What is methylation? At the most basic level, methylation and demethylation refer to the transfer of methyl groups (simple structures of one carbon and three hydrogen molecules (CH3)), to and from various bioactive compounds in the body. These compounds (e.g. proteins, enzymes, hormones) must be methylated in order to function optimally or to create other substances required by the body.

For example, methylation is essential for the production of certain bioactive vitamins (e.g., folate and vitamin B12), amino acids, neurotransmitters, hormones, red blood cells, DNA, RNA, and antioxidants that directly impact cardiovascular, neurological, reproductive health, energy production, detoxification pathways, and more.

The process of DNA methylation, a unique subset of methylation physiology, is somewhat different and specifically refers to the attachment of methyl groups to certain segments of DNA, which in turn tells the body what genes should be turned on and off. DNA is the code or instructions for a wide array of functional proteins to be made throughout our body, from signalling molecules and neurotransmitters to hormones and antibodies.

Typically, DNA methylation turns genes off, while demethylation turns genes on.

DNA methylation is an example of epigenetics – that is, changes in the physical structure of DNA caused by your behaviour (including nutrition and lifestyle) or environment, which can be passed down from parent to child.

The pivotal and fascinating process of DNA methylation is relevant to life and health.

The methyl groups that participate in methylation come from a variety of micronutrients in your diet collectively dubbed ‘methyl donors,’ which include folate (B9), vitamin B12, vitamin B6, riboflavin (B2), betaine, choline, and several others. You’ll notice the prominence of essential B vitamins in this lineup. Folate is probably the most well-known methyl donor in the B vitamin family, so we’ll use it as an example to highlight exactly how methylation works.

Once you consume folate from food or folic acid (found in fortified foods and certain supplements), the enzyme methylenetetrahydrofolate reductase (MTHFR) theoretically (the MTHFR gene codes for the MTHFR enzyme, more on that later) converts vitamin B9 into its bioactive form called methylfolate or 5-methyltetrahydrofolate (5-MTHF), which is fully activated and can now serve as a methyl donor for those widespread health functions mentioned earlier (think heart, brain, detox, energy, immunity).

Specifically, this bioactive folate (5-MTHF) donates a methyl group to the amino acid homocysteine to convert it to the amino acid methionine. Not only does this directly support healthy homocysteine levels (helps them from getting too high) in the body, but also methionine can then be utilised to form S-adenosylmethionine (SAM-e).

SAM-e is incredibly important because it functions as a ‘universal methyl donor’ for all biological methylation processes in the body, including DNA methylation, which means it donates methyl groups to all sorts of acceptor molecules to support optimal physiological functioning globally in the body.

After SAM-e has donated its methyl groups, it’s converted back to homocysteine, which can go on to produce cysteine (another amino acid) and then master antioxidant glutathione, or to accept another methyl group from 5-MTHF and repeat the cycle. Taken together, the activation of folate (aka, the folate cycle) and the homocysteine conversion onto methionine and ultimately SAM-e (dubbed the methionine cycle) enable and fuel methylation.

What Is The Role Of Methylation?

A biochemical and epigenetic process with truly systemic reach and implications, methylation plays several big roles in the body. One of those big roles briefly mentioned above is the recycling of the amino acid homocysteine to keep its levels in a healthy, optimal range. As nutrition scientist Ashley Jordan Ferira, Ph.D., RDN explains, “Your health care practitioner can measure homocysteine levels with a simple blood test.”

Ferira goes on to say, “Achieving and maintaining healthy homocysteine levels is required for the optimal production of numerous amino acids, neurotransmitters, hormones, and antioxidants, which participate in processes throughout the body and mind.”

Indeed, this biomarker has massive implications for our overall health, but especially for cardio-protective blood vessel functioning and neuro-protective actions for thriving brain function.

