand the potential interactions and impacts of NMN. Here are some considerations based on current knowledge and research.

Dosage and Effects

Human studies have indicated that a dosage of 1000 mg over 10 days can raise NAD levels about two-fold, and dosages as high as 2000 mg can triple the amount. However, the long-term safety, efficacy, and optimal dosage of NMN are still under investigation, and more comprehensive studies are needed to establish concrete guidelines for NMN supplementation. ^{[Citation needed]}

David Sinclair takes 1000 mg/day NMN in the morning.

Types of NMN Administration

Nicotinamide Mononucleotide (NMN) can be administered in various forms, each with its unique considerations. Below is a breakdown of the common types of NMN administration:

• Oral Powder (Dissolved in Water): NMN powder can be dissolved in water and consumed as a drink. The benefit of this method, compared to capsules, is that the dosage can be easily adjusted, for example, reduced if side effects appear. In animal studies, particularly with mice, NMN is often mixed into the animals' drinking water.
• Oral Powder (Mixed with Food): NMN powder can also be mixed with food items such as yogurt. This method is considered oral ingestion, similar to dissolving it in water, and subjects the NMN to the digestive process. Mixing NMN with food can be convenient for those who prefer not to take it sublingually or in capsule form and may help mask any unpleasant taste of the NMN powder when dissolved in water. However, the effectiveness and bioavailability of NMN when mixed with food have not been extensively studied, and the presence of other food components and the acidic environment might potentially influence the stability and absorption of NMN.
• Capsule Form: NMN is encapsulated for easy consumption, offering a convenient and taste-neutral method. Like oral powder, capsules subject NMN to the digestive process. Capsule form is often used in clinical trials as it allows for precise dosing and is generally well-accepted by participants. It also enables the blinding of participants in placebo-controlled trials, maintaining the integrity of the study, as it is easier to make placebo capsules or tablets that are indistinguishable from the active ones.
• Sublingual Powder: This form of NMN is taken by placing the powder directly under the tongue, allowing it to dissolve and be absorbed through the mucous membranes in the mouth. The general guideline is to hold the substance under the tongue for approximately 1 to 5 minutes to allow for adequate absorption through the sublingual gland. Some individuals believe sublingual administration offers better bioavailability due to direct absorption into the bloodstream, bypassing the digestive system. However, while this method is promoted in many YouTube videos, there is no evidence of any positive or negative effects and there is currently no clinical study utilizing sublingual administration. Furthermore, this method is relatively inconvenient, especially for those who might find the taste of sublingual powder too strong.

Optimal Timing for Supplementation

Our body has a natural rhythm where NAD+ levels fluctuate throughout the day rather than remaining constant, closely tied to our circadian rhythms. NAD+ plays a crucial role in regulating our body's internal clock. The Sirt-1 gene, which is influenced by NAD+, signals our body when it's time to eat or sleep.

Dr. David Sinclair suggests to take NMN in the morning when the natural rise in NAD+ and Sirt-1 activity should happen. Taking NMN e.g. at night might disrupt the NAD+ cycle and potentially affecting the sleep or hunger. This can be especially beneficial for frequent travelers trying to adjust to a new time zone, as a morning dose of NMN can help reset the body's internal clock and reduce jet lag.

A recent RCT clinial trial investigated the effects of the time-dependent intake of NMN (250 mg/day) on older adults (≥ 65 years) over 12 weeks. Aging-induced insufficient physical activity and deterioration of physical function result in fatigue. This symptom frequently occurs among the elderly and has been complained by 27–50% of community-dwelling older adults in their daily life. Overall, NMN intake in the afternoon (in contrast to the morning) effectively improved lower limb function and reduced drowsiness in older adults. These findings suggest the potential of NMN in preventing loss of physical performance and improving fatigue in older adults.

Combining NMN with Methyl Donors

There is a theoretical concern that consuming NMN could deplete methyl groups in the body. NMN is converted to NAD+ in the body, which can then be broken down into nicotinamide. Nicotinamide is then methylated by the liver to form N1-methylnicotinamide, which is excreted in the urine. This methylation process consumes a methyl group from S-adenosylmethionine (SAMe), the primary methyl donor in the body.

