Powering cellular energy and healthy ageing: behind the hype of NAD, NMN and NR supplements

Have you heard any of the buzz about NAD supplements? NAD is a molecule found in nearly every cell and sits at the heart of energy production and DNA repair. Our levels of NAD though can decline with age which has led to the idea that this could be one cause of many age-related diseases, chronic inflammation and cognitive decline. Enter the idea of boosting NAD levels by supplementing with NAD itself or its precursors called NMN and NR. A surface level reading of this topic will soon bring someone across all sorts of claims about benefits including extending lifespan, improving metabolic health and many more. In this podcast episode, I explain what these NAD family of molecules are and critique the clinical evidence to see how it stacks up in front of the health claims.

Links referred to in the podcast

• Review of effect of NR supplementation in humans https://www.science.org/doi/10.1126/sciadv.adi4862
• Review of NMN and NR supplementation on muscle mass and function https://pmc.ncbi.nlm.nih.gov/articles/PMC12022230

Episode transcript
To access the full episode transcript, go to the following link and select the individual podcast episode and then click on the ‘Transcript’ tab https://thinkingnutrition.buzzsprout.com

Connect with me
Instagram doctimcrowe
Facebook Thinking Nutrition
X CroweTim

Transcript

Have you heard any of the buzz about NAD supplements? NAD is a molecule found in nearly every cell and sits at the heart of energy production and DNA repair. Our levels of NAD though can decline with age which has led to the idea that this could be one cause of many age-related diseases, chronic inflammation and cognitive decline. Enter the idea of boosting NAD levels by supplementing with NAD itself or its precursors called NMN and NR. A surface level reading of this topic will soon bring someone across all sorts of claims about benefits including extending lifespan, improving metabolic health and many more. In this podcast episode, I’ll explain what these NAD family of molecules are and critique the clinical evidence to see how it stacks up in front of the health claims.

 NAD is an acronym that stands for nicotinamide adenine dinucleotide. NAD is actually made from the B-group vitamin niacin, or we can produce it from the amino acid tryptophan and also recycle it in the body. NAD is a critical component of how we generate cellular energy, repair DNA and regulate biological pathways linked to ageing.

NAD acts as a cofactor for metabolic enzymes in the mitochondria during oxidative phosphorylation which is part of the process of ATP production through the electron transport chain. Sorry for the flashback to those of you that have studied uni biochemistry. Outside of the mitochondria, NAD also supports glycolysis, helping generate ATP from glucose.

The levels of NAD are known to decline with age, which has fuelled interest in how supplementation with NAD may help with ageing especially considering NAD’s central role in energy production and cellular repair. The decline in NAD with age is caused by lower rates of its biosynthesis together with increased demand for it because of its importance in so many cellular reactions.

Tissues such as the brain, heart and muscle have high metabolic demands so need a lot of NAD. And it is these same tissues that show the greatest signs of defects with ageing which increases our risk of dementia, heart disease and loss of muscle mass and strength.

But it is important to say straight out that just because NAD levels fall with age doesn’t automatically mean it is the reason for many of the health problems with ageing. Wrinkles are certainly a sign of ageing, but we don’t say that wrinkles cause many of the health problems of ageing – this is a classic case of correlation not being causation. So, is there any truth to the NAD and healthy ageing story? Let’s dive in further.

Let’s look firstly at the different ways that NAD levels can be boosted with supplements. Now, don’t go looking for a bottle of NAD at your local health supplement store as the oral form of NAD has poor absorption and tends to be broken down in the gut. Instead, the popular ways to try and boost NAD levels come from taking its precursors. Two of the more popular ones are NMN and NR.

NMN stands for nicotinamide mononucleotide and it is the direct precursor for NAD. NMN occurs in small amounts in foods like avocados, broccoli and tomatoes but at levels much lower than that used in supplements studies.

At least in animals, NMN supplementation seems to improve mitochondrial function, improve insulin sensitivity and support cardiovascular and cognitive health. In human clinical trials some research shows that it may increase physical ability in older people as well as improving markers of vascular health though the effects are fairly modest and we certainly need some larger trials to unpack what is happening. So while it’s great news if you’re a rodent that taking NMN can be of benefit, the different physiology of humans and the overly cautious need to use lower doses in human trials means that the potential benefits are smaller.

Interestingly, NMN is legal in Australia for personal use if you wish to import yourself, but it is illegal to be sold commercially as it is not listed by the TGA as an approved therapeutic good for sale. In the United States, NMN is in a legal limbo as while it is technically banned, the FDA are currently not enforcing the ban so it is available while the FDA evaluates its status – go figure.

The legal status of another NAD precursor called NR is clearer as it is approved in both Australia and the USA for commercial sale as a dietary supplement. NR stands for nicotinamide riboside and it is also a precursor for NAD.

