What is Methylation?
By Sue Kira, Naturopath & Clinical Nutritionist
What can impair methylation
– Lack of the necessary precursors
– Lack of co-factors
– Enzyme polymorphisms
– Causes of Elevated Homocysteine
– Risks associated with elevated Homocysteine levels
– What is the hereditary predisposition MTHFR?
– Symptoms of MTHFR gene copying errors
B12 and Folate
– Four different types of B12
– Methylmalonic Acid (MMA)
– Folates, folic acid and unmethylated folic acid (UMFA)
Undermethylation and Overmethylation
– Undermethylation signs and symptoms
– Overmethylation signs and symptoms
– Testing for under and over methylation
– Supplementation to support methylation issues
Methylation regulates how our genes switch on and off, and also silences viruses
When functioning optimally, methylation keeps the less desirable genes switched off, such as those that cause birth defects, cancers and auto-immune disease, while allowing genes to switch on that help our body systems run effectively. We call this gene expression.
If working properly, the process of methylation is what keeps us healthy. Without methylation we cannot survive because methylation contributes biochemically to who we are, what we look like, how we act and is also central to our physical, mental, and emotional wellbeing.
We go about our day to day lives usually never being aware of these processes, but meanwhile methylation is making, maintaining, and repairing our DNA – our genetic coding.
Amazingly, the way we choose to live our lives affects our gene expression, which is known as epigenetics. This means that even if you have an inherited gene defect, the way you live your life can override the potential for damaging effects..
Gene expression is affected by your lifestyle. A self-destructive lifestyle with poor nutrition, smoking, alcohol, stress, emotional behaviours, lack of exercise and a poor environment, can all contribute to switching on ‘bad’ genes and hinder methylation. Conversely, a healthy, vital, self-loving lifestyle can switch off ‘bad’ genes.
Your lifestyle choices will either support or hinder the natural process of building and repairing your body.
It is currently estimated by scientists that there are 20,000 to 25,000 human genes (yet much is still to be determined despite the enormous advances that have been made over the last few decades). Each gene is responsible for a different job within the body, and many of our genes are constantly switching on and off on a day to day basis as needed e.g. digestion, repair, hair growth etc.
Following are three extremely simplistic (and not quite technically accurate) examples which may provide more understanding about methylation:
1. A man gets a small splinter lodged in his finger. An ‘inflammation gene’ switches on to create inflammation (immune protection) and to also expel the splinter from the body. This is seen as white puss around the splinter (the white blood cells at work). The splinter is expelled, then the repair gene goes to work and patches up the finger. Job done and the genes, not needed anymore, switch off.
2. An avid sugar eater consumes lots of cakes and biscuits, which switches on the inflammation gene which goes to work to deal with the invader. Unfortunately, the invader (sugar) keeps entering the body, which means increased inflammation to ward off the attack. If it continues, the inflammation gene cannot switch off, resulting in more inflammation throughout the body. At this stage, inflammation affects other organs and functions and the body is in crisis.
It happens with alcohol, cigarettes, stress – anything that is not natural.
3. A woman has inherited a gene that can create breast cancer. Yet even though the gene has been passed down, that does not mean the gene has been switched on. Indeed, by living a low stress, healthy, vital life, this may never happen. Or with disregard, the gene could activate with the potential for harm.
Sometimes adverse genes can be passed down for generations because subsequent lifestyles do not change. The dominate gene that is passed down is the faulty (bad) gene – which isn’t the best start to life for a baby. For example, a father with a propensity for alcohol, can pass the faulty gene for alcoholism on. The cycle can continue with each generation if similar lifestyles are followed.
Yet the pattern can be broken when one person in the chain chooses to live a healthy, self-loving life, hence switching off the faulty gene – a gift for future generations.
From these examples, we can get a tiny glimpse into the importance of methylation and its relationship to lifestyle.
You will find this article is somewhat scientific, which is necessary to impart information to understand methylation. Believe me, the science can get super scientific, particularly when getting into the biochemistry involved with methylation.
