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NMN (Nicotinamide Mononucleotide): Separating Hype from Hope in Menopause and Aging

Updated: Nov 25, 2023

Every day, as a doctor passionate about longevity medicine, I am frequently approached with inquiries regarding the value and credibility of NMN supplements. The market offers a wide array of options, with price tags ranging from $200 to $2000, accompanied by grandiose claims encompassing various domains such as anti-aging, energy enhancement, cognitive improvement, better sleep, enhanced athletic performance and menopause. In this article, my aim is to present you with unbiased facts, empowering you to make an informed decision about whether investing your hard-earned money in NMN is truly worthwhile.



The key role of NMN in humans

NMN holds significant importance in humans due to its crucial role in cellular metabolism and overall health. Here are several key reasons why NMN is important:

  1. NAD+ Boosting: NMN is a precursor to nicotinamide adenine dinucleotide (NAD+), a coenzyme that plays a fundamental role in various cellular processes. NAD+ is involved in energy production, DNA repair, gene expression, and maintaining the overall integrity and function of cells. NMN supplementation can increase NAD+ levels, which has the potential to optimise cellular health and function.

  2. Energy Metabolism: NMN is a vital component in the production of adenosine triphosphate (ATP), the primary energy currency of cells. By promoting efficient energy metabolism, NMN supports overall cellular vitality, organ function, and physical performance.

  3. Aging and Longevity: Declining NAD+ levels have been associated with aging and age-related health issues. NMN supplementation has shown promise in preclinical studies (mice) for its potential to counteract age-related cellular decline and promote healthy aging. By replenishing NAD+ levels (mice and humans), NMN may help mitigate age-related metabolic dysfunction, improve mitochondrial function, and support overall longevity.

  4. Cellular Health: NMN participates in various cellular processes, including DNA repair, epigenetic regulation, and cellular signalling. By supporting these critical mechanisms, NMN contributes to maintaining cellular health, reducing oxidative stress, and promoting optimal cellular function.

  5. Potential Health Benefits: Emerging research suggests that NMN supplementation may have several potential health benefits. These include improved cardiovascular health, enhanced cognitive function, neuroprotection, increased insulin sensitivity, and metabolic regulation.


NMN in animal studies

Scientists rely on animal models as proxies for healthy humans (in safety and toxicity testing) and for human diseases (in efficacy testing). Animal studies, particularly those conducted on mice, play a crucial role in unravelling the biological actions and potential benefits of NMN. These studies provide valuable insights into its mechanisms of action, metabolism, and physiological effects.

Mice are often used in scientific research due to their genetic similarities to humans and their ability to manipulate their genetic makeup. When investigating NMN, researchers administer the compound to mice and closely monitor their responses.


While animal studies provide valuable preliminary data, it is crucial to acknowledge that findings in mice may not always directly translate to humans. Human clinical trials are necessary to validate the efficacy and safety of NMN supplementation in humans.


The claims put forth by supplement companies often rely on data derived from mice or animal studies, which is often not explicitly disclosed in their marketing materials. Additionally, many marketing companies make bold health promises and assertions based on non-human data, and there is a lack of regulatory oversight to hold these companies accountable. In instances where a supplement or marketing company does not disclose clinical validation in humans, it is reasonable to assume that their claims are solely rooted in animal or cell research and are not directly applicable to human health.


Indeed, there have been human clinical research trials conducted to investigate the effects of NMN supplementation. However, it is important to first establish what constitutes high-quality human research.



Strength of evidence from human clinical trials for NMN

Double-blind randomized controlled trials (RCTs) in humans are considered the gold standard in clinical research for several important reasons:

  1. Minimizing Bias: Randomized controlled trials (RCTs) aim to reduce bias by randomly assigning participants to different treatment groups. This randomization helps ensure that any observed differences in outcomes between groups are more likely due to the intervention being studied rather than pre-existing factors or biases. In contrast, observational or non-controlled trials can be influenced by confounding variables and subject to selection bias, making it challenging to establish a cause-and-effect relationship.

  2. Control Group Comparison: RCTs include a control group that receives either a placebo or an alternative treatment. This allows researchers to compare the effects of the intervention being studied with those of the control group. By having a control group, RCTs can better assess the true effects of the intervention and provide a baseline for comparison.

  3. Randomization in RCTs ensures that participants are allocated to treatment groups without bias or preference. This helps distribute potential confounding factors evenly across the groups, making the groups more comparable and reducing the impact of confounding variables on the results.

