Nicotinamide Mononucleotide (NMN)

    From Longevity Wiki

    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. [1]

    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. [2]

    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.

    Controversy about NMN as Direct Precursor

    The primary issue is that NMN's role as a direct precursor is effective only when it is inside the cell. This raises questions about how NMN, when ingested or administered externally, enters the cell to contribute to NAD+ synthesis. The central controversy surrounding NMN as a precursor to NAD+ lies in its mechanism of cellular entry. While NMN is a direct precursor of NAD+ within the cell, the debate focuses on whether NMN can be directly absorbed by cells or if it must first be converted to Nicotinamide Riboside (NR). In that case, NR would hold an edge over NMN because NR would need on conversion less compared to NMN.

    Direct Transport Mechanism

    One hypothesis is that NMN can directly enter cells through specific transporters. The Slc12a8 transporter in the aged mouse ileum is an example, suggested to facilitate NMN's direct absorption[3]. However, this notion has faced challenges due to conflicting research findings[4][5], and the functionality of Slc12a8 in humans is yet to be conclusively determined.

    Dephosphorylation to NR as a Precursor

    An alternative and more widely accepted theory proposes that NMN is not directly used by cells. Instead, it is first converted to Nicotinamide Riboside (NR) through dephosphorylation before cellular absorption. This conversion is mediated by ectonucleotidases like CD73. Upon entry into the cell as NR via equilibrative nucleoside transporters (ENT1, ENT2, and ENT4), it is phosphorylated into NMN[5][6]. Studies, such as those by Kim et al., indicate that orally ingested NMN is predominantly converted to NR in intestinal tissue before absorption, challenging the direct precursor role of NMN[7][8].

    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:

    Prospects of increasing NAD+ by NMN[9]
    Potential health benefits in mouse models Results of published human clinical trials

    NMN NAD+ Mice.png
    • Brain: improved brain function, protected from neurodegeneration^55,82,83,92,103, enhanced new myelin generation^80
    • Lung: prevented pulmonary fibrosis, improved respiratory system function^33
    • Liver: improved liver function, reduced hepatic steatosis, increased capacity to regenerate^81,94
    • Heart: protected cardiomyocytes from injury caused by tachycardia^97,98,102
    • Eye: exerted neuroprotective effects on photoreceptors^100,87
    • Muscle: reduced atrophy, enhanced mitochondrial function and increased physical activity^100,101
    • Vasculature: protected vasculature^89,90,99, increased capillary density, neovascularization, blood flow^32
    • Inflammageing: improved immune cell function, reduced inflammation^34,53,84,96
    • Skin: protected the skin from photodamage caused by UVB irradiation^86
    • Reproduction: improved oocytes quality^88, increased the number of sperm^85
    NMN NAD+ Human.png
    • Safety: basically safe under the existing intervention dose and time
    • Sleep quality: no significant improvement[10]
    • Physical activity: prevented aging-related muscle dysfunctions and improving physical performance[10][11][12][13]
    • Ear: improved the right auditory ability of old men[11]
    • Cognition: no significant improvement[11]
    • Diabetes: increased muscle insulin sensitivity, insulin signaling, and remodeling in prediabetic women[1]
    • Telomere: increased telomere length[14]
    • 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.

    Safety and Dosage

    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

    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.

    Safety

    When it comes to NMN (Nicotinamide Mononucleotide) supplementation, safety is a primary concern, especially given the relatively early stage of human studies in this area. The current body of research, mostly comprising animal studies and limited human trials, suggests that NMN is generally well-tolerated at various dosages. However, there are several important safety considerations to keep in mind:

    • Human Study Limitations: Most research on NMN has been conducted in animal models, primarily mice. While these studies are promising, human biology can respond differently, and the long-term effects of NMN in humans are still not fully understood.
    • Dosage and Tolerance: The tolerability of NMN appears to be dose-dependent. Human studies have tested a range of doses, with some trials using up to 1,250 mg per day or 2,000 mg per day of the specialized NMN formulation MIB-626. These studies have generally reported good tolerability, but individual responses can vary.
    • Interactions with Medications: The potential interactions between NMN and various medications are not yet fully understood. Individuals taking prescription medications, particularly those for chronic conditions, should consult with a healthcare provider before starting NMN supplementation.
    • Long-term Safety: The long-term safety of NMN supplementation is an area that requires further research. While short-term studies have shown promising results, the effects of prolonged NMN use over years or decades are not yet known.
    • Purity and Quality of Supplements: The market for NMN supplements varies widely in terms of product purity and quality. It is crucial to source NMN from reputable suppliers who provide third-party testing and quality assurance to ensure the product is free from contaminants and accurately labeled in terms of dosage.
    • Population-Specific Effects: Different populations, such as the elderly, those with chronic illnesses, or those with specific genetic backgrounds, may respond differently to NMN supplementation. Tailored studies are needed to understand these variable responses better.

    In summary, while NMN supplementation is an exciting area of research with potential health benefits, especially related to aging and metabolic health, it is essential to approach it with caution. Ongoing research and clinical trials will continue to inform safer usage guidelines and help identify the full spectrum of NMN's effects in humans.

    Side Effects

    Overall, there have been no serious side effects in humans clinical trials that have been due to the use of NMN. When taken at higher doses than intended, you could be facing side effects such as nausea, diarrhea, indigestion, and stomach discomfort. However, these are common side effects of supplements when taken in amounts that are too high.[15]

    Some individuals reported in NMN forums low energy and tiredness potentially caused by methyl donor deficiency (see next section).[16] The side effects can occur from the beginning or after a longer period of use.

    It is important to monitor for any adverse reactions, especially when starting supplementation or changing dosages.

    Methyl Donor Deficiency

    There is a theoretical concern that consuming NMN could deplete methyl groups in the body and might lead to a Methyl Donor Deficiency associated with symptoms such as low energy and tiredness. 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.

