How Do You Know When Your Methylation is Balanced With MTHFR?

It’s great to talk about “balancing your methylation” and finding your right folate dose, but how do you know when you’re actually there? This question matters a lot because I’ve seen so many clients who are on a constant upward trend with their methylfolate dose – always pushing to take more simply because they can tolerate it.

The point is, do you need it? Is it helping you? This isn’t a contest in which the person who takes the most methylfolate wins a prize, this is about listening to your body and finding balance – balance meaning not too much and not too little. This goes for MTHFR folks, but also people without an MTHFR polymorphism, because you don’t have to have MTHFR to have imbalanced methylation.

So where is this elusive magical place in which balance is reached? It may not be nearly as elusive, nor as magical as you’re thinking.

Does Balanced Methylation Mean All My Symptoms Are Gone?

Goodness, I wish it did. It usually means most symptoms are better, and some of them are gone, but all of your symptoms being gone is not actually realistic. We’re all human and human bodies are built differently for lots of reasons. One of those is MTHFR, but each human has hundreds of polymorphisms along with a whole life history of pathogens, traumas, nutritional factors, lifestyles, and varying degrees of self-care. Balancing methylation can’t compensate for all of that, it just takes a big chunk out of the bottom.

Having said that, the process of balancing your methylation usually helps people tremendously – decreasing anxiety, softening depression, improving sleep, reducing inflammation, normalizing hormones and generally getting things closer to where they should be.

What Is The Easiest Way To Tell If My Methylation Is Balanced?

There are two great ways. The first is to look at the work you’re doing around methylation. The second is to look at your labs.

Caring For Your Methylation

You know you’re at a place where your methylation is balanced when these things are happening:

  • You understand the signals your body gives you when it needs more support and when you’re taking too much methylation support
  • You respond appropriately to those signals
  • You aren’t hitting major walls coming from detox symptoms or up and down methylation crashes
  • Your symptoms are slowly but surely softening and resolving. THey may not be fully resolved, but you’re on an upward trajectory. Some of this just takes time.
  • Your body’s basic needs are regularly met – you’re getting good nutrition, good sleep, gentle exercise.

I see the same panic-stricken look on many faces when I say this, especially from folks at the beginning of their journey. Don’t worry – this all becomes clear over time and this is a journey that takes time. In good news, the best way for it to all unfold, is softly. This is a lot like pregnancy in that you can’t really rush it – it’s best to just support the process. For everyone who has just muttered something grumpy under their breath, the next section is more concrete. I promise.

Ok – So What About Lab Work?

Basic bloodwork can tell you a lot about what your body is doing at that moment. Values that are most specific to methylation are:

  • Serum Folate
  • Serum B12
  • Serum homocysteine

There are also some tests that are suggested on various MTHFR forums that I am less inclined to use including:

  • Serum MMA
  • RBC Folate
  • Urine MMA
  • Urine FIGLU

We’ll go through the tests I use one by one. The tests I am less inclined to use we’ll cover in a different post.

Serum Folate Test

This is the standard folate testing t and sadly doesn’t differentiate between useful folate that is bioavailable and folic acid or worse, unmetabolized folic acid. So this test will tell us if there is an overt folate deficiency, but not much else. Still, knowing if you have a folate deficiency matters with MTHFR. Levels below 4 mcg/L indicate a folate deficiency, but outside of that, the guidelines are vague. I don’t like to see the numbers creep too high either and >8 mcg/L can also be a red flag for over-supplementation, or for high lingering folic acid and unmetabolized folic acid in the blood.

Serum B12 Test

This test measures levels of B12 in the serum and is reasonably accurate, but has a broad reference range. The reference value is typically 180 – 914 ng/L and anything in there is considered normal. Anything below 180 ng/L is considered to be deficient. Because it is such a broad range, I tend to look at anything even close to 180 ng/L with suspicion. Remember reference ranges give us the average numbers where people begin to experience symptoms, but that doesn’t mean it’s the ideal number for you, so aim for the middle of the range (somewhere between 450 – 650 ng/L). Also, if you test normal but still have symptoms of B12 deficiency, then extra supplementation could be warranted.