Some important compounds (i.e., hormones, neurotransmitters, coenzymes, and other bioactives) that require methylation to be manufactured include the following:

  • Coenzyme Q10 (CoQ10)
  • Glutathione
  • Melatonin
  • Epinephrine
  • Norepinephrine
  • Dopamine
  • Serotonin
  • Creatine
  • Cysteine
  • Taurine
  • Phosphatidylcholine

Methylation also supports natural detoxification pathways in the body by assisting in the appropriate breakdown and removal of various hormones and toxins by transforming them into a form that is easier to excrete.

Furthermore, methylation helps produce the powerful antioxidant glutathione, which binds to and helps safely remove toxins such as heavy metals from the body, according to functional medicine doctor Mark Hyman, M.D.

Finally, as mentioned above, DNA methylation can help silence genes that might otherwise up your risk for unruly processes in the body that can lead to sub-optimal organ function and worse.

What Are The Causes And Consequences Of Sub-Optimal Methylation?

One potential cause of poor methylation is having the MTHFR gene variant, which reduces the efficiency of transforming dietary folate and folic acid to their active methylfolate (5-MTHF) form. This can lead to a functional folate deficiency and a lack of methyl groups required for methylation (for all the essential biological actions described above).

While individual responses vary, this suboptimal methylation can manifest on a spectrum in terms of its health impact. And as Ferira points out, “Interestingly, the MTHFR genetic variant is not rare but rather widespread, with some estimates indicating that approximately 40% or more of the population could be impacted. That’s over a hundred million Americans alone.”

Certain diet and lifestyle habits can also interfere with optimal methylation. In addition to inadequate consumption of folate-rich nutrition and failing to take in bioactive forms of B vitamins and other methyl-donor nutrients, “too much alcohol or coffee consumption, smoking cigarettes, and high exposure to arsenic in food and water can all deplete the body of methyl groups needed for optimal methylation—unless you’re taking steps to replace them with food or supplements,” says Rountree.

So What Happens When Methylation Isn’t Top Notch?

“Methylation affects all physiological processes, so we see a wide range of problems when it’s compromised,” says functional medicine physician Karyn Shanks, M.D. Shanks says these potential issues can truly span the entire body, possibly manifesting as sub-optimal energy levels and cognitive function, or mood challenges and sub-par detoxification abilities.

More specifically, interference with neurotransmitters may contribute to low mood and feelings of anxiousness, lack of focus and difficulty sleeping, while an inability to adequately excrete toxins can drive inflammatory processes and negatively affect skin and energy, as well as gut, musculoskeletal, and reproductive health, according to Ali Miller, R.D., L.D., CDE, registered dietitian.

Ferira adds that elevated homocysteine levels resulting from poor methylation “is not only a lab test result you’ll want to avoid, but more importantly, over time, this imbalance can contribute to vascular issues that are directly pertinent to your heart and brain.”

She underscores this further explaining that, “normal methylation and healthy homocysteine levels are inextricable and pivotal to optimise cardio-protective and neuro-protective benefits throughout life.”

How To Learn About Your Own Methylation Cycle

Methylation influences nearly every aspect of your health, so it can be difficult to assess methylation function based on how you’re feeling alone. Echoing Ferira’s insights on the importance of healthy homocysteine levels, Rountree recommends a simple homocysteine blood test.

Because methylation is essential for homocysteine processing and recycling, elevated homocysteine levels could be a clinical biomarker indicator of sub-optimal methylation. Ferira shares that, “depending on the practitioner, they may consider age and gender-specific homocysteine ranges to test for normalcy.”

For example, for ages 18 to 60, a homocysteine result of less than 14.5 µmol/L is considered in the normal range. But in functional and integrative medicine, a more conservative homocysteine level (
less than 7 μmol/L) may be considered optimal.

In cases of elevated homocysteine, supplementing and eating more foods that are rich in methyl-donors in their bioactive formats can support methylation and bring homocysteine levels back to a healthier range.

Although quite common in integrative, functional, and precision medicine settings, genetic testing to determine if you have the MTHFR variant isn’t necessary to assess your methylation status. It’s definitely informative but typically not even recommended unless you have elevated homocysteine and specifically want to know if your genes are part of the equation.

