NMN (Nicotinamide Mononucleotide)

Potential Benefits of NMN (Nicotinamide Mononucleotide)

• Extends lifespan [1-12]
• Produces anti-aging effects [13-25]
• Improves cognitive function [26-40]
• Lowers the risk of cardiovascular disease [41-55]
• Fights cancer [56-63]
• Improves blood sugar levels and treats diabetes symptoms [16, 64-74]
• Fights inflammation [75-78]
• Improves fertility [79-85]
• Improves eye health [86-100]
• Boosts immune function [14, 101-110]
• Increases energy levels [111-117]
• Promotes weight loss [118-120]
• Treats stroke [121-124]
• Improves liver health [125-132]
• Improves kidney health [133-137]

What is NMN?

NMN (Nicotinamide mononucleotide) is a natural molecule produced by the body and is classified as a nucleotide. Nucleotides are involved in a wide array of important bodily functions, including as the building blocks of DNA. Within the cells, NMN is converted into another molecule called nicotinamide adenine dinucleotide (NAD+). NAD+ plays an integral role in energy production and regulation of vital cellular processes such as DNA repair, immune function, conversion of food into a usable form of energy called adenosine triphosphate (ATP), and regulation of circadian rhythm. In simple terms, NMN is the raw material and NAD+ is the refined version that the body can actually use to perform essential biological processes. In addition, the amount of NAD+ that the body can produce greatly depends on the available NMN.

NAD+ is not very bioavailable. This means that ingesting it directly will not achieve its therapeutic or desired effects. Therefore, one of the most effective ways of boosting NAD+ levels is through NMN supplementation.

How NMN Works

The health benefits of NMN can be attributed to its ability to boost NAD+ levels. Once NMN is converted into NAD+, activation of the sirtuin 1 (SIRT1) function in the nucleus of cells happens. SIRT1 is an enzyme that helps regulate proteins involved in cellular metabolism and processes associated with longevity, inflammation, and stress. In addition, the NMN-mediated increase in NAD+ levels counteracts age-related mitochondrial deterioration by promoting mitochondrial biogenesis, a process by which cells increase mitochondrial numbers.

Chemical Structure of NMN

Research on NMN

A. Extends Lifespan

Within the cells, NMN is converted into NAD+ which plays an integral role in energy production and regulation of vital cellular processes. By boosting NAD+ levels, NMN can contribute to a longer lifespan. Studies show that people with higher NAD+ levels have a longer lifespan compared to those with lower NAD+ levels. [1-5]

Another mechanism that increases longevity is through increasing sirtuin (SIRT) activity which is associated with stable telomeres (located at chromosomes ends). This in turn helps attenuate the age-related telomere shortening which is linked to a shorter lifespan. [6] NMN boosts NAD+ levels which cause activation of SIRT, resulting in stable and longer telomeres. This process helps extends lifespan.

In addition, the NMN-mediated increase in NAD+ levels promotes mitochondrial biogenesis via SIRT1 activation. Mitochondrial biogenesis is characterized by the production of new mitochondria (the powerhouse of cells) and is essential for a longer lifespan since mitochondrial dysfunction is linked to various age-related diseases and a shorter lifespan. [7-8]

The longevity effects of NMN are backed by a number of studies:

1. In mice, NMN maintained telomere length, reduced the DNA damage response, improved mitochondrial function, and rescued liver fibrosis (scarring) in a partially SIRT1-dependent manner. [9]
2. Increasing sirtuin activity is known to stabilize telomeres and attenuate age-related telomere shortening. [10] Since the NMN-mediated increase in NAD+ activates SIRT1, it can help achieve chromosome stability and longer telomeres.
3. In a rodent model of decompensated hemorrhagic shock, rats that received NMN had decreased inflammation, improved cellular metabolism, and increased survival. [11]
4. In mice with progressive neurodegeneration, the addition of NMN in the drinking water of the subjects normalized neuromuscular function, delayed memory loss, and extended lifespan. [12]