Serum Homocysteine Test

We’ve talked a lot about serum homocysteine and there is a normal range and also an optimal range. If you’re outside of normal, then obviously there’s a problem, and for MTHFR folks it’s a good idea to aim for optimal. The normal range is 5 – 15 umol/L with optimal being 6 – 9 umol/L (in my opinion. Follow the link to see my reasoning.) Homocysteine, remember is an inflammatory marker in the blood that is a direct measure of how well you’re methylating methionine and so is the clearest measure of MTHFR function.

Are There Other Tests?

There are other tests, namely serum MMA, urine MMA and urine FIGLU. These tests are less commonly used and deserve a post of their own when we have more time. I find the serum folate, serum B12 and homocysteine to be the most useful of the bunch.

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Fish Oil and MTHFR, What Is The Link?

We’ve all heard about fish oils and omega3 fatty acids for so many incredible reasons. They are strongly anti-inflammatory and perform almost as well as non-steroidal anti-inflammatory tests for pain relief, without side effects. 

They have been most strongly studied for heart disease and show an almost unbelievable array of benefits. Fish oils reduce the risk of sudden death from cardiac arrhythmias, reduce all-cause mortality in patients with known cardiac disease, and help to treat high cholesterol (hyperlipidemia) and high blood pressure (hypertension.) All of this, without significant side effects or drug interactions

Studies have also shown that countries with higher intake of omega-3 fatty acids have lower rates of depression. Fish oils have also shown beneficial effects in both research and clinical practice for diabetes, Alzheimer’s disease, stroke, and autoimmune disease. 

What about Fish Oil and MTHFR?

Most studies aren’t MTHFR-specific.  But, fish oil has benefits for so many of the long-term consequences of unbalanced methylation in MTHFR, that it makes sense that there would be some link.  What reserach has found is some kind of synnergy between fish oil and B vitamins, in which the combination works better than either therapy alone.

Omega-three fatty acids and B vitamins for cognitive decline

A randomized placebo-controlled  trial of people with mild cognitive impairment found that treatment with B vitamins lowered homocysteine and slowed the rate of cognitive decline. Researchers went back and re-analyzed the data from this study to see if baseline levels of omega-three fatty acids interacted wtih the results in any way. The study involved mental testing over the course of two years.They found that for all outcome measures, higher concentrations of DHA significantly enhanced the effects of B vitamins, while the levels of EPA had less of an impact.

Not only that, when omega-3 fatty acid levels are low, B vitamin treatment has no effect on cognitive decline, but when omega threes are in the high-normal range, B vitamin treatment becomes effective. There is some synnergy happening here that needs further investigation to fully understand, but since omega-three fatty acids are good for so many things and truly haven’t shown negative consequences it makes sense to add them in as a no-risk measure for seniors with cognitive decline.

Omega-three fatty acids and homocysteine

The methylation process itself seems to be involved in the metabolism and distribution of these polyunsaturated fats through your body, which means that MTHFR and omega-3s are intimately linked. Also, it has been theorized that omega-three fatty acids actually have expression control on enzymes within the methylation cycle, so effectively MTHFR controls omega-threes, which control MTHFR. There is not a big enough body of research yet to draw firm conclutions, but the evidence is pointing in this direction.  For MTHFR folks, the most important thing to understand is that using fish oils and B vitamins together produces a great reduction in homocysteine levels than using either one alone. 


This research suggests that omega-3 fatty acids (referred to here as PUFA or polyunsaturated fatty acids) actually stimulates the action of the MTHFR enzyme, which activates folate to generate SAMe, the methyl donor. PUFA also stimulates the MAT enzyme which converts methionine to SAM, the CCT enzyme which is involved in the conversion of choline to phosphatidylcholine, and the CGL enzyme which is involved in the conversion of Homocysteine to Glutathione. 

Inflammation, heart disease, cognitive decline, and high homocysteine are all problems that happen more frequently in folks who have MTHFR with unbalanced methylation, and since fish oils effectively address these problems, it almost seems like a gimme.

