If you are looking for information on methylation and the MTHFR gene, this is where to start.
If you do not know what methylation is, and would like to understand the basics, click open the introduction below:
An Introduction to Methylation
Methylation is profoundly important to our physical, mental, and emotional health. To properly discuss it, we should first define it.
You and I, and everything that lives upon the face of the earth, are made primarily of organic molecules, which are strings of carbon atoms that are bound mostly to hydrogen, but are sometimes bound to other atoms, such as nitrogen, oxygen, and sulfur. A single carbon atom that attaches to such a molecule at one point and is otherwise bound only to hydrogen is known as a “methyl group.” Methylation is the transfer of these methyl groups and is also known as one-carbon metabolism.
Most of your methylation is used to synthesize two molecules: creatine and phosphatidylcholine.
Creatine is best known for boosting muscular strength. Bodybuilders take it as a supplement to build muscle and many kinds of athletes take it to boost their power and performance. Less well known, creatine helps you make the stomach acid you need to digest your food, provides the energy you need to absorb the nutrients in your food, powers sperm as they swim up the vaginal canal, fuels the regeneration of healthy skin, and helps you see and hear.
Phosphatidylcholine is a critical constituent of your cell membranes throughout your body, but is especially important to helping you remove fat from your liver. Without enough of it, we are more vulnerable to fatty liver disease, which afflicts an estimated 70 million Americans. It also serves as a precursor for acetylcholine. Acetylcholine is a neurotransmitter with many roles. In the brain, it supports cognitive performance during tasks that require sustained attention. In your muscles, it’s what stimulates contraction and lets you push, pull, lift, throw, and move in whatever other way pleases you.
Methylation has many other roles as well. It helps get rid of histamine, best known for its contribution to allergic reactions. In the brain, it acts to make you mentally more flexible, and helps prevent you from ruminating on negative thought patterns that may contribute to anxiety and depression. In the liver, it contributes to detoxification of foreign chemicals and heavy metals. Our cells are constantly altering the expression of our genes according to the demands of our environment, and methylation is one of the key tools they use to do it.
There is such a thing as too much methylation. For example, too much methylation in the brain can make you so mentally flexible that you become too easily distracted and have difficulty focusing. It may also make you drowsy or interfere with your ability to break established habits. Too much methylation also seems to shorten lifespan.
So, we need to have proper balance. To achieve that balance, we use the amino acid glycine as a buffer of excess methyl groups. If we get a lot of methyl groups but not much glycine, we run the risk of running low in glycine, and this can hurt our detoxification system, destabilize our blood sugar, interfere with our sleep, weaken our bones, and make our skin age faster.
The best way to balance this system is to get plenty of everything, things that supply methyl groups on one hand and glycine as a buffer of the excess on the other.
These are the key nutritional players in the methylation system:
- Methionine is an amino acid found in all proteins, but which is especially rich in animal products. After being activated using ATP, the fundamental energy currency of the cell, methionine becomes the universal methyl donor.
- Once activated methionine donates its methyl group, it becomes homocysteine. Homocysteine needs to be recycled back to methionine so methylation can continue, and homocysteine itself is thought to be harmful by contributing to cardiovascular disease.
- Vitamin B12 and folate (vitamin B9) recycle homocysteine back to methionine. They take the methyl group from the metabolism of amino acids that we get from dietary protein.
- Alternatively, betaine (trimethylglycine, TMG), which is mainly derived from choline, recycles homocysteine back to methionine.
- Several other B vitamins, mainly thiamin (vitaminB1), riboflavin (vitamin B2), niacin (vitamin B3), and pyridoxine (vitamin B6), support B12 and folate in recycling methionine, even though they themselves are not methyl donors.
- Glycine is our buffer for excess methyl groups.
- A number of minerals are needed to support the enzymes involved in this system: iron, phosphorus, sulfur, magnesium, potassium, zinc, and possibly cobalt. Vitamin A is also needed to produce the enzyme involved in using glycine as a methyl buffer.
How to Eat to Nourish Your Methylation System
While there are a handful of nutrients that are notable for their specific contributions to the methylation system, the system operates within a framework that depends on most of the B vitamins and many of the essential minerals. It makes sense, then, to layer methylation-specific advice on top of some general rules of thumb that are always good to follow to make sure you obtain all your vitamins and minerals.