    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.[16]

    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. There could be also a compensatory mechanisms in place slowing down the conversion of NMN to NAD+ or the methylation of nicotinamide if methyl groups were being depleted.

    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.

    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.[17] 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.[18]

    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.[19]

    A recent RCT clinical 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.[10]

    Additionally, it's noteworthy that two MIB-626 trials utilized a twice per day administration regimen. This dosing schedule is significant because it could potentially offer more consistent NAD+ level support throughout the day, although the specific implications of this frequency in relation to circadian rhythms and overall efficacy remain an area for further research.[20][21]

    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 [22]
    • 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 [1] 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 [12] 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 [23] 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 [24] 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 [10] 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 [20] 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 [21] 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
    2022, Chronic nicotinamide mononucleotide supplementation elevates blood nicotinamide adenine dinucleotide levels and alters muscle function in healthy older men [11]
    2022, A Multicentre, Randomised, Double Blind, Parallel Design, Placebo Controlled Study to Evaluate the Efficacy and Safety of Uthever (NMN Supplement), an Orally Administered Supplementation in Middle Aged and Older Adults [13]
    2021, The Impacts of Short-Term NMN Supplementation on Serum Metabolism, Fecal Microbiota, and Telomere Length in Pre-Aging Phase [14]
    2023, Nicotinamide adenine dinucleotide metabolism and arterial stiffness after long-term nicotinamide mononucleotide supplementation: a randomized, double-blind, placebo-controlled trial [25]
    2023, Effects of nicotinamide mononucleotide on older patients with diabetes and impaired physical performance: A prospective, placebo-controlled, double-blind study [26]