Next week, we’ll talk about a few bits of research being done regarding fish oil and gene expression for MTHFR folks. The research is new, but it’s starting to get good.

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Lowering Homocysteine with MTHFR

As with everything to do with MTHFR, balancing your methylation and boosting your B vitamins, especially B2, folate or 5-LMTHF, and B12, is the first step. Balance your methylation! There are some other things you can look into as well.

MTHFR Isn’t The Only Cause of High Homocysteine

Of course, our focus is MTHFR, but high homocysteine has other causes as well and the sad truth is, you can have fleas and ticks on the same dog. That is one of my favorite Texas expressions. What I mean by that is that just because you have MTHFR, doesn’t mean you don’t have to also watch out for other causes of high homocysteine. It’s important to manage those too. Other Causes of high homocystein (or hyperhomocysteinemia) include:

  • Poor diet
  • Poor lifestyle
  • Smoking
  • Diabetes
  • Rheumatoid Arthritis
  • Thyroid imbalance
  • Chronic inflammatory diseases
  • Celiac disease
  • Crohn’s disease
  • Long-term use of corticosteroids
  • Prescription medications
    • methotrexate (because it lowers folate)
    • metformin (long term use because it interferes with B12 absorption)
    • hydrochlorothyazide
    • Fibrate type cholesterol-lowering medications
    • Levodopa
    • Anti-epileptic drugs (long-term use)
    • Possibly nicotinic acid or niacin, but research is very conflicted.

If you have one of these underlying conditions or are taking a medication known to elevate homocysteine, then working on that condition or talking with your physician about the medication can be a great place to start. Outside of that, let’s talk about useful steps.

The MTHFR Plan to Lower Homocysteine To Optimal

  1. Balance your methylation – I’ve said it already, but the first step is always boosting your methylation cycle because this is where we tend to stall out with MTHFR. This means following the To Health With That! Plan. Eliminate folic acid, add a methylation-friendly B complex, then add 5-LMTHF, or folinic acid, or whatever workaround you are using if you don’t tolerate folate. If you aren’t familiar with the plan you can start to walk through it here.
  2. Limit your protein intake – The more protein (and consequently methionine) you take in, the more homocysteine your body makes. There’s a full article about the methionine and homocysteine link here.
  3. Quit smoking – As though you needed one more reason why smoking is bad for your health. But yes, smoking raises your homocysteine levels.
  4. Take a look at your alcohol intake – alcohol blocks folate absorption, and so increased drinking can raise your homocysteine levels. This is probably mitigated by extra folate intake, but possibly not.
  5. Balance your coffee intake – As much as it pains me, too much coffee has consequences and high homocysteine is one of them.
  6. Zinc – zinc is a cofactor in some of the enzymes involved in the recycling of homocysteine to methionine, and so zinc deficiency can increase homocysteine levels while zinc supplementation can help to improve beneficial conversion.
  7. NAC – NAC, or N-acetyl cysteine, has been shown to lower homocysteine levels as well as folate supplementation in studies.
  8. Fish oils – in a magical synergy, fish oils + B vitamins work better together than they do apart.
  9. Make sure there aren’t other underlying causes – If you’re doing everything right and your homocysteine still isn’t where you want it to be, it matters to talk to your doctor about other underlying causes. If you’re living the perfect lifestyle, but you still have a low thyroid, then fixing your thyroid is probably the only thing to bring your levels back to balance.

Don’t forget that every little step you take towards getting healthy, counts. They all add together to contribute to your state of health, today. So every little step you take in the right direction, matters. Don’t get discouraged if things don’t move right away, just keep trying.

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MTHFR and Homocysteine By The Numbers

These past few weeks we’ve gone over some general information about MTHFR and homocysteine, the link between methionine and homocysteine, and the new information about MTHFR, homocysteine, and Covid-19. What we haven’t talked about is Homocysteine testing and parameters – what is normal, what isn’t, and what is considered normal but maybe shouldn’t be.

Testing Homocysteine

Homocysteine tests are simple blood tests that can be ordered by your doctor. It must be performed fasting for accurate results. Any protein you eat before your test can skew the numbers because methionine in your food may cause a temporary rise in homocysteine. The best way to ensure a blood test is fasting is to schedule your blood test early in the day before you have eaten anything. 8 – 12 hours of fasting (like you would get overnight) is best for the most accurate results.

