Today’s topic takes us down into the depths of a fundamental process called methylation. We consider its role through the Ancestral Lens – an evolutionarily appropriate view.
Methylation is necessary for many bodily processes – from neurotransmitters, to DNA expression, and histamine degradation. It is also highly dependent on nutrients that many people today do not consume in sufficient amounts.
The first thing we’re going to look at is what methylation means and what the functions are. This way, we’ll also understand what happens when it doesn’t work well and learn about the main nutrients we need to make it work.
Armed with the knowledge, we can think about how to optimize it. Last but not least, there is a small excursion into the world of genetics with the role of polymorphisms, such as the well-known MTHFR enzyme.
So much for our rough way, so let’s get going!
Methylation explained simply: what is it?
A small excursion into the World of Epigenetics
Epigenetics is a relatively new field, built on classical genetics. Everyone knows genetics with its hard-coded DNA. Epigenetics is an additional system based on and working hand in hand with the fixed DNA code. It works by changing various substances that exist around DNA:
Methylation is one such process of epigenetics in which methyl groups 1CH3 – A carbon with free hydrogen. It is the smallest functional group. are attached – or detached – to DNA. These functional groups turn genes on or off or activate & deactivate neurotransmitters. It is again an additional level of complexity to the base code, which is relatively fixed.
In addition to methyl groups, many other functional groups are added and removed, such as acetyl groups in acetylation, or butyrate & propionate. As a new field, new groups are discovered to this day and the effects are warmly discussed. 2https://www.britannica.com/science/epigenetics
One-Carbon Metabolism
Methylation, as the name suggests, depends on methyl groups. If you remember 8th-grade chemistry, methyl groups are the smallest functional group: a carbon with three hydrogens (CH³). Methylation is nothing more than the epigenetic process in which methyl groups are attached or detached to other molecules.
You can imagine it like with Lego – let methyl groups be the red bricks, which can be plugged to already existing constructions.
Why is Methylation important?
Methylation is a basic building block of epigenetics. It is needed to modify DNA depending on input from the environment. Cold temperatures in winter turn on certain genes that are responsible for thermogenesis. Brown fat is activated and we warm up due to mitochondrial uncoupling. Cold is the stimulus that forces your body to make epigenetic adjustments.
As a complex metabolic process, methylation has many inputs and few outputs, as we will see next. The main output is S-adenosylmethionine (SAMe). SAMe is the molecule that carries methyl groups around and functions as a donor. If enough SAMe is available, glutathione and a few others can also be synthesized.
SAMe in turn is mainly needed for creatine, phosphatidylcholine, neurotransmitter synthesis, and histamine degradation. Further SAMe is compellingly needed in 250 further reactions!3https://www.thorne.com/take-5-daily/article/what-is-methylation-and-why-should-you-care-about-it
SAMe
SAMe is your body’s main methyl donor – its job is to move a group from A to B. It transfers it from itself to another molecule. The whole purpose of the entire methylation cycle is to transfer dietary methyl groups to SAMe and make them usable.
SAMe can be thought of as the activated form of the amino acid methionine, which is one of the main inputs. It is often called AdoMet or, less commonly, methyl-homocysteine.
In the body, SAMe is involved in the following processes4S-Adenosyl-L-methionine (SAMe): from the bench to the bedside—molecular basis of a pleiotrophic molecule :
- Nitric oxide metabolism
- Neurotransmitter synthesis (serotonin, epinephrine, norepinephrine)
- Energy production (coenzymes Q10)
- Protein synthesis (melatonin, taurine, cysteine)
- Antioxidant protection (glutathione)
- Genetics (DNA, RNA, repair of which)
Creatine
Creatine is very well-known in sports to increase maximum strength – and does so splendidly (…because many people don’t get enough creatine in their diet).
The only source of creatine is animal muscle meat. It helps with maximum strength because creatine acts as a buffer for quick energy delivery. That’s why many other energy-hungry processes such as thinking, making sperm, seeing or hearing depend heavily on it.
