Everything to Know About Methylation & Why It Matters

The methylation cycle can be a complex concept to grasp, though it is simply vital to health. Discover all things methylation in this easy-to-digest guide.

Everything to Know About Methylation & Why It Matters

Even in the progressive wellness sphere, many people still solely equate health with weight. 

After all, if you fit into societies' ideals of health and beauty on the outside, you must be healthy on the inside... Right? Not exactly. 

Rather, cellular function is a better predictor and measure of general health and one particular mechanism called methylation greatly influences cellular health. 

Discover everything you need to understand methylation and more importantly, why it matters.

What Is Methylation?

Before diving into methylation, it is important to revisit other scientific concepts known as epigenetics and nutrigenomics

Essentially, epigenetics is the study of molecular modifications to DNA. It aims to elucidate how nutrition and lifestyle factors affect gene expression in terms of acquiring or avoiding chronic diseases. 

In other words, even though DNA sequencing is fairly permanent, epigenetics studies how certain genes or components of genes are turned on or off related to lifestyle habits and the environment. The study also shows how this manifests physically, mentally, and emotionally within the body.

Known epigenetic modification mechanisms include chromatin remodeling, histone tail modifications, non-coding RNA and microRNA gene regulation, and DNA methylation – the latter of which will be the focus of the rest of this article.

Recall that DNA consists of four bases called adenine, cytosine, guanine, and thymine. DNA methylation occurs when a methyl group consisting of one carbon and three hydrogen atoms is added to cytosine. 

If a methyl group is removed from cytosine, the gene becomes demethylated. SAMe, also referred to as S-adenosyl-L-methionine (SAM), is known as the universal methyl molecule that donates these methyl groups.

Methylation is fundamental for various biological processes such as producing and regulating hormones and neurotransmitters, creating immune cells, managing detoxification, clearing histamine, and, of course, modifying genetic expression.

Methylation has extensively been studied for its association with a variety of health concerns, including:

• Aging
• ADD/ADHD, autism, Down syndrome, and other behavioral changes
• Depression, anxiety, addiction, bipolar disorder, schizophrenia
• Alzheimer's, Parkinson's, dementia, multiple sclerosis
• Diabetes, neuropathy, hypertension, and atherosclerosis
• Fibromyalgia, ocular and thyroid diseases
• Cancer, chemical sensitivities, allergies, and asthma
• Pregnancy and lactation, fertility problems
• Athletic performance, insomnia, and chronic fatigue

The Methylation Cycle

DNA methylation occurs within the one-carbon metabolism pathway. This cycle is dependent on several enzymes that are dependent on micronutrient cofactors or "helpers" and include folate, choline, betaine, and some other B vitamins

DNA methylation begins when the amino acid methionine is converted to that universal methyl donor, SAM, and concludes after enzymes called DNA methyltransferases (DNMTs) attach methyl groups from SAM to the base, cytosine.

Simplified scheme of DNA methylation/synthesis cycle. Dihydrofolate (DHF), tetrahydrofolate (THF), methionine (MET), S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), homocysteine (Hcy), 5,10-methylenetetrahydrofolate reductase (MTHFR), thymidylate synthase (TS) methionine synthase (MS), methionine synthase reductase (MSR), betaine:homocysteine methyltransferase (BHMT), cystathionine-synthase (CBS), B6 vitamin (B6), and B12 vitamins (B12).

*image obtained from ResearchGate

Demethylation and Hypomethylation

While DNA methylation is a fairly stable and cyclic mechanism, it is more tightly regulated compared to demethylation. In fact, demethylation is quite passive and generally occurs during DNA replication. 

In this case, there is simply no addition of a methyl group to a newly synthesized DNA strand during the cell division/replication. 

When this passive demethylation mechanism due to nutrient deficiencies or other causes occurs too often, DNA can become undermethylated through the process called hypomethylation. This is problematic because hypo or undermethylation is associated with a variety of diseases, especially cancer.

Methylation Patterns

Furthermore, research shows that DNA methylation patterns change throughout the life cycle. Like many other physiological processes, DNA methylation slows and works less efficiently as one ages. 

However, practicing healthy lifestyle habits and obtaining sufficient micronutrients and other phytochemicals will help maintain proper DNA methylation.

MTHFR Gene Mutation

Methylation can be further understood through the commonly known MTHFR gene mutation.

MTHFR stands for methylenetetrahydrofolate reductase. It is relevant in the health and wellness sphere because genetic mutations of the gene that codes for MTHFR (an enzyme) are linked to certain health concerns.

The MTHFR gene is mostly responsible for helping the body process the B vitamin, folate. Specifically, it includes the instructions for the MTHFR enzyme to convert folic acid present in foods into methyl-folate, which is the active form of the vitamin.

Methyl-folate is vital for methylation, which is necessary to optimize DNA, hormone metabolism, proper detox, and more.

A mutation of this gene, and the resulting disruption of methylation, generally results in low B vitamin and folate levels. It can also result in high levels of the amino acid homocysteine since B vitamins break this down into other chemicals the body needs.

However, there are other causes of high homocysteine levels that can occur without the MTHFR gene mutation. Some of these causes include hypothyroidism, diabetes, and other metabolic diseases, and the medications – atorvastatin, fenofibrate, methotrexate, and nicotinic acid (a form of niacin).

Variants of the MTHFR Mutation

There are two variants of this mutation. So, someone can have no mutation, one mutation, or both mutations, otherwise called variants. Technically, variants are part of a gene's DNA that varies from person to person. 

One variant is considered heterozygous, which refers to inheriting different forms of a particular gene from each parent - or two different genes. This variant is less likely to contribute to disease symptoms.