Methylation begins with what is termed a ‘methyl group’ which is basically a carbon and three hydrogen atoms joined together, and this group is then transformed into another compound.
An analogy would be a work place where one person passes an envelope containing a group of objects to another person, who then has the job of making those bits into another component, which is then passed onto someone else to finish the job to have a completed job order.
There are certain points within the methylation cycle where each has a particular task, to begin, carry out and finish the job. In other words, each part has its role and ‘job description’ to complete the project.
Our nerve functions are highly dependent on proper methylation as each nerve requires proper insulation just like the wires in our house or car. Otherwise it will be like having exposed wires which can lead to symptoms of physical, emotional or behavioural changes.
Methylation (our genes switching on and off) also controls the production and breakdown of neurotransmitters. These are our chemical messengers in the brain and nervous system as well as in the gut and many other places of importance.
The nervous system communicates with immune cells, so a faulty methylation process can lead to immune imbalances, which can turn a simple cold or flu into pneumonia or an auto-immune disease. An efficient methylation system will create an efficient communication system to sound the alarm bells of immune invaders.
Methylation also immobilise fats and cholesterol so they can be removed by the body without clogging up arteries and organs. Improving methylation cycles can help the body naturally clear cholesterol and fats that would otherwise lead to heart attacks, high blood pressure, diabetes and fatty liver disease.
Methylation regulates histamine levels which is why someone who gets allergies is referred to as an under-methylator, because the body is unable to break down the histamine. Histamine is a hormone that is often overactive in cases of allergies, eczema, asthma, mast cell activation syndrome (MCAS) and anaphylactic reactions.
There are many other things that methylation supports such as hormones e.g. regulating oestrogen and testosterone, thyroid hormones, adrenal hormones and more.
You may have heard about the process of methylation relating to using more active forms of vitamins. For example, the active form of vitamin B6, also called Pyridoxyl 5 phosphate (P5P), is a ‘methylated’, active or more useable form for the body as the process of methylation has already been done for us in the laboratory.
Other forms of activated (methylated) vitamins include methylfolate or methylcobalamin, active folate and active B12 respectfully.
For a person who has good methylation capacity, the body itself does this methylation, conversion or activation process. For poor methylation it is preferable to use pre-methylated vitamins (active forms).
To summarise, methylation is involved in many of our most vital bodily functions, by offering support and/or managing, processes such as:
2) Controlling inflammation
3) Maintaining DNA
4) Immune function
5) Energy production
6) Mood balancing
Some of the conditions linked to poor methylation include, but are not limited to:
– cardiovascular disease
– neurological conditions
– autistic spectrum disorders
– chronic fatigue syndrome
– Alzheimer’s disease
– pregnancy problems
– immune system disorders
– digestive problems
– mood and psychiatric disorders
– the aging process
Effective Methylation requires certain precursors, co-factors, and genes to work efficiently. Precursors are the ‘pre’ needed constituents to start the process of methylation. Co-factors are things needed along the way to support the methylation process, and the correct genes are needed to complete the processes.
Studying our genes can be confusing because we know the process of methylation helps to switch our genes on and off as previously mentioned. But if we have certain gene defects, then the process of methylation can be impaired. Following are things that impair methylation.
1.Lack of the necessary precursors (substances needed to initiate methylation)
Methionine – an essential amino acid (from protein digestion) needed to create neurotransmitters. Found mainly in eggs, meat, and fish, and also in sesame seeds and Brazil nuts. Problems with protein digestion may result in insufficient methionine e.g. lack of stomach acid for digestion.
Choline – is required to make acetylcholine, essential for muscle control, memory, and a healthy mood. It is richly found in eggs. Only small amounts are found in vegetable proteins, so vegans may be deficient in this methylation precursor.
Betaine – serves a vital role in methylation processes as a methyl donor. Found in beetroot, seafood, and spinach (a book could be written on how amazing Betaine is). Super important for digestion as well.
Homocysteine – methionine, from protein, is broken down to create homocysteine. We need just the right amount of homocysteine to function optimally. It is just as important to have enough homocysteine to support methylation as it is to ensure we do not have too high a level of homocysteine. See more about homocysteine below.