“Normal” Levels

The current medical standard in the U.S. is a normal range from 5 – 15 umol/L (that is micro mols/Litre). Anything above 15 micro mols/L is considered high, or hyperhomocysteinemia. There is a growing body of evidence that the normal level should be adjusted:

  • A study published in the New England Journal of Medicine shows that carotid artery thickening and stenosis risk begins to increase for men by 9.2 umol/L (although the risk for women seems to remain stable until 11.4 umol/L). Both of these are significantly lower than the 15 umol/L that is considered normal.
    • Risk increases at 9.2 umol/L
  • A meta-analysis published in the Journal of the American Medical Association shows that a 3 umol/L decrease in homocysteine leads to an 11% lower risk of ischemic heart disease and a 19% lower risk of stroke.
  • A strong linear relationship exists between homocysteine levels and death in patients with coronary disease. The lowest risk group has homocysteine below 9 umol/L and the risk increases from there both within what is considered the normal level and outside of it.
    • Homocysteine <9 umol/L = 3.4% risk of death
    • Homocysteine 9 umol/L – 14.9 umol/L = 8.6% risk of death
    • Homocysteine >15 umol/L = 24.7% risk of death.
    • Risk increases at 9 umol/L
  • The study we discussed last week dealing with homocysteine levels as a predictive marker for worse outcomes with Covid-19 also showed an increased risk for pathological lung changes on CT at 8 umpl/L
    • Risk increases at 10.58 umol/L

If The “Normal” Levels aren’t Ideal, What Is?

All of the risks for negative health outcomes seems to be lowest around the 6 – 8 umol/L mark, so we’re going to call that “Optimal.” This is an estimation based on the research that we talked about above. Joe Pizzorno (a legend in the natural wellness community), estimates the ideal range to be 5.0 to 7.0. Ben Lynch, the epigenetic expert, estimates ideal to be between 6 to 9 umol/L.

If Homocysteine Is So Bad, Why Aren’t We Aiming for Zero?

Too much homocysteine is bad for sure, and with MTHFR and homocysteine that is the direction we usually trend, but remember that homocysteine is absolutely essential. If your homocysteine is too low (hypohomocysteinemia), then there are also health consequences. Without homocysteine you can’t make glutathione, which is one of your main defenses against oxidative stress. Without glutathione, things would go sideways pretty quickly.

Homocysteine is also the precursor for something called alpha-ketobutyrate, which is a vital ingredient in the process that makes cellular energy. Very few studies are done about low homocysteine levels (I mean VERY few. I can count them on two hands). By far the most interesting one shows a link between low homocysteine and peripheral neuropathy. It states that fully 41% of people with low homocysteine have peripheral neuropathy, which is hugely significant.

In my opinion, this implies that the lack of glutathione and consequent difficulty with free radicals is leading to higher levels of inflammation and nerve damage. Ben Lynch put forward a similar theory on his website here, and Joe Pizzorno, here.

I wouldn’t be surprised to see a link between low homocysteine and chronic fatigue, as well, although the research has never been done.

The bottom line is that we need homocysteine, but too much of it becomes a big problem. Aim for 6 – 8ish micro mols/L. Next week we’ll talk about ways to lower your homocysteine levels if they’re too high.

Has your homocysteine ever tested too low? I”d love to hear your comments here, or in Genetic Rockstars, our amazing MTHFR community.

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Homocysteine, MTHFR, and Covid-19. What We Know Now.

Of course in a pandemic we all want to know how it might affect us specifically, with all of our genetic differences. That research takes time and money and usually comes after the big stuff (like how does this spread and why does it kill people.)

In good-ish news, Covid-19 has now officially been around long enough for some of the smaller, more specific areas of research to be done. This includes the very first steps on research into the interplay between homocysteine, MTHFR and covid 19.

