NAD+ & TMG: What’s the Connection?

NAD+ & TMG: What’s the Connection?

From the Desk of Dr. Z:  AgelessRx Co-founder and Chief Medical Officer, Dr. Sajad Zalzala offers his insightful perspective on topics related to longevity. With a wealth of experience and a deep-seated passion for disease prevention and extending healthy lifespans, Dr. Z is dedicated to sharing his knowledge on the secrets to longevity. Today, he shares his knowledge on how TMG can be an important co-supplement to NAD+.

A quick overview of what we’ll cover in this blog post:

  • What TMG is
  • What role TMG plays in the body
  • How TMG potentially complements NAD+

Whether you’ve been taking NAD+ supplements for a while or you’re relatively new to them, you probably know that NAD+ is an important part of your body’s regular function. 

As a naturally occurring enzyme in the body, NAD+ helps with a lot of essential functions, including helping cells create energy from nutrients, cellular repair, and aging. It’s also something that declines with age, causing many age-related illnesses. That’s why supplementation could help you live a healthier life.

A common question we receive is about the role of TMG (trimethylglycine) when supplementing with NAD+. While the timing of taking TMG with NAD+ isn’t an exact science, our recommendations are based on emerging evidence and patient experiences. 

Whether you’re familiar with TMG or not, we’ll break down what it is, why it’s important to take with NAD+, and where you can get it.

What Is NAD+ & Why Is It Important?

NAD+ (nicotinamide adenine dinucleotide) is a critical coenzyme in every cell, playing an essential role in metabolism, DNA repair, and maintaining cellular health. NAD+ levels naturally decline with age, leading to impaired mitochondrial function, decreased energy, and the onset of age-related conditions. Supplementation can help reverse these effects, boosting energy production and supporting healthy aging.

However, NAD+ metabolism can deplete methyl groups, which are critical for various biological processes like gene regulation and detoxification.

What Is TMG’s Role in the Body?

Trimethylglycine (TMG) is a type of betaine and a key player in a biological process called methylation.

Methylation is the process by which cells “donate” methyl groups, or specific molecules, to other cells. These methyl groups help cells carry out key biological functions, such as the production of DNA or neurotransmitters.This process also helps regulate gene expression, detoxify harmful substances, and convert nutrients into usable energy.

TMG is important because it provides methyl groups to cells to carry out these functions (as the name suggests, it provides three methyl groups).

Why Take NAD+ & TMG Together?

As your body uses NAD+, it gets broken down into waste that needs to be excreted from the body. In order to do this, however, a methyl group is required to transport it out of your body. So, the more NAD+ supplement you take, the faster your methyl groups are depleted. That’s why TMG can be an important co-supplement on days you take NAD+, ensuring your body still has healthy levels of methyl groups available for other vital functions.

TMG also plays a role in the breakdown of amino acids called homocysteines, which, while helpful for cell metabolism, can cause problems when their levels are too high, such as damage to blood vessels. So TMG generally is important to your overall health.

During NAD+ supplementation, the body produces nicotinamide (NAM), which must be methylated and excreted. For individuals with impaired methylation due to genetic factors like MTHFR mutations, this increased demand can lead to issues if the body doesn’t have enough methyl donors available.

MTHFR Mutations & Methylation

Mutations in the MTHFR gene can reduce the body’s ability to efficiently methylate. This is especially relevant when taking supplements like NAD+, which increase the demand for methylation. 

The two most common MTHFR variants (C677T and A1298C) affect up to 40% of some populations and can lead to elevated homocysteine levels, which increase the risk of cardiovascular issues, depression, and cognitive decline​   For these individuals, supplementing with methyl donors like TMG or methyl-folate can help support proper methylation pathways.

TMG as a Methyl Donor: How Does It Help?

TMG is a well-known methyl donor that can replenish the body’s supply of methyl groups, supporting normal DNA function and detoxification processes. Taking TMG alongside NAD+ supplementation helps ensure that your methylation pathways are not depleted as the body metabolizes NAD+.

Not everyone requires TMG, especially those without methylation issues. Individuals with normal methylation capacity may find that their body manages NAD+ metabolism without any problems. However, for those with known MTHFR mutations or concerns about methylation, TMG can provide a useful safety net​.

Practical Recommendations for NAD+ & TMG Supplementation

  1. Timing and Dosage
    Based on current knowledge, TMG’s role as a long-acting methyl donor means it can be taken at any time of the day. There’s no evidence to suggest that TMG must be taken at the same time as NAD+. A typical dosage is 1,000mg of TMG daily, which should be more than enough to support methylation needs. However, for individuals who find daily TMG supplementation burdensome, taking it only on the days they use their NAD+ patch is also a viable option.
  2. Daily vs. Occasional Supplementation
    While some patients prefer to take TMG daily, others opt to only take it when using their NAD+ patches. Both methods are acceptable, and individual responses can vary based on personal methylation capacity.
  3. Methylation Testing
    Unfortunately, there aren’t yet precise tests to measure methylation efficiency or NAD+ metabolism in a way that would inform personalized TMG dosing. However, genetic testing for MTHFR mutations and measuring homocysteine levels can provide insight into your methylation capacity.

The Takeaway

While the precise timing and the amount of TMG patients should use with NAD+ are not set in stone, our approach is based on what seems to work for most people: either take TMG daily or on the days when you use NAD+ supplements, especially if you have known methylation issues. You can easily find TMG supplements at online retailers or most vitamin and supplement shops.

At AgelessRx, we’ll continue to monitor the latest research and provide updated guidance as more is understood about the interplay between NAD+ and methyl donors like TMG.


Note: The above statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.

Further Reading

  1. Sun W.P., et al. (2017). Comparison of the effects of nicotinic acid and nicotinamide degradation on plasma betaine and choline levels. Clin Nutr, 36(4): 1136-1145.
  2. Dean, L. (2012). Methylenetetrahydrofolate Reductase Deficiency. Medical Genetics Summaries.
  3. Obeid, R. (2013). The metabolic burden of methyl donor deficiency. Nutrients, 5(9): 3481-95.
  4. Shorter, K.R., et al. (2015). Consequences of dietary methyl donor supplements: Is more always better?. Prog Biophys Mol Biol, 118(1-2): 14-20.