2.Lack of co-factors (nutrients needed to support methylation)
B12 – a crucial vitamin needed in methylation. Found mainly in animal proteins, vegetarians/vegans need to take supplemental methylcobalamin, but even meat eaters are commonly deficient.
Folate (B9) – also called methylfolate, comes from foliage (especially greens) and is another important methyl donor. This is why ‘eating your greens’ is so important.
Zinc – a very important mineral for methylation. Found mainly in animal proteins and only small amounts found in vegetable sources. Supplementation needed for vegans/vegetarians as their diet is high in copper which is antagonistic to zinc, thus they will be zinc deficient.
B2, B3, B5 & B6 – all B vitamins are important for the process of methylation to function well
3.Enzyme polymorphisms (defective genes)
MTHFR (Methylenetetrahydrofolate reductase) – defects on these genes make the process of methylation difficult (see more below)
COMT (Catechol-O-Methyltransferase) – one of several enzyme processes that helps to break down neurotransmitters. Faulty genes of COMT affect proper methylation.
There are other important genes, however this gives you an idea of how methylation can be affected.
Now we look at how many of the above factors intertwine and affect each other.
Homocysteine is an important regulator of methylation. It’s a chemical in the blood that is produced when an amino acid called methionine is broken down in the body. Homocysteine is one of the methylation precursors; in other words, the right amount of homocysteine is required for proper methylation.
We all need some homocysteine in our blood, but high levels, also called hyperhomocysteinemia, may irritate the blood vessels. This can increase the risk for hardening of the arteries, which could eventually result in a heart attack and/or stroke, and blood clots in the veins, referred to as venous thrombosis.
Normally the issue is with high levels of homocysteine, but some can have low levels. The ideal level of homocysteine (Hcy) is 7 nmol/ml, with levels above 8 considered high and levels above 15 dangerously high. Levels below 6 are considered low, and below 5 dangerously low.
Low levels of Hcy means there is an impairment of glutathione production or depletion of glutathione. Glutathione is used by the liver to detoxify substances such as heavy metals, chemicals and other toxins. Low levels may also reflect taking too many methyl support nutrients like methionine, B6, B9 or B12, as these nutrients lower elevated homocysteine.
While we don’t want elevated levels of homocysteine, we also don’t want levels too low because we need to have good levels of glutathione. Thus, we need the ‘Goldilocks’ amount of homocysteine – not too high, not too low, just right.
Causes of elevated Homocysteine
– Deficiency of folate, B6 and/or B12
– Kidney disease
– Medications such as methotrexate
– Methylenetetrahydrofolate reductase (MTHFR)genetic fault
– Systemic lupus erythematosus
Risks associated with elevated Homocysteine levels
– Coronary artery disease
– Heart attack
– Peripheral arterial disease
– Venous thrombosis
– Pulmonary embolism
– Neural tube defects in children
Now we look at the main causes of elevated Homocysteine
One of the main causes of elevated homocysteine is the MTHFR gene mutation, so what does this mean?
MTHFR is a hereditary predisposition – an abbreviation of (and much easier to say than) Methylenetetrahydrofolate Reductase.
Some develop an elevated homocysteine level because of MTHFR, which creates the methylation defect that reduces the ability to convert folate into its active useable form which then creates problems with the regulation of homocysteine levels in the body.
We all have 2 MTHFR genes, one inherited from each parent for each of the two genes. Some people have a genetic mutation in one or both of their MTHFR genes. People with mutations in one MTHFR gene are called ‘heterozygous’ for the MTHFR mutation, but if mutations are present in both genes, the person is said to be ‘homozygous’ for the mutation.
The most common MTHFR mutation is called the MTHFR C677T mutation. Another common mutation is called MTHFR A1298C. To have any serious detrimental effect, mutations would usually be present in both copies of a person’s MTHFR genes.
Even when 2 MTHFR mutations are present, not all people will develop high homocysteine levels (because they eat their ‘greens’).
Although these mutations do impair the regulation of homocysteine, adequate folate levels essentially ‘cancel out’ this defect, especially if the folate is consumed from foods or the more active form of folate such as calcium folinate or better still – the 5MTHF.