B. Produces Anti-Aging Effects

Mitochondrial aging contributes to cellular senescence (also known as biological aging), increased inflammation, decreased stem cell activity, reduced healing rate, and a decline in tissue and organ function. [13] Interestingly, studies show that the NMN-mediated increase in NAD+ levels produces anti-aging effects such as increasing mitochondrial numbers, amelioration of mitochondrial dysfunction, and promotion of chromosome stability via activation of sirtuin 1 (SIRT1), stimulation of DNA repair, and maintaining telomere length:

1. The administration of NMN via injections in elderly mice reversed age-related mitochondrial deterioration. It was observed that declining NAD+ levels were associated with interruptions in the normal signaling between the cell’s nucleus and mitochondria and that raising NAD+ levels via NMN administration restored the communication between these cellular structures. [14]
2. In elderly mice, treatment with NMN improved blood flow and increased endurance via the promotion of SIRT1-dependent increases in capillary density. [15]
3. In mice, the administration of NMN prevented age-related weight gain and improved physical activity, energy metabolism, lipid profiles, and insulin sensitivity. [16]
4. In healthy men, the single oral administration of NMN was safe and effectively metabolized without any adverse effects, indicating a potential therapeutic strategy to mitigate disorders related to aging. [17-18]
5. NMN effectively mitigated the age-associated physiological decline in the lungs of old mice and bleomycin-induced pulmonary fibrosis in young mice. [19]
6. In aged mice, NMN treatment promoted mitochondrial rejuvenation and decreased inflammation. [20]
7. In pre-aging male mice, oral short-term administration of NMN significantly increased telomere length. [21]
8. Elevating NAD+ levels has been shown to slow down various mechanisms associated with aging such as decreased energy production in the mitochondria, oxidative stress, DNA damage, cognitive impairment, and inflammation. [22-23]
9. NMN has been shown to slow down age-related changes in the skin by restoring skin homeostasis, protecting against oxidative stress, increasing mitochondrial efficiency, and reducing excess melanin production. [24-25]

C. Improves Cognitive Function

A decline in NAD+ levels is associated with brain disorders such as Alzheimer’s disease, Parkinson’s disease, and other conditions that cause cognitive impairment. [26] By boosting NAD+ levels, NMN can lower the risk for these medical conditions. Another interesting mechanism is that the NMN-mediated increase in NAD+ levels can decrease the production of reactive oxygen species (ROS), which are linked to various brain disorders. Moreover, NMN can also help reverse the age-related cognitive decline by mitigating mitochondrial dysfunction.

A number of studies demonstrate the beneficial effects of NMN on cognitive function:

1. In an Alzheimer’s disease-relevant murine model, NMN treatment restored mitochondrial respiratory function in the brain. [27]
2. In an animal model of Alzheimer’s disease, NMN treatment significantly decreased the production of β-amyloid (abnormal protein structures), loss of nerve signaling, and inflammatory response. [28]
3. In a rat model of vascular cognitive impairment, NMN protected against cognitive decline. [29]
4. In older rats, NMN treatment at a dose of 100 mg/kg alleviated aging-induced memory impairment via modulation of mitochondrial function and apoptosis (programmed cell death) in the brain. [30]
5. In D-galactose-induced aging rat models, the combination of NMN and lycopene improved the ability of spatial location learning and memory. [31]
6. In rats, NMN ameliorated neuronal damage and cognitive impairment caused by severe hypoglycemia (low blood sugar levels). [32]
7. In rats, NMN protected against diabetes-induced memory deficits by preserving mitochondrial oxidative phosphorylation (OXPHOS) function and preventing neuronal loss. [33]
8. In the brain cells of aged rats, NMN treatment increased the formation of new blood vessels and decreased the production of oxidative stress. [34]
9. In a rat model of Alzheimer’s disease, NMN protected against β-amyloid oligomer-induced cognitive impairment and neuronal death. [35]
10. In aged mice, NMN supplementation improved cognitive function by ameliorating age-related cerebromicrovascular dysfunction. [36]
11. Studies found that NMN can help improve cognitive function by promoting the renewal of neural stem/progenitor cells (NSPCs) via SIRT1, SIRT2, and SIRT6. [37-38]
12. In old mice, short-term NMN supplementation improved the sensory processing aspect of some aversive stimuli, suggesting that the treatment can treat cognitive impairments and enhance the quality of life in old age. [39]
13. In a cellular model of Parkinson’s disease (PD), ameliorated mitochondrial inhibitor-induced impairments of energy metabolism and inhibited death of brain cells. [40]

