If you're interested in supporting health on a foundational or cellular level, you can't overlook methylation. Methylation is a simple yet vitally important biochemical process in the body that is widespread and helps regulate the activity of our neurological, cardiovascular, reproductive, and detox systems. To name a few.
Methylation takes place approximately one billion times per second and affects nearly every essential process in the body, according to functional medicine physician Robert Rountree, M.D. 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 well-being, from a cellular to whole-body level, will be suboptimal or worse.
Here, we break down what methylation is, what can interfere with it, and how to support methylation to enhance overall health.
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, and more) 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 amino acids, neurotransmitters, hormones, and antioxidants that directly impact neurological, cardiovascular, reproductive health, and more.
DNA methylation 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, in turn, is the code or instructions for a wide array of functional proteins to be made throughout our body, from signaling molecules and neurotransmitters to hormones, antibodies, and more.
Typically, DNA methylation turns genes off (and as it turns out, is relevant to life and health, from early development to immunity, memory formation, and more), while demethylation turns genes on. DNA methylation is an example of epigenetics—that is, changes in the physical structure of DNA caused by your behaviors (including nutrition, lifestyle, etc.) or environment, which can be passed down from parent to child.
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, so we'll use it as an example to highlight exactly how methylation works.
Once you consume folate or take a folic acid supplement, the enzyme MTHFR theoretically (more on the MTHFR gene mutation later) converts it into a bioactive form called methylfolate or 5-MTHF, which can now serve as a methyl donor for those widespread health functions mentioned earlier (think heart, brain, detox, etc.).*
Specifically, 5-MTHF donates a methyl group to the amino acid homocysteine to form the amino acid methionine; and methionine, in turn, can be activated to form S-adenosylmethionine (SAM-e). SAM-e is 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. The methylation cycle, that is.
Advertisement This ad is displayed using third party content and we do not control its accessibility features.What is the role of methylation?
An epigenetic process with truly systemic reach and implications, methylation plays several big roles in the body, including in the recycling of the amino acid homocysteine to keep its levels in a healthy 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 and especially for cardioprotective blood vessel functioning and neuroprotective actions for our brain function to thrive.
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 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 suboptimal organ functions and worse.
Advertisement This ad is displayed using third party content and we do not control its accessibility features.What are the causes & consequences of suboptimal methylation?
One potential cause of poor methylation is having the MTHFR genetic variant, which interferes with the efficient transformation of 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% 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 exposures 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 goes on to share that these potential issues can truly span the entire body, possibly manifesting as suboptimal energy levels and cognitive function, or mood challenges and subpar detoxification abilities.
More specifically, interference with neurotransmitters may contribute to low mood and feelings of anxiousness, lack of focus, difficulty sleeping, and more; 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 resulting from poor methylation "is not only a lab test result 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 optimize for cardioprotective and neuroprotective 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 suboptimal 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 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, personalized recommendations for lifestyle changes and nutrition protocols based on those results.
Advertisement This ad is displayed using third party content and we do not control its accessibility features.How to support methylation.
There are plenty of ways to support methylation—and nutrition plays the biggest role. Methylation relies heavily on 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 from food:
- Folate (vitamin B9): Spinach, asparagus, mustard greens, kale, broccoli, avocado, asparagus, beets, 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, whole grains, garlic, legumes, and prunes
- Choline: Meat, fish, poultry, dairy, eggs, shiitake mushrooms, legumes, cruciferous veggies
- Betaine: Quinoa, beets, spinach, whole grains, sweet potato, meats, and poultry
- Riboflavin (vitamin B2): Meats (especially organ meats), dairy, eggs, green vegetables (e.g., asparagus, broccoli, and spinach), fortified cereals and grains
Also, try not to consume anything to excess (good advice in general, not just for methylation health optimization!)—particularly alcohol or coffee, which can deplete your body of methyl donors and mess with methylation pathways, including DNA methylation.
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Shop now Smart supplements with methyl donors woven into the very fabric of their formulation (like mbg's ultimate multivitamin+, a truly comprehensive, high-potency vegan multi designed for women and men) 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) and other B vitamins (i.e., all the B's in their most bioactive formats) can help you absorb and utilize these methylation-essential nutrients more readily.*
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 underdiscussed, 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 optimization."
Finally, try to prioritize high-quality sleep and stress management practices, says Shanks, as both inadequate sleep and stress 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.
Advertisement This ad is displayed using third party content and we do not control its accessibility features.Bottom line.
Methylation influences just about every essential process in the body. It's needed for the production of amino acids, neurotransmitters, hormones, and antioxidants; for proper detoxification of hormones and toxins; and for determining whether certain genes will be expressed or not (the power of epigenetics). 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 well-being, from a cellular to whole-body level, will be suboptimal. The good news: A simple homocysteine test can help you get a glimpse of your own methylation cycle and help determine whether you need to make any dietary or lifestyle changes to support it.
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