Regardless of whether someone has an MTHFR mutation in both genes or not, the treatment for elevated homocysteine is the same – dietary intervention and supplementation with a good folate, B6 and B12.
If supplementing, then the quantity of supplements should be adjusted on the basis of the degree of homocysteine elevation, not genetic status. Levels also need to be monitored as we don’t want homocysteine to get too low as mentioned earlier.
Symptoms of MTHFR genetic errors
This is also referred to as gene copying errors, and SNPs (Single Nucleotide Polypeptides). These really mean the same thing – a genetic defect or error.
Symptoms include fatigue, anxiety, depression, cardiovascular disease, and other vague complaints such as aches and pains and other symptoms.
Here we look into the world of B12 and folate – regulators of both MTHFR and Homocysteine levels.
Four different types of vitamin B12
1. Cyanobalamin – this is a synthetic form of B12 that is unmethylated, cheaply and commonly used in supplements and added to some foods (fortification). This is not a preferable form to use as it is poorly utilised by the body, requiring good methylation processes to convert to an active form.
2. Methylcobalamin (methyl group plus B12)
– An active form of B12 (already converted into a form the body can use)
– This form of B12 is used by the enzyme methionine synthase to turn homocysteine (Hcy) into methionine (a methylation process).
– Methionine is further converted to the important methyl donor, S-adenosylmethionine also known as SAM or SAMe, which supports serotonin and melatonin production.
– Supports methylation and is great for memory and brain cognition as well as improving energy. Note: if it doesn’t seem to help then glutathione might be needed.
– Another active form of B12 useful for reducing elevated nitric oxide levels for those with chronic fatigue, fibromyalgia and auto-immune disease.
4. Adenosylcobalamin, also known as 5′-deoxyadenosylcobalamin
– Another active form of B12 often chosen for its ability to improve energy levels in the body and to support the mitochondria (fuel in cells)
Methylmalonic Acid (MMA)
Adenosylcobalamin (the above coenzyme form of B12) takes part in the conversion of methylmalonyl-CoA to succinyl-CoA.
When B12 is deficient at a cellular level then another substance called methylmalonyl-CoA levels increase. Methylmalonyl-CoA is then converted to methylmalonic acid (MMA) which then accumulates in the blood and urine.
MMA is an organic acid that can be tested to show hidden B12 deficiency. I say hidden because serum B12 tested by blood may show ‘normal levels’ of B12 but when tested via organic acid testing, it may show a different story. Since B12 is the only coenzyme required in this pathway, MMA levels are the best pathology test indicator of a true B12 deficiency compared to serum B12 levels.
High MMA levels can also (but rarely) be caused by genetic defects, kidney failure, low blood volume, gut bacteria changes, pregnancy, and thyroid disease.
Most of the time high MMA is a very good indicator that you need more B12 especially in the active form. A person with high MMA and normal or even high serum B12 shouldn’t use cyanobalamin form of B12 (commonly found in many supplements, especially multivitamins).
Folates, folic acid, and unmethylated folic acid are some of the different forms of folate, a vitamin found naturally in leafy green vegetables (foliage). Folate is the group name for related members of this B-vitamin family, sometimes called vitamin B9.
The synthetic form, folic acid (FA) is generally used in fortified foods and many dietary supplements, especially multivitamins and many commonly used pregnancy and preconceptual multivitamin blends (see video link below).
Following are the different forms of folate.
1. Folate. This is a natural form of the vitamin found in our green vegetables. If you eat about 1.5 cups of cooked greens three or more times a week, you will obtain enough natural folate to overcome almost any genetic copying defect related to MTHFR. Folate is also found in meats, eggs, and other foods, although not as much. Some folate can also be made in the intestinal tract by certain friendly bacteria in a healthy digestive system.
2. Folic acid.This is a synthetic, non-active, form of folic acid that is widely used in B vitamin supplements. This form is not converted as well into the active form of the vitamin in people with the copying weakness (MTHFR gene defects) and so creates UMFA – see below.