A common argument is that dietary creatine is not important because we can make it ourselves. This is not true and dietary creatine cannot be replaced. It is more of a double check, a survival mechanism, if there is no dietary creatine because of its importance. If you don’t eat creatine, SAMe will be devoured!
If you don’t get enough creatine from your diet, you need to make it yourself. This is possible to a certain extent, but it puts a lot of strain on the methylation process and eats up a lot of SAMe from the pool.
You can synthesize about 1.7g per day, but optimal levels seem to be at ~3-5g per day. Therefore, eat enough creatine in your diet – this will free up SAMe for other important processes.
Phosphatidylcholine
Phosphatidylcholine has two important roles in the body:
- It is a main component of cell membranes and is needed to channel fatty acids into cells.
- You need it to produce the neurotransmitter acetylcholine.
The first point is particularly exciting in relation to non-alcoholic fatty liver disease where choline deficiency plays a central role. A choline deficiency also leads to impaired cell membranes – couple that with lots of dietary PUFAs and you created a recipe for disaster.
Acetylcholine is again a substance that mediates activity and is needed for muscle contractions, higher thinking, and focus. During wakefulness it reaches its highest levels, in NREM sleep it is almost wiped out in the brain.
Choline, like creatine, is found in our food but can also be made by methylation. Choline & creatine are the two main consumers of SAMe. This again speaks to the importance of both, especially in times when food was scarce – it does not speak to the unimportance of choline in our diet!5The nutritional burden of methylation reactions
Histamine Degration
Histamine is a neurotransmitter.6Histamine in the brain Its task is to stimulate alertness, arousal & attention.
Too much histamine in the brain, or limited breakdown, promotes anxiety & panic attacks. It also causes the blood-brain barrier to become more permeable, allowing certain substances like those from food to pass into the brain.7This is probably why histamine-free diets show promise with some mental illnesses like recurrent panic attacks.
As you can clearly see it is neither good nor bad, but a balance is crucial. Histamine is also found in food and often gets only negative press because of its powerful effects. Methylation is needed to get excess histamine out of your brain8This is mediated in the brain, intracellularly, by the enzyme histamine N-methyltransferase (HNMT). In the body, extracellularly, diamine oxidase (DAO) gets rid of histamine.
The Methylation Cycle
Methylation is an interplay of three different biochemical cycles:
- Folate cycle
- Methionine cycle
- Transsulfuration pathway
These three provide for the supply of methyl groups from food, facilitate the conversion of methionine to SAMe, and manage a breakdown product of SAMe, called homocysteine. Don’t worry, we’ll now take a closer look.
The important thing here is the enormous input from food sources:
- Specific amino acids (methionine, glycine & serine) come from animal dietary protein
- The amino acid glycine acts as a buffer for too much methylation or as a shortcut to save folate & methylcobalamin
- Methylfolate (B9) is one of two main methyl group inputs from food. It must be converted to its active form, called 5-L-methyltetrahydrofolate (5-L-MTHF).
- Methylcobalamin (B12) is the second main methyl group input.
- Choline and betaine are additional methyl group donors and help save folate & vitamin B12
- The B-Vitamins B2 & B6 serve as fuel for enzymes
Part 1: The Folat eCycle
In the picture above, the folate cycle is the very left cycle.
It starts with the dietary folate (not folic acid!) and ‘ends’ at the transition point to the methionine cycle where you see many arrows converge. This transition point is the methionine synthase enzyme (MTR/MTRR).
The folate cycle activates folate (L-5-MTHFR) and feeds it into the methionine cycle via the MTR/MTRR enzyme with the help of Vitamin B12. At this enzyme one methyl group is shifted from folate to homocysteine. And: Boom! You recycle homocysteine into methionine. As you can see, what mostly happens is that methyl groups are swapped around.