    See also

    Todo

    References

    1. ↑ 1.0 1.1 1.2 Yoshino M et al.: Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science 2021. (PMID 33888596) [PubMed] [DOI] [Full text] In rodents, obesity and aging impair nicotinamide adenine dinucleotide (NAD+) biosynthesis, which contributes to metabolic dysfunction. Nicotinamide mononucleotide (NMN) availability is a rate-limiting factor in mammalian NAD+ biosynthesis. We conducted a 10-week, randomized, placebo-controlled, double-blind trial to evaluate the effect of NMN supplementation on metabolic function in postmenopausal women with prediabetes who were overweight or obese. Insulin-stimulated glucose disposal, assessed by using the hyperinsulinemic-euglycemic clamp, and skeletal muscle insulin signaling [phosphorylation of protein kinase AKT and mechanistic target of rapamycin (mTOR)] increased after NMN supplementation but did not change after placebo treatment. NMN supplementation up-regulated the expression of platelet-derived growth factor receptor β and other genes related to muscle remodeling. These results demonstrate that NMN increases muscle insulin sensitivity, insulin signaling, and remodeling in women with prediabetes who are overweight or obese (clinicaltrial.gov NCT03151239).
    2. ↑ https://www.nmn.com/news/fda-bans-labeling-nmn-as-a-supplement
    3. ↑ [Source 160]
    4. ↑ [Source 161]
    5. ↑ 5.0 5.1 [Source 162]
    6. ↑ [Source 163]
    7. ↑ Kim LJ et al.: Host-microbiome interactions in nicotinamide mononucleotide (NMN) deamidation. FEBS Lett 2023. (PMID 37463842) [PubMed] [DOI] The nicotinamide adenine dinucleotide (NAD+ ) precursor nicotinamide mononucleotide (NMN) is a proposed therapy for age-related disease, whereby it is assumed that NMN is incorporated into NAD+ through the canonical recycling pathway. During oral delivery, NMN is exposed to the gut microbiome, which could modify the NAD+ metabolome through enzyme activities not present in the mammalian host. We show that orally delivered NMN can undergo deamidation and incorporation in mammalian tissue via the de novo pathway, which is reduced in animals treated with antibiotics to ablate the gut microbiome. Antibiotics increased the availability of NAD+ metabolites, suggesting the microbiome could be in competition with the host for dietary NAD+ precursors. These findings highlight new interactions between NMN and the gut microbiome.
    8. ↑ [Source 168]
    9. ↑ 9.0 9.1 Song Q et al.: The Safety and Antiaging Effects of Nicotinamide Mononucleotide in Human Clinical Trials: an Update. Adv Nutr 2023. (PMID 37619764) [PubMed] [DOI] The importance of nicotinamide adenine dinucleotide (NAD+) in human physiology is well recognized. As the NAD+ concentration in human skin, blood, liver, muscle, and brain are thought to decrease with age, finding ways to increase NAD+ status could possibly influence the aging process and associated metabolic sequelae. Nicotinamide mononucleotide (NMN) is a precursor for NAD+ biosynthesis, and in vitro/in vivo studies have demonstrated that NMN supplementation increases NAD+ concentration and could mitigate aging-related disorders such as oxidative stress, DNA damage, neurodegeneration, and inflammatory responses. The promotion of NMN as an antiaging health supplement has gained popularity due to such findings; however, since most studies evaluating the effects of NMN have been conducted in cell or animal models, a concern remains regarding the safety and physiological effects of NMN supplementation in the human population. Nonetheless, a dozen human clinical trials with NMN supplementation are currently underway. This review summarizes the current progress of these trials and NMN/NAD+ biology to clarify the potential effects of NMN supplementation and to shed light on future study directions.
    10. ↑ 10.0 10.1 10.2 10.3 Kim M et al.: 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. Nutrients 2022. (PMID 35215405) [PubMed] [DOI] [Full text] Deteriorating sleep quality and physical or mental fatigue in older adults leads to decreased quality of life and increased mortality rates. This study investigated the effects of the time-dependent intake of nicotinamide mononucleotide (NMN) on sleep quality, fatigue, and physical performance in older adults. This randomized, double-blind placebo-controlled study evaluated 108 participants divided into four groups (NMN_AM; antemeridian, NMN_PM; post meridian, Placebo_AM, Placebo_PM). NMN (250 mg) or placebo was administered once a day for 12 weeks. Sleep quality was evaluated using the Pittsburgh Sleep Quality Index. Fatigue was evaluated using the "Jikaku-sho shirabe" questionnaire. Grip strength, 5-times sit-to-stand (5-STS), timed up and go, and 5-m habitual walk were evaluated to assess the physical performance. Significant interactions were observed between 5-STS and drowsiness. 5-STS of all groups on post-intervention and drowsiness of the NMN_PM and Placebo_PM groups on mid- and post-intervention showed significant improvement compared with those in pre-intervention. The NMN_PM group demonstrated the largest effect size for 5-STS (d = 0.72) and drowsiness (d = 0.64). Overall, NMN intake in the afternoon 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.
    11. ↑ 11.0 11.1 11.2 11.3 Igarashi M et al.: Chronic nicotinamide mononucleotide supplementation elevates blood nicotinamide adenine dinucleotide levels and alters muscle function in healthy older men. NPJ Aging 2022. (PMID 35927255) [PubMed] [DOI] [Full text] Preclinical studies have revealed that the elevation of nicotinamide adenine dinucleotide (NAD + ) upon the administration of nicotinamide mononucleotide (NMN), an NAD + precursor, can mitigate aging-related disorders; however, human data on this are limited. We investigated whether the chronic oral supplementation of NMN can elevate blood NAD + levels and alter physiological dysfunctions in healthy older participants. We administered 250 mg NMN per day to aged men for 6 or 12 weeks in a placebo-controlled, randomized, double-blind, parallel-group trial. Chronic NMN supplementation was well tolerated and caused no significant deleterious effect. Metabolomic analysis of whole blood samples demonstrated that oral NMN supplementation significantly increased the NAD + and NAD + metabolite concentrations. There were nominally significant improvements in gait speed and performance in the left grip test, which should be validated in larger studies; however, NMN exerted no significant effect on body composition. Therefore, chronic oral NMN supplementation can be an efficient NAD + booster for preventing aging-related muscle dysfunctions in humans.
