The term "methylation" has become extremely popular within the health and longevity world over recent years, thanks in part to a gentleman by the name of Gary Brecka.
But this has also led to some confusion regarding what methylation actually means.
So, we thought it would be useful to help clarify some of the terminology used and simplify the science as best we can, then explain some of the genes and nutrients involved, before we delve into the world of epigenetics!
To begin with, it's probably a good idea to focus on the main methylation cycle rather than the larger network of biochemical pathways.
This first step will help to provide you with a foundation of knowledge and a bit more clarity surrounding the "core methylation cycle," before delving into a more complex course of events.
The Methylation Cycle (some of the genes and areas of interest!)
The methylation cycle is a fundamental biochemical process that occurs in every cell. It generates and transfers small chemical units called methyl groups, which are used in a wide range of functions, including metabolism, detoxification, and gene regulation.
For the purposes of today, there are two key areas of the methylation cycle we will focus on. The first is the production of methyl groups, specifically how the body synthesises S-adenosylmethionine (SAM), the primary methyl donor used in hundreds of biochemical reactions throughout the body. The second is the recycling of homocysteine back to methionine.
Homocysteine is a natural by-product of methylation, and the body's ability to efficiently convert it back to methionine, and subsequently back to SAM, is critical. When this recycling process is impaired, homocysteine can accumulate in the blood, which has been associated with increased risk of cardiovascular disease, cognitive decline, and other adverse health outcomes.
Both of these processes are heavily influenced by key genes and nutrients, which we will explore in more detail below.
DNA methylation is one way these methyl groups are used. In this process, methyl groups are added to specific regions of DNA as part of an epigenetic modification. This does not change the underlying genetic code, but it can influence how genes are expressed.
Rather than acting as a simple on/off switch, DNA methylation helps fine-tune gene activity depending on the needs of the cell.
Importantly, epigenetic patterns can be influenced by factors such as diet, environment, and lifestyle, although they are also shaped by genetics and other biological factors.
There are a variety of genes which we will come on to in a moment that are fundamentally important to the methylation cycle and, depending on the variations you have, can dramatically affect your ability to methylate effectively.
We also need to remember that your genes are, in many instances, only as effective as the stimulus they are given. If you do not provide them with the correct signals from your diet, lifestyle, and environment, then no matter how beneficial they are, you will never be able to maximise your true health and longevity potential.
Likewise, if you have genetic variations that are not as advantageous as they could be, but they are nurtured and nourished in the right way with the correct stimulus each day, then you can, in many instances, compensate for their effect.
Healthy methylation can be disrupted by various elements, such as:
- Your genetic variants (MTHFR, MTR)
- Age (65+) increased chance of vitamin B12 deficiency
- Dietary choices, such as following a vegan diet
- Low protein diets
- Lack of key nutrients such as B-vitamins, choline, zinc, and magnesium
- Alcohol, affects B-vitamin absorption and methionine levels
- Smoking reduces folate levels
- High stress and poor sleep
- Low stomach acid (poor stomach pH)
- Liver health, as the majority of methylation reactions occur in the liver
Reduced Methylation = High Homocysteine
As you can see from the picture below (and this is quite a basic representation), the methylation cycle involves quite a few genes, nutrients and pathways. This can get extremely confusing, so we'll try and keep it as simple as possible for today.
1. Homocysteine
As briefly mentioned above, homocysteine is an amino acid that forms in the body during the metabolism of methionine, an essential amino acid found in protein-rich foods. While it's a normal part of biochemical processes, elevated levels of homocysteine in the blood can be a risk factor for cardiovascular disease, cognitive decline, and other health concerns.
Lowering homocysteine and helping recycle it efficiently, requires healthy methylation. Supporting homocysteine clearance reduces the strain on the cardiovascular system, improving both longevity and quality of life.
2. MTHFR/Folate metabolism (Mild genetic risk)
MTHFR is one of the most widely discussed genes in this area, and one that Gary Brecka frequently highlights. Its primary role is to help convert folate (vitamin B9) from the forms found in food and supplements into the active form, 5-methyltetrahydrofolate (Methylfolate), which the body can readily use.
A "mild genetic risk" result suggests that your MTHFR enzyme is likely functioning normally, supporting efficient folate metabolism. This can be beneficial for maintaining adequate levels of active folate, although overall folate status still depends on diet, lifestyle, and other biological factors.
Folate is fundamentally important because it supports DNA synthesis and repair, contributes to normal methylation processes, and plays a key role in cell division and red blood cell formation. It also helps regulate homocysteine levels, which are linked to cardiovascular health.
