Nicotinamide mononucleotide (NMN): Benefits and Side Effects

NMN is a naturally occurring molecule and a popular dietary supplement marketed as a NAD+ booster.

What is NMN?

Nicotinamide mononucleotide (NMN) is a naturally occurring molecule present in all species. On the molecular level, it is a ribonucleotide, a basic structural unit of the nucleic acid RNA. It consists of a nicotinamide group, a ribose, and a phosphate group [1].

NMN is a precursor of nicotinamide adenine dinucleotide (NAD+), a molecule that may be useful in slowing down some aspects of aging. NAD+ serves many critical functions in our cells, such as electron transport, cell signaling, and DNA repair [1].

Nicotinamide Adenine Dinucleotide (NAD): Benefits and Research

Nicotinamide adenine dinucleotide (NAD) is a coenzyme found in all living cells. It is a dinucleotide, which means that it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base, and the other contains nicotinamide.
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Accumulating evidence suggests that as we age, our levels of NAD+ decline, increasing our risk of age-related diseases [2].

This is where the NAD+ precursor NMN comes in. Some researchers believe that if we can restore that lost NAD+, we could slow down aging and delay various age-related diseases. Whether or not restoring NAD+ metabolism in humans will slow down aging or support healthy longevity is still an unanswered question, though the animal data is promising [3].

What foods contain NMN?

NMN can be found naturally in foods such as avocado, broccoli, cabbage, cucumber, and edamame. Here is how much NMN is found in some common foods [2].

While these kinds of foods are an excellent source of nutrition, dietary NMN supplements are also available. These supplements typically come in doses of between 100 to 500 mg, although an optimal dose has yet to be determined in people.

Fasting and caloric restriction also appear to increase NAD+ levels and boost the activity of sirtuins, aka the longevity genes. It is suggested that their activity relies on the presence of NAD+. In mice, fasting boosted NAD+ levels and sirtuin activity, and it appears to slow down aging [4].

NMN is one of multiple NAD+ precursors

Other NAD+ precursors include nicotinamide riboside (NR) and nicotinic acid (niacin). This diagram shows how these precursors lead to the creation of NAD+ [1].

More recently, reduced nicotinamide mononucleotide (NMNH) has emerged as a possible contender for the most efficient NAD+ boosting precursor molecule [5]. However, NMNH is not currently a commonly available dietary supplement, and more research is needed before that happens.

How was NMN discovered?

The history of NMN research is naturally intertwined with the history of NAD+.

Back in 1963, Chambon, Weill, and Mandel discovered that NMN provided the cellular energy needed to activate an important nuclear enzyme [6]. This led to the discovery of poly(ADP-ribose) polymerases (PARPs). This family of proteins is involved in a number of cellular processes, such as DNA repair, genomic stability, and programmed cell death. PARPs and their activity are also linked to changes in lifespan in different species.

In 2014, a team of researchers led by Dr. David Sinclair demonstrated that NMN can extend the lifespan of mice [7]. In 2017, researchers used NMN to reverse DNA damage in mice by increasing NAD+ levels [8].

In 2020, researchers used NMN to improve blood flow and neurovascular health in aged mice [9]. It also appeared to reverse some age-related changes to gene expression. Of 590 genes that are different between young and old animals, treatment with NMN reversed 204 back towards youthful expression levels.

Also in 2020, a group of researchers demonstrated that treatment with NMN restores neurovascular coupling (NVC) in aged mice [10]. NVC deficiency appears to be a major factor in the age-related decline of cognitive and motor functions.

How is NMN created?

NMN is created in the human body with B vitamins as precursors. The enzyme that makes NMN is known as nicotinamide phosphoribosyltransferase (NAMPT). NAMPT attaches a form of vitamin B3 called nicotinamide to the sugar phosphate 5’-phosphoribosyl-1-pyrophosphate (PRPP).

NAMPT is the rate-limiting enzyme in the production of NAD+, which means that lower levels of NAMPT mean decreased NMN production and thus decreased NAD+ levels. This also means that by administering additional NMN, the rate of NAD+ production can be increased to somewhat address this shortfall.

It is also possible for NMN to be created from NR by the addition of a phosphate group. Some researchers suggested that NMN could not enter the cell without first becoming NR. However, in 2019, a new NMN transporter channel was identified showing that it can.