    12. ↑ 12.0 12.1 Liao B et al.: Nicotinamide mononucleotide supplementation enhances aerobic capacity in amateur runners: a randomized, double-blind study. J Int Soc Sports Nutr 2021. (PMID 34238308) [PubMed] [DOI] [Full text] BACKGROUND: Recent studies in rodents indicate that a combination of exercise training and supplementation with nicotinamide adenine dinucleotide (NAD+) precursors has synergistic effects. However, there are currently no human clinical trials analyzing this. OBJECTIVE: This study investigates the effects of a combination of exercise training and supplementation with nicotinamide mononucleotide (NMN), the immediate precursor of NAD+, on cardiovascular fitness in healthy amateur runners. METHODS: A six-week randomized, double-blind, placebo-controlled, four-arm clinical trial including 48 young and middle-aged recreationally trained runners of the Guangzhou Pearl River running team was conducted. The participants were randomized into four groups: the low dosage group (300 mg/day NMN), the medium dosage group (600 mg/day NMN), the high dosage group (1200 mg/day NMN), and the control group (placebo). Each group consisted of ten male participants and two female participants. Each training session was 40-60 min, and the runners trained 5-6 times each week. Cardiopulmonary exercise testing was performed at baseline and after the intervention, at 6 weeks, to assess the aerobic capacity of the runners. RESULTS: Analysis of covariance of the change from baseline over the 6 week treatment showed that the oxygen uptake (VO2), percentages of maximum oxygen uptake (VO2max), power at first ventilatory threshold, and power at second ventilatory threshold increased to a higher degree in the medium and high dosage groups compared with the control group. However, there was no difference in VO2max, O2-pulse, VO2 related to work rate, and peak power after the 6 week treatment from baseline in any of these groups. CONCLUSION: NMN increases the aerobic capacity of humans during exercise training, and the improvement is likely the result of enhanced O2 utilization of the skeletal muscle. TRIAL REGISTRATION NUMBER: ChiCTR2000035138 .
    13. ↑ 13.0 13.1 Huang H: A Multicentre, Randomised, Double Blind, Parallel Design, Placebo Controlled Study to Evaluate the Efficacy and Safety of Uthever (NMN Supplement), an Orally Administered Supplementation in Middle Aged and Older Adults. Front Aging 2022. (PMID 35821806) [PubMed] [DOI] [Full text] Objective: The purpose of the study was to evaluate the anti-aging effect of NMN and its safety in a double-blind, parallel, randomised controlled clinical trial. Methods: The study was carried out on 66 healthy subjects between the ages of 40 and65 years, instructed to take two capsules (each containing 150 mg. of NMN or starch powder) once a day after breakfast for 60 days. Results: At day 30, NAD+/NADH levels in the serum showed a noteworthy increase, i.e., by 11.3%, whereas the placebo group had shown no change at all. At the end of the study, i.e., day 60, the NAD+/NADH levels were increased further by 38% compared to baseline, against a mere 14.3% in the placebo group. In the case of SF 36, at day 60, the Uthever group showed a rise of 6.5%, whereas the placebo group was merely raised by 3.4%. At the end of the study, the mean HOMA IR Index showed a rise of 0.6% among the Uthever group and 30.6% among the Placebo group from baseline. Conclusion: The rise in the levels of NAD+/NADH at day 30 and day 60 illustrated the potential of Uthever to raise the levels of NAD+ in the cells, which is linked to higher energy levels and an anti-aging effect. Increased sensitivity to insulin has also been linked to anti-aging. There was no noteworthy change in HOMA score, in the Uthever group whereas there was a noteworthy rise in the placebo group, demonstrating the anti-aging effect of Uthever as in its absence, the parameters worsened. Clinical Trial Registration: (clinicaltrials.gov), identifier (NCT04228640 NMN).
    14. ↑ 14.0 14.1 Niu KM et al.: The Impacts of Short-Term NMN Supplementation on Serum Metabolism, Fecal Microbiota, and Telomere Length in Pre-Aging Phase. Front Nutr 2021. (PMID 34912838) [PubMed] [DOI] [Full text] Aging is a natural process with concomitant changes in the gut microbiota and associate metabolomes. Beta-nicotinamide mononucleotide, an important NAD+ intermediate, has drawn increasing attention to retard the aging process. We probed the changes in the fecal microbiota and metabolomes of pre-aging male mice (C57BL/6, age: 16 months) following the oral short-term administration of nicotinamide mononucleotide (NMN). Considering the telomere length as a molecular gauge for aging, we measured this in the peripheral blood mononuclear cells (PBMC) of pre-aging mice and human volunteers (age: 45-60 years old). Notably, the NMN administration did not influence the body weight and feed intake significantly during the 40 days in pre-aging mice. Metabolomics suggested 266 upregulated and 58 downregulated serum metabolites. We identified 34 potential biomarkers linked with the nicotinamide, purine, and proline metabolism pathways. Nicotinamide mononucleotide significantly reduced the fecal bacterial diversity (p < 0.05) with the increased abundance of Helicobacter, Mucispirillum, and Faecalibacterium, and lowered Akkermansia abundance associated with nicotinamide metabolism. We propose that this reshaped microbiota considerably lowered the predicated functions of aging with improved immune and cofactors/vitamin metabolism. Most notably, the telomere length of PBMC was significantly elongated in the NMN-administered mice and humans. Taken together, these findings suggest that oral NMN supplementation in the pre-aging stage might be an effective strategy to retard aging. We recommend further studies to unravel the underlying molecular mechanisms and comprehensive clinical trials to validate the effects of NMN on aging.
    15. ↑ https://www.dremilnutrition.com/post/will-i-get-side-effects-from-my-nmn-intake#:~:text=Potential%20NMN%20Side%20Effects%20%2B%20Other%20Safety%20Concerns&text=When%20taken%20at%20higher%20doses,amounts%20that%20are%20too%20high.
    16. ↑ 16.0 16.1 https://renuebyscience.com/forums/viewtopic.php?t=2575
    17. ↑ Peek CB et al.: Circadian clock NAD+ cycle drives mitochondrial oxidative metabolism in mice. Science 2013. (PMID 24051248) [PubMed] [DOI] [Full text] Circadian clocks are self-sustained cellular oscillators that synchronize oxidative and reductive cycles in anticipation of the solar cycle. We found that the clock transcription feedback loop produces cycles of nicotinamide adenine dinucleotide (NAD(+)) biosynthesis, adenosine triphosphate production, and mitochondrial respiration through modulation of mitochondrial protein acetylation to synchronize oxidative metabolic pathways with the 24-hour fasting and feeding cycle. Circadian control of the activity of the NAD(+)-dependent deacetylase sirtuin 3 (SIRT3) generated rhythms in the acetylation and activity of oxidative enzymes and respiration in isolated mitochondria, and NAD(+) supplementation restored protein deacetylation and enhanced oxygen consumption in circadian mutant mice. Thus, circadian control of NAD(+) bioavailability modulates mitochondrial oxidative function and organismal metabolism across the daily cycles of fasting and feeding.