For someone with no allergies or other reasons to restrict food groups, the following general principles help ensure that you’re meeting all your nutritional needs:
- Diversify your protein among meat, fish, shellfish or other invertebrates, eggs, and dairy. Get a half gram to a gram of protein per pound of bodyweight (if overweight, reduce this to your ideal bodyweight), which for a 150-pound person would be 75-150 grams of protein. Most people have plenty of wiggle room within this range, but if you are trying to lose body fat, gain muscle, or meet athletic goals, you should aim for the higher side of the range (and in some cases higher).
- Make an effort to eat “nose to tail” by utilizing parts of the animals we’ve been neglecting in our society. For example, try eating liver once a week and using bones to make broths, gravies, and sauces or eating the edible bones found in canned fish.
- Get about 1000 milligrams of calcium per day, which is easiest to get from several daily servings of dairy or edible bones, such as the ones found in canned fish.
- Diversify your carbohydrates among legumes, whole grains, starchy tubers, and fruits.
- Eat a large volume (several cups per day) of vegetables, diversifying them across colors with an emphasis on red, orange, yellow, and green. Always include dark green vegetables in the daily mix.
- Include foods or supplements that aid in digestion at every meal. Examples include ginger, lacto-fermented vegetables, kombucha, raw apple cider vinegar, Swedish bitters, and digestive enzyme supplements. The reasoning behind this one is simple: all those nutrient in your food are only useful if you digest your food well, breaking it down fully and absorbing everything it has to offer.
If you follow these recommendations, you will meet your needs for many methylation-related nutrients almost automatically. For example, the protein will supply your needs for methionine and for the amino acids that folate and B12 use to recycle homocysteine. The diversity of unrefined plant foods will ensure you get enough magnesium and potassium. The general diversity of whole foods of all kinds will ensure you get enough of most of the B vitamins involved in energy metabolism that indirectly support the methylation pathway.
Nevertheless, we can add some methylation-specific recommendations:
- Folate. 2-3 servings of liver, legumes, or leafy greens provide the daily requirement for folate. A serving is 100 grams or three to four ounces. For the liver, it can be measured before cooking but for the legumes and greens it should be measured after cooking. This is especially important for veggies, because most leafy veggies shrink a lot during cooking and you should actually eat twice this amount if you are eating them raw.
- Vitamin B12. Vitamin B12 is found almost exclusively in animal products. You can only absorb enough of it every four to five hours to last you one day. You can stock up on it to use later by consuming enough for one day at multiple meals, but the one-day’s-worth-per-meal rule puts a limit on how much you can stock up on. For example, if you get a day’s worth at 122 meals per year, you could stack all of these meals into four months as long as you spaced them apart by 4-5 hours, and you could eat a diet devoid of B12 for the other eight months, and you’d be fine. But you can’t eat a month’s worth of B12 in one day and be fine for the month, because you wouldn’t absorb most of it. This is important because some foods, such as liver, oysters, and clams, contain many days worth of B12 in a single serving. You can take advantage of them by eating small amounts at many meals, but you can’t take full advantage by eating large amounts in one meal.
Here are five ways to get a day’s worth of B12:
- 4-8 grams of liver.
- 8 grams of oysters or clams.
- 12 ounces of meat, poultry, or fish.
- 3 eight-ounce glasses of milk or 12 ounces of cheese.
- For the vegans: substitute green or purple laver (nori) for oysters and clams; or substitute black trumpet, chanterelle, or shiitake mushrooms for the meat.
Although B12 deficiency can be caused by poor dietary intake, especially in vegans and vegetarians, many people are deficient due to poor absorption. Pernicious anemia is an autoimmune disease that impairs B12 absorption, and it affects 0.1% of the general population and about 2% of the elderly. Chronic gastritis associated with H. pylori also impairs B12 absorption, even if it doesn’t cause any symptoms typically associated with gastritis, and it may be bad enough to cause B12 deficiency in 10-15% of the elderly. In these cases, B12 supplements or injections are needed.