This study found that the Slc12a8 gene encodes a specific NMN transporter that allows the molecule to enter cells without being converted to NR first. This discovery certainly came as an unpleasant surprise to the manufacturers and distributors of NR supplements [11].

Human studies of NMN

The bulk of studies on NMN have been carried out on mice and rats. These have shown positive effects on metabolism, liver, skin, muscle, and brain function as well as improved bone structure, vascular health, reproduction, immune system function, and lifespan. Human studies on people taking NMN are in their early days, but there is some limited data of interest.

In 2020, a Japanese lab conducted a human clinical trial of NMN, which showed that it is well tolerated when given as a single dose [12]. The results of a 2021 study suggested that NMN enhances aerobic capacity in amateur runners [13]. While the study did have some limitations, there were limited but measurable improvements.

Another 2021 human study suggests that NMN improved muscle glucose metabolism in prediabetic women and yielded clinically relevant results [14].

In May 2022, the data from a multicenter NMN clinical trial was published with some modest but interesting results [15]. The data suggested that NMN was increasing energy levels and could be interpreted as an anti-aging effect, albeit relatively small in this case. That said, NAD+ levels also increased in the placebo participants not taking NMN. These results require futher investigation and a larger study, as this one was fairly small at only 66 people.

NMN and aging

The age-related decline of NAD+ is not merely a symptom of aging but a contributing factor to the physiological deterioration associated with it. As we age, these decreased levels of NAD+ impair essential cellular functions, including energy metabolism, DNA repair, and genomic stability [1,2]. This impairment is a key driver of aging and is intimately linked to the development of age-related diseases.

Recent studies in mice have illuminated the potential of NMN to not only elevate NAD+ levels but also to enhance mitochondrial function [16], which is often compromised in aging cells. Mitochondria, the powerhouses of the cell, are essential for energy production, and their dysfunction is a hallmark of aging [17]. By boosting NAD+ levels, NMN can enhance mitochondrial activity, thereby potentially alleviating symptoms associated with aging and improving cellular health.

Moreover, the implications of NMN supplementation extend beyond mere energy production. In mouse studies, NMN’s role in activating pathways like SIRT1, a NAD+-dependent protein deacetylase, has been linked to various health benefits. These include improved DNA repair, reduced oxidative stress, and enhanced metabolic efficiency, all of which are vital in combating the biological challenges of aging. The activation of these pathways highlights the potential of NMN as a comprehensive anti-aging intervention [16].

As the aging population continues to grow, the significance of NMN in maintaining health and vitality becomes ever more pronounced. The ability of NMN to replenish NAD+ levels and thereby revitalize aging cells offers a promising avenue in our quest to extend both lifespan and healthspan, the period of life spent in good health.

Cardiovascular health and NMN

Cardiovascular health remains a critical area of concern in modern medicine, with ongoing research continuously seeking novel approaches to prevent and treat heart-related conditions. In this context, NMN has emerged as a molecule of interest, particularly for its potential benefits in cardiovascular health.

Recent advances in NMN research have shed light on its effects on the heart, especially for conditions that impair its ability to pump blood. A key factor in many heart conditions is mitochondrial dysfunction, which can lead to energy deficits in myocardial cells and contribute to the progression of heart failure. Mitochondria, being central to energy production in cells, are crucial for maintaining healthy cardiac function. This decline in mitochondrial efficiency is a critical factor in the development of various cardiac diseases [18].

A pivotal study focusing on heart failure linked to mitochondrial dysfunction has revealed the potential role of NMN in improving cardiac health. In this study, mice with a cardiomyocyte-specific knockout of the mitochondrial translation factor p32 developed heart failure due to dilated cardiomyopathy, a condition characterized by weakened and enlarged heart muscles [18]. This model was crucial in understanding how mitochondrial translation defects lead to mitochondrial dysfunction and a decrease in NAD+. This decrease impairs lysosomal acidification and autophagy, which are essential for cellular waste disposal and recycling [19].

In this scenario, NMN administration showcased a remarkable ability to compensate for the decreased NAD+ levels. Supplementation with NMN in the study led to reduced damaged lysosomes and improved autophagy, thereby ameliorating heart failure and extending lifespan in the mouse model. Interestingly, the study highlighted that the ameliorative effects of NMN supplementation were more pronounced on lysosomal function rather than directly on mitochondrial function. It was observed that lysosomal damage due to mitochondrial dysfunction could induce ferroptosis, a form of cell death linked to iron accumulation and lipid peroxidation. NMN’s role in improving lysosomal function, particularly in preventing lysosome-mediated ferroptosis, presents a novel mechanism through which NMN supplementation could support cardiac health [19].