Important for the function of the folate cycle is, in addition to all the cofactors, sufficient dietary folate. By this, I mean real folate and not artificial folic acid. Folic acid is not meant for human consumption– more about that here.
Part 2: The Methionine Cycle
In the image, you can see the methionine cycle at the right-hand.
It is easiest to understand if we start by methionine. This is a sulfur-containing amino acid that comes mostly from animal protein. Methionine is crucial to produce SAMe, our body’s active methyl donor.
Once SAMe is used up and has passed on its methyl group, it becomes S-adenosylhomocysteine (SAH) and eventually homocysteine. Homocysteine is a significant blood marker because the rise & fall indicates methylation disorders. At the same time, this is also only one piece of the puzzle and often overrated on its own.
Homocysteine can go down two ways – recycling or dismantling.
We’ll take care of recycling first. This is where our methyl group from the folate cycle is reattached to homocysteine to restore methionine.
Alternatively, homocysteine can be recycled without B12/folate via the ‘short route’, the shortcut uses betaine, choline & glycine. This allows enough choline and glycine to lower the dietary requirement for folate. The question of how much is not yet known, estimates go up to 50%.
The main purpose of the methionine cycle is to produce SAMe. SAMe is the activated methionine. SAMe performs the task of a truck transporter in the body, bringing methyl groups into various reactions. All reactions that involve a methyltransferase need SAMe – about 250 reactions.
Part 3: The Transsulfuration Pathway
Terrible name, isn’t it?
It’s the series of arrows you see going down from homocysteine. It’s best to think of it as an irreversible way to get rid of homocysteine. A salvage pathway if you want.
The body turns the homocysteine into other very useful things like taurine or your body’s main antioxidant called glutathione. Estimates think 50% of all glutathione is made this way. Therefore strong methylation leads to strong glutathione function.
So when is this pathway active?
When you have enough SAMe! The body shows this in certain rates, like the SAM/SAH ratio. When there is enough SAMe, your body goes to make glutathione.
Support your Methylation with these crucial Nutrients!
Hey, this was Methylation 101 – well done!
As we’ve seen, everything is insanely dependent on the dietary input. No folate means no methylation, and so does suboptimal methylcobalamin (B12) or methionine. That’s why we’re going to look at how to optimize each nutrient, where they occur, and why the best answer is a traditional nose-to-tail diet.
Methionine, Glycine & Serine
Alright, let’s start with the amino acids methionine, glycine & serine:
- Methionine is a sulfur-containing amino acid found mostly in animal protein.
- The same is true for glycine, with the addition that glycine is found exclusively in the connective tissue and collagen of animals. This is also why many are pro bone broth & collagen. Methionine & glycine should be in some sort of balance.
- Serine is also found most in animal protein and is an important building block for many enzymes.
As you can see, you already cover all of them if you eat animal-based and don’t avoid connective tissue & high-fat cuts. Don’t worry about these 3 then.
Fortunately, the methionine-to-glycine balance is bullshit. If you eat in accordance with nature, the problem will eliminate itself. The optimal percentage is around 7-9% glycine of your total protein. That’s why it’s important to prefer cuts that are rich in fat and also connective tissue. No human every would have eaten only tenderloin. That’s why I don’t think collagen makes sense for most people and rather harms people because of high deuterium.
Methylfolate (5-MTHF)
Folate is one of the main drivers of methylation. In addition, many people utilize folate slowly due to gene variants, also called polymorphisms or SNIPs.
The active form of folate is L-5-MTHF aka methylfolate* and folinic acid. Methylfolate is also what we find in animal products like liver. Plants use this as well.
Methylfolate is also a nutrient that many carnivores and animal-based eaters may miss out on if they don’t regularly eat organs like liver or kidney. What plays into their cards is a substance that can reduce folate requirements and is found greatly in animals – choline.
Choline & Betaine
Choline is a highly interesting vitamin-like substance and a zoonutrient.