Just like the case for NMN, animal studies with NR point to benefit for ageing, but the human clinical trials have not yet demonstrated robust anti-ageing effects with very mediocre results in the few trials done so far. And a nice summary of this to date was from a 2023 review paper on the effects of NR supplementation in humans that could critically assess 25 clinical trials to arrive at the conclusion which I’ll quote directly from the paper that: “Collectively, oral nicotinamide riboside supplementation has displayed few clinically relevant effects, and there is an unfortunate tendency in the literature to exaggerate the importance and robustness of reported effects.” So, there you go, a clear case of hype over real substance at this stage. And I’ll link to this review paper in the show notes. https://www.science.org/doi/10.1126/sciadv.adi4862

One final way to boost NAD levels is by IV therapy where NAD is given directly via a line into the body. Such a method is expensive and is linked to unpleasant side effects like nausea and chest discomfort. There is still a big question mark over the clinical benefits for anti-ageing using this method.

What to make of this all? Taking both NR and NMN have been shown in the research to consistently increase NAD levels in humans, but whether this translates into a meaningful clinical benefit is still unclear. Both NMN and NR are generally safe to take at recommended doses as no serious adverse health problems have been reported in clinical trials, but long-term effects require further study as there are still some unanswered questions especially for supplements promoted for their longevity benefits which would necessitate taking them for many years.

Beyond their proposed anti-ageing effects, NMN and NR have been investigated for their influence on metabolic health, including glucose regulation and lipid metabolism. Randomised controlled trials in humans have shown that supplementation can modestly increase NAD levels, but the downstream effects on insulin sensitivity, blood glucose and lipid profiles are minimal and often not clinically significant. For example, a recent review found that while NR supplementation slightly improved markers of liver fat in people with fatty liver disease, it did not translate into meaningful improvements in body weight, inflammation or overall metabolic health.

Emerging research has explored the potential of NAD precursors in supporting cognitive health, particularly in the context of neurodegenerative diseases. Preclinical studies suggest that boosting NAD levels may enhance neuronal resilience and reduce neuroinflammation, mechanisms implicated in conditions such as Alzheimer's and Parkinson's disease. However, human trials remain limited and have yet to demonstrate clear cognitive benefits from NMN or NR supplementation. While some small-scale studies report modest improvements in measures of cognitive function, the evidence is insufficient to support widespread use for neuroprotection at this time.

Just recently a review looked at the evidence for taking NMN or NR for its effect on muscle mass and function and even though the review could include 10 clinical trials with a mostly older population group who should benefit the most from the supplements, the results found little evidence for a clear benefit on muscle strength or physical function. And I’ll link to the review in the show notes. https://pmc.ncbi.nlm.nih.gov/articles/PMC12022230 

It could be that the benefits were too small to measure or alternatively perhaps it also needs exercise to go with it considering most of the trials didn’t include an exercise intervention. But for me, it is not a good look for the general health claims made about these supplements that they are a panacea for the metabolic ravages of ageing. 

The wash up of all this is that most clinical trials to date are small, short-term, and often underpowered to detect meaningful clinical outcomes. Add to this the substantial variability in dosing regimens, study populations, and outcome measures, makes it difficult to draw firm conclusions about health benefits.

Interestingly though, both NMN and NR can selectively stimulate the growth of beneficial bacteria such as Bifidobacterium and Lactobacillus which have been associated with improved gut health, including improved gut barrier function, reduced inflammation and immune system support. So, this could be one of the mechanisms that NMN and NR supplements could offer a health benefit. But I could list literally hundreds of beneficial food components that are known to favourably alter the gut microbiome, so it is hard to get too excited about this link with NAD precursors considering the cost of the supplements.

But do you want to know one surefire way to increase your NAD levels naturally? It’s exercise. How it does this is quite simple: the more exercise you do, the more NAD you need to produce energy so your body responds by making more of it. If the health benefits of regular exercise could be put in a pill, then it would be the biggest selling supplement of all time. Exercise cuts the risk of all the metabolic changes and diseases that are linked to ageing be it in our brain, muscles or blood vessels.

So, let’s wrap all this up. In the quest for longer healthier lives, the allure of reaching for the latest supplement is strong. Research into the NAD pathway and how to boost this with supplements is ongoing, but for now, the evidence for a real meaningful benefit is mostly unproven and where benefits have been found they are marginal and don’t really stack up to the huge benefits of getting the foundations right of regular exercise, good nutrition and quality sleep.

So that’s it for today’s show. You can find the show notes either in the app you’re listening to this podcast on, or else head over to my webpage www.thinkingnutrition.com.au and click on the podcast section to find this episode to read the show notes.

If you find this podcast of value, then please consider sharing it with your friends and colleagues. This all helps to increase the reach of the podcast, which means a big win for credible evidence-based nutrition messages and making the world a slightly less confusing place.

I’m Tim Crowe and you’ve been listening to Thinking Nutrition.