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Methylation is a simple chemical reaction that happens constantly in the human body and is central to many metabolic processes.
I’d never heard of methylation in a natural health context until I stumbled across it recently, while looking for answers on why my body was not responding as expected to my supplements.
But apparently not only is it essential for our health and well being, it can also go wrong in multiple ways, causing all kinds of unexpected effects.
Let’s see what methylation is and why we should make sure it’s working well for us.
- A definition of methylation
- Why is methylation important?
- Fact #1 – There are two key methylation roles
- Fact #2 – There’s one key methylation pathway
- Where does methylation occur?
- Methylation disorders
- How to improve methylation
- Methylation and your health
- Methylation studies
A definition of methylation
In its simplest terms, methylation is a chemical process that transfers a “methyl” group from one molecule to another.
A methyl group is composed of one carbon atom and three hydrogen atoms:
But don’t be fooled by the simplicity of this cute little group of atoms.
Methylation is a powerful driving force in a number of essential processes in the body.
So let’s dive a bit deeper into the role of methylation.
Why is methylation important?
The key to understanding why we need to care about methylation, is to understand exactly what it does in our bodies.
The basic truth is that it’s involved in so many different processes and pathways in our bodies that maybe we almost overlook it in favour of simpler, easier to understand factors.
If you go looking for articles on methylation, you might find yourself lost in a morass of technical and scientific terms, so let’s try to lay it out a bit more clearly for you with some key facts.
Fact #1 – There are two key methylation roles
This is probably the biggest source of confusion when it comes to understanding the importance of methylation in the human body.
There are two essentially distinct but equally important roles for methylation in the human body.
- DNA Methylation
- Metabolic Methylation
Of course there’s always some overlap because no system in the human body operates in isolation, but thinking about methylation in this way will help to clear up some confusion
DNA is made up of four building blocks called nucleotides, and one of them – cystosine – can be methylated.
When methyl groups are added to or removed from DNA, it fundamentally alters the expression of the gene encoded by that DNA.
In DNA, methylation acts like a light switch, and can turn genes completely on or off.
When the genes in DNA are expressed, they turn into proteins, which are then used throughout the body as enzymes, hormones, antibodies and more, so as you might appreciate, turning a gene on and off completely can have a huge impact on how our body functions.
Methylation of DNA in mature cells is relatively stable, and tends to happen at key moments, like cell division, differentiation and during formation of sperm and eggs, but apparently it can also be triggered by environmental factors including stress and smoking.
There is a second, related methylation that happens to histones – the protein “balls” that DNA is wrapped around to help pack it into the nucleus of the cell.
The methylation of histones changes much more over the life of a cell and can also affect the expression of genes.
This regulation of gene expression via methylation of DNA is also called epigenetics.
Defects in DNA and histone methylation have been linked to diseases including cancer, muscular dystrophy and various birth defects, and researchers are still working to fully understand their impact.
So that’s a whirlwind introduction to DNA methylation.
But this is not the methylation process that we’re most interested in here.
Although the expression of genes is definitely important in our health, the methylation of the molecules that operate our bodies on a daily basis is what’s most relevant to our health.
I like to think of this role as “metabolic methylation”, where key molecules in the human body are methylated in order to perform their required function in metabolic chemical reactions or change their behaviour – including proteins, neurotransmitters and fats.
The systems that are influenced by methylation of molecules are broad, and include:
- Nervous system
- Cardiovascular system
- Immune system
- Energy production
- Heavy-metal detoxification
- Hormone balance
- Gut health
All of this might sound quite vague and broad, so let’s tie it down with some specific examples.
- Methylation of lysine may affect expression of genes involved in nervous system disorders https://europepmc.org/article/med/31076097
- Methylation may influence the inflammatory response of microglia (brain immune cells) after exposure to high levels of alcohol https://www.grantome.com/grant/NIH/R21-AA025183-01A1
- Dysfunction in methylation of arginine may contribute to the risk of heart disease https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5319503/
- Methylation of adenosine in mRNA (messenger RNA that is turned into proteins) may play a role in cancer https://pubmed.ncbi.nlm.nih.gov/31142332/
- Methylation of the tuberculosis antigen protein in T cells helps the immune system defend against the infection https://www.nature.com/articles/nri1444
- Sleep deprivation may reduce the effectiveness of energy metabolism via methylation https://pubmed.ncbi.nlm.nih.gov/28860003/
- Demethylation of eye pigments may alter the effectiveness of vision and light detection https://pubs.rsc.org/en/content/articlelanding/2015/cp/c5cp01939g#!divAbstract
- Methylation of phosphatidylethanolamine (PE) may alter muscle fat composition and reduce the efficiency of energy transfer, contributing to obesity https://grantome.com/grant/NIH/R01-DK107397-01A1
- Methylation of toxic metals can affect their removal from the body https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1637412/
- The rate of methylation of neurotransmitters can be affected by hormone levels https://www.beyondmthfr.com/treating-comt-and-mao-the-hormonal-cause-of-stress-and-anxiety/
- Methylation in the nervous system might underlie depression and some affective disorders https://pubmed.ncbi.nlm.nih.gov/6146753/
That’s a pretty complicated list, isn’t it? And I’ve barely scratched the surface.
