Contents
Why stop taking NMN
Amazon removing NMN dietary supplements, citing FDA actions NMN, or nicotinamide mononucleotide, is one of the forms of vitamin B3, or niacin, that has been shown to enhance the levels of the coenzyme nicotinamide adenine dinucleotide (NAD+) in the cells of the body.
- Boosting these levels has in turn demonstrated significant benefits in staving off cellular senescence.
- that NMN is not allowed as a dietary ingredient because of its prior investigation as a drug.
- The agency made this determination after having been made aware of recent drug studies on the ingredient.
This reportedly came while doing due diligence on a recent New Dietary Ingredient Notification. In an email from the Amazon Restricted Products team to sellers, shared with NutraIngredients-USA on Thursday, the e-tailer stated: “On November 4, 2022, the Food and Drug Administration (FDA) announced that NMN is no longer considered a dietary supplement.
It is now considered a drug, or drug ingredient, that requires FDA approval. Products that contain NMN as an ingredient can no longer be sold or distributed as a dietary supplement by manufacturers or retailers in the United States. If you want to sell NMN on Amazon, you must show that you are approved by the FDA for over-the-counter sales.” Amazon confirmed that sellers may continue to offer NMN-containing products until March 13, 2023.
The retailer added: “If you do not submit a removal order for impacted ASINs within 30 days of receiving a removal notice, we may dispose of this unsellable inventory in accordance with the Service Terms and policies applicable to your listings. You won’t be able to cancel a required removal order once Amazon creates it.”
What are the problems with taking NMN?
Potential Risks and Side Effects of NMN – “NMN is generally considered safe, and no major side effects have been reported in humans,” says Sabat. “, since NMN is a relatively new supplement, long-term safety data is limited, and it’s always advisable to consult with a health care professional before starting any new supplement.” One small 2021 study in Frontiers in Nutrition observed 30 participants taking either 250 milligrams of NMN or a placebo daily for 12 weeks and concluded that NMN users may experience mild side effects including abdominal pain, diarrhea, gas and upper respiratory health issues Okabe K, Yaku K, Uchida Y, et al.
Is NMN banned in Europe
NMN is yet to be legalised as a supplement in the European Union, but retailers are permitted to sell it as a chemical for research and laboratory use.
Does NMN damage liver?
Nicotinamide Mononucleotide Is Safely Metabolized and Significantly Reduces Blood Triglyceride Levels in Healthy Individuals Monitoring Editor: Alexander Muacevic and John R Adler 1 Environmental Science, StateArt Incorporated, Tokyo, JPN Find articles by 2 Gene Therapy, StateArt Incorporated, Tokyo, JPN Find articles by 3 Anti-Aging, StateArt Incorporated, Tokyo, JPN Find articles by 4 Agriculture, StateArt Incorporated, Tokyo, JPN Find articles by 5 Biochemistry, StateArt Incorporated, Tokyo, JPN Find articles by 6 Basic Medicine, StateArt Incorporated, Tokyo, JPN Find articles by 7 Gene Therapy, Joint-Use Research Facilities, Hyogo Medical University, Nishinomiya, JPN Find articles by 8 Gene Therapy, Department of Education for Medical Research Base, Hyogo Medical University, Nishinomiya, JPN Find articles by
1 Environmental Science, StateArt Incorporated, Tokyo, JPN 2 Gene Therapy, StateArt Incorporated, Tokyo, JPN 3 Anti-Aging, StateArt Incorporated, Tokyo, JPN 4 Agriculture, StateArt Incorporated, Tokyo, JPN 5 Biochemistry, StateArt Incorporated, Tokyo, JPN 6 Basic Medicine, StateArt Incorporated, Tokyo, JPN 7 Gene Therapy, Joint-Use Research Facilities, Hyogo Medical University, Nishinomiya, JPN 8 Gene Therapy, Department of Education for Medical Research Base, Hyogo Medical University, Nishinomiya, JPN Corresponding author.
Shintarou Kimura © 2022, Kimura et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
An increase in nicotinamide adenine dinucleotide (NAD + ) levels alleviates age-related disease progression and promotes healthy life expectancy. Several studies have demonstrated that NAD + levels can be efficiently replenished via nicotinamide mononucleotide (NMN) intake; additionally, the safety of its oral ingestion has been confirmed in recent clinical trials.
NMN: Why Dr. Brad Stanfield Stopped Taking NMN & My Response
However, the efficacy and safety of intravenous NMN administration in humans remain unclear. Therefore, we verified its safety in 10 healthy volunteers. Intravenous administration of NMN did not affect electrocardiograms, pulse, and blood pressure, nor did it affect metabolic markers in the liver, heart, pancreas, and kidneys.
These results indicate that intravenous NMN administration is safe and beneficial in humans. Furthermore, NMN administration significantly increased blood NAD + levels without damaging blood cells and significantly reduced blood triglyceride (TG) levels. These findings imply that intravenous administration of NMN may lead to the prevention and treatment of diseases associated with increased TG levels, such as fatty liver and diabetes.
Keywords: anti-aging, obesity, sirtuin 1, triglyceride, nicotinamide adenine dinucleotide, nicotinamide mononucleotide The risk of type II diabetes mellitus, Alzheimer-type dementia, and cardiomegaly increases with age ; therefore, the suppression of aging is sought after to prevent aging-related disorders.
For this purpose, the use of nicotinamide (NAM) adenine dinucleotide (NAD + ) is attracting attention, NAD + works as a substrate for sirtuins, poly (ADP-ribose) polymerases (PARP), and cluster of differentiation 38 (CD38), Although NAD + is digested by these enzymes to produce NAM, NAM is acted upon by nicotinamide phosphoribosyltransferase (NAMPT) and converted to nicotinamide mononucleotide (NMN) so that NAD + is resynthesized via the salvage pathway,
NAMPT is the rate-limiting enzyme in NAD + synthesis, and its expression decreases with age, Therefore, in recent years, NMNs have attracted attention as NAD + precursors. In a recent study, Mills et al. orally administered 300 mg/kg NMN to 5-17 month-old mice for one year, which resulted in a 9% weight loss despite higher dietary intake than that in the control group; they found that not only was the aging-related increase in cholesterol level suppressed but there were also no significant changes in aging-related gene expression in the skeletal muscle, liver, and fat,
Recently, this group conducted clinical trials on oral administration of NMN in healthy individuals, demonstrating that NMN is safely metabolized in the blood without affecting glucose metabolism, lipid metabolism, liver, kidneys, and leukocytes, Based on their research reports, several clinics in Japan have begun to offer intravenous administration of NMN as a preventive measure against aging; although the safety of transient oral administration of NMN has been proven in humans, that of intravenous administration has not been confirmed.
Intravenous administration poses a higher risk of damage to major organs, such as the heart, pancreas, and kidneys than oral administration, because the nutrients and drugs administered circulate directly in the blood without going through the first-pass effect of the liver, the centre of detoxification.
- However, based on the findings of these studies, we speculated that NMN could be safely administered intravenously, as it is a metabolite produced in the body,
- In addition, in previous studies, no adverse events were observed with the intravenous administration of NAD + to humans,
- Mammalian cells import NAD + precursors for intracellular NAD + synthesis, as NAD + cannot cross the plasma membrane via passive diffusion because of its hydrophilicity, positive charge, and molecular size.