D. Lowers the Risk of Cardiovascular Disease

The NMN-mediated increase in NAD+ levels activates SIRT1, which in turn increases the production of cardioprotective molecules, such as MnSOD (antioxidants), Trx1 (antioxidants), and Bcl-xL (anti-apoptotic). [41] In addition, SIRT1 activation can also help protect the heart from inflammation and oxidative stress.

Compelling evidence supports the cardioprotective effects of NMN:

1. In mice, NMN protected against heart injury caused by insufficient blood flow (ischemia). [42]
2. A study suggests that NMN exerts its cardioprotective effects by generating adenosine triphosphate via glucose breakdown. [43]
3. In mice with ischemia, NMN (62.5mg/kg) dramatically ameliorated injury and significantly improved the neurological outcome. [44]
4. In mice, NMN treatment prevented post-ischemic depletion of mitochondrial NAD+, suppressed mitochondrial fragmentation, and reduced oxidative stress via SIRT3-dependent mechanisms. [45-46]
5. In the heart cells of mice, short-term administration of NMN preserved mitochondrial ultrastructure, reduced oxidative stress, and prevented cell death in the heart. [47]
6. Studies reported that NMN administration in patients with intractable cardiac diseases such as heart failure with preserved ejection fraction may produce beneficial effects. [48-49]
7. In rats, NMN attenuated doxorubicin-induced cardiotoxicity by reducing oxidative stress, inflammation, and programmed cell death. [50]
8. In aged male rats, NMN counteracted damage to the heart muscle by activating SIRT3/FOXO1 and reducing programmed cell death. [51]
9. In mice with heart scarring, NMN administration via injections reduced scarring by suppressing oxidative stress and Smad3 acetylation in a NAD+/SIRT1-dependent manner. [52]
10. In aged mice, NMN administration increased NAD+ levels and protected against ischemic heart injury. [53-55]

E. Fights Cancer

Mitochondrial respiration malfunction and increased glucose uptake are mechanisms observed in cancer cells. [56] The NMN-mediated increase in NAD+ levels has been shown to increase mitochondrial respiration and reduce glucose (blood sugar) uptake, indicating that NMN may help combat cancer. Another important mechanism is that NMN increases NAD+ levels which in turn activates SIRT1 and SIRT6, both of which inhibit the growth and spread of tumors.

A number of studies support the anti-cancer properties of NMN:

1. The NMN-mediated increase in NAD+ levels is associated with cell cycle arrest and programmed cell death of malignant cells, enhanced efficacy of chemotherapeutic drugs and radiation therapy, and prevention of cancer cell progression. [57-61]
2. NMN has been shown to combat cancer by boosting cellular energy and enhancing DNA repair activity. [62]
3. NMN has also been shown to enhance colorectal cancer cell-kill by the chemotherapeutic drug Tiazofurin. [63]

F. Improves Blood Sugar Levels and Treats Diabetes Symptoms

NMN has the ability to improve the body’s response to the hormone insulin, which helps blood sugar enter the cells. This process is called insulin sensitivity. With increased insulin sensitivity, blood sugar stays at healthy levels.