This particular study came about because there have been big differences in COVID disease severity, in particular in the death rate, between different geographic areas as well as between the genders. The study I am talking about was published in November 2020 in a journal called Medical Hypotheses, which is not peer-reviewed research, but rather includes important theoretical papers, so I do want to emphasize that this information is theoretical and has not been formally researched yet.

Here is a Summary from The Article Entitled: Life-threatening course in coronavirus disease 2019 (COVID-19): Is there a link to methylenetetrahydrofolate reductase (MTHFR) polymorphism and hyperhomocysteinemia?

At the date of publication of this research, Covid-19 was associated with an 8.8% mortality rate in those above 60 years of age, and 0.46% for patients aged below 60 years old. Countries with the highest mortality rates are Italy, Spain, France, Iran, and the USA. A recent report from Italy showed that the vast majority of those infected who were critically ill were older men, 68% of whom had at least one comorbidity. The worldwide mortality rate is higher among men almost by a factor of two.

Mortality rate Male:Female = 1.7:1

In Italy, high rates of ICU admission, ICU mortality, and overall mortality have been seen and the deaths from COVID-19 are often associated with high neutrophils, high levels of pro-inflammatory cytokines, abnormal coagulation tests, and disseminated inter vascular coagulation.

The most common comorbidities among the most critically ill were:

  1. Hypertension
  2. Cardiovascular disease
  3. Hypercholesterolemia
  4. Diabetes

The article goes on to summarize the high points of MTHFR:

  • The MTHFR enzyme is the most important in the methionine pathway.
  • It regulates fundamental processes such as DNA repair, neurotransmitter function, and membrane transport.
  • The C677T mutation has been suggested to be protective against certain cancers including colon and acute lymphatic leukemia.
  • The mutation leads to a thermolabile variant of the MTHFR enzyme in which the dissociation rate of the cofactor Flavin Adenine Dinucleotide (FAD) (this is from B2) is increased, thus reducing the activity of the MTHFR enzyme by 50% or more.
  • In people with a medium skin tone, the function of the MTHFR enzyme is largely preserved as long as they have sufficient dietary folate intake.
  • With insufficient folate intake, the production of 5-LMTHF is reduced, which leads to the accumulation of the key metabolite, homocysteine, to toxic levels.
  • MTHFR is the most common genetic cause of hyperhomocysteinemia.
  • Low folate status resulted in significantly higher levels of homocysteine in men.
  • Research suggests that the C677T mutation is associated with a significantly increased risk of coronary artery disease only in homozygous men.

Other risk factors for the development of high homocysteine are:

  • chronic kidney failure
  • hypothyroidism
  • cancers of the breast, ovary, and pancreas
  • smoking
  • alcohol consumption
  • physical inactivity
  • advanced age
  • male gender

Acute High Homocysteine

In addition to the risks of high homocysteine that we have talked about before, an acute high homocysteine situation can be triggered, independent of folate status, when a systemic inflammatory process is triggered (like, for instance, by a virus). This process boosts inflammation and releases a tremendous amount of reactive oxygen species (free radicals), which can overwhelm your antioxidant defense systems. This is potentially an even greater issue in MTHFR folks because we have the potential for lower glutathione than average. This whole ugly cascade activates something called nuclear transcription factor (or NF-kB), which accelerates viral replication in SARS Co-V. The study also cites a case report in which glutathione supplementation led to a rapid symptom improvement in two cases of Covid-19.

Interestingly, COVID-19 patients’ plasma homocysteine levels show predictive value for the progression of pathological findings on chest CT. This means the higher the patient’s homocysteine is, the more likely they are to show damaging changes in their lung tissue on a chest CT scan. Also, these changes began to show at a lower homocysteine level than the one that is usually used as a medical reference. Negative changes began to show at 10.58 umol/L rather than the 15 umol/L that is normally recognized as a “high” value.

In Covid-19 patients, the higher the patient’s homocysteine is, the more likely they are to show damaging changes in their lung tissue on a chest CT scan.