Consequently, using NAD +, which cannot penetrate the cell membrane, is unsuitable as no dedicated transporter has been identified in mammals. Therefore, NAD + is degraded into extracellular NAD + -consuming enzymes, such as CD38, CD73, and CD153, and then intracellularly incorporated into the cell with a transporter specific for NAD + precursors,
It has been suggested that NAM produced by the degradation of NAD+ through CD38 is synthesized into NMN by extracellular NAMPT and incorporated intracellularly, Therefore, we decided to investigate whether NMN is safely metabolized in humans after transient intravenous administration and is capable of increasing intracellular NAD + levels.
NAD + has been studied as a coenzyme required for activation of the sirtuin protein family members, which have an anti-aging function, Among the members of the sirtuin family, sirtuin 1 (SIRT1) has been studied as a factor that directly prevents aging via glucose metabolism, insulin secretion, lipid metabolism, angiogenesis, and elimination of reactive oxygen species (ROS),
Therefore, we evaluated NAD+ and SIRT1 activities in blood cells after the intravenous administration of NMN. Study population The administration was done starting from May 31, 2021, sample collection was conducted from June to July 2021, and data analysis was completed on September 30, 2021. NMN was purchased from Nordeste (Tokyo, Japan).
We conducted an open-label, single-arm exploratory study on 10 healthy individuals (Figure ), including five males and five females (age, 20-70 years), recruited from the Tokyo Tsukishima Clinic. This study was approved by the Japanese Organization for Safety Assessment of Clinical Research (#20210623-02; 23/06/2021) and registered with the University Hospital Medical Information Network (UMIN; Japan) (UMIN-ID: UMIN000047134; 09/03/2022).
- This article was previously posted to the Research Square preprint server on January 31, 2022 ().
- The subjects provided written informed consent before starting the clinical trial.
- The present study was conducted in accordance with the Declaration of Helsinki and Ethical Guidelines for Medical and Health Research Involving Human Subjects set by the Japanese Ministry of Health, Labor, and Welfare.
Individuals with a history of disease diagnosis, malignant neoplasms, serious infections, psychiatric disorders, ophthalmic disorders, allergic disorders, and metabolic disorders were excluded from the study. Flow diagram of the clinical trial. The subjects fasted for 12 h before intravenous administration of NMN until the end of the clinical trial but were provided free hydration.
Intravenous drip infusion was performed at 5 mL/min by dissolving 300 mg of NMN in 100 mL of saline and inserting an extension tube through a vein in the middle of the arm. The weights of the subjects were measured, and chest radiographs were obtained before and after the intravenous administration of NMN.
General disorders and administration site conditions were diagnosed by a physician, according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0-Japan Clinical Oncology Group (JCOG), before and after the intravenous administration of NMN.
- Body temperature, blood pressure, pulse, and oxygen saturation were measured at 0.5, 1, 2, 3, and 5 h before and after the intravenous administration of NMN, and blood was collected concomitantly.
- Blood collection tubes containing EDTA-2Na (ethylenediaminetetraacetic acid disodium; Falco Biosystems, Kyoto, Japan) were used to obtain 17 mL of blood samples, and 12 mL of the collected blood was sent to Falco Biosystems for hematological analysis.
The remaining blood was stored at −80 °C and used to measure blood NAD + levels and SIRT1 activation. Urine was collected 1, 3, and 5 h before and after the intravenous administration of NMN to the subjects; urinary urobilinogen, protein, glucose, pH, and occult blood levels were measured at the Tokyo Tsukishima Clinic.
- NAD + /NADH assay The amounts of NAD + and NADH in blood cells were assessed using the NAD/NADH Assay Kit-WST (Dojindo Laboratories, Kumamoto, Japan).
- Briefly, a 20 µL blood sample was dissolved in 300 µL extraction buffer, and 250 µL of the sample extract was transferred to an MWCO 10 K filtration tube for ultrafiltration.
The obtained filtrate was transferred to two new Eppendorf tubes (100 µL each), one of which was incubated at 60 °C for 1 h. The unheated sample was used as the total NAD + sample, and the heated sample was used as the NADH sample. The absorbance of these samples was measured at 450 nm using a Varioskan plate reader (Thermo Fisher Scientific, Yokohama, Japan).
- The amount of NAD + was calculated by subtracting the amount of NADH from the amount of total NAD +,
- SIRT1 assay Nuclear proteins were extracted from blood cells using the LysoPureTM Nuclear and Cytoplasmic Extractor Kit (FUJIFILM Wako Pure Chemical Corporation, Osaka, Japan).
- Briefly, 500 µL of blood was added to 500 µL of initial buffer, incubated on ice for 10 min, vortexed, and centrifuged at 500 × g for 10 min at 4 °C.
The supernatant was transferred to a new Eppendorf tube as a cytosolic fraction; buffer 1 was added to the pellet again, and the pellet was vortexed and centrifuged at 500 × g for 10 min at 4 °C. The supernatant was discarded, and 250 µL of buffer 2 was added, after which the mixture was vortexed and then incubated on ice for 30 min.
- The supernatant was collected as a nuclear extraction fraction after centrifugation at 2000 × g for 10 min at 4 °C.
- The cytoplasmic and nuclear fractions were evaluated for SIRT1 activation using CycLex® SIRT1/Sir2 Deacetylase Fluorometric Assay Kit Ver.2 (Medical & Biological Laboratories, Aichi, Japan).
Briefly, 25 µL distilled water, 5 µL SIRT1 assay buffer, 5 µL fluoro-substrate peptide, and 5 µL developer were added to a 50 µL nuclear extraction and cytosol fraction samples, in this order, mixed well, and the reaction was initiated by adding 50 µL enzyme sample following incubation at 37 °C for 30 min before quenching the reaction using 20 µL stop solution.
- The prepared samples were analyzed using a Fluoroskan microplate fluorometer (Thermo Fisher Scientific, Japan) at an excitation wavelength of 350 nm and an emission wavelength of 450 nm to detect SIRT1 activity.
- Quantitative reverse transcription polymerase chain reaction (RT-qPCR) analysis of NAMPT, NANOG, and p16 RNA was extracted from 250 µL of whole blood using RNAiso (Takara, Otsu, Japan).
The Thunderbird SYBR qPCR/RT Set (Toyobo, Osaka, Japan) was used for reverse transcription and RT-qPCR. RT-qPCR was performed using the StepOnePlus™ real-time PCR system (Applied Biosystems, Foster City, CA, USA). The sequences of the primers used are listed in Table,
For positive control, qPCR Human Reference cDNA and Total RNA (Takara, Otsu, Japan) was used. The cycling conditions were as follows: initial denaturation at 95 °C for 20 s, followed by 40 cycles of denaturation at 95 °C for 5 s, and annealing and elongation at 0 °C for 20 s. Melting curves were measured at 95 °C for 15 s, 60 °C for 1 min, and 95 °C for 15 s.