    18. ↑ Levine DC et al.: NAD+ Controls Circadian Reprogramming through PER2 Nuclear Translocation to Counter Aging. Mol Cell 2020. (PMID 32369735) [PubMed] [DOI] [Full text] Disrupted sleep-wake and molecular circadian rhythms are a feature of aging associated with metabolic disease and reduced levels of NAD+, yet whether changes in nucleotide metabolism control circadian behavioral and genomic rhythms remains unknown. Here, we reveal that supplementation with the NAD+ precursor nicotinamide riboside (NR) markedly reprograms metabolic and stress-response pathways that decline with aging through inhibition of the clock repressor PER2. NR enhances BMAL1 chromatin binding genome-wide through PER2K680 deacetylation, which in turn primes PER2 phosphorylation within a domain that controls nuclear transport and stability and that is mutated in human advanced sleep phase syndrome. In old mice, dampened BMAL1 chromatin binding, transcriptional oscillations, mitochondrial respiration rhythms, and late evening activity are restored by NAD+ repletion to youthful levels with NR. These results reveal effects of NAD+ on metabolism and the circadian system with aging through the spatiotemporal control of the molecular clock.
    19. ↑ 2021-12-27 - Interview Dr. David Sinclair - Huberman Lab Podcast - The Biology of Slowing & Reversing Aging
    20. ↑ 20.0 20.1 Pencina KM et al.: 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. J Gerontol A Biol Sci Med Sci 2023. (PMID 35182418) [PubMed] [DOI] BACKGROUND: Nicotinamide adenine dinucleotide (NAD) precursors, nicotinamide mononucleotide (NMN), or nicotinamide riboside (NR) extend healthspan and ameliorate some age-related conditions in model organisms. However, early-phase trials of NAD precursors have yielded varying results and their pharmacokinetics remain incompletely understood. Here, we report the pharmacokinetics and pharmacodynamics of MIB-626, a microcrystalline unique polymorph βNMN formulation. METHODS: In this double-blind, placebo-controlled study, 32 overweight or obese adults, 55-80 years, were block-randomized, stratified by sex, to 1 000-mg MIB-626 once daily, twice daily, or placebo for 14 days. NMN, NAD, and NAD metabolome were measured using liquid chromatography-tandem mass spectrometry. RESULTS: Participant characteristics were similar across groups. MIB-626 was well tolerated and frequency of adverse events was similar across groups. Blood NMN concentrations on Day 14 in MIB-626-treated groups were significantly higher compared to placebo (1.7-times and 3.7-times increase above baseline in 1 000 mg once-daily and twice-daily groups in mean AUClast, respectively). MIB-626 treatment was associated with substantial dose-related increases in blood NAD levels. Blood levels of NAD metabolites were higher in NMN-treated participants on Days 8 and 14 than at baseline. Changes in NMN or NAD levels were not related to sex, body mass index, or age. Very little unmodified NMN was excreted in the urine. CONCLUSION: MIB-626 1 000 mg once-daily or twice-daily regimens were safe and associated with substantial dose-related increases in blood NAD levels and its metabolome. These foundational data that were obtained using a pharmaceutical-grade βNMN, standardized sample collection, and validated liquid chromatography-tandem mass spectrometry assays, should facilitate design of efficacy trials in disease conditions.
    21. ↑ 21.0 21.1 Pencina KM et al.: Nicotinamide Adenine Dinucleotide Augmentation in Overweight or Obese Middle-Aged and Older Adults: A Physiologic Study. J Clin Endocrinol Metab 2023. (PMID 36740954) [PubMed] [DOI] CONTEXT: Nicotinamide adenine dinucleotide (NAD) levels decline with aging and age-related decline in NAD has been postulated to contribute to age-related diseases. OBJECTIVE: We evaluated the safety and physiologic effects of NAD augmentation by administering its precursor, β-nicotinamide mononucleotide (MIB-626, Metro International Biotech, Worcester, MA), in adults at risk for age-related conditions. METHODS: Thirty overweight or obese adults, ≥ 45 years, were randomized in a 2:1 ratio to 2 MIB-626 tablets each containing 500 mg of microcrystalline β-nicotinamide mononucleotide or placebo twice daily for 28 days. Study outcomes included safety; NAD and its metabolome; body weight; liver, muscle, and intra-abdominal fat; insulin sensitivity; blood pressure; lipids; physical performance, and muscle bioenergetics. RESULTS: Adverse events were similar between groups. MIB-626 treatment substantially increased circulating concentrations of NAD and its metabolites. Body weight (difference -1.9 [-3.3, -0.5] kg, P = .008); diastolic blood pressure (difference -7.01 [-13.44, -0.59] mmHg, P = .034); total cholesterol (difference -26.89 [-44.34, -9.44] mg/dL, P = .004), low-density lipoprotein (LDL) cholesterol (-18.73 [-31.85, -5.60] mg/dL, P = .007), and nonhigh-density lipoprotein cholesterol decreased significantly more in the MIB-626 group than placebo. Changes in muscle strength, muscle fatigability, aerobic capacity, and stair-climbing power did not differ significantly between groups. Insulin sensitivity and hepatic and intra-abdominal fat did not change in either group. CONCLUSIONS: MIB-626 administration in overweight or obese, middle-aged and older adults safely increased circulating NAD levels, and significantly reduced total LDL and non-HDL cholesterol, body weight, and diastolic blood pressure. These data provide the rationale for larger trials to assess the efficacy of NAD augmentation in improving cardiometabolic outcomes in older adults.
    22. ↑ Irie J et al.: Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men. Endocr J 2020. (PMID 31685720) [PubMed] [DOI] 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.
    23. ↑ Fukamizu Y et al.: Safety evaluation of β-nicotinamide mononucleotide oral administration in healthy adult men and women. Sci Rep 2022. (PMID 36002548) [PubMed] [DOI] [Full text] A decrease in the intracellular level of nicotinamide adenine dinucleotide (NAD+), an essential coenzyme for metabolic activity, causes various age-related diseases and metabolic abnormalities. Both in-vivo and in-vitro studies have shown that increasing certain NAD+ levels in cell or tissue by supplementing nicotinamide mononucleotide (NMN), a precursor of NAD+, alleviates age-related diseases and metabolic disorders. In recent years, several clinical trials have been performed to elucidate NMN efficacy in humans. However, previous clinical studies with NMN have not reported on the safety of repeated daily oral administration of ≥ 1000 mg/shot in healthy adult men and women, and human clinical trials on NMN safety are limited. Therefore, we conducted a randomized, double-blind, placebo-controlled, parallel-group study to evaluate the safety of 1250 mg of β-NMN administered orally once daily for up to 4 weeks in 31 healthy adult men and women aged 20-65 years. Oral administration of β-NMN did not result in changes exceeding physiological variations in multiple clinical trials, including anthropometry, hematological, biochemical, urine, and body composition analyses. Moreover, no severe adverse events were observed during the study period. Our results indicate that β-NMN is safe and well-tolerated in healthy adult men and women an oral dose of 1250 mg once daily for up to 4 weeks.Trial registration Clinicaltrials.gov Identifier: UMIN000043084. Registered 21/01/2021. https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000049188 .