By contrast, a higher genetic risk result for MTHFR means the enzyme converts folate into its active, usable form less efficiently. This matters because the body can only use folate once it's been converted, so a less efficient enzyme can lead to lower levels of active folate available for these processes, even if dietary folate intake looks adequate on paper.
The downstream effects can be significant. Since folate plays a direct role in recycling homocysteine, reduced MTHFR efficiency is one of the more common contributors to elevated homocysteine levels, which have been associated with increased cardiovascular risk, cognitive decline, and complications during pregnancy, including neural tube defects, as folate is critical for early foetal development.
Impaired folate metabolism can also compromise DNA synthesis and repair more broadly, since the body relies on a steady, adequate supply of active folate to maintain healthy cell division and replication.
This is why understanding your MTHFR status matters, not to cause alarm, but because it identifies exactly where targeted support (such as choosing Methylfolate over standard folic acid) can make a meaningful, practical difference.
MTR/Vitamin B12 metabolism (Mild genetic risk)
The MTR enzyme (methionine synthase) plays a key role in methylation by converting homocysteine back into methionine, a reaction that depends on vitamin B12 as a cofactor.
A "mild genetic risk" result for MTR suggests that this pathway is likely functioning normally, meaning your body is well-positioned to recycle homocysteine efficiently, provided adequate levels of vitamin B12 are available.
Vitamin B12, particularly in its active form Methylcobalamin, is essential for several metabolic processes. It supports DNA synthesis and methylation, both of which are important for normal cellular function and maintenance.
B12 also plays a critical role in the nervous system, contributing to myelin formation and supporting neurological health. Adequate levels are important for maintaining cognitive function.
By contrast, a higher genetic risk result for MTR means this recycling step runs less efficiently, so homocysteine isn't converted back into methionine as effectively, even when B12 intake looks sufficient on paper. This matters because MTR sits at a genuine bottleneck in the methylation cycle: it's one of only two ways the body can remethylate homocysteine, so reduced efficiency here places more pressure on the pathway as a whole, not just on this one step.
The downstream effects can be significant. Deficiency in vitamin B12, or reduced MTR efficiency more broadly, can lead to anaemia, neurological symptoms, and elevated homocysteine levels, which have been associated with increased risk of cardiovascular and other chronic conditions.
Because B12 is also critical for myelin formation, impaired MTR function can have a disproportionate impact on neurological and cognitive health specifically, beyond the general effects seen with reduced methylation elsewhere in the cycle.
This is why understanding your MTR status matters, not to cause alarm, but because it identifies exactly where targeted support (such as prioritising Methylcobalamin over other forms of B12) can make a meaningful, practical difference.
3. Methionine
Methylfolate and Methylcobalamin provide the methyl group that converts homocysteine into methionine, in a reaction that also depends on zinc as a supporting cofactor.
Healthy methionine production is also affected by protein consumption, which is why low protein intake can have a significant effect on healthy methylation and gene expression. Protein-rich foods supply the amino acid methionine directly, meaning that adequate dietary protein is essential not only for general health but also for maintaining the availability of methionine needed to keep the methylation cycle running efficiently.
4. Magnesium and ATP
Once homocysteine has been successfully remethylated and converted back into methionine, the next stage of the cycle requires the enzyme methionine adenosyltransferase (MAT), along with magnesium and ATP (adenosine triphosphate), to catalyse the conversion of methionine into SAMe (S-adenosylmethionine), the body's primary and most important methyl donor.
It is worth noting that ATP availability is directly tied to mitochondrial function and energy metabolism, meaning that poor energy production at the cellular level can impair SAMe synthesis even when all the necessary nutritional cofactors are present. This highlights why fatigue, poor sleep, and chronic stress can all negatively impact methylation, not just nutritional deficiencies.
5. SAMe (S-adenosylmethionine)
SAMe donates methyl groups to over 200 known biochemical reactions throughout the body, including the methylation of DNA, the metabolism of neurotransmitters such as dopamine, serotonin, and noradrenaline, the production of creatine, the metabolism of hormones, and the regulation of inflammation.
Without adequate SAMe production, the entire downstream methylation process becomes compromised. While SAMe plays a central role in methylation, its levels are not typically measured directly in routine clinical testing.