The results obtained were quantified using the standard method and corrected with actin beta (ACTB) expression. RT-qPCR primer sequences RT-qPCR: Quantitative reverse transcription polymerase chain reaction; NAMPT: Nicotinamide phosphoribosyltransferase
Gene | Forward | Reverse | Reference |
NAMPT | 5′-GCCAGCAGGGAATTTTGTTA-3′ | 5′-TGATGTGCTGCTTCCAGTTC-3′ | |
NANOG | 5′-CATGAGTGTGGATCCAGCTTG-3′ | 5′-CCTGAATAAGCAGATCCATGG-3′ | |
p16 | 5′-CTGTCCTGCGTGTTGAAAGA-3′ | 5′-TTGGGTAATTTTTGGGATCTACA-3′ |
Statistical analysis All results are expressed as mean ± standard deviation. Statistically significant differences between RT-qPCR were analyzed using Student’s t-test, and other statistically significant differences were analyzed using a one-way analysis of variance (ANOVA) with Bonferroni’s post-hoc test using the add-in software Statcel4 (Version 4.0; OMS Publishing, Inc., Tokorozawa, Japan). The significance levels were set at *p < 0.05 and **p < 0.01. Analysis performed by a physician indicated that there were no abnormalities or general disorders in administration site conditions, urinalysis, electrocardiograms, and chest radiographs before and after the intravenous administration of NMN (Tables -). There were no significant changes in body weight or body mass index before and 5 h after the intravenous administration of NMN. Demographic and clinical characteristics of healthy individuals after the intravenous administration of NMN. The results are expressed as mean ± standard deviation (n = 10). NMN: Nicotinamide mononucleotide.
Variable | Pre-treatment | Post-treatment |
Age (years) | 43.4 (±12.6) | 43.4 (±12.6) |
Weight (kg) | 66.1 (±9.6) | 65.7 (±9.6) |
Body mass index (kg/m 2 ) | 24.4 (±3.5) | 24.3 (±3.4) |
Electrocardiogram | Normal | Normal |
Chest X-ray | Normal | Normal |
Physician toxicity evaluation according to CTCAE v5.0-JCOG after NMN treatment. Results are expressed as mean ± standard deviation (n = 10). NMN: Nicotinamide mononucleotide. CTCAE: Common Terminology Criteria for Adverse Events; JCOG: Japan Clinical Oncology Group
Characteristics | Pretreatment | Post-treatment |
Chills | 0 (±0) | 0 (±0) |
Edema face | 0 (±0) | 0 (±0) |
Fatigue | 0 (±0) | 0 (±0) |
Gait disturbance | 0 (±0) | 0 (±0) |
Infusion site extravasation | 0 (±0) | 0 (±0) |
Injection site reaction | 0 (±0) | 0 (±0) |
Malaise | 0 (±0) | 0 (±0) |
Pain | 0 (±0) | 0 (±0) |
Characteristics of subjects after NMN treatment for urinalysis. Results are expressed as mean ± standard deviation (n = 10). NMN: Nicotinamide mononucleotide.
Test item | Baseline | 1 h | 3 h | 5 h |
Urobilinogen | Normal | Normal | Normal | Normal |
Proteins | Negative | Negative | Negative | Negative |
Glucose | Negative | Negative | Negative | Negative |
pH | 6.00 (±0.77) | 6.60 (±0.66) | 6.70 (±0.64) | 6.50 (±0.67) |
Occult blood | Negative | Negative | Negative | Negative |
Analyses of body temperature, systolic blood pressure, diastolic blood pressure, pulse, and oxygen saturation at 0.5, 1, 2, 3, and 5 h after the intravenous injection of NMN showed no significant differences in all parameters before and after administration (Figures -). No significant effects on plasma protein levels and glucose metabolism were observed at 0.5, 1, 2, 3, and 5 h after the intravenous administration of NMN (Figures -). Although LDL, HDL, and total cholesterol levels did not significantly differ before and 0.5, 1, 2, 3, and 5 h after the intravenous administration of NMN (Figures -), triglyceride (TG) levels decreased significantly from 0.5 to 5 h after administration, and after 5 h, there was a slight tendency to return to the level before administration, notwithstanding a significant difference (Figure ). Changes in clinical parameters and sugar, lipid, and protein metabolism markers due to intravenous administration of NMN. (a) Body temperature, (b) blood pressure, (c) pulse, and (d) SpO2 were measured before and 0.5, 1, 2, 3, and 5 h after intravenous administration of NMN. Protein metabolism was evaluated in the plasma before and after the intravenous NMN administration based on (e) TP, (f) ALB, and (g) A/G; glucose metabolism was evaluated based on (h) BS and (i) HbA1c; lipid metabolism was evaluated based on (j) TG, (k) TC, (l) LDL, and (m) HDL. Data were analyzed via a one-way analysis of variance with Bonferroni’s post-test and expressed as mean ± standard deviation (n = 10, ** p < 0.01). NMN: Nicotinamide mononucleotide; TP: Total protein; ALB: Albumin; BS: Blood sugar; HbA1c: Hemoglobin A1C; TG: Triglyceride; TC: Total cholesterol; LDL: Low-density lipoprotein; HDL: High-density lipoprotein; SpO2: Oxygen saturation We investigated the pharmacokinetics specific to metabolic markers of the liver, heart, pancreas, and kidneys after the intravenous administration of NMN because drugs administered intravenously can rapidly reach organs throughout the body and may burden specific organs even if the substances are safe for oral administration. Liver-, pancreas-, heart-, and kidney-related metabolism marker levels in the plasma measured 0.5, 1, 2, 3, and 5 h after the intravenous injection of NMN showed no significant differences when compared to those before administration (Figure ). Furthermore, analyses of red blood cells, white blood cells, platelets, and related markers in the blood showed no significant changes before and at 0.5, 1, 2, 3, and 5 h after the intravenous administration of NMN (Figure ). Effects of intravenous NMN administration on metabolic markers of liver, pancreas, heart, and kidney. Levels of metabolic markers of the liver, pancreas, heart, and kidney were measured in plasma obtained from subjects before and at 0.5, 1, 2, 3, and 5 h after intravenous NMN administration. The effects of the intravenous NMN administration on liver metabolism were evaluated via (a) T-Bill, (b) I-Bill, (c) D-Bill, (d) AST, (e) ALT, (f) ALP, (g) γ-GT, (h) Ch-E, and (i) LD; pancreatic metabolism was evaluated based on (j) AMY; cardiac metabolism was observed based on (k) CK and (l) CK-MB; renal metabolism was evaluated based on (m) UN, (n) UA, (o) eGFR, and (p) CRE. The results are expressed as mean ± standard deviation (n = 10). NMN: Nicotinamide mononucleotide; T-Bill: Total bilirubin; I-Bill: Indirect bilirubin; D-Bill: Direct bilirubin; AST: Aspartate transaminase; ALT: Alanine aminotransferase; ALP: Alanine phosphotransferase; γ-GT: Gamma-glutamyl transferase; LD: Lactate dehydrogenase; Ch-E: Cholinesterase; AMY: Amylase; CK: Creatine kinase; CK-MB: CK myocardial band; UN: Urea nitrogen; CRE: Creatinine; UA: Urinalysis; eGFR: Estimated glomerular filtration rate Effects of intravenous NMN administration on immune marker levels and blood cells. Immune markers (a) IgA and (b) CRP were measured in plasma obtained from patients before and 0.5, 1, 2, 3, and 5 h after the intravenous NMN administration. Blood cells, red blood cell markers, and leukocyte fractions were analyzed in blood obtained from patients before and 0.5, 1, 2, 3, and 5 h after the intravenous NMN administration. The damage to blood cells was measured based on the number of (c) RBC, (d) WBC, and (e) PLT; the effect of NMN administration on erythrocytes was observed based on (f) MCV, (g) MCH, (h) MCHC, and (i) RET; the effect of NMN administration on the leukocyte fraction was observed in (j) Neut, (k) Eosin, (l) Mono, (m) Basso, and (n) Lymph. The results are expressed as mean ± standard deviation (n = 10). NMN: Nicotinamide mononucleotide; IgA: Immunoglobulin A; CRP: C-reactive protein; RBC: Red blood cell; WBC: White blood cell; PLT: Platelet; MCV: Mean corpuscular volume; MCH: Mean corpuscular hemoglobin; MCHC: Mean corpuscular hemoglobin