  4. Blinding: Double-blind trials involve both the researchers and participants being unaware of which treatment group they belong to. Blinding helps minimize bias and placebo effects, ensuring that the assessment of outcomes remains objective. In observational studies, blinding is not possible, which can introduce bias and influence the interpretation of the results.

  5. Statistical Rigor: RCTs typically employ rigorous statistical methods to analyze the data, providing robust and reliable results. These methods help determine the statistical significance of the observed effects and evaluate the strength of the evidence supporting the intervention's efficacy.

  6. Generalizability: RCTs, when properly designed and conducted, provide more reliable evidence for generalizability to the broader population. By randomly selecting participants and employing rigorous methods, RCTs aim to represent a diverse range of individuals, making the findings more applicable to the wider population.

Up until a 2022 review published here, there were 8 double-blind RCTs using NMN supplementation in humans.


Below is an image of their findings, which I like as it also provides lifestyle methods that increase NAD+ levels and the results on supplementation impact on various conditions from human trials:


PMID: 37619764


From this review, you can see that there is good safety data on doses ranging from 250mg-1250mg and for a period of 4-12 weeks.

There was no significant improvement in sleep quality, vision or cognition.


It improved physical endurance in healthy exercisers and in overweight and obese individuals older than 65.


In post-menopausal and pre-diabetic women aged 55-77 a 250mg dose over 10 weeks increased muscle insulin sensitivity.


After menopause, the low levels of estrogen predispose women to insulin resistance. Insulin resistance is a condition in which the body's cells become less responsive to the hormone insulin. Insulin is produced by the pancreas and plays a crucial role in regulating blood sugar levels by helping skeletal muscle and liver (the predominant organs for glucose storage) take up glucose from the bloodstream. In individuals with insulin resistance, the cells do not efficiently absorb glucose from the bloodstream, leading to elevated blood sugar levels. Over time, this can contribute to the development of type 2 diabetes and other metabolic disorders.


However, just because NMN improves muscle insulin sensitivity does not mean diabetes can be prevented or delayed with supplementation or that is just as effective as nutrition and exercise interventions. In research, an observation does not equate to a clinical effect or outcome. This remains to be tested, but the effect of NMN on muscle insulin sensitivity is interesting and warrants further investigation.



In fact, when it comes to the prevention of diabetes, intensive lifestyle intervention in this review of the Diabetes Prevention Program, showed a risk reduction of 58%. This study also evaluated the effectiveness of the drug Metformin (which is used to treat Type 2 Diabetes) in reducing the risk of developing diabetes. Metformin reduced the risk by 31%. However, this drug has not been approved for this purpose by the FDA, although doctors can still prescribe it. There are specific groups who benefit more and there are potential side-effects that require monitoring if taken long-term. You should always speak to your doctor first before starting any medicines.


Telomeres play a vital role in the biology of aging and longevity. They are repetitive DNA sequences located at the ends of chromosomes that serve as protective caps. Think of them as the protective plastic tips at the end of shoelaces that prevent fraying.

A reduced leucocyte telomere length has been associated with an increased risk of cardiovascular disease. However, apart from this, telomere length is not a strong proxy for other diseases or death used on its own and when compared to epigenetic age biomarkers. NMN supplementation in a small group of 10 men elongated telomere length and appeared to be safe in the short term.

In comparison, in a study of older participants between 60-85, vitamin D supplementation lengthened telomeres and reduced epigenetic age by 0.25 years.


However, further research, including human clinical trials, is needed to fully understand and validate these potential benefits.


NMN supplement quality and regulations

Selecting quality supplements requires a different set of skills to understand marketing claims. Supplement claims are not regulated, which comes as a surprise to many. The quality, efficacy and safety testing vary from country to country.

Recently, the FDA concluded that because it is under investigation by pharmaceutical companies as a potential new drug, supplement companies can no longer market NMN.


Here are a few things to note when choosing a high-quality supplement.


1. Strict manufacturing standards have a GMP (Good Manufacturing Practice) label or logo that helps to verify the quality of the supplement.

2. The USP (U.S Pharmacopeia) is an independent, scientific nonprofit organization focused on building trust in the supply of safe, quality medicines and supplements. They help ensure the quality of dietary supplements by providing auditing and testing services to verify the quality of dietary supplements through the USP verification program. Look for a USP-verified logo.

3. Therapeutic Goods Administration (TGA) is Australia's government authority responsible for evaluating, assessing and monitoring products that are defined as therapeutic goods. This includes medicine, supplements, vitamins and herbs. You can search for a list of approved products on their website.


