Why your Methylation issue is not an MTHFR issue

If there is one genetic mutation, which got into mainstream, it is the MTHFR genetic mutation, causing low methylation.

Methylation is the process in which one carbon is added to a molecule. This is done via so called methyl groups (CH3), which can be attached to other carbon chains.

This process is so important, as it literally is involved everywhere:

• cell division

• gaba/glutamate ratio

• estrogen homeostasis

• insulation of nerve cells

• gluthathione metabolism

• phosphatdylcholin metabolism

• regulation of calcium channels

You can see where this is going? Without proper methylation, there are a lot of issues involved.

MTHFR gene, is a gene coding for an enzyme important in methylation. It is catalyzing the last step of the so called folate cycle, where Methyl B9 is won.

How tragic that studies show that only 15% of people have adequate MTHFR function.

So, now you might think that your methylation is the issue, right?

After all, there is a huge chance that this gene is not working to its fullest capacity = low methylation, right?

Let me tell you, that this is utter non sense and just a way of them trying to chunk money out of your pocket for expensive testing, supplements or other stuff you do not need.

Testing has its place, but not everyone needs to buy a test because they have read a newspaper article about this “new genetic mutation everyone should know about”.

What is the real deal?

Methylation issues are lifestyle driven

Genetic mutation of MTHR is SO common, that we can argue our ancestors possibly had the same variation in genes for this enzyme.

As you might guessed it, these guys didn’t have any problems at all. So how could that be?

The simple answer is nose to tail eating.

Studies show that adequate intake of Riboflavin (Vitamin B2) is needed to get the MTHFR enzyme firing again, so that genetic mutation of the enzyme’s gene matter less (if at all).

Here is the first hint: A bad lifestyle, driven by low intake of adequate micronutrients in itself leads to methylation issues, not the genetic variation.

Our ancestors ate liver, heart, kidney, thyroid & every thing the animal had. Just eating some sort of liver & heart will fill up your Riboflavin, so that any issue with that gene is gone.

Also, believing that one gene is responsible for a whole cycle to be disrupted, is plainly wrong.

When explaining the cycle (below) you will get a grasp on the dimensions this cycle involves.

For example, if your thyroid doesn’t work, we can suspect your methylation to be at least altered too (you will see why).

So having a genetic defect somewhere else in the system, which is linked to methylation, will also bring methylation to sub optimal rates.

We probably have 100s of genetic mutations in our body, leading to optimal/ suboptimal function of specific metabolism pathway.

Blaming one genetic mutation isn’t the reason for your low methylation.

But what is it then?

Methylation 101: Understand the cycles

To understand how we can treat low methylation, we gotta first take a look at how methylation actually works.

Methylation cycle is actually comprised of two cycles which feed each other at certain times:

Methionine & Folate cycle

Deep understanding requieres a look into both cycles:

Methionine cycle

This one is normally associated with methylation, as it is the cycle where the methylation endproduct SAMe is built.

SAMe is the universal donor for a one carbon group, aka methyl group. The most important thing is the recycling of SAMe, when SAMe donated its methyl group and turned into SAH.

And this recycling is often times where the most amount of friction is located. As you can see in the picture above, homocysteine is a metabolite in this cycle.

High homocysteine is an inflammatory marker, associated with lots of disease.

We gotta ensure that there is opitmal recycling of it. So how do we accomplish that?

There are two ways:

The traditional route metabolizes homocystein via Methyl B12 back into methionine, where the cycle starts again.

This step NEEDS the aformentioned folate cycle, as the enzyme cataylzing the reaction of homocysteine to methionine is dependend on the Methyl B9.

Another route is the so called BHMT metabolism.

Primarly used when the system is running low on Methyl B9, homocysteine is turned into BHMT, which further is converted into methionine.

This step depends on betain (TMG) as a co-factor.

Folate Cycle

Here is where the fun begins. Most people have insufficient production of Methyl B9, which is needed for proper methylation cycles.