Of course, it’s possible that we understand so little about how methylation functions in the body that all of these effects are all just a result of regulation of gene expression via DNA methylation.
But the fact that it can affect so many different systems in the body says to me that it’s really important and worth exploring further.
So let’s dive into a bit of biochemistry. I’ll keep it as simple as I can, I promise!
Fact #2 – There’s one key methylation pathway
Perhaps looking at the pathways involved in methylation will help us understand better what it does in the human body.
There is one central metabolic process that handles methylation in the human body called “the methylation cycle”, composed of two parts – the methionine and folate cycles.
This is also referred to as “one carbon metabolism” because all of the reactions involve the transfer of single-carbon groups, such as a methyl (CH3) group.
At the heart of the methionine cycle is a molecule called SAMe (S-Adenosyl-L-Methionine). This is the primary “methyl donor” in the body, which means it’s what provides the methyl groups that are added to DNA, RNA, fats and protein.
If the methionine or folate cycles aren’t working correctly, then SAMe isn’t generated appropriately, and methylation can go out of balance.
If SAMe is not regenerated, then blood levels of homocysteine can become elevated, which is associated with blood clots and vessel damage,
Imbalances in B12, B6, B2 and folate may also impact the efficiency of the methylation pathway, as these are direct co-factors in these chemical reactions.
Also directly connected to these pathways are other cycles to do with:
- Converting tryptophan to serotonin (deficiencies are associated with depression, insomnia and anxiety)
- Converting tyrosine to dopamine (the reward and motivation neurotransmitter)
- Creation of glutathione (a powerful detoxification molecule)
- Generation of ammonia as a toxic by-product, leading to brain fog
- Nitric oxide, an important messenger molecule for circulation, nerves and immunity that can also cause damage under specific conditions
So again you can see that issues with these methylation cycles may throw a variety of systems out of balance.
Methylation and MTHFR
One of the key enzymes in the folate cycle is MTHFR (Methylenetetrahydrofolate reductase), and there are many people with genetic variations in the MTHFR enzyme that seem to alter its efficiency in the folate cycle.
It uses up homocysteine in its regeneration of SAMe, and so can reduce levels of homocysteine when it’s working effectively.
Two common variants (or mutations) seen in 10 to 25% of different populations can cause high homocysteine levels, and contribute to birth defects, glaucoma, mental health issues and cancer.
Identification of a specific MTHFR mutation requires a genetic test, and is not usually recommended unless someone has very high homocysteine levels or other signs of methylation issues.
Where does methylation occur?
In order to further appreciate the importance of methylation in the human body, I went looking for a list of the systems that are affected by methylation.
And here’s what I found
- Stress response
- Hormone regulation
- Gene expressions
- Antioxidant activity
- Neurotransmitter production
- Energy production
- Fat metabolism
- Digestive issues
- Thyroid issues
Now I don’t have sources for most of these, as I was aiming for more of a consensus approach, but as you can see, this list seems to describe almost every system in the human body.
So although we can’t see from this exactly how methylation affects each of these systems, we can get a sense of the importance of having a methylation system that’s in balance.
Another way to understand the role of methylation in the human body is to look at what happens when things go wrong with the methylation pathways.
There are two main forms of methylation disorders – over-methylation and under-methylation.
Over-methylation signs and symptoms
Over-methylation, also called histaptenia or hypermethylation, occurs when the conversion of homocysteine back to SAMe is not working properly.
This generally leads to low levels of histamine, an important substance for immunity, and elevated levels of serotonin, dopamine and adrenaline. As a result they may not experience allergies or headaches.
Some of the common signs and symptoms of over-methylation include:
- Low motivation
- High pain threshold
- Busy mind
- Creativity (artistic or musical)
- Upper body pain
- High energy
- Poor concentration
- Frustrated easily
- Heavy body hair growth
Other less common symptoms may include:
- Chemical sensitivities
- High anxiety or panic attacks
- Pacing or constant movement
- Adverse reactions to oestrogen therapy, anti-histamines and SAMe
- Sleep disorders
Over-methylators tend to do better on a plant-based diet due to the high level of folate, versus an animal-foods diet, with the high levels of methionine found in meat, eggs and dairy.
Methylation deficiency + symptoms
Under-methylation, also referred to as methylation deficiency or histadelia, is the more common form of methylation issues, and happens when SAMe fails to donate its methyl group effectively.
This can be associated with low levels of calcium, magnesium, methionine and B6, and high levels of folic acid. People with low methylation also have low levels of serotonin and dopamine, and sub-optimal glutathione and B12 processing.
Common symptoms and signs of under-methylation include:
- High achievers
- Addictive tendencies
- Obsessive compulsive tendencies
- Low pain tolerance
- Self-motivation at school
- Adherence to rituals
- Highly competitive
- High inner tension
- Adrenal exhaustion
Other less common signs may include:
- Strong willed
- Seasonal allergies
- Social isolation
- Excess tears or saliva
People who are under-methylated are often described as “Type A” personalities. Sometimes undermethylation combines with pyrroluria, an imbalance in zinc and B6, to complicate things further.
