What is Methylation?

Age related illnesses | November 28, 2017 | Author: Naturopath

age related, liver

What is Methylation?

You've probably heard about methylation – it's a huge deal in the natural therapies world and the medical fraternity. It's not just a buzzword – methylation is a chemical process that is essential for hundreds of physiological functions.

We'll keep the chemistry quick and simple:

A methyl group contains one carbon and three hydrogen atoms. Methylation is when a methyl group is attached to a molecule or substance (such as a protein or DNA). When a methyl group is detached, the reaction is called de-methylation. Methylation and de-methylation act like an on/off switch for molecules – they signal the molecules to activate, deactivate, allow other chemical reactions to occur, or to perform a function.

Methylation occurs constantly throughout the body. Some key areas where methylation is required include:

  • MethylationDNA and gene promotion
  • Aging processes
  • Liver detoxification pathways
  • Hormone metabolism
  • Neurotransmitter synthesis & elimination
  • Energy producing pathways
  • Immune function

The Methylation Cycle

The methylation cycle is like a factory that produces methyl groups. The cycle is a metabolic process that involves nutrients like vitamin B12, folate, and vitamin B6 and riboflavin (vitamin B2) to help metabolise products within the body such as homocysteine, methionine, and S-adenosylmethionine (SAMe). Folate and B12 are key factors in the methylation cycle and are essential for the production of methyl groups, while the other B vitamins are needed for enzyme activity in the cycle.

The enzymes within the methylation cycle have some funky scientific-sounding names and are often shortened to acronyms that don't make it much easier to understand. The most commonly talked about enzyme is  MTHFR or “methylenetetrahydrofolate reductase” – say that three times fast.

Rumour has it that 45% of people have a mutation of their MTHFR gene, causing this enzyme to react at a sluggish pace. As part of the methylation cycle, the MTHFR enzyme converts folic acid to methylfolate (5-MTHF) by attaching a methyl group. With an MTHFR mutation, the folic acid struggles to be converted and incorporated into the rest of the methylation cycle.

  • NOTE: Supplements and fortified foods use man-made “folic acid” form of folate. This requires MTHFR for its conversion to methylfolate. Methylfolate is the form of folate found in nature. If you have an MTHFR mutation, you can still boost your methylation cycle by getting your folate from natural sources or a specialised methylfolate supplement.


A major outcome of the methylation cycle is the metabolism of homocysteine into methionine, cysteine or glutathione. Homocysteine is a pro-inflammatory amino acid that has important functions within the body, but high levels have been linked to:

  • Homocysteine​​​Heart disease
  • Stroke
  • Recurrent miscarriages
  • Poor fertility
  • Psychiatric conditions
  • Dementia and Alzheimer disease
  • Anaemia
  • Renal dysfunction [1] [2] [3]

Major causes of homocysteine are diets rich in animal protein, and sluggish methylation cycles. A high homocysteine reading on a blood test can indicate that the methylation cycle may be struggling to keep up with demand for its metabolism.

Do You Have a Methylation Problem?

As we touched on earlier, methyl groups are needed for hundreds of physiological processes and chemical reactions in the body. Some notable pathways that require methylation include:

Genetic Processes

Methylation is required for gene expression and it's needed for healthy embryonic development and chromosome stability. In adults, methylation is needed for healthy cell differentiation and may be linked to preventing cancer [4].

Cellular Energy Production

Methyl groups are used to create ATP. Without adequate methyl groups, this process becomes down-regulated and can result in symptoms like fatigue, poor memory, slow wound healing and frequent infections.

Liver Detoxification Pathways

A major phase II liver detoxification process is the methylation pathway. As you can guess, this requires methyl groups! In this pathway, the liver attaches a methyl group to an otherwise toxic substance to make it safe and possible to excrete out of the body.

With inadequate methylation, this process becomes backed-up and symptoms of a sluggish phase II can occur – fatigue, headaches, moodiness and weight gain or appetite changes.

Antioxidant Synthesis

One “end point” for the methylation pathway is the synthesis of the master antioxidant, glutathione.

Immune Cell Synthesis

Methylation is involved in controlling T cell production, fighting infections and viruses, and regulating the activation of the immune system. Researchers are linking autoimmune diseases to compromised methylation pathways [5].

Symptoms of low methylation include:

  • Ongoing fatigue
  • Frequent headaches
  • Sensitivity to medications
  • Poor memory
  • Migraines
  • Sluggishness
  • Weight problems
  • Depressive mood
  • Appetite changes
  • Addictive personality
  • Autoimmune conditions [1] [2] [3]

NOTE: It's possible to over-methylate, too! Too many methyl groups can cause a surge in serotonin and dopamine, leading to issues like depression, frustration, anxiety, hyperactivity, dry skin, and sleep disorders.

What Causes Methylation Problems?