There is very little of it in plants. By definition, it is not a vitamin, since we can produce it ourselves, but it was called a B-vitamin in the past. Self-production of phosphatidylcholine puts a heavy and unnecessary burden on methylation. Therefore it should be 400-600mg of choline per day, as it reduces the amount of folate you need. Estimates are up to 40%.
Choline has many tasks:
- As phosphatidylcholine, it is a major component of cell membranes
- Eating enough saves SAMe, otherwise much would go into its manufacture
- Choline is necessary for the transport of fatty acids into the mitochondria
- It is the precursor of acetylcholine
- Together with betaine, it is involved in cell volume control, also called osmoregulation.
Betaine is also called trimethylglycine (TMG) and can be built from choline. However, it only works in this direction. You cannot metabolize betaine to choline. So, in conclusion, if you eat enough choline, you will have enough betaine. 9Betaine in human nutrition
B-Vitamins such as Methylcobalamine & Riboflavin
B vitamins are generally necessary for all aspects of energy production. In terms of methylation, you need thiamine (B1), riboflavin (B2), niacin (B3), pyridoxal (B6), folate (B9), and methylcobalamin (B12).
The main roles are played by folate & methylcobalamin. Both serve as the dietary methyl donors needed to recycle homocysteine. 10Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects This is how the methyl groups from your food are incorporated into your body.
The other four vitamins – B1, B2, B3, B6 – support folate and methylcobalamin in their task. While they do not push methyl groups around, they are needed for the enzymes to function. So without them, no functional methylation either!
Creatine
Creatine is another guzzler of SAMe. Estimates go towards 50% of the total SAMe!
GAMT, the enzyme that makes creatine, acts as a safety net. Creatine is important and people haven’t always had access to much food. In those times, it helps to provide creatine. But it comes at the expense of SAMe, which is then not available in other places.11Creatine supplementation decreases homocysteine in an animal model of uremia
Therefore, you should definitely eat sufficient creatine per day. THat will free p a lot of SAMe for other tasks such as detoxification or neurotransmitter production. You can read more about creatine and its function here.
Per day it should be 3-4g creatine, which corresponds to about 300-500g of red muscle meat. If you eat animal-based or carnivore, this certainly doesn’t sound like a lot and you certainly are already meeting it.
No need to worry, if you eat like a Human
Everything makes sense when you eat the way humans have always eaten. It’s just as simple in the end with more complex issues like methylation. Eating animal-based and nose-to-tail provides you with exactly the substances your body needs. Coincidence?
While the subject is certainly complex, the solution is not. That’s the beauty of Ancestral Health. It’s reflected in so many issues. But if you deviate from it and eat plant-based or all-meat carnivore, you have a problem. If you don’t, then you’ll be fine.
Special Case – the MTHFR Polymorphisms:
As a small bonus, I must of course mention the polymorphisms12https://www.ncbi.nlm.nih.gov/books/NBK596 gene variants, which can down-regulate the function of many enzymes. The most common and well-known one here is the polymorphism in the MTHFR gene, which makes the enzyme of the same name called methylenetetrahydrofolate reductase. Yep, now that’s a name!
Polymorphisms are quite common and worth a separate post in themselves. The two best known are the 677 C -> T & 198 A -> C variants. For more information on this I can recommend this article by Dr. Chris Masterjohn, as he specifically discusses how to adjust the diet.
And with that short digression, I’ll end the post and have covered everything I wanted to give you about everything on methylation. Big topic, there is a lot more, but this is the most important for planning.
As always, thanks for reading, and feel free to share the post if it helped you out!
Fußnoten & Quellen
- 1CH3 – A carbon with free hydrogen. It is the smallest functional group.
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- 7This is probably why histamine-free diets show promise with some mental illnesses like recurrent panic attacks.
- 8This is mediated in the brain, intracellularly, by the enzyme histamine N-methyltransferase (HNMT). In the body, extracellularly, diamine oxidase (DAO) gets rid of histamine
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