Methylation 101

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The study of epigenetics demonstrates how our environment, diet, and lifestyle impact our gene expression and metabolism leading to good health or disease. Methylation is a primary player in this process and impacts our health, aging, and the development of various conditions from cardiovascular disease to depression to cancer.

What is “Methylation”?

Methylation is a biochemical process with numerous reactions that occur in every cell of our bodies in which a methyl group (CH3) is added to a substrate such as hormones, DNA, neurotransmitters, and immune cells.

This simple biochemical reaction is involved in the production of genetic material, regulation of gene expression, as well as metabolic processes, and can have a positive or negative impact on nearly every system in our bodies!

Why is Methylation Important?

Methylation is used throughout the body for some of these functions:

The methylation cycle is part of a larger chain of events that, all together, create a domino effect resulting in either good or poor health outcomes. If one link in the chain is not working properly, there is a “backup” of the entire system and downstream effects.

Impaired function of the methylation cycle can lead to a wide range of health challenges and conditions, including:

●       Autism

●       Allergies

●       Alzheimer’s disease

●       Anxiety/Depression

●       Autoimmune disorders

●       Birth defects

●       Cardiovascular disease

●       Cancer

●       Diabetes

●       Infertility and Miscarriage

●       Parkinson’s disease

●       Schizophrenia

●       Thyroid disease

●       Chronic viral infections

What Can Impair Methylation?

Many factors impact the methylation cycle, such as genetic mutations called SNPs (single nucleotide polymorphisms), diet, lifestyle, and environment. The most commonly looked at SNP that influences methylation activity is MTHFR.

It starts with MTHFR: We need a critical B vitamin, 5-MTHF (a.k.a, active folate or methylfolate), to start the methylation cycle. MTHFR (methylenetetrahydrofolate reductase) is an enzyme that converts the inactive form of folate to methylfolate to be used in this cycle. There are MTHFR gene variants or SNPs that reduce the function of this enzyme, and some research estimates that up to 40% of people in the U.S. have a MTHFR genetic mutation.

Here is a general flow of how methylation flows from a systemic process point of view:

Folate metabolism

Graphic from: Luciano-Mateo F, Hernández-Aguilera A, Cabre N, Camps J, Fernández-Arroyo S, Lopez-Miranda J, Menendez J, Joven J. Nutrients in energy and one-carbon metabolism: learning from metformin users. Nutrients. 2017;9(2):121.


Diet & Lifestyle Factors: While MTHFR SNPs have received a lot of attention, there are many other factors that influence methylation. These include:

Assessing Methylation Status

How can you tell if methylation is an issue for you? It comes down to looking at the whole picture, starting with your genes, key lab markers, and health history of symptoms.

Genetic Profiling: Through common genetic testing, such as 23andme, or more specific panels for the methylation pathway, we are now able to identify genetic variances that may have an impact on our health.

Two of the most studied SNPs have been MTHFR C677T and MTHFR A1298C.

Having MTHFR C677T heterozygous (one copy) causes a reduction in enzyme function by about 30%, whereas MTHFR C677T homozygous (two copies) results in 70 – 75% loss of enzyme activity.

However, having a genetic blueprint does not mean a particular gene or genetic mutation is expressed. Therefore, if you have been tested and found to have SNPs, it does not necessarily mean it is expressing or active. Currently, the most accurate way to assess the function of this pathway is through lab testing for functional biomarkers.

Function Lab Biomarkers for Methylation: Here are some lab levels to watch out for:

  • Low or high homocysteine
  • Low or high serum folate
  • Low RBC folate
  • Low serum vitamin B12
  • High urine methylmalonic acid (MMA), a marker of low vitamin B12
  • High urine FIGLU, a marker of low folate
  • Low methionine
  • SAMe:SAH

Ways to Support the Methylation Pathway

When it comes to methylation, the goal is balance. Both under-methylation (hypomethylation) and over-methylation (hypermethylation) may lead to problems, and the recent popularity in high-dose supplementation of methyl B vitamins has not been studied long term. Some research has found that over-supplementation of folate can be problematic.

Start with Food First

Nutrient deficiencies are a major cause of impaired methylation, and supporting the balance of methylation activity with food is safe and effective. Support for methylation consists of nutrient cofactors and methyl donors, including folate, B12, B6, betaine; minerals such as zinc, magnesium, iron; and sulfur proteins such as methionine.

A colorful and diverse diet high in phytonutrients with lots of folate-rich green vegetables is key!

Here are some foods that support proper methylation:

  • Methionine: Meats, poultry, fish, shellfish, eggs, nuts, seeds (sesame seeds and pumpkin seeds), spirulina, teff, and soybeans
  • Vitamin B12: Meats, especially organ meat (liver and kidney), poultry, fish, shellfish, and eggs
  • Vitamin B6: Meats, nuts (pistachios), garlic, whole grains, seeds (sesame and sunflower seeds), legumes (chickpeas and lentils), and prunes
  • Betaine: Quinoa, beets, spinach, whole grains (rye, kamut, bulgur, amaranth, barley, and oats), sweet potatoes, meats, and poultry
  • Folate: Beans and legumes (mung beans, adzuki beans, chickpeas, and lentils), liver, nuts, seeds (sunflower seeds), spinach, asparagus, mustard greens, and avocado
  • Magnesium: Seeds (pumpkin seeds and sesame seeds), beans, nuts (Brazil nuts and almonds), and whole grains

Methylation Regulators

Certain nutrients can act as epigenetic regulators that impact the overall balance of methylation in the body, as is the case with anti-cancer compounds in many herbs and spices. Some top foods that regulate methylation include cruciferous vegetables (arugula, broccoli, kale, cauliflower, cabbage), berries (blackberries, blackcurrants, blueberries, raspberries, and strawberries), mushrooms (shiitake), turmeric, and rosemary.

Support a Healthy Gut Microbiome

Gut microbes are key players in supporting methylation, producing folate, and influencing local DNA methylation patterns, modulating epigenetic activity. Eating fermented foods, taking probiotics, and incorporating prebiotic foods, such as onions, leeks, garlic, asparagus, and Jerusalem artichoke, can all be supportive for methylation.

Reduce Oxidative Stress

Stress has a huge impact on methylation, and taking steps to reduce stress in all ways will support methylation balance, such as reducing heavy metals, balancing blood sugar and insulin, addressing chronic infections, supporting sleep hygiene, and daily physical activity and exercise.

Medications that Interfere with Methylation

It’s important to be aware that medication may impede methylation activity through a variety of mechanisms, such as depleting certain B vitamins. Common drugs that inhibit methylation include antacids and PPIs, antibiotics, cholestyramine, colestipol, oral contraceptives, nitrous oxide, and metformin.

While methylation is a complex process and issue, there are clearly many ways to support this pathway using diet and lifestyle with a holistic approach tailored to the individual. Be sure to speak to your healthcare practitioner for more information about healthy methylation.




1 Comment

  1. Ranka

    Thank you very much for such simple and clear explanation of that very important process for our health.


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