    24. ↑ Yi L et al.: 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. Geroscience 2023. (PMID 36482258) [PubMed] [DOI] [Full text] In animal studies, β-nicotinamide mononucleotide (NMN) supplementation increases nicotinamide adenine dinucleotide (NAD) concentrations and improves healthspan and lifespan with great safety. However, it is unclear if these effects can be transferred to humans. This randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial included 80 middle-aged healthy adults being randomized for a 60-day clinical trial with once daily oral dosing of placebo, 300 mg, 600 mg, or 900 mg NMN. The primary objective was to evaluate blood NAD concentration with dose-dependent regimens. The secondary objectives were to assess the safety and tolerability of NMN supplementation, next to the evaluation of clinical efficacy by measuring physical performance (six-minute walking test), blood biological age (Aging.Ai 3.0 calculator), Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), and subjective general health assessment [36-Item Short Form Survey Instrument (SF-36)]. Statistical analysis was performed using the Per Protocol analysis with significant level set at p = 0.05. All 80 participants completed the trial without trial protocol violation. Blood NAD concentrations were statistically significantly increased among all NMN-treated groups at day 30 and day 60 when compared to both placebo and baseline (all p ≤ 0.001). Blood NAD concentrations were highest in the groups taking 600 mg and 900 mg NMN. No safety issues, based on monitoring adverse events (AEs), laboratory and clinical measures, were found, and NMN supplementation was well tolerated. Walking distance increase during the six-minute walking test was statistically significantly higher in the 300 mg, 600 mg, and 900 mg groups compared to placebo at both days 30 and 60 (all p < 0.01), with longest walking distances measured in the 600 mg and 900 mg groups. The blood biological age increased significantly in the placebo group and stayed unchanged in all NMN-treated groups at day 60, which resulted in a significant difference between the treated groups and placebo (all p < 0.05). The HOMA-IR showed no statistically significant differences for all NMN-treated groups as compared to placebo at day 60. The change of SF-36 scores at day 30 and day 60 indicated statistically significantly better health of all three treated groups when compared to the placebo group (p < 0.05), except for the SF-36 score change in the 300 mg group at day 30. NMN supplementation increases blood NAD concentrations and is safe and well tolerated with oral dosing up to 900 mg NMN daily. Clinical efficacy expressed by blood NAD concentration and physical performance reaches highest at a dose of 600 mg daily oral intake. This trial was registered with ClinicalTrials.gov, NCT04823260, and Clinical Trial Registry - India, CTRI/2021/03/032421.
    25. ↑ Katayoshi T et al.: Nicotinamide adenine dinucleotide metabolism and arterial stiffness after long-term nicotinamide mononucleotide supplementation: a randomized, double-blind, placebo-controlled trial. Sci Rep 2023. (PMID 36797393) [PubMed] [DOI] [Full text] Many animal studies have shown that oral administration of the nicotinamide adenine dinucleotide (NAD+) precursor nicotinamide mononucleotide (NMN) prevents the reduction of NAD+ levels in organs and tissues, helping alleviate aging-related diseases. However, there are very few clinical reports of NMN supplementation in humans. Thus, this study aimed to investigate the influence of a 12-week NMN oral supplementation on biochemical and metabolic health parameters. A 12-week randomized, double-blind, placebo-controlled, parallel-group clinical trial was conducted. A total of 36 healthy middle-aged participants received one capsule of either 125 mg NMN or placebo twice a day. Among the NAD+ metabolites, the levels of nicotinamide in the serum were significantly higher in the NMN intake group than in the placebo group. Pulse wave velocity values indicating arterial stiffness tended to decrease in the NMN intake group. However, no significant difference was found between the two groups. Long-term NMN supplementation at 250 mg/day was well tolerated and did not cause adverse events. NMN safely and effectively elevated NAD+ metabolism in healthy middle-aged adults. Additionally, NMN supplementation showed potential in alleviating arterial stiffness.
    26. ↑ Akasaka H et al.: Effects of nicotinamide mononucleotide on older patients with diabetes and impaired physical performance: A prospective, placebo-controlled, double-blind study. Geriatr Gerontol Int 2023. (PMID 36443648) [PubMed] [DOI] OBJECTIVE: Nicotinamide adenine dinucleotide regulates various biological processes. Nicotinamide mononucleotide (NMN) increases its intracellular levels and counteracts age-associated changes in animal models. We investigated the safety and efficacy of oral nicotinamide mononucleotide supplementation in older patients with diabetes and impaired physical performance. METHOD: We carried out a 24-week placebo-controlled, double-blinded study of male patients with diabetes aged ≥65 years with reduced grip strength (<26 kg) or walking speed (<1.0 m/s). The primary end-points were to determine the safety of NMN oral administration (250 mg/day), and changes in grip strength and walking speed. The secondary end-points were to determine the changes in various exploratory indicators. RESULTS: We studied 14 participants aged 81.1 ± 6.4 years. NMN was tolerable without any severe adverse events. The changes in grip strength and walking speed showed no difference between the two groups: 1.25 kg (95% confidence interval -2.31 to 4.81) and 0.033 m/s (-0.021 to 0.087) in the NMN group, and -0.44 kg (-4.15 to 3.26) and 0.014 m/s (-0.16 to -0.13) in the placebo group, respectively. There were no significant differences in any exploratory indicators between the two groups. However, improved prevalence of frailty in the NMN group (P = 0.066) and different changes in central retinal thickness between the two groups (P = 0.051) was observed. CONCLUSION: In older male patients with diabetes and impaired physical performance, NMN supplementation for 24 weeks was safe, but did not improve grip strength and walking speed. Geriatr Gerontol Int 2023; 23: 38-43.
