Methylation

“You keep using that word. I do not think it means what you think it means.” – Inigo Montoya, The Princess Bride

Sometimes that’s what I think when I hear someone mention methylation. While methylation has become a buzzword in the health and wellness community, back in chemistry class it just meant adding a methyl group (one carbon atom attached to three hydrogen atoms) to another chemical structure. But what does methylation have to do with my health and why should it matter to me? And why does Thorne include a methyl donor in their nicotinamide riboside (NR) supplements?

Let’s start with methylation in the body

Physiologically speaking, putting a methyl group onto other molecular substances happens for many reasons. For example, when a person mentions methylation in the body, they could be talking about how the body uses methyl groups in DNA replication. Methyl groups are also used to turn genes on or off – a process known as epigenetics.

Methylation is a liver detoxification function as well – breaking down toxic substances and hormones, like excess estrogens, into water-soluble molecules to be eliminated from the body. Neurotransmitters that affect our nervous systems and mood are both made and broken down utilizing the transfer of methyl groups. Cardiovascular health, immune function, energy production, and even digestion all require methylation to function properly.

With so many physiological processes requiring methylation, where do the methyl groups come from? 

Methyl donors are chemical structures, or nutrients in the case of the human body, that will readily donate a methyl group to another substance. This occurs through the process known as the methylation cycle. There are several nutrients that can provide methyl groups to the methylation cycle – folate being one of the most well-known.

“Pardon me, do you have any methyl groups?”

In its most bioavailable, ready to use form, folate is called 5-methyltetrahydrafolate (methyl-folate or 5-MTHF for short). Think of it like that famous mustard commercial: methyl-folate pulls up next to the methylation cycle with an extra methyl group on board, the amino acid homocysteine rolls down its window and politely asks for an extra methyl group, and methyl-folate is happy to oblige.

Homocysteine then takes in the methyl group and converts to another amino acid – methionine. (OK, I know we’ve deviated a bit from the commercial, but bear with me). Methionine pushes on through the cycle, takes in other nutrients, and becomes SAM-e, a master at delivering its methyl groups to substances like DNA, enzymes, and hormones that must be methylated to function or transform properly. After SAM-e donates its methyl groups, it is converted back to homocysteine, which continues around the cycle to folate where it can pick up methyl groups (like mustard in the commercial) and start the cycle all over again.

Vitamin B12 (methylcobalamin) can offer assistance to folate and donate a methyl group to homocysteine, as needed. Meanwhile, betaine (or trimethylglycine) can enter the methylation cycle directly, with three methyl groups available for use. The more homocysteine that arrives for conversion, the more methyl donors are needed. And while folate might be the most well-known methyl donor, betaine’s three available methyl groups make it the most efficient.

Vitamin B6 and several other nutrients also cruise the methylation cycle, looking to provide cofactors for the different conversions to occur. However, those most important methyl donors (betaine, folate, vitamin B12) need to be present in sufficient amounts to keep the cycle running smoothly.

What happens if you don’t methylate efficiently?

By now you might be thinking, ok this all sounds great, but would I know if my methylation cycle isn’t working optimally?

Over time, if there aren’t enough methyl donors available to efficiently convert homocysteine, then the level of homocysteine in the blood begins to rise. Although a high blood level of homocysteine can be an indication of a vitamin B12 or folate deficiency, it is also associated with an increased risk for cardiovascular disease. Additionally, if there aren’t enough methyl donors available to keep up with the body’s demand, other physiological processes that require methyl groups might not function as well either.

So, what does this have to do with nicotinamide riboside (NR) and the addition of methyl donors to Thorne’s NR supplements? 

Taking NR increases nicotinamide adenine nucleotide – or NAD+, a key substance present in every cell in the body. NAD+ is necessary for cellular energy production and plays a critical role in both metabolism and DNA repair. As the body uses NAD+, it either recycles it into more NAD+ or converts it to be eliminated. It does the latter by breaking down NAD+ to nicotinamide (NAM) and placing a methyl group onto it, creating methylnicotinamide (MeNAM), which is removed from the body through urine. This process uses up valuable methyl groups.

Including a methyl donor with NR supplements is important for several reasons:

1. To maintain optimal homocysteine levels*

As just discussed, one way NAD+ is metabolized is by placing a methyl group onto it. So, if NAD+ increases in your body, you will make more MeNAM, and in order to make MeNAM, you need methyl groups. This process increases demand on the methylation cycle, and as mentioned earlier, if there aren’t enough methyl donors present to meet methylation cycle demands, blood levels of homocysteine can start to rise.1 Because high levels of homocysteine are associated with increased cardiovascular risk, supporting adequate methylation to help maintain a healthy level of homocysteine just makes sense.* High levels of homocysteine are also associated with increased risk for osteoporosis and cognitive dysfunction.*

2. To maintain optimal neurotransmitter function*

There can only be as many methyl-dependent processes functioning in the body as there are methyl donors to support them. A 2017 study considered the effects of increased use of methyl groups by nicotinamide metabolism and found that other methyl-dependent processes, like neurotransmitter functions, were negatively affected.1 Adequate methyl groups are necessary for metabolism and elimination of the catecholamines epinephrine and norepinephrine.* Because these neurotransmitters regulate cardiovascular functions via the sympathetic nervous system, high levels circulating in the blood can have negative cardiovascular effects.*2 In the 2017 study, the authors also found that supplementing with the methyl donor betaine helped to reverse the methyl group deficit and corresponding blood levels of metabolites, whereas supplementation of non-betaine methyl donors was not as efficient.*1

3. To maintain optimal DNA methylation*

Increased demand on methyl donors can lead to hypomethylation of DNA,1 a process linked with development of several adverse health conditions. DNA methylation regulates development and plays a particularly important role in this process early in life.3 While some hypomethylation is a normal part of the aging process, a lack of methyl donors can amplify the effect.* Hypomethylation of DNA has been linked epigenetically to several inflammatory conditions.3

As you can see, having sufficient methyl donors available to promote efficient methylation has a positive impact on health and wellness.* Increased demand for methyl groups, whether from NR supplementation, environmental factors, or other increases in methylation functions, can stress existing pools. Supplementing with a methyl donor, like betaine, helps support efficient methylation.*

Check out Thorne’s NR suite of products - NiaCel 400, ResveraCel®, and Collagen Plus, all with betaine, and the multivitamin Advanced Nutrients, with 5-MTHF, methylcobalamin, and cofactors for added methylation support.*


References

  1. Sun W, Zhai M, Li D, et al. Comparison of the effects of nicotinic acid and nicotinamide degradation on plasma betaine and choline levels. Clin Nutr. 2017;36(4):1136-1142. doi:10.1016/j.clnu.2016.07.016
  2. Sun W, Li D, Lun YZ, et al. Excess nicotinamide inhibits methylation-mediated degradation of catecholamines in normotensives and hypertensives. Hypertens Res. 2012;35(2):180-185. doi:10.1038/hr.2011.151
  3. Borchiellini M, Ummarino S, Di Ruscio A. The bright and dark side of DNA methylation: a matter of balance. Cells. 2019;8(10):1243. doi:10.3390/cells8101243