The implications of this study are profound for cardiovascular medicine. NMN supplementation offers a potential strategy for mitigating the effects of heart failure while addressing underlying mitochondrial and lysosomal dysfunctions. This aligns with the growing understanding that targeting cellular health at a fundamental level can have far-reaching benefits for overall organ function and disease prevention.

A recent study also investigating NMN’s effects on atherosclerosis, a major contributor to cardiovascular disease, offers further insights into the role of NMN in cardiovascular health. This study was conducted on ApoE-/- mice, a model widely used in atherosclerosis research, and revealed that NMN significantly reduced atherosclerotic plaque by 36% and the necrotic core by 48%. Furthermore, NMN improved lesion composition by decreasing lipid area by 43% and increasing collagen content by 51%. These findings demonstrate that NMN has potential in reducing key risk factors for cardiovascular diseases and highlight its role in enhancing vascular cell function, which is vital for preventing and treating atherosclerosis [20].

As research continues to unravel the multifaceted benefits of NMN, its role in cardiovascular health represents a promising frontier, offering new hope for people affected by heart diseases and highlighting the interconnected nature of cellular health and organ function.

NMN, inflammation, and immune response

The same study that reported NMN’s anti-atherosclerotic effects also brought to light its potential in managing chronic inflammatory diseases. NMN administration was observed to lower serum levels of malondialdehyde (MDA), a marker of oxidative stress, and increase activities of antioxidant enzymes. Notably, it reduced the expression of pro-inflammatory cytokines while enhancing the expression of anti-inflammatory factors in aortic tissues. These results suggest that NMN’s capacity to mitigate oxidative stress and modulate inflammatory responses could be pivotal in addressing various chronic inflammatory conditions [20].

Another study involving human cells, including lung microvascular endothelial cells and  coronary artery endothelial cells (HCAECs), has shown that NMN supplementation can mitigate the inflammatory response induced by poly(I:C), a synthetic analog of double-stranded RNA. This effect is partly attributed to the downregulation of major inflammatory mediators, including IL6 and PARP family members, under NMN exposure. Such findings illustrate NMN’s capacity to influence inflammatory pathways at the molecular level [21].

The implications of these findings are substantial. For chronic inflammation, which is often a silent and insidious process contributing to various age-related diseases, NMN’s potential to modulate immune responses and reduce inflammatory markers can be a game-changer. This could lead to novel approaches in treating conditions in which chronic inflammation is a key component, such as in certain autoimmune diseases, metabolic syndrome, and even some neurodegenerative disorders.

In the context of acute inflammation, which is typically a rapid and intense response to injury or infection, NMN’s role is equally promising. The ability to control and limit acute inflammatory responses could enhance recovery and healing processes, potentially reducing the risk of complications such as tissue damage and scarring [22].

Cognitive function and metabolic health

The exploration of NMN in the realms of cognitive function and metabolic health has yielded promising insights. Cognitive function, which encompasses memory, attention, and other mental capabilities, often deteriorates with age. Metabolic health, crucial for the body’s energy balance and overall well-being, can also be compromised by lifestyle factors and aging. NMN’s role in these areas offers a glimpse into its broader therapeutic potential.

Recent studies have indicated that NMN can have a significant impact on cognitive function. In a study focusing on the combined effects of NMN and sugars called neoagarooligosaccharides (NAOS), researchers explored how these compounds can improve brain health and reduce cell damage and inflammation. The study used two models: an aging-accelerated mouse breed known as SAMP8 and human lung cells treated with hydrogen peroxide (H2O2) to simulate stress.

The combined treatment of NMN and NAOS was found to significantly improve learning and memory in the mice, as observed in the passive avoidance test and the Morris water maze test, which are standard methods to assess cognitive abilities in animals. This combination increased proteins that are essential for maintaining healthy mitochondria in the brains of these mice. Specifically, the levels of OPA1 and mitofusin 2, two proteins important for mitochondrial function, were increased significantly.