As you can see, this one might seem pretty complex and it is in comparison to the methionine pathway.

To make this one simple & short, you have to know that there are three main ways in which we can achieve the end goal Methyl B9:

1. MTHFD1 Tri Enzyme Complex

2. SHMT Glycine Pathway

3. FTCD Enzyme Pathway

The first of the pack is the primary one!

MTHFR enzyme is at the interplay of all those pathways, metabolizing the endproduct of the three pathways (Methylene THF) into Methyl B9, hence why it is so crucial.

The methylfolate then is used in methionine cycle at the step mentioned above. We will get back to this, when we talk about the nutrients needed for proper methylation.

So now, how can we achieve optimal methylation functioning?

Heal your “MTHFR defect”

As you know from the introduction, having an (un)known MTHFR issue is not a problem at all. It is rather that our lifestyle, which misses key nutrients involved in the whole methylation cycle, exposes us to the non optimal enzyme function.

Aside from that, there are so many genes directly or indirectly involved in methylation, that the chance of having perfect methylation is near impossible, even for our ancestors.

How can we get there then?

I have 4 pillars which you need to understand to combat poor methylation:

1. Filling in the micronutrient gaps

2. ATP & Methylation

3. Circadian Impact

4. Fasting vs Feeding State

Let’s dive in.

Methylation needs close to 30 nutrients

We all heard of the typical adivse to increase intake of Folate & Cobolamin for enhancing methylation.

If you are a little bit into it, maybe you heard of Zinc, Riboflavin or Niacin.

Digging down deep into the connection of methylation to other metabolism pathways, we quickly grasp the dimensions of methylation needs.

We need close to 30 micronutrients for effecte methylation. This is far from the 4-5 your doctor tells you to take.

As I believe there is a cluster of micronutrients missing, we will cover the most needed in terms of importance or deficiency.

Combatting the elephant in the room

MTHFR is the enzyme responsible for catalyzing the last step of folate cycle, actually turning folate into the usable Methyl B9.

FAD, the active form of Vitamin B2 is responsible for taking on electrons provided by NADPH, then transfer it onto the now forming Methyl B9.

For this conversion to happen, we need:

• Zinc

• Mangan

• Thiamine

• Riboflavin

• Magnesium

Zinc & Vitamin B2 are needed for the enzyme itself, the rest of the pack is needed for an efficient pentose phosphat pathway, which is the main driver of NADPH content in the body.

As you can see, there are multiple levers to this enzyme & the fact that close to 90% of people are deficient in one of these:

• Thiamine

• Riboflavin

• Magnesium

Shows that you do not need a MTHFR genetic mutation to have impacted methylation. Just a micronutrient deficiency.

So, how do we get these missing nutrients?

Thiamine & Magnesium are strong contenders for clever supplementation.

I have experimented and used high dosage for both, as these are two of the most crucial, but missing micronutrients.

For Magnesium, I like Magnesium Chloride. Get in pills or the flaky salt in plenty amounts. 5-10gr a day serves a good spot.

For Thiamine, it depends on many factors, but i like Benfothiamine or TTFD (which is more expensive)

Take anywhere from 1-2gr per day, for some weeks. Lower dosage after that for maintenance. Someday, if also living healthy, you might be saturated enough to just take it in times of high carb intake (aka summer).

Riboflavin is the prime example why nose to tail eating is so important. Highest amount it is found in heart, so eating only liver as your organ source is not sufficient.

Eating 50-100gr of heart a week is a good staple to incorporate.

Nutritional yeast, 10-15gr a day, also provides you with good amounts of B2 (with other B-Vitamins included).

Go for a good mix here!

Activate that FAD & heal “MTHFR”

FAD is the active form of Riboflavin (B2) used to shuttle electrons onto the then created Methyl B9.

I wanna highlight that missing B2 is the most common cause of simple methylation issues.

But not only low levels, but also low levels of conversion into the form we need, which is FAD.

An important co-organ in this conversion is thyroid. We need active T3 (thyroid hormone) to convert B2 into FAD.