The blood sugar-lowering effects of NMN and its benefits on diabetes symptoms are backed by a number of studies:

1. In mice, the administration of NMN prevented age-related weight gain and improved physical activity, energy metabolism, lipid profiles, and insulin sensitivity. [16]
2. In prediabetic women, NMN supplementation at 250 mg/day increased muscle insulin sensitivity. [64]
3. In obese mice, increased NAD+ levels induced by NMN improved blood glucose and lipid homeostasis by increasing the activity of SIRT1 and SIRT3. [65-66]
4. In old mice with type 2 diabetes, NMN improved glucose intolerance and lipid profiles. [67]
5. In mice, NMN treatment ameliorated NAD+ deficiency and improved insulin secretion. [68]
6. In mice fed with fructose, a type of sugar, administration of NMN restored insulin secretion by correcting inflammation of the islet of the pancreas (responsible for insulin production). [69]
7. Studies found that NMN supplementation for 12 months decreased insulin resistance in mice. [70-71]
8. In mice fed with a high-fat diet, NMN administered via intravenous injections improved glucose tolerance. [72]
9. A cell study found that NMN can stimulate insulin secretion. [73]
10. In lean type 2 diabetic patients with secondary failure to sulphonylureas (anti-diabetic medication), NMN improved insulin secretion and metabolic control. [74]

G. Fights Inflammation

NMN has the potential to suppress inflammaging, which is the age-related increase in inflammation. Specifically, NMN has been found to suppress cyclooxygenase-2 (COX-2), an enzyme that synthesizes the proinflammatory mediators known as prostaglandins. With this effect, NMN can help treat and ward off a wide array of inflammatory conditions.

A convincing number of studies support the anti-inflammatory effects of NMN:

1. In mice, NMN inhibited lipopolysaccharide (LPS)-induced inflammation and oxidative stress via suppression of COX-2. [75]
2. In aging mice, NMN reduced inflammatory markers such as tumor necrosis factor alpha (TNF-α). [76]
3. In mice with inflammation of the abdomen due to blood infection, NMN prevented clinical deterioration and improved survival. [77]
4. A cell study found that NMN inhibited endothelial inflammation and improved the function of nitric oxide (a substance that widens the blood vessels). [78]

H. Improves Fertility

NMN has the capacity to improve male and female fertility. It does this by improving the quality of both the egg cell and sperm cell. This in turn ensures successful fertilization and pregnancy. In addition, NMN can also help reverse some of the effects of aging on the reproductive system.

The beneficial effects of NMN on male and female reproductive health are backed by a number of studies:

1. In animal subjects, NMN supplementation protected egg cell quality against environmental pollutant-induced deterioration, contributing to improved fertility. [79]
2. In aged animals, treatment with the NAD+ metabolic precursor NMN rejuvenated egg cell quality, leading to the restoration of fertility. [80-81]
3. NMN supplementation improved the quality of porcine egg cells under heat stress by restoring cell division. [82]
4. Supplementation of NMN improved the quality of postovulatory aged porcine egg cells. [83]
5. In female mice, NMN supplementation improved egg cell quality by restoring mitochondrial structures. [84]
6. In streptozotocin-induced diabetic mice, NMN treatment significantly increased the area and diameter of seminiferous tubules and the number of spermatogenic cells and sperms. [85]

I. Improves Eye Health

Restoration of NAD+ through NMN supplementation can help protect photoreceptors (special cells in the retina that converts light into signals that are sent to the brain) against light-induced retinal damage. [86-87] The exact mechanism of NMN-induced eye protection can be attributed to SIRT1 activation since it is essential in the development and survival of the retina. Alterations in SIRT1 activity have been linked to various eye conditions such as aged retina, diabetic retinopathy, light-induced retinal degeneration, and oxygen-induced retinal damage. [88-93]

Studies show that NMN supplementation is essential for eye health:

1. NMN treatment increased NAD+ levels and improved cell viability, reduced programmed cell death, and decreased lactate dehydrogenase (LDH) release in corneal epithelial cells. [94]
2. In high-glucose-treated human corneal epithelial cells, NMN increased cell viability by reversing cell damage, reducing programmed cell death, increasing cell migration, and restoring the structures of corneal cells. [95]
3. A study reported that NMN supplementation can treat glaucoma and age-related macular degeneration by correcting NAD+ pool depletion and mitochondrial dysfunction. [96]
4. In a mouse model of retinal ischemia-reperfusion injury (cellular dysfunction and death after the restoration of blood flow to tissues with previously impaired blood circulation), NMN injection significantly suppressed retinal functional damage and inflammation and protected against oxidative stress-induced cell death. [97]
5. In a photoreceptor degenerative model of retinal detachment, NMN administration exerted neuroprotective effects on photoreceptors and against oxidative injury. [98]
6. In mice, NMN effectively prevented ultraviolet B light-induced tissue damage and endothelial cell death in the mouse cornea. [99]
7. In mice with corneal injury, the replenishment of NMN or NAD+ slowed down corneal nerve fiber degeneration by restoring the activation levels of SIRT1. [100]

J. Boosts Immune Function

The age-related shortening of telomeres adversely affects immune function, thus, increasing the risk of severe infection, inflammatory conditions, and chronic diseases. [101-103] Interestingly, NMN boosts NAD+ levels which in turn activates SIRT1. As a result, the telomeres lengthen and become more stable. Moreover, NMN has anti-inflammatory effects and the ability to regulate the activity of certain cells of the immune system.

A good deal of evidence supports the immune-boosting effects of NMN:

1. Treatment of 24-month-old mice with NMN for 1 week significantly reduced the levels of inflammatory markers such as TNFα and IL-6 in the skeletal muscle. [14]
2. In young and older mice, NMN augmented the cytotoxic activity of natural killer cells of the immune system. [104]
3. The NMN-mediated increase in NAD+ levels can help improve immune function by promoting cell survival, DNA repair, and enhanced intercellular communication. [105-106]
4. Restoring normal NAD+ levels via NMN can decrease the severity of immune reactions in patients with COVID-19 infection. [107]
5. An increase in NAD+ levels was associated with significant immunomodulatory effects such as modulation of cytokine action, regulation of the intercellular adhesion molecules, blockage of mast cell degranulation, and inhibition of protease release from leukocytes. [108-110]

K. Increases Energy Levels

Sirtuins play a critical role in regulating various cellular functions including energy metabolism, stress resistance, and circadian rhythm neuronal function – all of which are essential for increasing energy levels. [111-112] Since NMN activates SIRT1 by increasing NAD+ levels, it may help boost energy levels and reduce fatigue. Moreover, NAD+ is essential for the production of adenosine triphosphate (ATP), which is needed by the cells to perform various biological functions.

An increasing number of studies support the beneficial effects of NMN on energy levels and medical conditions that cause fatigue:

1. In older adults, NMN intake in the afternoon for 12 weeks effectively improved sleep quality, fatigue, and physical performance as evidenced by improved lower limb function and reduced drowsiness. [113]
2. In amateur runners, NMN supplementation for 6 weeks increased the aerobic capacity during exercise training via enhanced O2 utilization of the skeletal muscle. [114]
3. In healthy young and elderly mice, NMN supplementation at 500 mg/kg/d with exercise training increased endurance performance. [115-116]
4. Raising intracellular NAD+ levels through NMN supplementation can improve the quality of life of patients with chronic fatigue syndrome by improving neurological function, promoting energy production, and lowering fatigue. [117]

L. Promotes Weight Loss

NMN can help promote weight loss via different mechanisms such as increased energy expenditure and enhanced insulin sensitivity. Increased energy expenditure prevents excess fat storage. With enhanced insulin sensitivity, the body responds well to the effects of insulin which in turn prevents high blood sugar (hyperglycemia) which is associated with increased adiposity.