– Karst M, Hollenhorst J, Achenbach J. Life-threatening course in coronavirus disease 2019 (COVID-19): Is there a link to methylenetetrahydrofolic acid reductase (MTHFR) polymorphism and hyperhomocysteinemia?. Med Hypotheses. 2020;144:110234. doi:10.1016/j.mehy.2020.110234
-(Paraphrased by Amy Neuzil at tohealthwiththat.com)

What Do We Do About High Homocysteine, MTHFR and Covid-19?

This study makes some suggestions.

  • Patients at high risk with Covid-19, such as the elderly with comorbidities, should also be screened for high homocysteine.
  • Those with 8 umol/L Homocysteine or above should implement a folate-rich whole foods diet (fruit, vegetables, whole grains, good protein sources.)
  • These individuals should also add 5-MTHF supplementation.
  • Folic acid should be avoided by these individuals as supplementation can have the opposite of the desired effect, especially in individuals with the MTHFR polymorphism. This is thought to be because unmetabolized folic acid accumulates, which inhibits MTHFR and also folic acid competes at binding sites with 5-MTHF.
  • B6, B12, and B2 should be added as well as they are cofactors for the MTHFR enzyme, or in the methionine pathway.
  • Supplements with demonstrated anti-viral properties can be added, including vitamins A, C, D, E, selenium, zinc, iron, and omega-3 fatty acids.
  • Strong antioxidants including vitamin C and glutathione have shown positive results for Covid-19 outcomes.

At the end of the day, it looks like taking care of yourself appropriately for MTHFR and following the positive steps to balance your methylation that we have been talking about, is actually the best defense for those of us with MTHFR against the worst of the outcomes with Covid-19. Taking positive steps to manage your MTHFR doesn’t mean that you won’t get Covid-19, but hopefully, it will help to reduce your risk of dying from Covid-19. Keep in mind that this study represents a well-researched theory, and it has yet to be proven in clinical trials.

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Methionine, MTHFR, and Homocysteine.

The link between MTHFR and homocysteine is clear – if you aren’t familiar with that part of the picture, you can brush up with last week’s topic. The link between methionine and homocysteine is clear as well since they loop together in the methionine cycle with dietary methionine converting into homocysteine as a by-product, then being recycled back to methionine using MTHFR.

It’s easy to get into a situation where you assume methionine is “good” and homocysteine is “bad,” but actually for MTHFR, methionine itself is a double-edged sword.

Recommended Intake of Methionine

When it comes to suggested protein intakes per day, it’s pretty hotly debated and the criteria are updated every few years. Generally, requirements for infants are much higher (according to intake in mg/kg body weight) than those of children, and children are in turn higher than those of adults. Again, this is based on an mg/kg measure and not an absolute number.

  • Infants (3-4 months) – 58 mg/kg body weight/day
  • Children 2 years old – 27 mg/kg body weight/day
  • Children 10-12 years old – 22 mg/kg body weight/day
  • Adults – 13 mg/kg body weight/day.

This means for the average 150 pound (or 68 kg) adult, the daily requirement for methionine is 884 mg. That is found in 100 g (or 3.5 oz) or less of a lot of meats. This means that while vegetarians are probably getting the right amount, most meat eaters are significantly overdoing it.

Recommended Daily Protein Intake

This data is also debated, but the best researched reference data from the World Health Organization is below.

AgeProtein intake in grams/kg body weight/day
Infant1.2-1.4 g/kg body weight/day
Children0.8 – 0.97 g/kg body weight/day
Adolescents0.67 – 0.79 g/kg body weight/day
Young Adult0.75 g/kg body weight/day
Adult0.6 g/kg body weight/day
Elderly0.75 g/kg body weight/day
Pregnant0.92 g/kg body weight/day
LactatingBasic rate plus 15 g per day for the first 6 months, 12 g per day thereafter.

This works out to about 46 grams per day for the average woman and 56 grams per day for the average man. In the west, we tend to overdo protein. Most American adults eat about 100 g of protein per day, which is twice the recommended amount. Not only that, the latest trends in nutrition mean that 60% of Americans report that they are trying to increase their protein intake according to the Hartman Group.