concentration; RET: Reticulocyte; Neut: Neutrophil; Eosin: Eosinophil; Mono: Monocyte; Basso: Basophil; Lymph: Lymphocyte Next, the total amount of NAD + and NADH, and the ratio of NAD + to NADH in the blood were measured to determine whether intravenously administered NMN could efficiently increase the amount of NAD + in blood cells (Figure ). NAD+/NADH blood levels measured 0.5, 1, 2, 3, and 5 h after the intravenous NMN administration showed a significant increase in NAD + levels from 0.5 to 3 h compared to those before administration (Figure ) and a significant increase in total NAD + level except 4 h after administration (Figure ). In contrast, NADH levels and the NAD + /NADH ratio could not be measured accurately because the measured NADH values varied considerably (Figures, ). Effect of NMN administration on increased NAD+ level and SIRT1 activation. The amount of NAD+ and the activity of SIRT were measured in blood obtained from patients before and 0.5, 1, 2, 3, and 5 h after intravenous administration of NMN (a-f). NAD+-consuming enzyme-related genes were measured in blood cells before and 5 h after the intravenous administration of NMN (g). The results were analyzed via a one-way analysis of variance with Bonferroni's post-test and are expressed as mean ± standard deviation (n = 10, * p < 0.05, ** p < 0.01). NMN: Nicotinamide mononucleotide; NAD+: Nicotinamide adenine dinucleotide; NADH: Reduced nicotinamide adenine dinucleotide; SIRT1: Sirtuin 1 To suppress aging, NAD + should be utilized by sirtuin family proteins as a coenzyme during an increase in its levels ; therefore, we sought to determine whether SIRT1, which is considered to be particularly important for aging, is activated via intravenous administration of NMN. The activation of nuclear SIRT1 also increased, similar to the trend of NAD + synthesis, after the intravenous NMN administration (Figure ); however, no significant difference was observed because of the large variation in the measured values. Cytosolic SIRT1 activation showed almost no change before and after the intravenous administration of NMN (Figure ). Genes transcriptionally regulated by SIRT1, PARP1, and CD38 activation in blood cells were analyzed via RT-qPCR before and 5 h after the intravenous administration of NAD + (Figure ). In the present study, of all the genes whose mRNA transcription was altered via SIRT1 activation, NAMPT was selected. The mRNA expression of NAMPT was significantly increased after the intravenous administration of NMN. NANOG was selected from the list of genes whose transcription is altered via PARP1 activation. The mRNA expression of NANOG did not change before or after the intravenous administration of NMN. p16 was selected from the list of genes whose transcription is altered via activation of CD38. The mRNA expression of p16 was significantly reduced after the administration of NMN compared with that before the intravenous administration of NMN. NMN, which is a precursor of NAD +, has been proven to increase NAD + levels via uptake into the body in both rodents and humans, Although NMN has been studied using various administration methods, such as oral, intraperitoneal injection, and intravenous injection, to enhance NAD + synthesis, the efficacy and safety of intravenous administration in humans have not been verified. Our study showed that a single intravenous dose of 300 mg of NMN enhanced NAD + activity in blood cells without affecting the levels of erythrocytes, leukocytes, and platelets, nor those of major markers in the liver, heart, pancreas, and kidneys. Unexpectedly, TG levels were significantly reduced after the intravenous administration of NMN without affecting low-density lipoprotein (LDL) levels in the blood. No reduction in TG levels was observed in previous clinical trials upon oral administration of NMN, suggesting that NMN may be metabolized via different pathways when administered orally and intravenously. This is thought to be caused by NMN being metabolized in cells throughout the body by avoiding the first passage through the liver via intravenous administration. A previous study reported that the increase in TG levels in the plasma and liver of mice deficient in adipocyte-specific NAMPT1, an enzyme that synthesizes NMN from NAM, indicates that increased intracellular NMN synthesis plays a critical role in decreasing TG levels, We hypothesize that the SIRT1 activated by NAD + synthesized via NAMPT in adipocytes regulates adiponectin expression through deacetylation of PPARγ (peroxisome proliferator-activated receptor gamma) (Figure ). Adiponectin in adipocytes reduces the amount of free fatty acids (FFAs) released into the blood; subsequently, FFAs in the blood are taken up by the liver, and TG is synthesized, The activation of PPARγ by NAMPT leads to the suppression of TG synthesis in the blood. The markedly elevated mRNA expression of NAMPT in blood cells in the present study suggests that similar phenomena may occur in adipocytes. It is extremely difficult to conclude that there was no change in blood cholesterol levels in the present study. The blood clearance of LDL requires the enhanced expression of LDL receptors on the cell membrane surface, LDL protein expression might not have increased 5 h after the intravenous administration of NMN. Since the decrease in TG levels due to the intravenous administration of NMN is a very interesting phenomenon, we would like to investigate the detailed mechanism by conducting cell experiments in the future, including its relationship with LDL and HDL. Schematic showing the mechanism of NMN metabolism. CD38: Cluster of differentiation 38; NAD: Nicotinamide adenine dinucleotide; NAM: Nicotinamide; NAMPT: Nicotinamide phosphoribosyltransferase; NMN: Nicotinamide mononucleotide; NMNAT: Nicotinamide mononucleotide adenylyltransferase; SIRT1: Sirtuin 1 Increased intracellular NAD + levels lead to SIRT1 activation, but an increase in nuclear SIRT1 expression required the same time as that for NAD + expression, with no significant difference observed in the present study. This might have been because SIRT1 was already moderately activated, as the study was performed under fasting conditions (12 h before administration of NMN). We analyzed the genes whose expression was altered owing to SIRT1, PARP1, and CD38 activation since NAD + is involved in activating CD38 and PARPs in addition to sirtuins, Expectedly, the mRNA expression of NAMPT was increased in the blood cells after the intravenous administration of NMN. Therefore, we hypothesize that AMPK (AMP-activated protein kinase) is activated by SIRT1 via LKB1 deacetylation and that the intravenous administration of NMN increased the mRNA expression of NAMPT via this pathway. The expression of pluripotent stem cell markers, such as NANOG, is regulated by PARP1, No large fluctuations in the expression of the NANOG gene were observed, suggesting that PARP1 was not significantly activated even after the intravenous administration of NMN. Aging marker genes, such as p16, are regulated by CD38, The mRNA expression of p16 in blood cells was reduced by intravenous administration of NMN; thus, it is suggested that CD38 may not be activated. In addition, p16 is known as a marker gene that upregulates not only aging but also DNA damage, suggesting that intravenous administration of NMN is safe. To accurately determine whether the marker gene levels investigated this time were altered by the activation of SIRT1, PARP, and CD38, it is necessary to investigate the activation of PARP, CD38, and SIRT1 in the future. Our clinical study demonstrated that 300 mg NMN administration is