Accompanied by that, nutrients like selenium, iodine & molybdenum for proper conversion.

Focussing on improving thyroid is key for methylation, highlighting the interconnectedness of the body!

Now, here comes the kicker:

B2 is needed for activation of Vitamin B6 into its active form, PLP, which is an important co-factor in many methylation reactions.

We not only miss B6 overall, but we also miss B2, which makes B6 a bottleneck in sufficient methylation.

Eating high muscle meat increases the need for B6, so eating a diverse diet with plant food, organs, loads of egg yolks & muscle meat is needed for B6.

Increasing intake of egg yolks with increasing volume of muscle meat is needed here.

So, we first need enough B2, which is converted by proper thyroid (& nutrient) status, to activate Vitamin B6, which is also needed for methylation.

You can see, if one of these is broken, how methylation is hindered, right?

ATP is the ever missing link in methylation

We all know how important sufficient ATP is. After all, it is our most important ressource we have. This molecule is our energy supply, giving life force to us.

But how does it come that so few talk about a “simple” energy deficit as a cause of poor methylation?

If you look closer (see pic above), in several key enzymatic steps ATP is needed for the cycle:

1. Conversion of Methionine to SAMe

2. MTHFD1 Tri Complex Enzyme System

Apart from that, the recycling of SAH to homocysteine is impacted by higher levels of adenosine, instead of ATP.

These are critical steps, as without these, we are missing SAMe in the first place & miss sufficient recycling of SAH.

Sufficient ATP is crucial for proper methylation.

So what do we need (or what do we miss) for proper ATP production?

In terms of nutrients, there are a few which certainly are important in the realm of mitochondria:

• Iodine & Selenium for proper thyroid function (see above)

• Copper for complex 4 of respiratory chain

• Sulfate (hence good transulfuration) for Iron-Sulfate Complexes

• Sodium as a transporter

• DHA (& omega-3s) for proper electron shuttling

• Vitamin E & Taurine for membrane stabilization

These are just a few, but crucial factors in energy production.

Apart from that, the most impactful thing to do, to improve your methylation is respecting the

Natural rhythms of nature & methylation

In biology, in life, everything is of rhythmic nature:

Good & Bad

Black & White

Ying & Yang

Night & Day

Feeding & Fasting

The two latter of those are what will impact your methylation the most. Let us analyze why that is:

Conquering night & day

Having a tuned in circadian rhythm, which means you max out natural light at day, while maxxing out the dark when sun is set, is key.

This, on one hand, lowers the amount of inflammation hindering your methylation, but also increases ATP production, as there are several pathways positevly impacted by sunlight or absence of light.

All B Vitamins have the tendency to be degraded by blue light, if blue light is high in relativity to other natural light (like red light) accounting for that.

As you know, every B-Vitamin is somewhere involved in methylation, so exposing yourself to blue light in the evening, without the right counter measures predisposes you to insufficient methylation.

Blue light also lowers structured water content, which acts as a battery in your body, providing energy (electrons) needed for proper energy production.

Blue light lengthens the route electrons have to go through in ETC, predisposing you for ROS, less ATP & therefore disease.

On the other hand is the rhythmic secretion of hormones dependend on the sun. Now, you know that thyroid impacts methylation, so for thyroid to have an impact, it has to be secreted in the right amounts, at the right time.

Exposing yourself to the sun dials in this clock.

Red & NIR light in the early morning or evening sun directly increases respiration rate, as it impacts complex 4 at the mitochondria.

Having a dialed in circadian rhythm also acts as a signal for methylation cycle, as the body now knows when to properly start which cycle.

Having the doctrine of:

Maxxing out natural light at day

Ditching blue light at night

Will massively boost methylation & ATP production.

The juggle between fasting & feeding state

The methylation cycle has a fasting & feeding state, which we gotta emphasize on, if we want proper methylation.

You remember that the methionine & folate cycle are BOTH needed for proper methylation, right?