Evidence suggests that NMN is beneficial for achieving a healthier weight because of its fat-burning properties:

1. In healthy individuals, the intravenous administration of NMN significantly reduced blood triglyceride (TG) levels and fat accumulation in the liver. [118]
2. In mice with severe insulin resistance, NMN treatment reduced visceral adipose tissue (VAT) and adiponectin (a hormone produced by fat cells). [119]
3. In obese female mice, NMN reduced adiposity and improved glucose and markers of mitochondrial function. [120]

M. Treats Stroke

A stroke occurs when the blood supply to the brain is cut off. NMN has the ability to widen the blood vessels which can help restore blood flow to the brain. In addition, the anti-inflammatory effects of NMN can help relieve brain swelling associated with stroke.

A number of studies suggest that NMN treatment is beneficial in treating the symptoms of stroke and improving recovery outcomes:

1. In mice with brain injury caused by stroke, NMN treatment for 7 days markedly promoted the recovery of body weight and neurological function via suppression of brain inflammation and oxidative stress. [121]
2.  In a rodent model of hemorrhagic shock due to stroke, NMN significantly improved survival after resuscitation. [122]
3. NAD replenishment with NMN protected blood-brain barrier integrity and attenuated brain changes caused by significant bleeding. [123]
4. NMN treatment attenuated traumatic brain injury in mice via restoration of NAD+ levels. [124]

N. Improves Liver Health

NMN boosts NAD+ levels resulting in SIRT1 activation. This process is essential in liver health as SIRT1 activation improves cholesterol, fat, and lipid transport as well as fatty acid homeostasis in the liver. [125-127]

Studies show that NMN can improve liver function and protect against liver disease:

1. NMN treatment can help protect against liver injury by raising NAD+ levels. [128]
2. An increase in NAD+ has been shown to protect against aging-induced non-alcoholic fatty liver disease-like liver dysfunction in mice. [129]
3. Increased NAD+ levels can prevent the progression of non-alcoholic fatty liver disease by influencing the oxidative stress response, programmed cell death, and inflammatory response. [130]
4. In mouse models of liver cirrhosis (scarring), NMN treatment inhibited the production of substances that cause liver inflammation and scarring. [131]
5. In aged mice, NMN administration protected against oxidative stress-induced liver injury. [132]

O. Improves Kidney Health

The anti-aging effects of NMN can also help address the age-related decline in kidney function. Reduced levels of NAD+ are associated with reduced sirtuin activity which in turn causes deterioration in the overall function of the kidneys. The ability of NMN to boost NAD+ levels activates SIRT1 which can possibly mitigate the negative effects of aging on the kidneys.

Evidence suggests that NMN can help address kidney problems associated with aging and certain medical conditions:

1. In old mice with acute kidney injury, NMN supplementation improved kidney function via restoration of renal SIRT1 activity and NAD+ content. [133]
2. In human kidney cells, NMN suppressed DNA damage and senescence induced by hydrogen peroxide and hypoxia (low oxygen). [134]
3. In mice, short-term NMN treatment ameliorated adriamycin-induced kidney damage by increasing SIRT1. [135]
4. In mice with kidney complications due to diabetes, NMN treatment increased kidney concentrations of NAD+ and SIRT1, improved survival rates, and alleviated kidney scarring. [136-137]

Associated Side Effects of NMN

NMN side effects are very uncommon. There have been some side effects associated with the use of this drug wherein the patient had one of the issues listed below at some point while being on NMN. However, these side effects weren’t confirmed to be associated with the treatment and could have been a coincidence and not related to the use of NMN. Despite this, it was listed as a side effect associated with NMN even though these associated side effects are very uncommon.

Side effects associated with NMN may include the following:

• Abdominal distension
• Abdominal pain
• Belching
• Diarrhea
• Fatigue
• Fever
• Flatus
• Joint pain
• Muscle pain
• Sense of hunger

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