tolerated by humans because it does not cause significant damage to blood cells, the liver, pancreas, heart, and kidneys when injected intravenously and effectively increases the amount of NAD+ in blood cells. Furthermore, the increase in intracellular and plasma levels of NAD+ and NAD+ metabolites, such as methyl nicotinamide (MNA), N-methyl-2-pyridone-5-carboxamide (2Py), and N-methyl-4-pyridone-5-carboxamide (4Py), by intravenous administration of NMN should be examined by precise analysis using liquid chromatography-mass spectrometry (LC-MS). In addition, the feasibility of intravenous administration of 300 mg NMN suggests that NAMPT may be activated and TG levels may be suppressed, which may help improve obesity and prevent aging. Since NAMPT levels are increased by intravenous administration of NMN, it is expected that NAD may be continuously synthesized via the salvage pathway with a single administration. Further studies should examine the effects of LDL and HDL as well as blood TG on long-term intravenous administration of NMN and the relationship between changes in these values and body weight and body fat percentage. We would like to express our gratitude to the doctors, nurses, and staff of the Tokyo Tsukishima Clinic for their cooperation in this clinical study. The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. The authors have declared financial relationships, which are detailed in the next section. Shintarou Kimura, Misa Ichikawa, Suzuka Sugawara Tomoko Katagiri, Yumi Hirasawa, Takahiro Ishikawa declare(s) employment from StateArt Inc. SK, MI, SS, TK, YH, and TI are employed as researchers at StateArt Inc. WM and AG have no conflicts of interest. Consent was obtained or waived by all participants in this study. Japanese Organization for Safety Assessment of Clinical Research issued approval 20210623-02. This study was approved by the Japanese Organization for Safety Assessment of Clinical Research (#20210623-02; 23/06/2021) and registered with the University Hospital Medical Information Network (UMIN; Japan) (UMIN-ID: UMIN000047134; 09/03/2022) Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue.1. The role of cellular senescence in ageing and endocrine disease. Khosla S, Farr JN, Tchkonia T, Kirkland JL. Nat Rev Endocrinol.2020; 16 :263–275.2. Cellular senescence in aging and age-related diseases: Implications for neurodegenerative diseases. Wissler Gerdes EO, Zhu Y, Weigand BM, Tripathi U, Burns TC, Tchkonia T, Kirkland JL. Int Rev Neurobiol.2020; 155 :203–234.3. Cardiac aging: from basic research to therapeutics. Yan M, Sun S, Xu K, et al. Oxid Med Cell Longev.2021; 2021 :9570325.4. NAD+ metabolism and its roles in cellular processes during ageing. Covarrubias AJ, Perrone R, Grozio A, Verdin E. 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Characterization of recombinant human nicotinamide mononucleotide adenylyl transferase (NMNAT), a nuclear enzyme essential for NAD synthesis. Schweiger M, Hennig K, Lerner F, et al. FEBS Lett.2001; 492 :95–100.12. A pilot study investigating changes in the human plasma and urine NAD+ metabolome during a 6 hour intravenous infusion of NAD. Grant R, Berg J, Mestayer R, Braidy N, Bennett J, Broom S, Watson J. Front Aging Neurosci.2019; 11 :257.13. Syntheses of nicotinamide riboside and derivatives: effective agents for increasing nicotinamide adenine dinucleotide concentrations in mammalian cells. Yang T, Chan NY, Sauve AA. J Med Chem.2007; 50 :6458–6461.14. Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds. Bonkowski MS, Sinclair DA. Nat Rev Mol Cell Biol.2016; 17 :679–690.15. Sirtuins as potential targets for metabolic syndrome. Guarente L. Nature.2006; 444 :868–874.16. Silencing insulin resistance through SIRT1. Zabolotny JM, Kim YB. Cell Metab.2007; 6 :247–249.17. Sirtuin 1 in lipid metabolism and obesity. Schug TT, Li X. Ann Med.2011; 43 :198–211.18. SIRT1 controls endothelial angiogenic functions during vascular growth. Potente M, Ghaeni L, Baldessari D, et al. Genes Dev.2007; 21 :2644–2658.19. Crosstalk between oxidative stress and SIRT1: impact on the aging process. Salminen A, Kaarniranta K, Kauppinen A. Int J Mol Sci.2013; 14 :3834–3859.20. NAD+ metabolism governs the proinflammatory senescence-associated secretome. Nacarelli T, Lau L, Fukumoto T, et al. Nat Cell Biol.2019; 21 :397–407.21. Downregulation of PARP1 transcription by promoter-associated E2F4-RBL2-HDAC1-BRM complex contributes to repression of pluripotency stem cell factors in human monocytes. Wiśnik E, Płoszaj T, Robaszkiewicz A. Sci Rep.2017; 7 :9483.22. Downregulation of cytoplasmic DNases is implicated in cytoplasmic DNA accumulation and SASP in senescent cells. Takahashi A, Loo TM, Okada R, et al. Nat Commun.2018; 9 :1249.23. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Yoshino M, Yoshino J, Kayser BD, et al. Science.2021; 372 :1224–1229.24. NAMPT-mediated NAD(+) biosynthesis in adipocytes regulates adipose tissue function and multi-organ insulin sensitivity in mice. Stromsdorfer KL, Yamaguchi S, Yoon MJ, et al. Cell Rep.2016; 16 :1851–1860.25. Niacin, an old drug with a new twist. Song WL, FitzGerald GA. J Lipid Res.2013; 54 :2586–2594.26. The mammalian low-density lipoprotein receptor family. Hussain MM, Strickland DK, Bakillah A. Annu Rev Nutr.1999; 19 :141–172.27. CD38 deficiency alleviates D-galactose-induced myocardial cell senescence through NAD+/Sirt1 signaling pathway. Wang LF, Cao Q, Wen K, et al. Front Physiol.2019; 10 :1125. : Nicotinamide Mononucleotide Is Safely Metabolized and Significantly Reduces Blood Triglyceride Levels in Healthy Individuals
Can you take NMN long term?
Long-Term NMN Safety Trials Are Required – The bottom line is that, to date, no single study of NMN’s safety has shown that the compound has any adverse effects when it comes to humans’ blood chemistry or cardiovascular health. Not only that, but NMN has been shown to improve muscle function, immunity, and metabolism.
How long should NMN be taken
What NMN Doses Have Been Used in Human Studies? – A research team from Japan ran a human clinical study testing the safety of oral doses of NMN up to 500 mg and found no alterations in physiological measurements like heart rate or blood pressure. Results from this study support that one NMN dose of up to 500 mg is safe and well-tolerated.
A study from scientists at the Washington University School of Medicine in St. Louis showed that oral 250 mg doses per day of NMN for 10 weeks improves older women’s muscle insulin sensitivity and structure, These findings show that more affordable NMN doses of 250 mg per day can be safe and effective in improving muscle insulin sensitivity.
Another study from the University of Tokyo has shown that 250 mg per day oral doses of NMN for 12 weeks improves muscle function in men over age 65, NMN supplementation improved walking speed, the ability to rise from a chair, and grip strength in the aged men.
Is it OK to take NMN everyday
Is NMN safe, and does it have side effects? NMN is an ideal supplement to increase cellular levels of NAD because it’s well-tolerated, and both human and animal studies have observed it had minimal side effects. Research in humans has shown that doses of up to 1,200 mg daily are safe to consume.
How long will NMN be banned?
Following recent FDA ruling, Restricted Products Team of online retail giant issues notice to NMN sellers. – Back in November, we covered the news that the FDA had ruled that the popular longevity supplement ingredient beta-nicotinamide mononucleotide (NMN) could no longer be sold as a dietary supplement in the US because it “has been authorized for investigation as a new drug”.