The other variant is homozygous, which means inheriting the same version of the gene from each parent - or two matching genes. The homozygous variant may lead to more serious health complications.

Specific MTHFR Variant Mutations

The specific MTHFR gene variants include:

• C677T
• A1298C
• C677T + A1298C

These mutations will cause varying symptoms from person to person. Some people might also never know they have this mutation if they do not experience obvious symptoms.

Speaking of MTHFR symptoms, there really is not a list perse, because this gene mutation has only been shown to be associated with certain medical and health conditions and not a direct cause. Thus, the symptoms have more to do with the associated condition if it leads to one at all.

Because the MTHFR gene mutation is linked to methylation problems, many of the associated conditions are the same as the ones already mentioned in the first paragraph. Nonetheless, research has looked into the correlation between the mutation and the following conditions:

• Thromboembolic and heart diseases like blood clots, heart attacks, and stroke
• Depression, anxiety, bipolar disorder, schizophrenia, and autism
• Autoimmune conditions and thyroid problems
• Colon cancer and leukemia
• Chronic pain and fatigue, nerve pain, and migraines
• Recurrent miscarriages, neural tube defects like spina bifida
• Digestive issues like IBS
• Hormone problems like PCOS

Various different genetic tests can assess for the MTHFR mutation and tend to be very expensive. It is important to work with a qualified health professional that can guide you to the best test based on your health history, conditions, and symptoms and correctly interpret the results.

Diet and Methylation

Various nutritional factors support and reduce methylation. The same influences that contribute to chronic conditions like obesity, heart disease, type 2 diabetes, autoimmune diseases, and gut inflammation also reduce the effectiveness of methylation. 

In other words, a high intake of pro-inflammatory foods such as refined carbs, added sugars, hydrogenated oils, and poor quality saturated fat diminish this important mechanism. 

Although more research is needed, a component of soy - known as genistein - also appears to reduce methylation. However, consuming in moderation likely will not negatively impact the mechanism too much.

Conversely, various specific nutrients are known to promote a healthy amount of methylation. These include the following B vitamins, methionine, polyphenols, and omega-3 fatty acids. 

B-Vitamins

B vitamins - especially folate/folic acid, vitamin B6, vitamin B12, and choline - help promote methylation. 

In general, B-vitamins are prevalent in high-quality whole grains like brown rice and quinoa, beans and legumes, meat and eggs, dark leafy greens and other green veggies, citrus fruits, fortified cereals, organ meats, and some dairy.

Methionine

Methionine, an amino acid, is present in high protein foods like turkey, beef, fish, and beans.

Polyphenols

Polyphenols are only present in plant foods rich in fiber and antioxidants, especially fruits, vegetables, and fermented foods.

Omega-3 Fatty Acids 

Omega-3 fatty acids are found in fatty fish like salmon, trout, and sardines as well as edamame, shitake mushrooms, and seaweed.

Various Spices

Various spices are considered methylation adaptogens, meaning they can increase or decrease methylation based on signals from the body.

• Chamomile, ginger, and mint
• Cilantro, basil, dill, rosemary, and parsley
• Cumin, turmeric, and black pepper
• Garlic, sage, and thyme

Lifestyle Factors and Methylation

Finally, certain lifestyle factors help maximize healthy methylation. 

1. Support detoxification

• 25+ grams of fiber per day
• Eat mostly whole, anti-inflammatory foods
• Exercise consistently
• Hydrate adequately
• Avoid endocrine disruptors like conventional makeup, cleaning products and detergents, and pesticides
• Supplementation from milk thistle, glutathione, L-glutamine, sulfur, and magnesium

2. Reduce or minimize alcohol intake

3. Manage stress effectively

4. Take a multivitamin with folic acid (not folate or any other inactive form)

5. Heal underlying gut issues

6. Quit smoking

The Bottom Line

Methylation is technically a process by which a methyl group is added to cysteine via the universal methyl donor, SAM. This process is fundamental for physiological processes such as: 

• Producing and regulating hormones and neurotransmitters
• Creating immune cells
• Managing detoxification
• Clearing histamine
• Modifying genetic expression

When methylation is insufficient or disrupted, it can lead to numerous conditions and diseases. These are mostly related to accelerated aging, mood disorders, neurological problems, pregnancy issues, metabolic conditions, and autoimmunity.

The MTHFR gene mutation is the most well-known defect of methylation, where the enzyme methylenetetrahydrofolate reductase does not properly add a methyl group to folate to make it folic acid, resulting in depletion of folic acid and other B-vitamins and elevated homocysteine levels.

Consuming a healthy diet of colorful fruits and vegetables, high-quality lean protein and whole grains, and healthy fats including omega-3 fatty acids optimize methylation. Reducing inflammatory foods and managing stress can be helpful as well.

References:

Anderson OS, Sant KE, Dolinoy DC. Nutrition and Epigenetics: An Interplay of Dietary Methyl Donors, One-Carbon Metabolism, and DNA Methylation. The Journal of Nutritional Biochemistry. 2012. https://doi.org/10.1016/j.jnutbio.2012.03.003. 

Berzin R. MTHFR Mutation and 6 Natural Ways to Manage Symptoms. Parsley Health. Published April 18, 2018. https://www.parsleyhealth.com/blog/mthfr-mutation/

Marcin A. What You Need to Know about the MTHFR Gene. Healthline. Updated September 6, 2019. https://www.healthline.com/health/mthfr-gene#diet.

Seladi-Schulman J. Methylation: Definition, Research, Testing, and Support Methods. Healthline. Updated May 22, 2018. https://www.healthline.com/health/methylation#research.

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