    27. ↑ Qiu Y et al.: NAD+ exhaustion by CD38 upregulation contributes to blood pressure elevation and vascular damage in hypertension. Signal Transduct Target Ther 2023. (PMID 37718359) [PubMed] [DOI] [Full text] Hypertension is characterized by endothelial dysfunction and arterial stiffness, which contribute to the pathogenesis of atherosclerotic cardiovascular diseases. Nicotinamide adenine dinucleotide (NAD+) is an indispensable cofactor in all living cells that is involved in fundamental biological processes. However, in hypertensive patients, alterations in NAD+ levels and their relation with blood pressure (BP) elevation and vascular damage have not yet been studied. Here we reported that hypertensive patients exhibited lower NAD+ levels, as detected by high-performance liquid chromatography-mass spectrometry (HPLC-MS), in both peripheral blood mononuclear cells (PBMCs) and aortas, which was parallel to vascular dysfunction. NAD+ boosting therapy with nicotinamide mononucleotide (NMN) supplement reduced BP and ameliorated vascular dysfunction in hypertensive patients (NCT04903210) and AngII-induced hypertensive mice. Upregulation of CD38 in endothelial cells led to endothelial NAD+ exhaustion by reducing NMN bioavailability. Pro-inflammatory macrophages infiltration and increase in IL-1β generation derived from pro-inflammatory macrophages resulted in higher CD38 expression by activating JAK1-STAT1 signaling pathway. CD38 KO, CD38 inhibitors treatment, or adeno-associated virus (AAV)-mediated endothelial CD38 knockdown lowered BP and improved vascular dysfunction in AngII-induced hypertensive mice. The present study demonstrated for the first time that endothelial CD38 activation and subsequently accelerated NAD+ degradation due to enhanced macrophage-derived IL-1β production was responsible for BP elevation and vascular damage in hypertension. NAD+ boosting therapy can be used as a novel therapeutic strategy for the management of hypertensive patients.
    28. ↑ North BJ et al.: SIRT2 induces the checkpoint kinase BubR1 to increase lifespan. EMBO J 2014. (PMID 24825348) [PubMed] [DOI] [Full text] Mice overexpressing the mitotic checkpoint kinase gene BubR1 live longer, whereas mice hypomorphic for BubR1 (BubR1(H/H)) live shorter and show signs of accelerated aging. As wild-type mice age, BubR1 levels decline in many tissues, a process that is proposed to underlie normal aging and age-related diseases. Understanding why BubR1 declines with age and how to slow this process is therefore of considerable interest. The sirtuins (SIRT1-7) are a family of NAD(+)-dependent deacetylases that can delay age-related diseases. Here, we show that the loss of BubR1 levels with age is due to a decline in NAD(+) and the ability of SIRT2 to maintain lysine-668 of BubR1 in a deacetylated state, which is counteracted by the acetyltransferase CBP. Overexpression of SIRT2 or treatment of mice with the NAD(+) precursor nicotinamide mononucleotide (NMN) increases BubR1 abundance in vivo. Overexpression of SIRT2 in BubR1(H/H) animals increases median lifespan, with a greater effect in male mice. Together, these data indicate that further exploration of the potential of SIRT2 and NAD(+) to delay diseases of aging in mammals is warranted.
    29. ↑ Sharma A et al.: Potential Synergistic Supplementation of NAD+ Promoting Compounds as a Strategy for Increasing Healthspan. Nutrients 2023. (PMID 36678315) [PubMed] [DOI] [Full text] Disrupted biological function, manifesting through the hallmarks of aging, poses one of the largest threats to healthspan and risk of disease development, such as metabolic disorders, cardiovascular ailments, and neurodegeneration. In recent years, numerous geroprotectors, senolytics, and other nutraceuticals have emerged as potential disruptors of aging and may be viable interventions in the immediate state of human longevity science. In this review, we focus on the decrease in nicotinamide adenine dinucleotide (NAD+) with age and the supplementation of NAD+ precursors, such as nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR), in combination with other geroprotective compounds, to restore NAD+ levels present in youth. Furthermore, these geroprotectors may enhance the efficacy of NMN supplementation while concurrently providing their own numerous health benefits. By analyzing the prevention of NAD+ degradation through the inhibition of CD38 or supporting protective downstream agents of SIRT1, we provide a potential framework of the CD38/NAD+/SIRT1 axis through which geroprotectors may enhance the efficacy of NAD+ precursor supplementation and reduce the risk of age-related diseases, thereby potentiating healthspan in humans.
    30. ↑ Bertoldo MJ et al.: NAD+ Repletion Rescues Female Fertility during Reproductive Aging. Cell Rep 2020. (PMID 32049001) [PubMed] [DOI] [Full text] Reproductive aging in female mammals is an irreversible process associated with declining oocyte quality, which is the rate-limiting factor to fertility. Here, we show that this loss of oocyte quality with age accompanies declining levels of the prominent metabolic cofactor nicotinamide adenine dinucleotide (NAD+). Treatment with the NAD+ metabolic precursor nicotinamide mononucleotide (NMN) rejuvenates oocyte quality in aged animals, leading to restoration in fertility, and this can be recapitulated by transgenic overexpression of the NAD+-dependent deacylase SIRT2, though deletion of this enzyme does not impair oocyte quality. These benefits of NMN extend to the developing embryo, where supplementation reverses the adverse effect of maternal age on developmental milestones. These findings suggest that late-life restoration of NAD+ levels represents an opportunity to rescue female reproductive function in mammals.