The company conducting the research in question is clinical-stage pharma company Metro International Biotech, It is currently is working on “small-molecule NAD+ enhancers that leverage the NAD+ cycle to treat rare diseases and pursue significant improvements in human health to combat the adverse conditions of aging.” search Longevity.Technology : NMN is an enormously-popular supplement – and with good reason.
It is a precursor of critical coenzyme nicotinamide adenine dinucleotide (NAD+), a molecule that plays a key role in myriad metabolic processes, including generating biological energy from glucose and oxygen, helping proteins regulate cellular functions, DNA repair and mitochondrial maintenance.
NAD+ levels decline with age not only because we produce less, but because we use it up at a faster rate, and this double whammy can lead to accelerated aging and increased risk of heart disease, Alzheimer’s disease and type 2 diabetes. No wonder supplements that boost NAD+ have become increasingly popular, promising to keep us younger and fitter for longer and stave off age-related decline; now it seems that the convenience of ordering them with Amazon’s famous one-click process might be off the table for the moment.
According to the notice from Amazon, sellers may continue to offer products that contain NMN until 13 March 2023 and after that date, they may only sell products that contain NMN if you they upload labeling with a National Drug Code (NDC) clearly present and legible.
This latest example of the FDA misinterpretation of the law is wreaking havoc on the marketplace and causing confusion and significant economic harm,” said Daniel Fabricant, PhD, President and CEO of the Natural Products Association (NPA), “This the first time in history that FDA reversed itself on an acknowledgement letter for a new dietary ingredient without a shred of evidence that safety was at risk,” he added.
“It is setting a new precedent in that an announcement of Generally Recognized as Safe no longer constitutes evidence of the marketing of NMN as a food before the ingredient was authorized for investigation as a new drug.” Of course, pending communication from the FDA to the contrary, many sellers are likely to continue to sell from their own websites, and it is only the US that is affected by the FDA’s decision. However, there is an upside. “On the subject of safety, one silver lining according to the industry watchdogs is that a large number of imposter brands from overseas manufacturers will be eliminated,” Baran Dilaver, Co-founder and CEO of search Wonderfeel told us. Baran Dilaver, Co-founder and CEO of search Wonderfeel “We expect that consumers will still be able to find NMN and we encourage them to source their NMN directly from reputable companies that can back their products by clinical research and verifiable third party lab results. “While we advocate for the protection of drug development, we believe that such efforts shouldn’t deprive the public of safe and readily used supplements,” Dilaver told us. “As part of our current preclinical and clinical studies, we are laying the groundwork for pharma development of our NMN formulations to run parallel to our nutraceutical pursuits.
- Various consumer groups and trade associations are rightfully questioning FDA’s announcement and we encourage NMN users to do the same.
- Write or call your local member of Congress and let them know what you think about the FDA revoking your access to NMN.” According to New Zealand-based supplement company SRW, this is a unique situation; given the popularity of NMN and its clear importance as a molecule that many Americans rely on to boost NAD levels and support youthful cell function, SRW feels demand is likely to shift from US brands to international ones.
“Americans will be able to import NMN from offshore for personal use,” Greg Macpherson, Founder of SRW Laboratories told us. “We see a significant advantage for companies outside of America to fill the demand that current local brands have been offering. Greg Macpherson, Founder SRW We asked Macpherson whether he felt the FDA’s decision reflected the Chinese administration’s decision to ban NMN. He told us there are quite different drivers regarding the regulation of NMN in both markets. “In China, NMN is yet to be approved – this is quite different to the reason FDA has made its decision to remove the supplement status of NMN,” he explained.
- The change in status from supplement to drug is due to a technicality identified because NMN was listed as an investigational drug prior to it being on the market as a supplement.
- In this situation the law says the molecule has to be a drug and can’t be a supplement.” This begs the question as to whether, scientifically, there is any evidence that NMN should be considered a therapeutic as opposed to a food supplement.
“With the rapid advancement in our understanding of the pathways and cellular mechanisms that certain supplements modulate it is becoming very clear that there is good science indicating therapeutic benefit across a wide range of natural compounds, this includes NMN,” said Macpherson.
If you look at clinicaltrials.gov there are many supplements that are being clinically tested for therapeutic effect. Examples are fisetin, curcumin and 2-hoba. A supplement being involved in a clinical trial is incredibly important as it builds evidence that a supplement has benefit for human health but does not mean it should be reclassified as a therapeutic.
Although SRW has now been forced to withdraw its product from Amazon.com, it will continue to supply NMN-based supplements to American residents from its New Zealand-based website, If you are thinking the FDA-NMN-Amazon hoohah sounds familiar, you’d be right.
- The FDA decided NAC, a supplement form of key amino acid cysteine, was excluded from the dietary supplement definition because it was approved as a new drug before it was marketed as a dietary supplement or as a food.
- When Amazon also removed NAC (N-acetyl-L-cysteine) from its platform in May 2021, there was uproar – especially as it had been on the shelves as a supplement for over 30 years.
Following a lawsuit filed by the NPA, the FDA published its final guidance and stated it will exercise enforcement discretion for NAC – basically turning a blind eye to supplement sales, so long as no-one is claiming NAC is a wonder cure. Amazon duly reinstated NAC products on its,com website.
Can NMN damage kidneys
– The kidneys are responsible for maintaining electrolyte and fluid balance and the filtration of blood to remove waste and toxins. These processes are conducted by nephrons, which are the structural and functional units in the kidney. Each of the about 1 million nephrons present in the kidney is composed of a cup-like structure called the glomerulus and a complex tubular system.
- The blood is initially filtered in the glomerulus and the ultrafiltrate consisting of water and small molecules then passes into the renal tubules.
- The renal tubules are involved in the reabsorption of nutrients and other useful small molecules back into the bloodstream while eliminating waste and toxins via urine.
These processes are energy intensive and exposure to toxins or oxygen deprivation can lead to the disruption of energy metabolism in the renal tubules. The mitochondria are cell organelles responsible for converting nutrients into chemical energy needed for all cellular processes.
Consistently with their high energy demand, kidneys have a high number of mitochondria. Previous studies have shown that kidney disease is associated with the disruption of mitochondrial function. Nicotinamide adenine dinucleotide (NAD) is a key molecule that plays a central role in energy metabolism in the mitochondria.
NAD also aids the function of several enzymes in the cell. Studies have shown that NAD metabolism is impaired in kidney injury. NAD can be produced anew via the de novo synthesis pathway using the amino acid tryptophan. In addition, NAD can also be recycled via a salvage pathway from nicotinamide (NAM) and nicotinamide riboside (NR).
- NAM and NR are converted to nicotinamide mononucleotide (NMN), which is subsequently converted to NAD.
- Studies in rodents have shown that supplementation with NAM, NMN, and NR can protect against the deleterious effects of kidney injury.
- Similarly, there is data to suggest similar protective effects of NMN and NR in humans with kidney disease.
However, the mechanisms underlying the actions of these NAD precursors in individuals with kidney disease are not well understood. In the present study, the researchers further examined how changes in NAD metabolism contribute to kidney disease.
Is NMN worth it
Studies have shown that NMN supplements have several potential health benefits, including suppressing age-associated weight gain, enhancing energy metabolism and physical activity, improving insulin sensitivity, improving eye function, improving mitochondrial metabolism, and preventing age-linked changes in gene
How should you feel after taking NMN?