Methylation and oestrogen
I’ve been working on a solution to my oestrogen dominance issue, which is one of the ways I found myself in the middle of exploring methylation.
Imbalances in the methylation cycle can lead to hormone imbalances, including oestrogen dominance. This can happen because the pathways that would normally break down oestrogen don’t work as well, allowing oestrogen to accumulate.
Oestrogen, along with testosterone and progesterone, can also affect the enzymes that lead to the creation of essential neurotransmitters, including serotonin and dopamine.
Methylation and depression
As we’ve seen many times already, imbalances in the methylation processes can directly impact levels of key neurotransmitters, especially serotonin and dopamine.
When serotonin or dopamine levels are too low, depression can result, as well as lethargy, anxiety, low motivation and panic attacks.
Methylation and autism
There has also been extensive discussion of the potential of methylation to be involved in conditions including autism, aspergers and ADHD.
Some, including Dr Amy Yakso (Amazon affiliate link), have theorised that autism may in fact simply be a childhood form of a methylation disorder, and have developed protocols to help rebalance the body’s systems, with some degree of success.
Of course there are likely to be multiple factors contributing to these conditions, including diet, environment, gut health, heavy metals and more, but it’s definitely worth exploring further.
Methylation and Chronic Fatigue Syndrome
Alongside the association with autism, is the suggestion that methylation problems may also lie at the heart of Chronic Fatigue Syndrome, fibromyalgia and Multiple Sclerosis.
Again, practitioners have developed protocols to help rebalance the methylation systems, and address these debilitating health conditions, again with good success.
This whole area of nutrigenomics is fascinating and one that I will continue to explore.
Methylation and aging
As we age, the rate at which our DNA becomes methylated appears to increase, which is directly correlated with age-related diseases including Alzheimers, cardiovascular disease and cancer.
Environmental stressors can age us more rapidly, and have been shown to also increase the rate of DNA methylation, and apparently our lifespan can be estimated from the level of methylation in our cells.
Wow! That’s a lot of systems going out of balance when methylation issues arise.
How to improve methylation
Hopefully by now you have a much better appreciation of the importance of methylation.
But of course one of the main questions that arises out of all of this is, how do you improve methylation?
Unfortunately there’s no simple answer to that question, because the cycle is complex and has so many points that could be the problem.
In some cases, certain supplements may help, but for others, it may make things significantly worse, so I would recommend working with your health practitioner to diagnose you if you think this might be the issue, and also to create a suitable treatment plan.
With that said, here are some of the more common things you can do to affect the performance of the methylation cycle.
Vitamins B2, B6, B12 and folate are key co-factors in the methylation cycle, so ensuring you have healthy, appropriate amounts of each in your body is important for healthy methylation.
That said, depending on the specific methylation issue, increasing your folate intake may be the opposite of what is required.
One of the reasons I started exploring methylation is because my B-complex was creating brain fog, and so I began to explore possible reasons why.
There are a number of herbs that can help the body naturally rebalance the methylation cycle, including:
- Curcurmin (from turmeric)
Many of these you will get in abundance if you’re eating a nutrient-dense, whole food, unprocessed diet.
Clean up your diet
Aim to eliminate sugar, caffeine, alcohol and packaged or processed foods.
By eating an organic whole food diet, we reduce the amount of toxins entering our bodies, making it easier for our detoxification systems to work effectively.
We also maximise the nutrients we’re getting with our food, giving our body all of the things it needs to function at optimal levels.
Heal your gut
Ensuring that your gut is functioning effectively will help you get the nutrients you need from your diet.
Having the right balance of healthy microbes in your gut can also keep the methylation cycle in balance.
Clean up your environment and reduce the strain on your body. Minimise conventional drug use and eat as few pesticides as you can manage.
This is the one I see in almost every article I read about natural health, and maybe that’s because stress is the biggest disease we have in our modern society.
Do what you can to reduce stress and you will be helping your body regain its balance, including meditation, getting enough sleep and spending time on things you enjoy.
There are many other potential supplements that may improve your methylation status, including:
- Vitamin D
But with all of these, it’s important to understand that one supplement may not be right for you, or make the right difference, and to carefully navigate all of your options until you find what works for you.
Methylation and your health
As you can see, methylation is a fundamental process in the human body, that sometimes goes out of balance and causes all kinds of health problems.
I hope that you learned something useful about methylation and its role in your body, and that you’re inspired to learn more on your journey to achieving optimal health and happiness.
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And have a wonderful day.
If you’d like to know more about methylation, there’s a couple of books I came across in my research that might be of interest to you.
Feel Good Nutrigenomics: Your Roadmap to Health (Amazon affiliate link)
By Dr Amy Yasko
Toxic: Heal Your Body (Amazon affiliate link)
By Dr Neil Nathan
And here’s a collection of articles that I found especially helpful as I was exploring the topic, if you want to read more about it.