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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 ranging 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 (a molecule of a single carbon and three hydrogens) 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, and metabolic processes. It can positively or negatively impact nearly every system in our bodies.

Why is Methylation Important?

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

• Cellular energy + mitochondrial function
• Detoxification + liver health
• DNA production + expression
• Fertility + fetal development
• Immune cell creation + function
• Neurotransmitter production

The methylation cycle is part of a larger chain of events creating a domino effect, resulting in positive or negative health outcomes. If one link in the chain is not working correctly, there is a “backup” of the entire system and downstream effects.

A key part of methylation is the methionine-homocysteine cycle, which creates S-adenosylmethionine (SAM) to donate a methyl group. When the methionine-homocysteine cycle leads to an excess of homocysteine, usually due to a deficiency in the cofactors needed to re-methylate homocysteine, such as folate and vitamin B12, problems may arise. Most of the high-homocysteine research points to potential associations between high homocysteine levels and cognitive dysfunction, metabolic syndrome, and cardiovascular diseases. Some studies have found that high homocysteine levels directly damage endothelial cells and can contribute to oxidative stress and inflammation.

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

• Autism
• Allergies, including histamine intolerance
• Alzheimer’s disease
• Anxiety and Depression
• Asthma
• Autoimmune disorders
• Birth defects
• Cardiovascular disease  
• Cancer 
• Diabetes
• Infertility and Miscarriage
• Lupus
• Multiple sclerosis
• Parkinson’s disease
• Psychiatric disorders, including  Schizophrenia
• Psoriasis
• Rheumatoid arthritis
• Thyroid disease
• Chronic viral infections
• Changes to brain structure and function

 What Can Impair Methylation?

Many factors impact the methylation cycle, such as genetic mutations called SNPs (single nucleotide polymorphisms), diet, lifestyle, and the environment. One of the more commonly studied SNPs that influences methylation activity is the MTHFR (methylenetetrahydrofolate reductase) gene.

It starts with MTHFR: We need a critical B vitamin, 5-MTHF (also known as active folate or methylfolate), to start the methylation cycle. MTHFR (methylenetetrahydrofolate reductase) is an enzyme that converts the inactive form of folate to methylfolate, which is used in this cycle. The active form of folate is then used to break down the amino acid homocysteine into another amino acid, methionine, which is used to make proteins and other compounds in the body. A disruption in enzyme activity can lead to an increased risk of cardiovascular disease, cancer, anxiety, depression, pregnancy issues, and migraines. As each individual carries two copies of the MTHFR gene, there can be several different gene variants, or SNPs, some of which reduce the function of this enzyme. 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.

COMT (catechol-o-methyltransferase) is another gene involved in how the methylation process works and can potentially have profound effects if the gene contains any mutations or if an individual has a less than optimal methylation process. The COMT gene aids in the breaking down of certain neurotransmitters, including norepinephrine, epinephrine, dopamine, and certain hormones like estrogen, as well as certain drugs, into inactive metabolites. Improper functioning of the COMT gene can result in mood disorders, cardiovascular disease, inability to manage stress, estrogen imbalances/dominance, and cancer.

Diet & Lifestyle Factors: While SNPs, including MTHFR, have received considerable attention, many other factors influence methylation. These include:

• Aging
• Alcohol
• Stress—oxidative stress, emotional stress, and early life trauma
• Toxic elements such as lead, mercury, arsenic
• Sleep deprivation
• Inflammation and infection
• Occupational Exposures
• Gut dysfunction and dysbiosis
• Nutrient deficiencies, especially folate/folic acid and vitamin B12
• Environmental toxins – pesticides, BPA, phthalates, mold toxins, etc.

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 or more specific panels for the methylation pathway, we are now able to identify genetic variances that may impact our health. 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 expressed 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 monitor through your health practitioner:

• 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. Although studies have shown the benefits of supplementing nutrients such as vitamin B12 and folate, it is important to keep in mind that over-supplementation can become problematic.

Start with Food First

Nutrient deficiencies are a significant 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, and betaine; minerals such as zinc, magnesium, and 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 nutrients and their food sources 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 found in many herbs and spices, as well as fruits and vegetables. 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, influencing local DNA methylation patterns, and 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 significant impact on methylation. Thus, implementing steps to mitigate stress by reducing toxic metals, balancing blood sugar and insulin, addressing chronic infections, supporting sleep hygiene, and incorporating daily physical activity and exercise will support methylation balance.

Medications that Interfere with Methylation

It’s important to be aware that certain medications may impede methylation activity through various 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 many ways to support this pathway, such as using diet and lifestyle modifications with a holistic approach tailored to the individual. If you have questions about methylation, contact your healthcare practitioner for more information.