DNA Methylation: How Methylation Influences Health Outcomes

With the recent increase in public awareness of methylation, research, and the availability of genetic and functional tests, it is important for us to keep abreast on clinical context of methylation. In addition, contradictory messages regarding the prescription of methyl donor nutrients make it challenging for a patient to determine best treatment approach. Our practitioners can guide you through an evidence-based and practical perspective on methylation, incorporating this into their functional medicine toolkit, to enhance the understanding and treatment of conditions such as cardiovascular disease, dementia, mood disorders, fatigue and reproductive issues.

By Caryn Levick, ND

What Is Methylation And Why Does It Matter?

Methylation is currently a hot topic within the health industry, and with good reason. It is a major pathway to focus on in understanding autoimmune and neurological diseases such as multiple sclerosis, seizure disorders, dementia, chronic fatigue syndrome, lupus, depression, anxiety and autism spectrum disorders.  Methylation is responsible for making, maintaining and repairing DNA.

This biochemical process is involved in almost all body functions, and not surprisingly, methylation disturbances have been linked to many chronic disease states which are now endemic. Since the early 2000s, scientists have been actively exploring the specific mechanisms through which methylation can become compromised.

DNA Methylation

The methylation cycle is a biochemical pathway that manages or contributes to a wide range of biochemical functions: detoxification, supporting DNA (turning genes on and off), producing energy, reducing inflammation, synthesising neurotransmitters, homocysteine metabolism, protein methylation, phase 2 liver detoxification and supporting immune function. 

Coupled with the more recent availability of genetic testing enabling the identification of specific mutations affecting the methylation pathway, has resulted in Practitioners becoming increasingly conscious of this potential dysfunction when assessing and treating patients. However, the emerging enthusiasm and emphasis on this also presents some risk.

The temptation to focus treatment on ‘fixing’ one biochemical pathway (albeit vital) or compensating for a single gene amongst thousands, can detract from the myriad of other physiological and lifestyle factors that not only interrupt methylation but also directly cause disease to manifest.

Just as we’ve discovered the role of serotonin in depression is comparatively small compared to the amount of hype it has received over the years as a primary treatment target, focusing on the inner workings of the methylation process alone, for any condition, will yield incomplete and inconsistent results if other factors are not effectively addressed.

Methylation is very important, but is only a piece of a much larger puzzle – a puzzle that our Practitioners are more than adept at putting back together following their traditional, evidence-based, holistic mode of practice.

The Methylation Cycle

Methylation is the process whereby methyl groups (that is, a single carbon molecule with three hydrogen atoms) are added to a wide variety of “acceptor” molecules to catalyse a biochemical reaction critical to healthy cell function. In other words, it is the process of donating methyl groups to catalyse important cellular functions.

Interestingly, it would appear that energy production may be one of the body’s most methyl-greedy processes, with an estimated 40% of methylation reactions involved in the synthesis of creatine, a molecule used for the rapid mobilisation of ATP (energy). 

Of course, DNA production and epigenetic regulation are also critical methylation dependent processes. Looking at these downstream outcomes, it is understandable how various conditions may arise from a reduced methylation capacity.

The symptoms most commonly associated with impaired methylation are mood disorders (thought to be driven by neurotransmitter (brain chemical) imbalances) or an impaired detoxification capacity. Yet, neurotransmitter regulation and detoxification make up less than 1% of total methylation reactions in the body. As the majority of methyl groups are spent on creatine and phospholipid synthesis, impaired methylation is more likely to affect energy and cell membrane health before neurotransmitter levels or detoxification capacity. 

In order to ‘keep up’ with all of the methylation reactions occurring within the body, a sufficient store of methyl groups is needed. One well known source of these comes from folate, hence the hype around this nutrient in current discussions. However, the amino acids serine and methionine, and the phospholipid choline, also provide methyl groups to fuel the methylation cycle. 

This is a nice reminder that a diverse diet rich in green leafy vegetables, protein rich foods, and choline containing foods (e.g. eggs, beef, chicken, cauliflower, whole grains), is one of the best strategies we can implement to ensure an adequate supply of methyl donors are available to drive the methylation cycle.

Food Sources Of Methylating Nutrients

1. Folate (Vitamin B9): serves as a precursor for methyl groups in the body. It is involved in DNA synthesis and repair, as well as the methylation of various molecules. Folate is naturally found in beans and legumes (especially mung beans, adzuki beans, chickpeas and lentil), liver, seeds (especially sunfolower seeds), spinach, asparagus, and avocado.