Food Sources of Methionine

Methionine is an amino acid, which is the building block of protein, so naturally, it is high in protein-rich foods. The top ten categories of foods according to my food data are:

FoodMethionine
per 100g
Methionine per 6 ozSimilar Foods
Ground Turkey931 mg1583 mgChicken breast, thigh, drumstick.
Beef (skirt steak)905 mg1539 mgOther cuts of beef, lamb, veal, buffalo
Tuna885 mg1505 mgGrouper, salmon, snapper, tilapia, mahi mahi
Lean Pork Chops850 mg1445 mgPork ribs, lean ham, pork bratwurst,
Firm Tofu211 mg532 mgEdamame, soybean sprouts, soy milk
Milk88 mg431 mgYogurt, buttermilk
Low fat ricotta284 mg528 mgParmesan, gruyere, Swiss (other cheeses)
Brazil nuts1124 mg1914 mgHemp, squash, pumpkin, chia, sesame seeds.
Large white beans146 mg196 mgNavy, kidney, black beans.
Quinoa96 mg133.5 mgTeff, wild rice, kamut.

So… Too Much Protein?

In the West, we love our protein. We’re all working on building muscle and improving our lean bodyweight… Except that in reality, most of us aren’t. Most of us are actually working on holding down our office chair and staring at a screen. Still, we’re obsessed with the idea of being fit and lean so we overconsume in different ways than we used to. Most of us eat more than we need in general, and those of us who are “working on our health” are especially prone to working to get too much protein This, of course, leads to the modern issues of obesity and heart disease,

For people with an MTHFR issue, this takes on an added dimension because eating more protein means adding more burden to the methionine (or methylation) cycle and hence the MTHFR enzyme which ties methylation into the folate cycle. Remember how those two cog together like gears?

the MTHFR lifestyle matters because of the way these cycles all interconnect.

Extra protein means your folate cycle has to work harder, your body needs more active folate and more methyl donors, and homocysteine is going to build up. We already talked about how bad homocysteine is when it builds up.

Plus, Lower Methionine Intake Might Mean You Live Longer

Research has long shown that calorie-restricted diets are effective in promoting lifespan. Meaning, the people who eat less usually live the longest, even to the fact that some of the humans with the longest life spans on record have gone through periods of food shortage. Further research has found that limiting methionine intake specifically extends lifespan. That is with or without actual calorie restriction. Also, intermittent fasting, which is one of my favorite health hacks, is a great way to actually have minor calorie restrictions without too much fuss.

Also, methionine restriction is showing promise as a therapeutic approach to limiting the growth of certain types of cancer. This isn’t because methionine is bad – it’s essential for human growth, development, and healthy functioning. We do get more than we need, but also cancer cells have fewer ways to adapt to methionine limitation, while healthy cells can protect themselves better.

In a fascinating study, researchers are also limiting methionine with the use of an oral medication that breaks down methionine (called an oral methionase) to treat Covid-19. The RNA of the coronavirus needs to be methylated, using SAMe, in order to initiate viral replication. Limiting methionine (which limits SAMe) interferes with that step and so slows the viral replication and can potentially reduce viral load. This generally makes me wonder about all of us MTHFR folks and Covid-19. Do we have a survival advantage because it’s harder for us to produce SAMe? Also, should people supplementing with SAMe consider taking a break if they’re in a high-risk situation for COVID?

Even though we are obsessed with getting more protein – I mean, who doesn’t have jerky in their purse right now? We are clearly overdoing it. Reducing protein intake, specifically methionine, would help us all live longer, healthier lives. But it is especially important for MTHFR folks.

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MTHFR and Homocysteine – The Basics

High homocysteine is often the first indication of an MTHFR issue, and it’s certainly the one that doctors take the most seriously. There is a good reason for this. Homocysteine is implicated in heart disease including heart attack and stroke, so it shouldn’t be taken lightly. 

What is Homocysteine?

Homocysteine is an amino acid that is made within your body as a part of methionine metabolism. Amino acids are the basic building blocks of protein, and we take in amino acids every time we eat protein-containing foods.

We need homocysteine in order to make ATP, our cellular energy, and also to make cysteine and ultimately glutathione, which is our master antioxidant. The problem comes when levels get too high, and this happens when your body is unable to recycle homocysteine back into methionine.