SAMe (S-adenosylmethionine) donates methyl groups for numerous methylation reactions, including:
- DNA methylation (regulation of gene expression)
- Neurotransmitter metabolism (dopamine, serotonin, and noradrenaline)
- Detoxification processes in the liver
- Cell membrane integrity via phospholipid methylation
Without sufficient SAMe, the body cannot carry out these methylation reactions efficiently, with wide-ranging consequences for health and cellular function.
The Methylation Burden: Creatine and Phosphatidylcholine
It is estimated that the vast majority of the body's methylation capacity, somewhere in the region of 40–50%, is devoted to creatine synthesis, with phosphatidylcholine synthesis accounting for a further significant proportion.
Together, these two processes consume the largest share of available methyl groups. Creatine is essential for energy metabolism in muscle, brain, and immune cells, whilst phosphatidylcholine is a critical structural component of every cell membrane in the body.
The remaining methyl groups are then available for hundreds of further reactions, including dopamine and oestrogen regulation, the production of stress hormones, gene regulation, and a wide range of other essential biochemical processes.
This is why consuming creatine and phosphatidylcholine directly through diet or supplementation can help reduce the methylation burden, freeing up methyl groups for these other vital functions.
Your methylation cycle operates with finite resources, specifically a limited pool of methyl groups, which are drawn upon across hundreds of competing reactions: switching genes on and off, processing hormones, detoxifying chemicals, producing neurotransmitters, and repairing DNA.
Supplementing with creatine is therefore a great way to support the methylation cycle, as it bypasses the need for the body to synthesise creatine itself, one of the most methylation-intensive processes in the body.
The result is that a significant proportion of methyl groups are freed up for other essential tasks, such as regulating the stress response, reducing inflammation, and supporting neurotransmitter balance. This is why creatine is not just a supplement for athletes; it is a valuable tool for genetic and metabolic support more broadly.
COMT (Catechol-O-Methyltransferase)
COMT is an enzyme responsible for breaking down neurotransmitters, particularly the catecholamines, and uses SAMe to methylate and clear the following:
- Dopamine (focus, reward, and motivation)
- Norepinephrine (attention, energy, and stress response)
- Epinephrine (adrenaline), the fight-or-flight hormone
COMT also plays an important role in clearing oestrogens and certain environmental toxins from the body. This is why inefficient methylation, whether due to poor nutrition lacking in B vitamins, zinc, and choline, or as a result of lifestyle factors, can have a significant impact on mental health and hormonal balance.
- If COMT activity is too slow (Worrier), neurotransmitters such as dopamine and adrenaline can accumulate, potentially leading to anxiety, overstimulation, or mood instability.
- If COMT activity is too fast (Warrior), dopamine is broken down too rapidly, which may result in low motivation, reduced pleasure response, and a persistently flat or low mood.
Check your Muhdo DNA results to see whether you are a Worrier or a Warrior.
6. S-Adenosylhomocysteine (SAH)
SAH is formed as a by-product of methylation reactions that utilise SAMe. It acts as a potent inhibitor of methyltransferases, the enzymes responsible for carrying out methylation reactions throughout the body. SAH is subsequently converted back into homocysteine, at which point the cycle begins again.
This conversion is highly dependent on nutritional status, particularly adequate levels of B vitamins (B2, B6, B9/folate, and B12), as well as other key methylation cofactors including zinc, magnesium, and choline.
If these nutrients are deficient, or if homocysteine levels become elevated, the methylation cycle can become sluggish or dysfunctional, with downstream effects on gene expression, detoxification, neurotransmitter production, and overall cellular health.
One further important consideration is that the liver is the primary site of methylation activity in the body. Factors such as smoking, regular alcohol consumption, a diet high in processed foods, certain medications, and conditions such as non-alcoholic fatty liver disease (NAFLD) can all significantly impair methylation capacity, regardless of how favourable an individual's genetic profile may be.
Liver Function
The liver is a major site of methylation and metabolic activity, making liver health an important factor in overall biochemical balance. It is responsible for processing and recycling many of the key molecules involved in the methylation cycle, including homocysteine, methionine, and SAMe, and plays a central role in detoxification pathways that are themselves highly methylation dependent.
Blood tests such as ALT (alanine aminotransferase), AST (aspartate aminotransferase), ALP (alkaline phosphatase), and GGT (gamma-glutamyltransferase) can provide valuable insight into liver function and health.
Elevated levels of these markers can indicate liver stress, inflammation, or damage, all of which may compromise the liver's ability to carry out its methylation and detoxification responsibilities effectively. It is important to note, however, that these markers reflect liver cell integrity and biliary function rather than directly measuring methylation capacity itself.