There could be compensatory mechanisms in place; if methyl groups were being depleted at a concerning rate, the body would likely slow down the conversion of NMN to NAD+ or the methylation of nicotinamide. If not, the potential concern is that excessive NMN supplementation might lead to a Methyl Donor Deficiency associated with symptoms such as low energy and tiredness.

For this reason, some individuals who take NMN also supplement with methyl donors such as Trimethylglycine (TMG) or Vitamin B Complex to ensure that they are not depleting their body's supply of methyl groups. Some individuals take methyl donors as a precautionary measure, while others may begin supplementation after experiencing sleepiness attributed to NMN.

However, there is no clear evidence yet as clinical trials are lacking. While the biochemical pathway is known, the actual impact of NMN supplementation on the global status of methyl groups is not well-established in humans. It would likely require substantial NMN consumption coupled with an insufficient intake of dietary methyl donors to significantly affect these groups.

Risks of NMN Supplementation

While NMN supplementation holds promise due to its potential anti-aging benefits and ability to enhance cellular metabolism, it is crucial to be aware of the potential risks involved. Here are some risks and considerations based on current knowledge and research:

• Limited Human Studies: Most of the studies on NMN have been conducted in animal models, and there is limited data on its effects in humans. Therefore, the safety and efficacy of NMN supplementation in humans are not fully understood, and caution is advised until more research is conducted.
• Potential Interaction with Medications: The interaction of NMN with various medications is not well studied, and there could be potential risks when combined with certain drugs. Individuals on medication should consult with a healthcare professional before considering NMN supplementation.
• Methyl Donor Deficiency: There are theoretical concerns regarding NMN’s potential to deplete methyl groups in the body, which could impact various biological processes, including DNA methylation and neurotransmitter synthesis.
• Over-Supplementation Risks: Excessive supplementation of NMN may lead to unknown side effects due to the lack of long-term human studies. Over-supplementation might also disrupt the natural balance of NAD+ and its related compounds in the body, potentially leading to unforeseen consequences.
• Purity and Quality Concerns: The purity and quality of NMN supplements can vary, and impurities or contaminants in the supplements pose additional risks. It is essential to choose high-quality, reputable brands and sources for NMN supplements to minimize risks associated with impurities and contaminants.

Clinical Trials

Starting in 2020, with the assessment of the safety of a single dose administration of NMN, there have been around 10 randomized controlled trials (RCTs) exploring the compound's effects in various contexts. The trials have varied in duration, with the longest running for 12 weeks. In terms of dosage, they have explored a range of quantities, with the highest being 1,250 mg of NMN per day and 2,000 mg (2 g) of MIB-626, a specific formulation of NMN, per day. The following table provides a comprehensive overview of these trials, detailing their design, participant demographics, dosages, and key findings:

Clinical Trials of NMN

Clinical Trial	Design	Participants	Outcome
2020, Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men	singe admission of up to 500 mg oral admission at 9 AM	10 healthy men 40-60 years	admission was safe and well-tolerated
2021, Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women	RCT, 10 weeks placebo (n=12) 250 mg/day (n=13)	25 postmenopausal women with prediabetes overweight or obese (BMI 25.3 - 39.1) 56 - 66 years	increase in skeletal muscle insulin signaling, insulin sensitivity, and muscle remodeling improvement in muscle insulin sensitivity is clinically relevant and is similar to the improvement observed after ~10% weight loss
2021, Nicotinamide mononucleotide supplementation enhances aerobic capacity in amateur runners: a randomized, double-blind study	RCT, 6 weeks placebo (n=12) 300 mg/day (n=12) 600 mg/day (n=12) 1200 mg/day (n=12)	48 young and middle-aged recreationally trained runners 35 years in average	The combination of NMN supplementation and exercise further improves ventilatory threshold even among healthy young and middle-aged people. The improvement of aerobic capacity is in a dosage-dependent, large dosage of NMN with exercise has better effects. The improvement is muscle, not cardiac, related.
2022, Safety evaluation of β-nicotinamide mononucleotide oral administration in healthy adult men and women	RCT, 4 weeks placebo (n=15) 1250 mg/day (n=16)	31 healthy adult men and women 20–65 years	Oral administration of 1250 mg of NMN, when administered once daily for up to 4 weeks, was safe and well-tolerated in healthy adult men and women. Oral administration of NMN in humans has a low adverse effect on renal function. Results indicate that NMN can be administered orally to humans at doses 1250 mg once daily for up to 4 weeks without causing hepatotoxicity and vasodilative flushing, and is believed to have a higher upper tolerable limit compared to NAM and NA.
2023, The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial	RCT, 8.5 weeks (60 days) placebo (n=20) 300 mg (n=20) 600 mg (n=20) 900 mg (n=20)	healthy males and females 40-65 (49.3 in average) years BMI between 18.5 and 35	Oral administration of NMN up to 900 mg/day for 60 days was safe and well tolerated blood NAD concentration was significantly and dose-dependently increased significant improvement of six-minute walking test, blood biological age, and SF-36 scores 900 mg/day oral dose did not give significantly better efficacy than 600 mg/day dose
2022, Effect of 12-Week Intake of Nicotinamide Mononucleotide on Sleep Quality, Fatigue, and Physical Performance in Older Japanese Adults: A Randomized, Double-Blind Placebo-Controlled Study	RCT, 12 weeks placebo, before 12 pm placebo, after 6 pm 250 mg, before 12 pm 250 mg, after 6 pm	108 older adults ≥65 years	NMN intake in the afternoon is more effective in improving lower limb function and reducing drowsiness in older adults.
2023, MIB-626, an Oral Formulation of a Microcrystalline Unique Polymorph of β-Nicotinamide Mononucleotide, Increases Circulating Nicotinamide Adenine Dinucleotide and its Metabolome in Middle-Aged and Older Adults	RCT, 14 days 1g MIB-626 once daily 1g MIB-626 twice daily placebo	32 overweight or obese adults 55-80 years	MIB-626 was well tolerated Blood NMN concentrations significantly higher in treated groups compared to placebo Substantial dose-related increases in blood NAD levels and its metabolome Changes in NMN or NAD levels not related to sex, BMI, or age Very little unmodified NMN excreted in urine Facilitates design of efficacy trials in disease conditions
2023, Nicotinamide Adenine Dinucleotide Augmentation in Overweight or Obese Middle-Aged and Older Adults: A Physiologic Study	RCT, 28 days 500mg MIB-626 twice daily placebo	30 overweight or obese adults ≥45 years	MIB-626 treatment increased circulating NAD and metabolites No significant change in muscle strength, muscle fatigability, aerobic capacity, and stair-climbing power Significant reduction in body weight, diastolic blood pressure, total LDL, and non-HDL cholesterol Insulin sensitivity and hepatic and intra-abdominal fat unchanged Adverse events similar between groups Provides rationale for larger trials on NAD augmentation for cardiometabolic outcomes in older adults

See also

• Nicotinamide Adenine Dinucleotide (NAD+)
• NAD+ Boosters
• NAD+ Precursor
• NMN Manufacturer
• Wikipedia article about NMN

Todo

• 2023, The Safety and Antiaging Effects of Nicotinamide Mononucleotide in Human Clinical Trials: an Update
• 2023, NAD⁺ exhaustion by CD38 upregulation contributes to blood pressure elevation and vascular damage in hypertension , https://www.nmn.com/news/nmn-lowers-blood-pressure-in-patients-with-hypertension-latest-human-trial
• 2014, SIRT2 induces the checkpoint kinase BubR1 to increase lifespan
• 2023, Potential Synergistic Supplementation of NAD+ Promoting Compounds as a Strategy for Increasing Healthspan
• 2020, NAD⁺ Repletion Rescues Female Fertility during Reproductive Aging
• 2022, SIRT1 activation and its circadian clock control: a promising approach against (frailty in) neurodegenerative disorders
• 2018, Sirtuin 3-dependent mitochondrial redox homeostasis protects against AGEs-induced intervertebral disc degeneration
• https://www.nmn.com/news/nmn-tablet-blood-nad-levels-humans
• https://link.springer.com/article/10.1007/s13668-023-00475-y
• https://www.lifespan.io/topic/nmn-nicotinamide-mononucleotide-benefits-side-effects/
• https://novoslabs.com/frequently-asked-questions/nmn-nicotinamide-mononucleotide/can-you-take-nmn-if-you-have-a-mthfr-mutation-or-suffer-from-reduced-methylation/
• https://ajtm.journals.publicknowledgeproject.org/index.php/ajtm/article/view/2535