The primary recycling pathway relies on the MTHFR enzyme, as well as active folate and B12. There is a secondary pathway called the BHMT pathway that ramps up when homocysteine levels start to rise and this relies on other methylators like betaine, trimethylglycine (TMG), and choline. 

Why does Homocysteine Get High?

As usual, there are a number of reasons and many of them are related to MTHFR.

  • MTHFR compromise – your body recycles homocysteine into methionine in an MTHFR-dependent process. It requires the active form of folate for the process so if your MTHFR is running slowly or inefficiently then homocysteine levels can build up causing inflammation and damage.
  • Folate deficiency – Whether or not you have an MTHFR issue, if you don’t have folate then the recycling doesn’t happen either.
  • B2 or B12 deficiency – Like folate, these vitamins are necessary for methionine recycling, and not having enough of them can raise your homocysteine to an unhealthy level.
  • Too Much Protein intake – This is certainly a first-world problem and a bigger one recently with everyone doing fad diets from Keto to Atkins to Paleo. If you’re taking in higher levels of methionine than your body can easily process, then homocysteine is going to build up. Also, meats and dairy have some naturally occurring homocysteine in them. We’ll talk more about the methionine situation next week.
  • Other medical conditions – thyroid disease, rheumatoid arthritis, and diabetes are linked to higher homocysteine levels.
  • Medications that decrease folate absorption – proton pump inhibitors, birth control pills, antifolate agents, and some anticonvulsant medications interfere with folate absorption or metabolism.
  • High coffee intake – I am sorry to say, high coffee intake is also linked to elevated homocysteine.

What Does Homocysteine Do That’s So Bad?

So many things. Homocysteine is vital, of course, but in this situation, too much of a good thing becomes toxic.

  1. Inflammation – Inflammation is the most well-documented issue to do with homocysteine. It is specifically damaging to cell membranes and the lining of your blood vessels, which is part of why it is so linked to heart disease.
  2. Clotting – Clotting in the blood vessels can lead to heart attack, stroke, pulmonary embolism, and deep vein thrombosis, none of which are good. This is thought to be due to a combination of factors. One is that nitric oxide metabolism is compromised and so blood vessels aren’t able to dilate properly. The other is that thromboxane A2 (TXA2) activity is increased in both blood vessels and platelets, possibly because of a higher free radical burden. This promotes clotting.
  3. Neurological issues – High homocysteine levels are implicated in a number of neurological disorders including stroke and Alzheimer’s disease, but extending to disorders like epilepsy, Parkinson’s, multiple sclerosis, and ALS. The research is unclear in terms of whether homocysteine is actually a causative factor in its own right or just a marker of low B-vitamin status.
  4. Fractures –  Research shows that homocysteine significantly increases fracture risk and it appears to be independent of other risk factors, but it is unclear whether or not B vitamin supplementation decreases that risk.
  5. Microalbuminuria – Microalbuminuria is an abnormal protein in the urine and it indicates a high future risk of cardiovascular disease as well as kidney dysfunction. Every 5 umol/L increase in homocysteine levels is associated with an increased risk of developing microalbuminuria.
  6. Atherosclerosis – As a consequence of the increased inflammation in your arteries, your body is more likely to lay down arterial plaque to protect itself. This isn’t the direction you want to go. High blood pressure – possibly because of the issues with blood vessel dilation, blood pressure and homocysteine go hand in hand. High homocysteine increases the thickness of arterial walls, reduces the elasticity of arteries, and increases the production of stiffer collagen fibers in the vascular system. 
  7. Pregnancy complications – High homocysteine levels have been implicated in spontaneous abortion, placental abruption, and preeclampsia. 

Is There Anything Good About Homocysteine at All?

Homocysteine is certainly an issue for MTHFR folks, but it’s also incredibly helpful for us as a biomarker. Testing your homocysteine gives you an easy way to see if your methylation is becoming unbalanced at the moment. While it’s a small silver lining, it’s still a good one.

We’ll talk more about the role of methionine in this conversation as well as testing homocysteine and optimal levels in the next couple of weeks.

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