If supplements containing NMN as a single ingredient have the above verifications, it is probably of good quality.


Considerations before supplementing with NMN

The cheapest monthly cost of an NMN supplement that I was able to find was around $300 based on the dosage and quality criteria. While this is safe, it is also important to consider the reasons why you would want to take a supplement. A supplement by definition is intended to add to or supplement a diet, it is not a replacement or substitute for healthy lifestyle behaviors.

In terms of aging, there are no validated methods to assess the impact that NMN supplementation has on human biological aging. Epigenetic clocks are validated biomarkers that have been used to assess the impact of lifestyle strategies that slow down aging. Various epigenetic clocks can be used to assess how your current diet, lifestyle and exercise habits impact on you biological age.

How will you objectively measure the impact of NMN supplementation?


Objective measurement of the impact of NMN supplementation becomes challenging since subjective improvements could be influenced by the placebo effect. The placebo effect occurs when a person experiences perceived improvements in physical or mental health after taking a placebo or inert treatment. One study found that self-reported improvements of 30% were reported by supplement users without clinically measurable differences in health.


Objective measurements, such as insulin levels, blood sugar, and physical performance, can potentially be used to assess the impact of NMN supplementation. However, it's important to note that many individuals simultaneously adopt healthy behaviours when starting a supplement regimen, making it difficult to solely attribute improvements to supplementation. Additionally, the Hawthorne Effect may come into play, where subjects modify their behaviour simply because they are being evaluated or studied. While positive changes are observed, is it worth a monthly cost of $300 or more? Are there free and sustainable alternatives available to achieve your goals?


Summary

NMN supplementation seems to be safe, but the evidence for its actual impact on human health is still in the early stages and quite limited. While we can measure some biomarkers like insulin, glucose, and physical performance as indicators of how it might affect our longevity, scientists still have a long way to go before they can definitively say whether NMN supplementation has a significant clinical effect on disease prevention, improving our health and lifespan. On the other hand, there are lifestyle strategies that have a large body of evidence supporting their role in preventing diseases and promoting healthy aging. The catch is, that these strategies require more effort on your part compared to simply taking a pill.


So, it's all about finding a balance and considering what works best for you.


For more information on how to improve your healthspan with a personalised approach to healthy longevity, you can contact us via Email or WhatsApp


References:

  1. Song Q, Zhou X, Xu K, Liu S, Zhu X, Yang J. The Safety and Antiaging Effects of Nicotinamide Mononucleotide in Human Clinical Trials: an Update. Adv Nutr. 2023 Aug 22:S2161-8313(23)01359-5. doi: 10.1016/j.advnut.2023.08.008. Epub ahead of print. PMID: 37619764.

  2. Hostalek U, Campbell I. Metformin for diabetes prevention: update of the evidence base. Curr Med Res Opin. 2021 Oct;37(10):1705-1717. doi: 10.1080/03007995.2021.1955667. Epub 2021 Jul 28. PMID: 34281467.

  3. Vaiserman A, Krasnienkov D. Telomere Length as a Marker of Biological Age: State-of-the-Art, Open Issues, and Future Perspectives. Front Genet. 2021 Jan 21;11:630186. doi: 10.3389/fgene.2020.630186. PMID: 33552142; PMCID: PMC7859450.

  4. Valentin Max Vetter, Dominik Spira, Verena Laura Banszerus, Ilja Demuth, Epigenetic Clock and Leukocyte Telomere Length Are Associated with Vitamin D Status but not with Functional Assessments and Frailty in the Berlin Aging Study II, The Journals of Gerontology: Series A, Volume 75, Issue 11, November 2020, Pages 2056–2063, https://doi.org/10.1093/gerona/glaa101

  5. https://healthnews.com/longevity/longevity-supplements/fda-b-nmn-can-no-longer-be-sold-as-a-dietary-supplement-in-the-us/

  6. Paranjpe MD, Chin AC, Paranjpe I, Reid NJ, Duy PQ, Wang JK, O'Hagan R, Arzani A, Haghdel A, Lim CC, Orhurhu V, Urits I, Ngo AL, Glicksberg BS, Hall KT, Mehta D, Cooper RS, Nadkarni GN. Self-reported health without clinically measurable benefits among adult users of multivitamin and multimineral supplements: a cross-sectional study. BMJ Open. 2020 Nov 4;10(11):e039119. doi: 10.1136/bmjopen-2020-039119. PMID: 33148746; PMCID: PMC7643504.

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