2. Vitamin B12: acts as a cofactor for methionine synthase, an enzyme involved in the conversion of homocysteine to methionine. Vitamin B12 is naturally found in meats and meat products (especially liver and kidney), poultry, fish, shellfish and eggs.

3. Betaine (Trimethylglycine): can donate methyl groups and is involved in the methylation of homocysteine to form methionine. Betaine is found in quinoa, spinach, whole grains ( especially rye, amaranth, barley and oats), sweet potato, meats and poultry.

4. Choline: It can donate methyl groups. Choline is found in beef, beef liver, egg yolks, poultry, broccoli and fish.

5. Methionine: is an essential amino acid that serves as a precursor for S-adenosylmethionine (SAMe), a key methyl donor in many methylation reactions. Methionine is naturally found in meats, poultry, fish, shellfish, egg, nuts (especially brazil nuts), seeds (especially sesame seeds and pumpkin seeds), spirulina, soybeans.

6. Vitamin B6: is involved in numerous biochemical reactions in the body, including those related to methylation. Vitamin B6 is naturally found in meats, nuts (especially pistachio), garlic, whole grains, seeds (especially sesame and sunflower seeds), legumes (especially chickpeas and lentils), and prunes.

These nutrients are crucial for maintaining optimal health and function, and deficiencies in any of them can lead to disruptions in methylation processes, potentially contributing to various health issues.

Methylation Testing Options

It is important that we get the full picture when assessing a patient’s methylation status. There are a range of testing options available to assess markers associated with this. 

As with any testing, there are a few things we need to consider when looking at ordering tests for our patients. Will the test results change the treatment recommended? If not, what value will these results add for the patient? Is the test being used to help to increase a patient’s compliance to treatment? What is the cost versus benefit to the patient? Of all the testing options available, which tests will be the highest priority for this patient?

If we can clarify the answers to these questions, these testing options, if indicated, may help to give a clearer idea of a patient’s methylation status, and help to direct treatment.

Some of the common tests we use to assess a patient’s status include: 

Nutrient testing – 

Active Vitamin B12, Homocysteine, Methionine, S-Adenosyl Homocysteine (SAH), S-Adenosyl Methionine (SAMe), SAMe:SAH, Serum Folate, 5-methyl tetrahydrofolate (5MTHF), Folinic acid, Tetrahydrofolate (THF)

Methylation genetic testing –

MTHFR 677, MTHFR 1298, MTR, MTRR, COMT

What Are The Other Pieces Of The Puzzle?

Methylation is an important piece of a much larger puzzle. Impaired methylation has been implicated in a number of conditions including cardiovascular disease, cognitive decline, mood disorders, and cancer. Yet it is not the only driving factor.

• Stress can shut down methylation
• Thyroid status alters MTHFR capacity
• Thyroid function affects homocysteine concentrations 
• Inflammation influences methylation as well as the development of chronic disease 
• And the list goes on…

As we can see, a broad number of factors can influence methylation, meaning a holistic approach is needed to support healthy outcomes in our patients.

It is important to see it as part of the picture of these conditions, and not forget the rest of the drivers of these conditions. Therefore, we like to first assess and address drivers of the patient’s presenting condition, as these may be impacting how a patient methylates. It is important to remember here that while it is a broad reaching and important mechanism, it is rarely the sole driver behind a condition or symptoms. Therefore restoration is best achieved through treating the patient as a whole, as well as supporting methylation directly.

Diet and exercise interventions, stress reduction, ensuring healthy thyroid function and glucose control, reducing inflammation, toxicity, and supporting a healthy gut are all needed for a comprehensive approach. Methylation is not an isolated process, and a reductionist approach trying to pinpoint a single defect in the pathway or employing a heroic dose of a single nutrient is unlikely to improve it, or more importantly, patient outcomes.

Holistic Medicine Is Best Practice

Stress, thyroid dysfunction, insulin resistance, inflammation, toxicity and dysbiosis have also been shown to drive many of these above mentioned conditions, as well as disrupt methylation directly. Conversely, methylating nutrients, alongside diet and lifestyle interventions, support both methylation and overall health, as outlined above. Therefore, assessing and addressing all of these factors, should become key targets when treating these, and other, conditions.

This highlights how methylation is another key example of why Holistic Medicine is Best Practice. By viewing it in the context of our well-established Naturopathic principles, our Practitioners have confidence their interventions will not only improve methylation, but also have a flow-on effect to achieving clinical success, and helping our patients achieve their health goals.

If you are left questioning how it may be effecting your health, or your health effecting your methylation cycle – our practitioners are here to help.