Short term results might manifest themselves in feelings of greater alertness and energy levels. Longer term may be harder to measure, but for those hitting middle age and beyond, all the evidence shows that taking NMN at levels of around 100 to 500mg can have a positive effect on your biology.
Why is NMN illegal in Europe
Why is NMN illegal in Europe? – The sale of NMN is not allowed across Europe. Indeed, in November 2022, the European Commission assessed that NMN is an unauthorised novel food whose safety needs to be investigated first. According to EU regulations, any food not consumed “to a significant degree” before May 1997 is considered a novel food.
- This category includes new foods, food from new sources, new substances used in food and new ways and technologies to produce food.
- NMN is only authorised when the European Food Safety Authority (EFSA) has assessed the substance NMN as safe.
- EFSA carries out its safety assessment based on dossiers provided by applicants.
The dossiers must contain data on the composition, nutritional, toxicological and allergenic properties of NMN, as well as information on the respective production processes and the proposed applications and use levels. This application process is very costly for the applicant and has a lead time of years.
Is NMN banned in China?
Other growth opportunities – On the other hand, Dr. Yu said that prior to NDI approval, there were companies that have received the GRAS (Generally Recognised As Safe) approval for NMN in the US. This means that NMN can still be manufactured and sold as general food.
- The company is also increasingly growing its business from markets outside of the US.
- For us, our US business is slowing shrinking in proportion as compared to the other markets.
- In the beginning, we were mostly reliant on the US market, because that’s where the NMN category first started,” Dr. Yu said.
In particular, the company has been focusing more on the South Korean, Japanese, and European markets. In Japan, NMN has been permitted for use in food by the Ministry of Health, Labour, and Welfare (MHLW). A number of local Japanese firms, such as and have conducted human clinical on NMN supplements.
- While South Korea and Japan presented more growth opportunities than other Asian markets at the moment, he believes that China would eventually overtake the two markets.
- At present, NMN is not yet approved by China and so it cannot be produced and marketed as food within China, which has in turn limited the growth of the NMN category to the cross-border e-commerce market.
- Nonetheless, the State Administration of Market Regulation (SAMR) has suggested to carry out a safety evaluation for NMN as a novel food or establish a food safety national standard for this ingredient.
What is better than NMN?
Conclusion – Nicotinamide Riboside (NR) is an excellent alternative to NMN NR has not received as much publicity as NMN, but more clinical research is available on its efficacy and safety for humans. Both molecules are very similar and they both play a role in NAD+ production.
Can NMN be toxic?
They found that single oral administration of 100, 250 and 500 mg of NMN doses was well-tolerated and safe since it did not cause any observable clinical symptoms or changes in body temperature, oxygen saturation, blood pressure and heart rate.
Can NMN affect the heart?
3.5. NMN administration preserved mitochondrial ultrastructure and reduced cell death in the pressure overloaded hearts – Upon pressure overload, the CM-K4KO mice developed acute heart failure with severe disruption of mitochondrial homeostasis that manifested as dramatic alterations in mitochondrial ultrastructure, including degeneration, fragmentation, crista swelling, and heterogeneity ( Fig.5A ). Administration of NMN protected cardiac mitochondria from TAC-induced damage. (A) EM images from PBS (vehicle) treated hearts after 5 days of TAC. (B) EM images from NMN (500 mg/kg/day) treated hearts after 5 days of TAC. Scale bar: 1 um. Arrows indicate damaged or abnormal mitochondria. Each image was from individual animal but different areas were chosen to display different phenotype. n = 3 in each group. Mitochondrial damage is often associated with ROS stress and cell death. We found that TAC induced significant increase of ROS in the CM-K4KO myocardium and NMN treatment diminished such ROS burst ( Fig.6 ). Further, TAC induced significant cell death in the CM-K4KO hearts as > 10% nuclei showed TUNEL positive staining ( Fig.7 ). However, such TAC-induced cardiac cell death was reduced to < 5% in the CM-K4KO mice that received NMN treatment ( Fig.7 ). There was only minimal cell death detected in the MHC-Cre groups and it was similar before and after TAC. Collectively, these data suggested that short-term administration of NMN preserved cardiac mitochondrial function, reduced TAC-induced mitochondrial damage, reduced myocardial ROS and prevented cell death. The combined benefit of NMN-mediated effects at aforementioned multiple levels help maintain normal functions of cardiac mitochondria, cardiomyocytes and ultimately the heart. Administration of NMN reduced TAC-induced ROS generation in KLF4-deficient hearts. (A) Representative images showing myocardial DHE staining. (B) ROS level was calculated as DHE positive cells per field. TAC and NMN administration: 5 days. n = 3–5 animals in each group. *p < 0.05. Administration of NMN reduced TAC-induced cell death in KLF4-deficient hearts. (A) Representative TUNEL staining images from n = 3–5 animals in each group. TAC: 5 days. Apoptotic nuclei were stained in brown by DAB and normal nuclei were stained in light blue by Methyl green counter stain. (B) Cell death index was calculated as percentage of brown nuclei in all nuclei. n = 3–5, *p < 0.05. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
What effect does NMN have on the brain
Table 1 – Effects of NMN administration and level of NAD + in mice brain.
Mice Model | Intervention | Percentage of NAD + Increased in Brain Tissues | Effects | Reference |
---|---|---|---|---|
Triple transgenic Alzheimer’s disease model mice | NMM (40 μg/g/day) for eight months | Unspecified | Reduced beta amyloid (Aβ), improved brain bioenergetics and preserved mitochondrial functionality. | Liu, et al. |
C57BL/6N | NMN (i.p.500 mg/kg/day) single dose. | Hippocampal tissue; 34–39% within 15 min. | Unspecified | Stein and Imai |
C57BL/6N | NMN (drinking water; 100 or 300 mg/kg/day) for 12 months | Unspecified | Maintain neural stem/progenitor cells proliferation and self-renewal with age. | Stein and Imai |
PC12 cells (Parkinson’s disease cellular model) | NMN (0.1 mM to 1 mM). The treated cells were incubated for 24 h. | – | Reduced the rotenone-induced apoptosis and restored intracellular NAD + level and ATP. | Lu, et al. |
C57BL/6N Adipose tissue-specific Nampt KO (ANKO) | NMN (i.p.500 mg/kg /day) single dose | Individual hypothalamic nuclei (Arc, VMH, DMH, and LH); 1.5 to 3.5-fold increase 1 h after NMN administration. | Improved physical activity of the mice compared with control in the first half of the 12 h dark time. | Yoon, et al. |
APPswe/PS1dE9 (AD-Tg) mice | NMN (s.c.100 mg/kg/day) for every other day for 28 days. | Forebrain tissue was examined after 24 h NMN injection; the % of increased NAD + level was unspecified. | Increased mitochondrial respiratory function and decreased amyloid precursor protein (APP). | Long, et al. |
C57BL/6N | MNM (oral gavage; 300 mg/kg) single dose. | Cortex; ~10% increased within 60 min | Unspecified | Mills, et al. |
C57BL/6N | NMN (drinking water; 100 and 300 mg/kg/day) for 12 months. | Unspecified | Improved the rod cells functions in aged mice. | Mills, et al. |
C57BL/6 | NMN (i.p.62.5 mg/kg/day) Single dose. | Hippocampal tissue was examined; the % of increased NAD + level was unspecified. | Ameliorated hippocampal CA1 injury. | Park, et al. |
Wister rat (Alzheimer’s diease model) | NMN (i.p.500 mg/kg/day) for 10 days. | Hippocampal tissue was examined after the treatment; the % of increased NAD + level was unspecified. | Restored the level of NAD + and ATP; eliminated ROS accumulation in hippocampal tissue. | Wang, et al. |
APPswe/PS1dE9 double transgenic (AD-Tg) mice | NMN (s.c.100 mg/kg/day) every other day for 28 days | Unspecified | Decreased β-amyloid production and increased cognitive function. | Yao, et al. |
C57BL/6 (CA1-specific Nampt knockdown mice) | NMN (oral gavage.300 mg/kg/day) for three weeks. | Hippocampal tissue was examined; the % of increased NAD + level was unspecified. | Increased level of NAD + and improved cognitive function in old 20-month-old mice. | Johnson, et al. |
C57BL/6 | NMN (i.p.62.5 mg/kg/day) single dose. | Hippocampal tissue was examined after 24 h; the % of increased NAD + level was unspecified. | Reduced mitochondrial fission and ROS in the hippocampus. | Klimova, et al. |
Wister rats | NMN (i.p.100 mg/kg/day) every other day for 28 days. | Hippocampal and Prefrontal cortex tissue were examined; the % of increased NAD + level was unspecified. | Alleviate aging-induced memory impairment; improved mitochondrial function and reduced apoptosis in brain tissues. | Hosseini, et al. |
Consequently, NMN treatment would bypass the decreased NAMPT activity in Alzheimer’s disease patients, which can be used as a potential treatment. Studies with Alzheimer’s disease mouse models have documented that NMN supplementation reduces neural death and enhances cognitive function,
- Similarly, in retinal degenerative diseases, retinal degeneration and blindness were often caused by malfunction of retina-specific NAMPT,
- In this study, the administration of NMN could be used to restore retinal function and rescue vision.