Here’s an interesting video on the dangers of folic acid and understanding MTHFR by Dr. Ben Lynch Folic Acid is Affecting You Negatively
3. Folinic acid.This is a supplemental active form of folate that is well utilised by most with the gene copying defect on MTHFR.
4. Methyl folate.This is the most active supplemental form of folate that is well-utilised by those with the copying defect. Sometimes called 5MTHF
With increased consumption of folate fortified grains and the popularity of vitamin supplements, many people are getting too much synthetic folic acid.
Unlike natural folate, synthetic folic acid is processed very slowly in the body. Even at the Recommended Dietary Allowance (RDA) intake of 400 mcg per day (for adults) UMFA can be found in the blood stream for extended periods of time.
UMFA should be monitored for anyone who takes vitamins and/or consumes products with fortified enriched grains and cereals. Monitoring is also strongly recommended for women who are pregnant or trying to become pregnant.
UMFA has been known to increase the feelings of ‘morning sickness’, so nutritional supplements with the synthetic folic acid are not advisable with those who have the MTHFR gene defects, who, apart from a nutritious diet, should use the more active forms such as Folinic Acid or Methyl Folate .
What is the danger of too much UMFA?
– Depressed immune function
– Enhanced development and progression of certain cancers
– Anaemia, poor cognition, and impaired memory especially with low B12 levels
When folate is properly processed it can support the body with:
– Making red blood cells
– Proper nerve function
– Bone health
– Healthy brain and memory
– Proper immune system function
– Cell production, especially in skin and the digestive tract
– Prevention of neural-tube defects (cleft lip and palate, spina bifida) in a developing foetus
– Preventing miscarriage
Some people have an over expression or overactive methylation cycle commonly called overmethylation or may be called an overmethylator. Others have a poor ability to methylate properly so they are called undermethylators.
As mentioned before, methylation is when methyl molecules (CH3) are available to add to enzymes, neurotransmitters, hormones and DNA to ‘methylate’ or convert one component or substance into another, or to switch a particular gene on or off.
To undermethylate means that we don’t have enough methyl molecules to do these jobs. To overmethylate means we have too many methyl molecules. Technically speaking an undermethylator is said to have histadelia (high histamine) and an overmethylator is said to have histapenia (low histamine). Overall it means both are not doing their job efficiently.
Undermethylation signs and symptoms
As proper methylation is a major factor in the production of serotonin, dopamine, and norepinephrine in the body, undermethylation can lead to a depletion of these three essential neurotransmitters and can also result in some of the following characteristics:
– delusional behaviour
– obsessive compulsive disorder (OCD)
– frequent headaches
– seasonal allergies
– often a high achiever
– has a strong will
– often highly motivated
– prone to addictive behaviours
– may have a calm demeanour but high inner tension
– prefer to be on their own
– commonly has sparse hair growth
– generally sleeps well
Overmethylation signs and symptoms
Overmethylation can lead to some of the following characteristics:
– high anxiety
– paranoia or panic attacks
– may have been a poor achiever at school
– low motivation (especially for undesirable or non-fun things)
– very creative
– artistic or musical ability
– low libido
– can get easily frustrated
– commonly has sleep disorders
– depression is common
– prone to self-mutilation
– tinnitus (ringing in the ears)
– food and or chemical sensitivities
– commonly has a high pain threshold
– history of or current ADHD
– hyperactive psychosis
– hirsutism (excess hair growth)
– eczema or dry skin.
Interestingly, you can get an undermethylator with anxiety, or an overmethylator who sleeps really well and has addictive behaviours.
The items on the above lists are not set in stone and there can be many variations. But when looking at the two lists, if someone has methylation imbalances, they tend to have more characteristics of one list over the other.
If each list has fairly equal number of characteristics, then it is quite likely that even if someone has been told they are an over or under methylator, they may still have issues with methylation, but are not specifically an over or undermethylator, which means other factors are contributing to their symptoms.
For example, it’s common for many of my first-time clients to call themselves an undermethylator, but their signs and symptoms are not really that clear. Because 80% of methylation disorders tend to be under methylators, it’s easy to guess and get it right, but this is not always the case.
