NMN is a substance that has shown to reduce various aging symptoms in studies (R,R,R,R,R), and has shown to improve insulin resistance, muscle metabolism and aerobic metabolism in humans (R,R,R).

However, when you take NMN, some waste products of NMN require proper methylation to be disposed. So taking NMN could increase the need for more and proper methylation. 

The MTHFR enzyme is needed for methylation, and it’s here that the MTHFR mutation comes into play.

People with the MTHFR mutation can suffer from reduced methylation.

Why methylation is paramount for health

Methylation involves enzymes putting methyl groups on DNA and proteins so they can function properly. Methyl groups are small molecules consisting of a carbon atom and 3 hydrogen atoms (-CH3).

Methylation is very important for proper DNA function. Putting methyl groups on the DNA “covers” the DNA strand, switching genes off.

Some proteins need to be methylated to carry out their function properly.

MTHFR stands for “methylenetetrahydrofolate reductase”. It is an enzyme that converts methylenetetrahydrofolate (methylene-THF) into methyl-tetrahydrofolate (methyl-THF), which is needed convert homocysteine into methionine.

To be more precise, methyl-THF transfers its methyl group to create methionine. Methionine then undergoes a series of reactions to transfer its methyl group to DNA or proteins, so these get methylated.

Methylenetetrahydrofolate stems from folic acid (vitamin B9).

The most common MTHFR mutations are C677T and A1298C. If you have these mutations, it could mean that less methyl-THF is made from folic acid (or methylene-THF), and less methylation can happen.

Around 5 to 14% of the U.S. population is homozygous for C677T, meaning that they have two mutations (one on each chromosome). Between 20 to 40% of whites and hispanics in the U.S. are heterozygous, meaning one of the two chromosomes have a mutation, with rates much less common for blacks. For those with the heterozygous mutation, enzymes function at ≈65% of normal. For those who are homozygous for C677T, enzymes function at only ≈30% of normal.

These mutations could reduce the ability of the body to properly methylate DNA or proteins, which could increase the risk of heart disease, depression and dementia.

How to improve methylation

If you have a MTHFR mutation, it can be helpful to take specific vitamins and minerals to improve these methylation pathways. 

Often people are recommended to take methyl donors or substances that improve methylation, like methyl-folate, trimethylglycine (TMG or betaine) or SAMe (S-adenosylmethionine).

However, some people do not react well to TMG, which can for example cause gastro-intestinal distress and sleep problems after a while. These are also complaints that can arise in people who don’t have a MTHFR mutation but take TMG in the long term.

Some people take methyl-folate or SAMe to improve methylation. Some feel better taking these ingredients. Others experience no effects, or even feel worse. Everyone is different and one should try out whether these substances work or not. 

Regarding the fact that some people feel worse with methyl-folate, SAMe and TMG, this could be because these substances are already too deep down into the methylation pathways, forcing the cells to use these substances, or actually by inhibiting or interfering with other methylation pathways. 

Therefore, some people prefer substances that allow the cells to choose themselves when and how to use these substances. 

These substances could for example be a vitamin B complex with doses that are a few times higher than the standard official RDAs. B vitamins are needed for proper methylation. A vitamin B complex contains all B vitamins, like vitamin B12, B9, B6, B3, B1, B2 and so on. 

Another example is choline, which is more at the beginning of important methylation pathways. We would recommend choline chloride, not choline bitartrate which can make some people more tired after a few days of taking it. We wrote more extensively about the benefits and risks of choline here. 

Some people also take phosphatidylcholine, a substance that  contains choline. Phosphatidylcholine is also an important component of cell membranes, especially in brain cells. 

NMN and methylation

Whether you have a MTHFR mutation or not, you can take NMN. In fact, NMN can give people more energy and confer other longevity benefits, with or without MTHFR mutations.

We do recommend taking substances that improve methylation, like B vitamins, whether one has an MTHFR mutation or not. It’s always important to make sure you take enough B vitamins, choline and phosphatidylcholine to enable proper methylation. 

Some people only look at homocysteine levels to decide if they need to take these extra supplements. After all, when methylation is not working properly, homocysteine levels increase. 

However, normal homocysteine levels does not mean one is out of the woods. Homocysteine levels can be normal despite suboptimal methylation. Despite normal homocysteine levels many other things can still go wrong regarding methylation and epigenetic health.

Epigenetic health is crucial for longevity. Therefore, we also added other substances to NOVOS Core that epigenetically impact longevity, like alpha-ketoglutarate (a substrate of the TET enzymes for example, works synergistically with vitamin C in this regard), micro-dosed lithium, glycine, and more.