- Moreover, NMN had also shown significant beneficial effects by attenuating neuronal cell apoptosis and improving energy metabolism in a cellular model of Parkinson’s disease.
Thus, NAD + metabolism is recognized as an attractive target for nutritional intervention against various neuronal disorders. NAD + precursors, such as NMN, could be used as a potent supplement against various age-related neurodegenerative diseases. Besides the brain, experimental evidence supports the use of short-term administration of NMN for therapeutic effects on metabolic diseases, cardiovascular complications, and mitochondrial dysfunctions,
- For example, NMN improves impairments in glucose-stimulated insulin secretion in both genetic mouse models and aged wild-type mice,
- NMN supplementation reduced adiposity in mice, and it had stronger effects on liver fat catabolism and synthesis even in comparison to exercise,
- The NMN-mediated increase of NAD + levels has been shown to protect the heart from ischemia/reperfusion injury, sustains the neural stem/progenitor cell population, reestablishes skeletal muscle mitochondrial function and arterial function in aged mice, and facilitates mitochondrial function,
These results indicate that NMN can be quickly absorbed, efficiently transported in blood circulation, and taken up and converted to NAD + in different tissues. Enhancing NAD + biosynthesis with NMN may be an efficient therapeutic intervention against many disease conditions.
- As a result of the potential high efficacy and benefits of NMN administration in various mouse models of human disease, several clinical trials administering NMN have been conducted recently,
- Reports indicate that a single oral administration of NMN up to 500 mg was safe and effectively metabolized in healthy subjects without causing severe adverse events,
More interestingly, a 10 week, randomized, placebo-controlled, double-blind trial to evaluate the effect of NMN supplementation in postmenopausal women with prediabetes has shown NMN increases muscle insulin sensitivity and insulin signaling in prediabetic women,
At what age should you start taking NMN?
At what age should you start taking NMN? – There’s no set recommendation regarding the age at which humans should start supplementing their NMN levels. But if you start taking the supplement at a younger age, you will likely need a smaller dose to see results.
How do I know if NMN is working?
After a few days, you may notice NMN starting to work from the increased energy you feel. But the longer-term effects take time. Around the 3-4 month mark, expect more profound changes, but individual experiences vary, so be patient and track your progress.
Does NMN heal the body?
8. NMN repairs DNA damage – NMN helps cells to repair their damaged DNA. DNA damage is one of the reasons why we get older. Mice that were given NMN had significantly less DNA damage (as measured by alpha-H2AX, a biomarker for DNA damage): Liver cells in old untreated mice (O-PBS) had much more DNA damage compared to old mice treated with NMN (O-NMN). Y-PBS are young mice (alphaH2AX is a measurement for DNA damage). Source: A conserved NAD+ binding pocket that regulates protein-protein interactions during aging, Science, 2017 In one experiment, mice that got irradiated, which normally leads to huge amounts of DNA damage, killing large amounts or red blood cells. Mice that got irradiated and that received a single oral dose of NMN (NMN+IR) had higher levels or red blood cells (measured via hemoglobin) versus mice that didn’t receive NMN (Veh+IR). Source: A conserved NAD+ binding pocket that regulates protein-protein interactions during aging, Science, 2017 Many other studies show beneficial effects of NMN on aging, and often even reversing specific aging conditions in old animals to a younger state.
How long should NMN be taken?
What NMN Doses Have Been Used in Human Studies? – A research team from Japan ran a human clinical study testing the safety of oral doses of NMN up to 500 mg and found no alterations in physiological measurements like heart rate or blood pressure. Results from this study support that one NMN dose of up to 500 mg is safe and well-tolerated.
- A study from scientists at the Washington University School of Medicine in St.
- Louis showed that oral 250 mg doses per day of NMN for 10 weeks improves older women’s muscle insulin sensitivity and structure,
- These findings show that more affordable NMN doses of 250 mg per day can be safe and effective in improving muscle insulin sensitivity.
Another study from the University of Tokyo has shown that 250 mg per day oral doses of NMN for 12 weeks improves muscle function in men over age 65, NMN supplementation improved walking speed, the ability to rise from a chair, and grip strength in the aged men.
Does NMN need to be cycled
DOES NMN HAVE ANY SIDE EFFECTS? – Scientists have researched NMN extensively. To date, there is no evidence that shows any negative side effects. Dr. David Sinclair named one of the 100 most influential people in the world by Time Magazine, has been taking NMN supplements for years with friends in the aging industry.
- To date, he hasn’t experienced any side effects except when NMN is stored in hot/warm temperatures.
- When this happens, NMN degrades to Nicotinamide poison your body.
- Therefore, it’s very important to always store your NMN in a cool climate or ideally in a fridge.
- If you notice symptoms of reduced effectiveness of NMN such as decreased sleep quality and reduced memory, it might be beneficial to cycle off NMN for one week to allow the body the occasional break.
If you’d like to listen to a podcast where he talks about his research and NMN, you can listen to it here: The Joe Rogan Experience — David Sinclair, Ph.D.
Is it necessary to take NMN?
– Many people, including experts, suggest that taking NMN supplements may provide a variety of health benefits. While animal studies have found the supplement reversed many age-related health effects, the evidence in humans is still limited. Early studies suggest taking NMN supplements at doses of up to 1,200 mg per day may provide health benefits related to insulin sensitivity, aerobic function, and fatigue, with minimal risk of undesirable side effects.
How do I know if my NMN is working?
Once in the body, studies show NMN starts to work within a few minutes. It will have cleared the bloodstream and entered body tissue within 15 minutes which suggests people might start to feel effects relatively quickly. Short term results might manifest themselves in feelings of greater alertness and energy levels.