If you’re interested in genetic testing, consider working with an integrative or functional medicine practitioner who can run a comprehensive panel and make targeted, personalised recommendations for lifestyle changes and nutrition protocols based on those results.

How To Support Methylation

There are plenty of ways to support methylation, and nutrition plays the biggest role.

Methylation relies heavily on fully activated folate, along with other methyl donor nutrients such as vitamin B12, vitamin B6, choline, and betaine, says Miller.

In addition to those key players, Ferira adds an oft-forgotten B vitamin into the methylation mix: “Riboflavin, aka vitamin B2, is a required cofactor for the MTHFR enzyme, required for folate recycling, so it can be the amazing methyl donor it’s designed to be,” she explains.

Here’s how you can get your fill of each methyl donor from food:

  • Folate (vitamin B9, but remember, it’s not in its fully bioactive 5-MTHF form yet): Spinach, asparagus, mustard greens, kale, broccoli, avocado, asparagus, beetroot, citrus, animal proteins (particularly beef liver), legumes, nuts, and seeds
  • Vitamin B12: Meats and meat products, poultry, fish, shellfish, and eggs
  • Vitamin B6:Meats, whole grains, pistachios, sesame seeds, sunflower seeds, garlic, legumes, and prunes
  • Choline: Meat, fish, poultry, dairy, eggs, shiitake mushrooms, legumes, and cruciferous veggies
  • Betaine: Quinoa, beets, spinach, whole grains, sweet potato, meats, and poultry
  • Riboflavin (vitamin B2): Meats (especially organ meats), dairy, eggs, fortified cereals and grains, and green vegetables (e.g., asparagus, broccoli, and spinach)

Also, try not to consume anything to excess (good advice in general, not just for methylation health optimisation!) – particularly alcohol or coffee, which can deplete your body of methyl donors and mess with methylation pathways, including DNA methylation

Smart supplements with methyl donors woven into the very fabric of their formulation can come in handy too. For example, if you’re seeking to support healthy homocysteine levels, or you know you have the MTHFR gene variant, taking a supplement that already contains the bioactive form of folate (methylfolate, aka 5-MTHF) plus the fully activated forms of other B vitamins can help you absorb and utilise these methylation-essential nutrients most efficiently.

While there’s still some debate on the best interventions and approach, Rountree has been using and recommending methylfolate in his clinical practice for the past 20 years. Ferira concurs, adding, “This precision approach of delivering bioactive methyl donors and other key methylation cofactors is shared by most practitioners in the integrative medicine and nutrition sectors.”

We hope more methylation health discussions will go mainstream, because, “the methylation cycle and DNA methylation are probably some of the most under-discussed, yet wide-reaching and essential, physiological processes in the body. I’m ready for their prime time because so many people would benefit from methylation optimisation,” says Ferira. She goes on to say that, “The right combo of bioactive B vitamins and bioactives are a gene-focused and bio-hacking nutrition approach to maximise your methylation potential.”

Finally, try to prioritise high-quality sleep and stress management practices, says Shanks, as both stress and inadequate sleep have been shown to negatively affect DNA methylation.

Boosting your daily physical activity levels can help with both, as well as promote detoxification and possibly even lower homocysteine levels.

The Bottom Line

Methylation influences just about every essential process in the body. It’s needed for the production of amino acids, neurotransmitters, hormones, red blood cells, DNA, RNA, and antioxidants; for proper detoxification of hormones and toxins; and for determining whether certain genes will be expressed or not (the power of epigenetics). It’s a big deal.

But when this vital process is compromised (which can happen as a result of a variety of dietary, lifestyle, and genetic factors) your physical and mental wellbeing, from a cellular to whole-body level, will pay the price.

The good news: A simple homocysteine test can help you get a glimpse of your own methylation cycle health and help determine whether you need to make any dietary or lifestyle changes.