Factors such as excess alcohol consumption, a poor diet, chronic inflammation, and certain medications can all impair liver function and, by extension, negatively impact the methylation cycle. Supporting liver health through adequate nutrition, hydration, and lifestyle habits is therefore an important, and often overlooked, component of maintaining healthy methylation overall.
DNA Methylation (Epigenetics): Eat, Sleep, Train, Repeat
Remember in the film Jurassic Park when the scientists were explaining the DNA of the dinosaurs? They described the DNA double helix as being like a twisted ladder, comprising four nucleotide bases: adenine (A), thymine (T), cytosine (C), and guanine (G), with each rung of the ladder made up of two of those bases paired together.
The Four Nucleotide Bases
What Is DNA Methylation?
DNA methylation is one of the key mechanisms by which epigenetic regulation occurs. It involves the addition of a methyl group (as mentioned above) to a DNA molecule, typically at cytosine bases that are immediately followed by guanine. These specific locations are known as CpG sites (cytosine-phosphate-guanine sites).
CpG methylation is an epigenetic modification, also referred to as an epigenetic mark, whereby a methyl group is chemically attached to the DNA strand without altering the underlying DNA sequence itself. Think of it less like editing the text of a book and more like adding a highlight or annotation that changes how that passage is read and interpreted, without changing the words themselves.
This process directly affects how your genes are read and expressed and can be influenced by a wide range of factors including your lifestyle, environment, diet, exercise habits, and stress levels.
The Nutrients That Support DNA Methylation
The body requires a range of key nutrients and cofactors to carry out methylation effectively. These include B vitamins, specifically B2 (riboflavin), B6 (pyridoxine), B9 (folate), and B12 (cobalamin), as well as choline, zinc, magnesium, and methyl donors such as SAMe (S-adenosylmethionine).
These nutrients supply the essential building blocks and biochemical signals required to support methylation reactions, which occur an estimated billions of times every second throughout the body and are vital to overall health. They regulate gene expression, DNA repair, detoxification, and the production of essential molecules such as neurotransmitters, collectively influencing almost every biological process in the body.
For DNA methylation to occur efficiently, the methylation cycle needs to run as smoothly as possible, which is why nutritional status, lifestyle, and genetic variants all play such an important role.
What Your Muhdo Tests Can Tell You
The section above has provided a brief overview of the methylation cycle, some of the key genes involved, and how they influence your body's ability to produce and utilise methyl groups effectively.
The Muhdo DNA test allows you to understand your methylation-related genes, including MTHFR, MTRR, and COMT, and can provide meaningful insight into how efficiently your body manages each stage of the cycle. People with certain genetic variants in these genes may benefit from additional support through targeted dietary changes and supplementation.
Our DNA + Epigenetics test then takes this a step further by measuring how key longevity genes are actually methylating in real time, and how this is influencing your rate of biological ageing. In addition to methylation analysis, we also examine a range of other epigenetic areas, including:
- Hearing, Memory and Eyesight Ages
- Inflammation (Pro, Anti and Total)
- Muscle Degeneration
- Epi Vitality
- ImmunoScore
- Heart Age (coming soon)
To give a real example: my own Memory Age came back at 35, 12 years younger than my chronological age. That's not an abstract number on a page, it's a direct reflection of how my brain is actually ageing at a cellular level, and a sign that whatever I'm doing for sleep, stress, and cognitive health is paying off where it matters.
This isn't just a consumer product built for marketing appeal, either. It's the exact same test currently being used by PREDICTOM, the €21m EU-funded dementia research consortium we're part of, alongside Novo Nordisk, GE HealthCare, Siemens Healthineers, and King's College London.
Researchers there are using our epigenetic testing to study the biological signatures of cognitive decline, at exactly the scale and scrutiny you'd expect from a study of that size. When you take this test, you're getting access to the same methodology being used in frontline dementia research, not a simplified or consumer-only version of it.
That's the real value of this kind of testing. It doesn't just tell you what you did yesterday, the way a step count or sleep score does. It tells you whether your organs and systems are ageing faster or slower than the calendar suggests, and gives you a concrete, individual number to track over time, backed by the same science being used to study one of the biggest health challenges of our time.
You don't need to guess how your methylation is performing; you can test and support it. Optimising methylation means unlocking better energy, clearer thinking, emotional balance, and long-term protection against chronic disease.
To find out more about our DNA + Epigenetics kit and to receive 25% off until the 19th of September, please use code EPI25 and click here. https://muhdohub.com/collections/main-shop/products/dna-epigenetic-kit