If you expect, on average, to fall short of consuming a third of a day’s worth of B12 at most of your meals, or a day’s worth of B12 at a third of your meals, I recommend taking one capsule per day of Pure Encapsulations Adenosyl/Hydroxy B12.
- Choline and Betaine. It is betaine, not choline, that directly supports methylation. However, while you can obtain betaine in the diet, most people consume more choline than betaine, and we convert choline into betaine as needed. Since they are interchangeable with respect to methylation, I recommend thinking of a general “choline requirement” that can be partly met by betaine. Since choline does some things that betaine cannot — making acetylcholine as a neurotransmitter or phosphatidylcholine to support cell membranes and prevent fatty liver disease — I recommend getting up to half of the choline requirement from betaine but getting at least half from choline itself.
A simple way to think of the choline requirement is as “egg yolk equivalents.” You want to consume 2-3 egg yolk’s worth of choline per day, but you can mix and match different foods to do it.
Each of these foods is equivalent to one egg yolk:
- An egg yolk itself, or a whole egg.
- 50 grams of liver (you can use this as one egg yolk equivalent up to four times per week).
- 200 grams of nuts or cruciferous vegetables. (I would not consume more than 200 grams per day of either of these categories because of some anti-nutrients they contain.)
- One tablespoon of lecithin. I recommend this one.
- Two 300-mg capsules of alpha-GPC. I recommend using this if you have symptoms of low acetylcholine, such as muscular weakness, difficulty performing well at tasks that require sustained attention, or, in the elderly, any form of dementia.
You can obtain one egg yolk’s worth of choline as betaine from the following foods, and you can use these options to supply up to half of your choline requirement:
- 25 grams of wheat germ.
- 100 grams of cooked or canned beets.
- 200 grams of raw beets.
- 100 grams of cooked spinach.
Additionally, one 500-mg capsule of trimethylglycine (TMG) counts as two egg yolk equivalents in betaine.
Overall, you want to consume 2-3 foods per day from among those in either list. At least half of this, meaning at least 1-2 foods per day, should come from the first list. Choosing foods from the second list is optional. Two capsules of the alpha-GPC counts as one food from the first list, while one capsule of the TMG counts as two foods from the second list.
- Glycine. If you eat a largely plant-based, moderate-protein diet and make an effort to consume skin or bones whenever you eat animal products, you probably get enough glycine. However, most of us eat a lot of methionine-rich animal flesh without eating enough glycine-rich skin and bones to match it.
I recommend the following rule of thumb. For a protein intake of 0.5 grams protein per pound of bodyweight, consume one gram of supplemental gelatin or collagen for every ten grams of animal protein, but ignore your plant protein. As you go above 0.5 grams protein per pound of bodyweight, consume one gram of supplemental gelatin or collagen for every 10 grams of plant protein and for every 5 grams of animal protein. For example, if you weigh 150 pounds and consume 150 grams of animal protein, add 7.5 grams of collagen for the first 75 grams of protein and 15 grams of collagen for the next 75 grams, bringing the total to 22.5 grams of collagen.
Instead of gelatin or collagen, you can use bone broth, as long as you know the amount of protein per serving. 10 grams of bone broth protein is equivalent to 10 grams of collagen. The collagen brands I trust most are Great Lakes and Vital Proteins. For bone broth, Kettle and Fire and Kitchen Basics both have 10 grams of protein per serving.
Out of these foods, folate is most stable in liver, even in the freezer, but you can only eat one or two servings of liver per week without overdosing on other nutrients. Folate is also very stable in dried legumes, making these the easiest way to get a lot of folate. In vegetables, folate is very unstable, even in the freezer. In fact, frozen vegetables should not be trusted at all as a source of folate. For fresh veggies, it is best to purchase them from a farmers market where you can have more trust in how fresh they are, and to use them up within 3-5 days.
If you rinse or wash your veggies, do so before you cut, dice, or shred them. Otherwise, they will lose a lot of folate in the rinsing water. Cooking degrades folate, and causes loss of folate in cooking water. Here, as in storage, folate is very stable in liver and least stable in veggies. If you cook all your folate-rich foods and throw out the cooking water, you should increase the number of servings from 2-3 to 3-5. It is best to cook gently (for example, steaming), and to consume the cooking water whenever there are not downsides to doing so (for example, you could stew vegetables in a soup where the folate runs into the broth and you consume the broth, but if you are cooking beans you might hurt your digestion if you consume the cooking water).