Furthermore, the treatment with NMN and NAOS also helped in reducing cell death (known as apoptosis) in both the aging mice and the human lung cells under stress. This effect was evidenced by the decrease in certain proteins (Bax and caspase-3) that are markers of cell death, and a reduction in the activity of a cellular pathway (p53/p21/p16) known to be involved in this process. In addition, this combination also lessened inflammation by downregulating a specific inflammatory pathway (TLR4/MyD88/NF-κB) in the cells [23].  Improved mitochondrial function in neural cells ensures better energy supply and may help in the maintenance and repair of neuronal networks, thereby supporting cognitive health.

In another study, researchers focused on a condition known as postoperative cognitive dysfunction (POCD), in which patients experience a decline in mental functions like memory and concentration after surgery, often linked to general anesthesia. A key factor contributing to this condition is oxidative stress, a harmful process caused by an imbalance in the body’s ability to detoxify harmful substances.

Previous research has shown that a decrease in NAD+ and its associated protein sirtuin 1 (SIRT1) can lead to increased oxidative stress. The study aimed to explore whether using NMN before surgery could improve both brain function and oxidative stress in POCD.

To simulate POCD, researchers used a common laboratory mouse breed (C57BL/6J) and induced cognitive impairment through 6 hours of isoflurane anesthesia, a type of anesthesia used in surgeries. These mice were given NMN injections for 7 days before being exposed to anesthesia. To assess the effects, the study measured the levels of oxidative stress and evaluated cognitive functions. They used flow cytometry, a technique to analyze the properties of cells, and specific test kits to measure oxidative stress. Additionally, they conducted the fear conditioning test and the Y-maze test, standard methods to assess memory and learning in animals.

The results showed that the mice undergoing anesthesia experienced cognitive difficulties and higher levels of oxidative stress, along with a decrease in NAD+ and SIRT1 protein levels in the hippocampus, a crucial brain region for memory and learning. However, mice pre-treated with NMN showed a prevention of NAD+ decline and reduced oxidative stress and cognitive issues post-surgery.

The study suggests that NMN supplementation before surgery might protect cognitive functions by influencing the NAD+-SIRT1 signaling pathway, a crucial route in the body for regulating cellular health and stress response. This indicates that NMN preconditioning could be a valuable strategy to reduce brain damage from oxidative stress and improve cognitive outcomes in patients undergoing surgeries [24].

Bioavailability and formulation advances

In the quest to maximize the efficacy of NMN as a supplement, significant strides have been made in enhancing its bioavailability. Bioavailability is a crucial factor in the effectiveness of any dietary supplement, determining how much of the compound reaches the bloodstream and becomes available for use by the body. Innovations in NMN formulation, such as by combining it with hydroxyapatite (NMN-HAP), represent a breakthrough in addressing absorption and utilization challenges.

Utilizing a wet chemical precipitation and physical adsorption method, researchers have developed a formulation that significantly enhances the encapsulation efficiency and drug loading capacity of NMN. These NMN-HAP nanoparticles, characterized by their rod-shaped morphology and optimal size of approximately 50 nanometers, demonstrate a remarkable improvement in the controlled release of NMN compared to its free form. Such an approach ensures a more steady and sustained release of NMN into the body, potentially maximizing its biological impact.

In vivo studies of NMN-HAP have shown promising results, with extended circulation time and improved bioavailability compared to free NMN. This formulation has displayed a notable increase in the plasma levels of NMN, NAD+, and nicotinamide riboside (NR), indicating a more efficient delivery system. Furthermore, the tissue-specific distribution observed in these studies, particularly the substantial accumulation of NMN, NAD+, and NR in the brain and liver, highlights the targeted effectiveness of this advanced formulation [25].

Another bioavailability study focused on improving the stability and effectiveness of lycopene (LYC) and NMN by embedding them into tiny, porous gel-like particles called microgels, after incorporating LYC into tiny fat-like particles called liposomes. Various tests, including measuring the size of the particles, their electrical properties, how well they encapsulate LYC and NMN, and how they release these substances, showed that the microgels were very effective in containing high levels of LYC and NMN (99.11% and 68.98%, respectively) and were stable and released their contents effectively.

The study then examined how these microgels could protect against acute liver injury caused by a substance called lipopolysaccharide (LPS) in C57BL/6 mice. The mice were given these microgels for 28 days before being exposed to LPS. The results were promising: the microgels with LYC and NMN significantly reduced liver injury caused by LPS, along with decreasing inflammation and oxidative stress.