Now, you gotta understand that at most times, these two are not working at the same time.

Methionine = feeding state

Folate = fasting state

This makes sense, as when we eat we ingest the biggest amount of methionine in our system through (animal) protein. This shifts the methylation cycle to producing the most amount of SAMe, as we just had a new ingestion of precursors AKA methionine.

The fed state inhibits important enzymes in the whole cycle, like MTHFR (folate cycle) and BHMT (the enzyme responsible for converting homocystein into methionine again).

So we have a HUGE influx of SAMe. Our body has the ability to store abundant methyl groups via the glycine buffer system.

We need enough glycine so that this system can work. Here we have a reason to improve methionine:glycine ratio, as we need enough glycine for methyl group buffering.

Hence why anyone, really anyone, should eat glycine, collagen & bone broth daily.

For simple explanation:

When eating, the top priority is to produce methyl groups, store them & tap into homocysteine catatbolism aka transulfuration pathway.

The fasted state then reactivates folate cycle (& homocysteine) recycling.

How is that done?

As MTHFR activity increases, there is an influx of Methyl B9.

Methyl B9 inactivates the glycine buffer system as we do not need to store anything. We wanna USE the methyl groups in the fed state, to repair & detox.

We recycle excess homocysteine back into methionine.

But why do I tell you that?

I wanna show you the importance of NOT snacking 24/7, else we have an abundance of methionine cycle which could possibly lead to high levels of homocysteine, lower levels of methyl b9 and can induce hypermethylation.

Hypermethylation is only a thing if you do not run an efficient cycle of methionine & folate.

The takeaway:

Eat 3-4 times a day, leave plenty of digestion time between meals & buffer protein intake with sufficient collagenous meat which contains glycine.

This is how you respect the cycle.

The supplement game

I will start this one of: YOU DO NOT NEED ANY SUPPLEMENTS

If you start with supplementation before trying for 3-6 months, you are simply not strong enough and will create dependence. TY.

But in some instances I believe supplementation is valid. So what supplements are good for methylation?

• Thiamine → TTFD/ Benfothiamine

• Magnesium → Magnesium Glycine/ Chloride

• Glycine/ Collagen

These are good staples of mine, because they overall achieve good results in any domain.

If there are known methylation issues, the most common supplements I’d use are:

• Folate

• Riboflavin

• Vitamin B6

Riboflavin is chronically undereaten, as we never eat organs. If we do so, liver is the most common, but this is not enough.

A natural desicated heart supplement, eating heart or getting riboflavin as a supplement is a good route.

Folate in my experience is often times low in carnivore people, as they believe their meat is sufficient for adequate folate.

Surprise, it is not. Cooking green vegetables in animal fats for a long time daily, is a good route.

But, if that is not you, you may be good with a temporary methyl folate supplement.

The same goes for Vitamin B6, which we lack if we do not diversify the diet. You might opt for a B6 supplement.

These are the supplements I’d go for, as everything else is either easy or BETTER via diet.

Everything is better done via diet, but I aknowledge, that for many, this is just not the way.

Last but not least, the last supplement in severe cases might be NDT, or natural desiccated thyroid in people with really severe issues.

There is a chicken and egg problem, but people with low methylation often have problems with energy, frequent bowl, high estrogen/ prolactin/ cortisol/ serotonin & hypothyroidism.

Hypothyroidism is a state where your thyroid is not producing sufficient thyroid hormone.

Thyroid is a missing link, aiding in combatting high estrogen, infrequent bowl movement, lower energy & in this case aids in converting B2 into FAD (& subsequently activation of B6).

It might be a good route, but I wanna emphasize that early usage of this will create a dependence, although only mental, a serious one to be for sure.

Use it wisely.

So this was it, my small talk about methylation & how to combat it. There is a lot of nuance, which I cannot cover in a single letter, but 85% of issues will be gone after implementing these things over a long time horizon.

Now, if you suffer from

• poor energy

• chronic disease

• metabolic problems

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Cheers