  • MTHFR mutation – A mutation of the gene that codes the MTFHR enzyme can cause sluggish processing of folic acid through the methyl cycle. Speak to a Doctor, naturopath or nutritionist who can order functional testing to see if you have this mutation.What Causes Methylation Problems?
  • Stress – Methyl groups are needed in greater amounts during times of physical, emotional and mental stress.
  • Inadequate nutrition – The B group vitamins are essential for the methylation pathway, and a rich supply of vitamins and minerals is needed to support the enzyme reactions that use methyl groups.
  • Exposure to Toxins – When exposed to environmental toxins, the methylation liver detox pathway is up-regulated. This demands a high amount of methyl groups which can cause a deficiency in other areas of the body. Methyl groups are also used by other processes to remove toxins from the body, such as heavy metal chelation.
  • Infections – Some conditions such as systemic lupus erythematosus may impair DNA methylation [6].

Natural Therapies to Boost Methylation

Methylation Diet

To reduce the load on your methylation pathway, consider cutting down on foods that are rich in homocysteine – this means cutting out animal proteins and going vegan, or close to it. Lots of fresh fruits, vegetables, grains and legumes can boost your B vitamin intake and antioxidant levels to support healthy methylation and reduce the risk of damage from residual homocysteine in your system [7].

Methyl-Folate (5-MTHF)

Supplementing with folate has been shown to boost methylation, particularly the elderly [8]. The 5-MTHF form of folate is found in green leafy vegetables, and now is available in many supplements specially created for people with MTHFR mutation. Speak to a nutritionist or naturopath to confirm that this is the right form of folate for you. If you do not have a MTFHR gene mutation, you may be able to supplement with simple folic acid.

Vitamin B12

Vitamin B12As a key part of the methylation pathway, vitamin B12 works with folate to create methyl groups, boost DNA methylation, and regulate homocysteine levels. Having a vitamin B12 deficiency or a low-level insufficiency can cause serious damage to nerves and mood, and getting your levels checked is easy – a simple blood test will confirm your levels. Vitamin B12 can be found as a supplement in many forms including bioavailable sublingual tablets and sprays, and supplementing has been shown to boost methylation processes [7].

B Group Vitamins

While vitamin B12 and folate are the stars of the methylation pathway, they aren't the only B vitamin needed for healthy methylation. All of the Bs work in conjunction with one another throughout the body, and supplementing with one in isolation may throw the rest of out of balance. Don't forget that vitamin B6, vitamin B2, and vitamin B3 are all needed to metabolise homocysteine. Supplementing with activated B vitamins can help to boost methylation pathways, ATP synthesis and relieve symptoms of fatigue [8].


Methylation enzymes require zinc as a cofactor. It is the “key” to the lock. Great sources of zinc include oysters, seeds, and eggs and it is available as a supplement. NOTE: Long-term use of zinc can disrupt other nutrients like copper and iron.


Vitamin C and bioflavonoids are potent antioxidants that can protect the body against damage caused by high levels of homocysteine. While you boost your methylation pathways, strengthen your antioxidant forces to reduce any ongoing systemic inflammation and cell damage. Antioxidants can be found in all fruits and vegetables, particularly the brightly coloured ones. Supplementing with vitamin C, bioflavonoids, vitamin E and carotenoids can help, and a great way to get all the antioxidants is with a concentrated powdered berries like acai and blueberries 

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[1] Jeve, Y. B. & Davies, W. (2014) Evidence-based management of recurrent miscarriages. J Hum Reprod Sci., 7:3, 159 – 169. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4229790/

[2] Ganguly, P. & Alam, S. F. (2015) Role of homocysteine in the development of cardiovascular disease. Nutr J., 14, 6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326479/

[3] Ravaglia, G., et al. (2005) Homocysteine and folate as risk factors for dementia and Alzheimer disease. Am J Clinic Nutr., 82:3, 636 – 643. https://www.ncbi.nlm.nih.gov/pubmed/16155278

[4] Phillips, T. (2008) Role of Methylation in Gene Expression.Nature Education  https://www.nature.com/scitable/topicpage/the-role-of-methylation-in-gene-expression-1070

[5] Renaudineau, Y. & Youinou, P. (2011) Epigenetics and autoimmunity, with special emphasis on methylation. Keio J Med., 60:1, 10 – 16. https://www.jstage.jst.go.jp/article/kjm/60/1/60_1_10/_article

[6] Strickland, F. M. & Richardson, B. C. (2008) Epigenetics in human autoimmunity. Autoimmunity, 41:4, 278. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2819669/

[7] DeRose, D. J., et al. (2000) Vegan diet-based lifestyle program rapidly lowers homocysteine levels. Prev Med., 30:3, 225 – 233. https://www.ncbi.nlm.nih.gov/pubmed/10684746

[8] Kok, D. E. G., et al. (2015) The effects of long-term daily folic acid and vitamin B12 supplementation on genome-wide DNA methylation in elderly subjects. Clinic Epigenetics., 7, 121. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4644301/

[9] Kennedy, D. O. (2016) B Vitamins and the Brain: Mechanisms, Dose and Efficacy—A Review. Nutrients, 8:2, 68. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4772032/

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