It’s easier to pick an overmethylator, because they always have very low histamine levels rather than the normal to high levels seen in an undermethylator, and their copper seems to be a lot higher than others. Also if they have been unfortunate enough to have been put onto antidepressants, they will commonly have a very negative experience with them and some have unfortunately even felt suicidal. See article on SSRI warning.
I want to reinforce that you do not have to be an over or undermethylator. You can still have some issues with methylation that can be supported with certain nutrients without the need to be classified as one or the other.
Testing for under and overmethylation
While there are no specific tests that reflect disordered methylation, we do have indicators. I call them indicators because they, along with a careful health history and symptom profile, help the practitioner decide if someone has methylation issues.
The main test used to decide methylation status (under or over) is histamine levels. But other indicators can include: basophil count (a type of white blood cell); zinc and copper levels; MMA/B12; homocysteine; heavy metal and other minerals apart from zinc and copper; levels of neurotransmitters, amino acids and organic acids; which all help to give clues towards someone with methylation imbalances, and what types of imbalances.
Commonly those with undermethylation may have:
1. High blood histamine
2. High basophil count
3. Low plasma zinc
4. Elevated serum copper
5. High heavy metals
6. Low levels of the neurotransmitters serotonin, dopamine and norepinephrine.
Commonly those with overmethylation may have:
1. Low blood histamine
2. Low basophil count
3. Low plasma zinc
4. High levels of copper
5. Elevated levels of the neurotransmitters serotonin, dopamine and norepinephrine.
Supplementation to support methylation issues
Those with undermethylation often respond well to methionine, SAMe, 5HTP, calcium, magnesium, omega-6 essential oils such as borage and evening primrose oil, B-6, inositol, and vitamins A, C, and E, plus zinc, TMG or DMG.
They should avoid supplements containing folic acid but can tolerate the more active forms where there is MTHFR defect, especially if homozygous for the defect.
This condition is the biochemical opposite of undermethylation. Those with overmethylation usually respond well to folic acid, B-12 (active forms), niacinamide (B3), DMAE, choline, manganese, zinc, omega-3 essential oils (DHA and EPA) from fish oils and vitamins C and E, but should avoid supplements of methionine, SAMe, inositol, TMG and DMG.
Just to thrown in another level of confusion – I commonly find that even though someone may appear to be a clear cut under or over methylator, that doesn’t mean that the nutrients listed will help or are right for them.
In fact, there are many times I see people react to the very nutrients they need. This is partly due to certain imbalances in other areas that need to be addressed first. After dealing with the other imbalances, the doses of the nutrients they need can then be reintroduced slowly at low dosages.
Some of these other imbalances can include things such as: intestinal overgrowth of bacteria; fungi and/or parasites; leaky gut or intestinal permeability; and heavy metal toxicity. There are many more, but you get the picture.
Jumping in to take the above-mentioned nutrients can trigger a detox response, or dump certain metals and minerals, or even set off a dieback reaction from the bad bugs that just sets the body ‘on fire’ with reactions.
The same supplements, after you are more balanced, can bring greater harmony to your body.
We have seen how methylation supports the body to detoxify and adjust and rebuild components needed for all bodily processes, including the control of inflammation, maintain good DNA transcription, support the immune and cardiovascular systems, provide the energy needed for daily tasks, and give us a healthy brain and mood.
We have also seen the importance of having the correct levels of supportive methylation nutrients and to monitor the levels while taking the supplements, as both too low and too high can create issues. Balance is the key.
I hope you have enjoyed this article as I have found that many with pyroluria like to thoroughly research the subject. Most importantly, never self-diagnose or self-prescribe. Always seek the guidance of a qualified health practitioner and go with low doses of supplements and build slowly.
Better still, eat your ‘greens’ and talk to someone who can help you gain a deeper understanding of how the right diet for you can help support methylation and create balance for your body.
If you have a comment to share that you feel can be of value to others, please do so. If you have any questions, please direct these to your health practitioner or use the contact form link to email me.