NMN and Methylation

The body is made up of trillions of tiny cells. These cells need energy to do everything — from helping you breathe, think, move, and grow to repair damage. That energy-making process comes from NAD+ (short for Nicotinamide Adenine Dinucleotide).

The body isn't as efficient at directly consuming NAD+. Converting another compound into NAD+ within the cells is more efficient. One of the most studied compounds for this NAD+ conversion is NMN or nicotinamide mononucleotide.

When your body turns NMN into NAD+, it makes a leftover substance that needs to be cleaned up. This cleanup process is called methylation, which also helps control things like how your genes work, how your body gets rid of waste, and how your brain makes chemicals.

What is Methylation?

Methylation is a natural chemical process in every body cell, and it's important for gene expression, detoxification, neurotransmitter production, and cardiovascular function. Inside the cell, a methyl group (one carbon atom and three hydrogen atoms) is transferred to another molecule, which changes how that molecule behaves.

This reaction requires a steady supply of nutrients known as methyl donors, like folate, vitamin B12, and betaine (aka trimethylglycine or TMG).

So, where does NMN come in?

NMN Role In Methylation

NMN supports NAD+ production through the salvage pathway, a series of biochemical steps the body uses to recycle vitamin B3 derivatives (many of which are precursors to NAD+). Boosting NAD+ is beneficial for overall healthy cellular function.

Still, there’s a biochemical trade-off: when the body uses NMN, it creates something extra called nicotinamide, or NAM.

NAM is like the wrapper left over after opening a protein bar — it’s not useful anymore, so your body needs to get rid of it. That's where methylation comes in, which adds a methyl group to NAM, allowing it to be flushed out through urine.

Remember that methylation needs methyl donors to complete this process, and the body only has so much to go around.

This means that if you're using NMN often, your body requires more methyl groups to keep cleaning out that extra NAM produced, leaving fewer supplies for other important roles of methylation, like keeping your heart healthy, neurotransmitter production, and maintaining healthy DNA.

So even though NMN helps your cells, it also makes your body work harder behind the scenes, and that’s something to be aware of, especially if your body is already low on those methyl donors.

TMG and NMN Together In Methylation Support

Trimethylglycine (TMG) is a compound naturally found in foods like spinach or beets. It's a methyl donor, which gives the body extra methyl groups as part of the methylation process.

If you regularly take NMN supplements, it is also a good idea to take some methylation support supplements like TMG. 

Taking TMG with NMN may support your body’s methylation system by replacing the methyl groups that are being used up. This way, your body can keep clearing out the NAM byproduct while still having enough methyl groups for everything else it needs to do.

What Are The Benefits of Taking TMG?

TMG supplements are typically taken to support health methylation, which in turn benefits the following systems in the body:

1. Healthy homocysteine levels: TMG helps convert homocysteine, an amino acid, into methionine, which is used to build proteins. Keeping homocysteine at normal levels is important for cardiovascular and metabolic health [1].

2. Supports healthy liver function: TMG may support the liver’s natural detoxification function by helping process fats and removing byproducts that build up [2].

3. Contributes to cellular metabolism: TMG is involved in one-carbon metabolism, which supports reactions key to DNA synthesis, repair, and overall cellular function [3].

How does MTHFR Mutation Occur?

The MTHFR mutation isn’t something you develop — you’re born with it. It’s a genetic variation (a polymorphism) in the MTHFR gene. This gene carries instructions for making an enzyme called methylenetetrahydrofolate reductase.

This enzyme is needed for methylation in the following ways:

• Convert folate (vitamin B9) from food into its active form (5-MTHF)

• Process homocysteine into methionine, which is used to build proteins

The mutation happens when there's a small change in the DNA sequence of the MTHFR gene. There are two common types:

• C677T

• A1298C

You inherit one copy of the MTHFR gene from each parent so that you can have:

• No mutation (typical enzyme function)

• One copy (heterozygous) – mild change in enzyme function

• Two copies (homozygous) – reduced enzyme activity, which can affect how your body handles folate and methylation

An MTHFR mutation doesn’t guarantee health problems, but it can affect how efficiently your body carries out methylation, especially if your diet is low in nutrients like folate, B12, and B6.

Some people with this mutation might take methylated forms of B vitamins or TMG to help support this pathway.

Should You Supplement TMG When Taking NMN?

Whether or not to supplement TMG with NMN, NR, or other NAD+ precursors depends on the individual, and it may be helpful to discuss this with your healthcare professional. 

NMN supplements are fairly safe, and research is behind their ability to support healthy NAD+ levels in the body to support a healthy aging process [4].

Most healthy individuals don't have to worry about depleting their methyl group reserves by taking moderate doses of NMN. You get plenty of methyl donors to keep the methylation process running smoothly as long as you eat a balanced diet that includes foods rich in vitamin B12, folate, and choline (think leafy green veggies and legumes).

That being said, there might be some people who should consider taking TMG alongside NMM, for instance:

• You're taking higher doses of NMN or other NAD+ precursors (600 mg+ daily)

• You're using NAD+ supplements long-term (6 months+)

• You're concerned about methylation support (older individuals, those with genetic factors that affect methylation, people under chronic stress, or those with a diet low in methyl-donor nutrients).

If you're unsure where you fit in, it's a good idea to speak with a healthcare professional and consider factors like your diet, supplement routine, and any known genetic or metabolic concerns related to methylation.

Resources:

1. Kumar, A., Palfrey, H. A., Pathak, R., Kadowitz, P. J., Gettys, T. W., & Murthy, S. N. (2017). The metabolism and significance of homocysteine in nutrition and health. Nutrition & metabolism, 14, 1-12.

2. Mukherjee, S. (2020). Role of betaine in liver disease-worth revisiting or has the die been cast?. World journal of gastroenterology, 26(38), 5745.

3. Kalecký, K., Ashcraft, P., & Bottiglieri, T. (2022). One-carbon metabolism in Alzheimer’s disease and Parkinson’s disease brain tissue. Nutrients, 14(3), 599.

4. Liao, G., Xie, Y., Peng, H., Li, T., Zou, X., Yue, F., ... & Rong, L. (2024). Advancements in NMN biotherapy and research updates in the field of digestive system diseases. Journal of Translational Medicine, 22(1), 805.