Although the data are too limited to make definite recommendations, eggs from pasture-raised chickens might be a very potent source of folate, and sprouting your legumes or buying them sprouted may cut the amount you need to eat by 75 percent.
If you expect to have difficulty meeting these targets, I recommend taking one or two capsules of Jarrow Methylfolate on each day where you are unable to meet the folate requirement from food.
Click open the next link for my protocol for adapting your diet and supplements to the common genetic variations in the methylation pathway, most notably MTHFR:
The MTHFR Protocol
MTHFR is an enzyme that uses folate (vitamin B9) to support the process of methylation. It’s the last in a series of enzymes that construct a methyl group on the folate molecule to make methylfolate. That methyl group is then used, with the help of vitamin B12, to recycle homocysteine to methionine.
There are variations in the MTHFR gene. Common genetic variations are known as polymorphisms. Specific variants in polymorphic genes are known as alleles. The two common polymorphisms in the MTHFR gene are known as the C677T allele and the A1298C allele. You have two alleles for every genetic polymorphism, one from your mother and one from your father. If you have the same allele from both parents you are homozygous for that allele, and if you have different alleles from each parent you are heterozygous for each allele of that polymorphism. Your own combination of alleles is your genotype.
There’s a good chance you have an MTHFR polymorphism. In some populations, the percentage of people who do not have either at least one C677T allele or one A1298C allele is only 15%!
Most of the research is on the homozygous C677T allele because it’s the strongest variant. But actually the two alleles and their combinations simply cause a graded decrease in the activity of the MTHFR enzyme. One A1298C allele decreases its activity by 17%. One C677T decreases it 33%. Two A198C decrease it by 39%. One of each decreases it 53%. Two C677T decrease it by 75%.
So, two things are clear. First, having at least one of these is so common that this should just be viewed as a variation in metabolism that requires different dietary emphasis, not any kind of disorder or defect. Second, the degree to which you need to follow my recommendations below increases in proportion to the level of decrease in your enzymatic activity. And even your genes are operating in the context of a complex physiology. The numbers above are averages. So you don’t need to follow everything, but testing with my blood test recommendations and testing against your symptoms and sense of well being should help you decide how strictly you should follow them.
How to Know If You Have an MTHFR Polymorphism, or Other Closely Related Polymorphisms
I recommend getting 23andMe Health and Ancestry and then running your raw data through StrateGene. You can just get the “Ancestry” option if you are trying to save money, but 23andMe’s health reports included in the “Health and Ancestry” option are interesting and useful in their own right.
StrateGene will tell you about MTHFR, but will also tell you about two other genes that are important for making methylfolate. The first is SLC19a1, a folate transporter, and the second is MTHFD1, the enzyme immediately prior to MTHFR that helps MTHFR make methylfolate. If you transport folate into your cells less effectively, you have less folate with which to make methylfolate. If your MTHFD1 enzyme functions less effectively, you have less of the direct precursor to methylfolate from which to make methylfolate. So, these two polymorphisms can decrease your methylfolate production just like MTHFR.
We do not have rigorous data about how these polymorphisms combine to affect methylfolate levels. However, we can guestimate the effect by multiplying all the effects together. StrateGene will tell you the estimated percentage decrease in your SLC19a1 and MTHFD1. For example, being homozygous for the common SLC19a1 polymorphism decreases its activity by 50%. Being homozygous for the common MTHFD1 polymorphism decreases its activity by 34%. Being heterozygous for the A1298C allele of MTHFR decreases its activity by 17%. If you have all these polymorphisms, we could imagine that you start with 50% of the normal amount of folate, and then make the precursor to methylfolate from it at 66% of the normal rate, and then make methylfolate from the precursor at 83% of the normal rate. Multiplying these, we get 0.5*0.66*0.83=0.274, suggesting you make methylfolate at 27.4% of normal, or that your methylfolate production is reduced by 73%. This is just a guestimate, but it gives you a sense of how strictly you should follow the protocol below.