Furthermore, the study found that LYC and NMN in the microgels worked on a specific part of the cell (TLR4/MD2 complex) and regulated certain microRNAs related to this receptor, which play a role in controlling inflammation. This action helped inhibit a specific signaling pathway in the body (TLR4/NF-?B) known to be involved in inflammation. Additionally, the microgels helped increase the presence of beneficial gut bacteria that produce short-chain fatty acids, while reducing harmful bacteria.

In summary, the study concluded that LYC and NMN, when delivered through these specially designed microgels, could protect against acute liver injury caused by LPS. They do this by reducing oxidative stress and inflammation and by helping regulate the balance of bacteria in the gut [26].

These advancements in NMN formulation have broad implications for its therapeutic use. By improving the delivery and absorption of NMN, these innovations increase the potential for NMN supplementation to effectively impact health outcomes. This is particularly important in the context of aging and age-related diseases, where NMN’s role in boosting NAD+ levels and supporting cellular functions is critical.

Moreover, the use of biocompatible materials like hydroxyapatite in the formulation of NMN-HAP underscores the commitment to safety and efficacy in the development of NMN supplements. As research continues to progress, these formulation advances are expected to pave the way for more effective and targeted NMN-based therapies, potentially revolutionizing the approach to health supplementation and the management of age-related conditions.

The future of NMN research

Although human data looks encouraging, we still do not have a complete picture, but that has not stopped NMN from being enthusiastically marketed as a dietary supplement and a NAD+ booster. It has proven popular with people who are confident of its usefulness as an anti-aging compound despite the lack of strong human evidence.

However, the high cost may be prohibitive to some people seeking the fountain of youth. It could be that more cost-effective precursors such as NMNH or other methods may replace it.

After all, to be truly effective in slowing down aging, a supplement not only needs to work, it also needs to be affordable. Currently, the price of NMN and NR is beyond the reach of the average person, and that is a problem that needs to be solved.

However, we have not yet been able to firmly conclude that NMN supplements actually work to slow down aging. Fortunately, there are more human trials underway that will hopefully tell us just how useful NMN is in this respect.

Nonetheless, recent clinical trials have predominantly affirmed the safety and tolerability of NMN supplementation in humans. For instance, studies involving daily oral administration of NMN in varying dosages have demonstrated that NMN can be safely consumed without significant adverse effects. These trials have varied in their specific focus, ranging from investigating the impact of NMN on blood NAD+ levels to assessing broader health outcomes such as cognitive function, metabolic health, and cardiovascular wellness.

A key finding across these trials is the notable increase in plasma NAD+ levels following NMN supplementation, underpinning the primary mechanism through which NMN exerts its beneficial effects. In addition to elevating NAD+ levels, some studies have reported improvements in various markers of health, including enhanced physical performance, stabilization of blood biological age, and better overall health assessment scores. These outcomes suggest that NMN supports cellular health, contributes to improved general well-being, and possibly delays the physiological aspects of aging [27].

However, one interesting aspect that has emerged from these trials is the variability in individual responses to NMN supplementation. This variability highlights a nuanced picture of NMN’s effects, indicating that individual factors such as genetics, lifestyle, and baseline health status might influence how someone responds to NMN. Such variability underscores the importance of personalized approaches in NMN supplementation, suggesting that future research and applications might need to tailor NMN dosages and regimens to individual needs and contexts.

The safety profile of NMN, as evidenced by these trials, is particularly encouraging, reinforcing the potential of NMN as a supplement for long-term use. The lack of significant adverse effects in trial participants, even at higher doses, is a testament to NMN’s suitability for widespread use [27].

NMN side effects

While the data for long-term administration of NMN in humans is not complete, large numbers of people take it as a dietary supplement with few negative reports. However, more studies focused on long-term safety and efficacy should be conducted.

Early adopters who take NMN supplements are essentially self-experimenting. Anyone experiencing adverse side effects should cease consumption and consult a medical professional.

Disclaimer

This article is only a summary and is not intended as an exhaustive guide. The article is based on the interpretation of research data, which is speculative by nature. This article is not a substitute for consulting your physician about which supplements may or may not be right for you. We do not endorse supplement use nor any product or supplement vendor, and all discussion here is for scientific interest.

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