    31. ↑ Ribeiro RFN et al.: SIRT1 activation and its circadian clock control: a promising approach against (frailty in) neurodegenerative disorders. Aging Clin Exp Res 2022. (PMID 36306110) [PubMed] [DOI] [Full text] With the increase in life expectancy, the incidence of neurodegenerative disorders and their impact worldwide has been increasing in recent years. Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, have complex and varied mechanisms of pathogenesis. Importantly, they share the common feature of disrupted circadian rhythms. This hallmark is believed to underlie the symptoms of such diseases and even potentially contribute to their onset. In addition, the association of physical frailty with dementia and neurodegenerative disorders has been demonstrated. In fact, frail persons are 8 times more likely to have some form of dementia and population studies report a significant prevalence for frailty in older patients with AD and PD. SIRT1 regulates the acetylation status of clock components and controls circadian amplitude of clock genes. However, the mechanisms responsible for this circadian clock control have been the subject of contradictory findings. Importantly, the activation of SIRT1 has been shown to have very relevant therapeutic potential against neurodegeneration. Nevertheless, few studies have attempted to connect the therapeutic reestablishing of SIRT1 as an approach against circadian disruption in neurodegenerative diseases. In this review, we address: circadian rhythms as an important early biomarker of neurodegenerative disorders; mechanisms for SIRT1 activation and the novel sirtuin-activating compounds (STACs); SIRT1 circadian paradox and subsequent studies in an unprecedented way in the literature; the beneficial role of SIRT1 activation in neurodegeneration; innovative proposals of how circadian-based interventions (e.g., SIRT1 activators) may become an important therapeutic approach against neurodegenerative disorders and how non-pharmacologic interventions (e.g., Mediterranean-style diet) might help in the prevention and/or treatment of these high-burden disorders, while tackling frailty and enhancing robustness.
    32. ↑ Song Y et al.: Sirtuin 3-dependent mitochondrial redox homeostasis protects against AGEs-induced intervertebral disc degeneration. Redox Biol 2018. (PMID 30216853) [PubMed] [DOI] [Full text] Intervertebral disc (IVD) degeneration contributes largely to pathoanatomical and degenerative changes of spinal structure that increase the risk of low back pain. Apoptosis in nucleus pulposus (NP) can aggravate IVD degeneration, and increasing studies have shown that interventions targeting NP cell apoptosis can ameliorate IVD degeneration, exhibiting their potential for use as therapeutic strategies. Recent data have shown that advanced glycation end products (AGEs) accumulate in NP tissues in parallel with the progression of IVD degeneration and form a microenvironment of oxidative stress. This study examined whether AGEs accumulation aggravates NP cell apoptosis and IVD degeneration, and explored the mechanisms underlying these effects. We observed that the viability and proliferation of human NP cells were significantly suppressed by AGEs treatment, mainly due to apoptosis. Furthermore, activation of the mitochondrial apoptosis pathway was detected after AGEs treatment. In addition, the molecular data showed that AGEs could significantly aggravate the generation of mitochondrial reactive oxygen species and prolonged activation of the mitochondrial permeability transition pore, as well as the increased level of Bax protein and decreased level of Bcl-2 protein in mitochondria. These effects could be reduced by antioxidant (2-(2,2,6,6-Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl) triphenylphosphonium chloride (MitoTEMPO) and Visomitin (SKQ1). Importantly, we identified that impairment of Sirtuin3 (SIRT3) function and the mitochondrial antioxidant network were vital mechanisms in AGEs-induced oxidative stress and secondary human NP cell apoptosis. Finally, based on findings that nicotinamide mononucleotide (NMN) could restore SIRT3 function and rescue human NP cell apoptosis through adenosine monophosphate-activated protein kinase and peroxisome proliferator-activated receptor-γ coactivator 1α (AMPK-PGC-1α) pathway in vitro, we confirmed its protective effect on AGEs-induced IVD degeneration in vivo. In conclusion, our data demonstrate that SIRT3 protects against AGEs-induced human NP cell apoptosis and IVD degeneration. Targeting SIRT3 to improve mitochondrial redox homeostasis may represent a potential therapeutic strategy for attenuating AGEs-associated IVD degeneration.
    33. ↑ Covarrubias AJ et al.: NAD+ metabolism and its roles in cellular processes during ageing. Nat Rev Mol Cell Biol 2021. (PMID 33353981) [PubMed] [DOI] [Full text] Nicotinamide adenine dinucleotide (NAD+) is a coenzyme for redox reactions, making it central to energy metabolism. NAD+ is also an essential cofactor for non-redox NAD+-dependent enzymes, including sirtuins, CD38 and poly(ADP-ribose) polymerases. NAD+ can directly and indirectly influence many key cellular functions, including metabolic pathways, DNA repair, chromatin remodelling, cellular senescence and immune cell function. These cellular processes and functions are critical for maintaining tissue and metabolic homeostasis and for healthy ageing. Remarkably, ageing is accompanied by a gradual decline in tissue and cellular NAD+ levels in multiple model organisms, including rodents and humans. This decline in NAD+ levels is linked causally to numerous ageing-associated diseases, including cognitive decline, cancer, metabolic disease, sarcopenia and frailty. Many of these ageing-associated diseases can be slowed down and even reversed by restoring NAD+ levels. Therefore, targeting NAD+ metabolism has emerged as a potential therapeutic approach to ameliorate ageing-related disease, and extend the human healthspan and lifespan. However, much remains to be learnt about how NAD+ influences human health and ageing biology. This includes a deeper understanding of the molecular mechanisms that regulate NAD+ levels, how to effectively restore NAD+ levels during ageing, whether doing so is safe and whether NAD+ repletion will have beneficial effects in ageing humans.
    34. ↑ Ito N et al.: Slc12a8 in the lateral hypothalamus maintains energy metabolism and skeletal muscle functions during aging. Cell Rep 2022. (PMID 35905718) [PubMed] [DOI] Sarcopenia and frailty are urgent socio-economic problems worldwide. Here we demonstrate a functional connection between the lateral hypothalamus (LH) and skeletal muscle through Slc12a8, a recently identified nicotinamide mononucleotide transporter, and its relationship to sarcopenia and frailty. Slc12a8-expressing cells are mainly localized in the LH. LH-specific knockdown of Slc12a8 in young mice decreases activity-dependent energy and carbohydrate expenditure and skeletal muscle functions, including muscle mass, muscle force, intramuscular glycolysis, and protein synthesis. LH-specific Slc12a8 knockdown also decreases sympathetic nerve signals at neuromuscular junctions and β2-adrenergic receptors in skeletal muscle, indicating the importance of the LH-sympathetic nerve-β2-adrenergic receptor axis. LH-specific overexpression of Slc12a8 in aged mice significantly ameliorates age-associated decreases in energy expenditure and skeletal muscle functions. Our results highlight an important role of Slc12a8 in the LH for regulation of whole-body metabolism and skeletal muscle functions and provide insights into the pathogenesis of sarcopenia and frailty during aging.
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