If you get StrateGene, then, I would make this calculation and follow the protocol below with increasing strictness and consistency as you approach a 75% estimated decrease in methylfolate production.
There are a number of other polymorphisms that intersect with the methylation system, but I do not cover them here because I do not consider them to have a clear, quantitative impact on the degree to which you should change your diet along the lines described below.
A Dietary Strategy for Low Methylfolate Production
- Because you are less good at making methylfolate, you use choline as an alternative methyl donor more often.
- Methylfolate is the off-switch for the glycine buffer system, so low levels of methylfolate make you methylate glycine more often, even when you shouldn’t. This makes you waste methyl groups and can deplete your glycine levels.
This strategy is not based on compensating for low methylfolate production with high doses of methylfolate supplements. In fact, there’s no way on earth you can compensate for low methylfolate in this way. The reason is that every folate molecule you consume gets methyl groups added to it 18,000 times a day. It is not safe or wise to take supplements providing 18,000 times the normal amount of methylfolate.
The strategy, then, is based instead on these principles:
- We double the normal choline intake, to ensure an adequate supply of methyl groups and to conserve methylfolate.
- We supplement with creatine, to cut the demand for methyl groups in half and thereby conserve methylfolate even further.
- We supply a normal or slightly higher amount of methylfolate, but make sure it is spread out evenly across the day, ensuring that there is always some methylfolate around, no matter how bad you are at producing it.
- By constantly supplying methylfolate and by conserving it as much as possible, we hope to suppress the unnecessary use of the glycine buffer system. Nevertheless, our success on this point will only be partial, so we add extra glycine to compensate for what we are losing.
3) Consume 4-5 egg yolks worth of choline per day, at least half as choline and up to half as betaine. Use the same food and supplement equivalents listed in the Choline and Betaine section of How to Eat to Nourish Your Methylation System, but consume 4-5 foods or supplements from the two lists combined rather than 2-3, and make sure that at least 2-3 come from the first list instead of 1-2.
4) Boost your glycine intake. Unfortunately there are no studies documenting how much more glycine needs to be taken to match low methylfolate production. However, I suggest the following rule of thumb: Supplement with one gram of gelatin or collagen for every five grams of protein in your diet. Instead of gelatin or collagen, you can use bone broth, as long as you know the amount of protein per serving. 10 grams of bone broth protein is equivalent to 10 grams of collagen. The collagen brands I trust most are Great Lakes and Vital Proteins. For bone broth, Kettle and Fire and Kitchen Basics both have 10 grams of protein per serving.
Click open the section below if you are interested in lab testing related to methylation:
Lab Testing Related to Methylation
The rest of this page compiles all the resources I have made related to methylation. If you feel confident that you have the basics, choose any of the links below to continue learning.
Searchable Databases Related to Methylation
Podcast Episodes Related to Methylation
Chris Masterjohn Lite Episodes Related to Methylation
Blog Posts Related to Methylation
Off-Site Articles Related to Methylation
Guides Related to Methylation
Testing Nutritional Status: The Ultimate Cheat Sheet contains a comprehensive approach to assessing and managing your status for all of the essential vitamins, minerals, and fatty acids. It outlines three different approaches depending on whether time or money are your most limiting resources. It includes guidance for dietary analysis, lab testing, and analyzing your signs and symptoms.
It is called a “cheat sheet” because, although it is 78 pages long, the first five pages give you complete instructions and hold your hand through a step-by-step process to read only those other sections of the guide as are most important for your particular situation. When you identify an issue with a nutrient, it leads you to the section for that nutrient, where you are given signs and symptoms of deficiencies and toxicities, dietary patterns and other risk factors that would cause a problem with that nutrient, and a way to fix the issue and monitor how effective your fix is. Eight pages are devoted to methylation-related nutrients, and many more pages are devoted to the B vitamins and minerals that indirectly support methylation.
To purchase it, use this link and copy and paste the discount code METHYLATION5 to get $5 off.
For Even More
Try searching the site for “methyl,” “methylation,” or any of the specific nutrients discussed on this page. Try doing the same on Google and adding “masterjohn” to turn up things I have written on this site or elsewhere.