Nitric Oxide, MTHFR, and NOS3

MTHFR is well known for causing heart health issues. It’s directly responsible for raising homocysteine levels, it’s implicated in troublesome blood clotting, and it’s indirectly responsible for making it harder to make adequate nitric oxide.

All of this is compounded if you have MTHFR and another gene SNP called NOS3.

What is Nitric Oxide?

Nitric oxide is the primary substance responsible for keeping your blood vessels open and relaxed so that blood can flow through easily. Without it, your blood vessels tighten and constrict, which drives up blood pressure and reduces oxygenation of your tissues. The primary function of your blood is to carry oxygen to all of the muscles, organs, and tissues that need it, and nitric oxide helps make that happen.

Nitric oxide also helps to keep your platelets, those tiny flakes in your blood that make up blood clots, nice and smooth and slippery. It inhibits platelet aggregation and adhesion, and even helps to destabilize any small clots that have formed.

Blood that clots when you’re injured are a good thing – they keep you from losing too much blood. Blood clots that happen for no reason, are deadly. That is what lies underneath the bulk of the heart attacks and strokes out there. You want blood that is smooth and free of clots.

Nitric oxide also helps with the growth and formation of new blood vessels.

Why Does MTHFR Affect Nitric Oxide?

MTHFR is part of the folate cycle, turning inactive folate into the active form, which is 5-LMTHF. The folate cycle needs to spin in order for a linked pathway, the BH4 pathway, to also spin. The BH4 pathway is most known for neurotransmitter formation because this is where we see serotonin and dopamine formation. BH4 is also necessary for nitric oxide synthesis. There is a detailed pathway document in the show notes, if you really want to dive in, but suffice to say if MTHFR is sluggish, then nitric oxide synthesis is also sluggish.

Let’s Talk NOS

NOS stands for nitric oxide synthease and there are three different forms, depending on where they are located in your tissues. NOS1, is also called neuronal NOS (or nNOS). NOS2 is also called iNOS, or inducible NOS, and NOS3 is epithelial NOS, or eNOS. eNOS, or NOS3 is extremely important here because it is most represented in the epithelium, which lines your blood vessels and so has the greatest direct impact on vessel dilation as well as clotting.

Nitric oxide is made from arginine, which is one of the building blocks of protein, and so that matters for proper functioning, as does calcium. Under normal circumstances, NO synthesis is dependent on the level of calcium within the cell and so that must be adequate. NO synthesis can also be influenced by injuries, such as shear stress, that require changes to blood flow.

NOS “Uncoupling”

There are many factors, mostly implicated in heart disease, that can set up a bad situation with your NOS. These factors include diabetes, ongoing high blood pressure, high cholesterol, aging, and metabolic syndrome and they all lead to higher percentages of oxygen radicals, which can in turn cause NOS to break off of BH4, or “uncouple” and bond with a reactive oxygen species. This establishes a cascades of enhanced free radical production that does nobody any good. This is part of why your doctor is so eager to treat diabetes, high blood pressure, and cholesterol before they have a chance to do long-term damage.


The NOS3 gene SNP, as you might have guessed, has its biggest consequences in heart and cardiovascular health, but also influences some tissues that rely heavily on constant, tightly regulated blood flow like your brain or a developing fetus. It is especially likely to create problems in situations with overlapping pathology, like NOS3 Gene SNP with diabetes, which also decreases circulation.

Common signs of NOS3 problems:

  • Chest pain with exertion or away from it
  • Cold hands and feet (poor circulation)
  • High blood pressure
  • Erectile dysfunction
  • Migraines
  • Stroke
  • Chronic sinus issues
  • Blood clots
  • Congenital heart defects (in babies born from mothers with untreated NOS3 polymorphisms)
  • Arteriosclerosis or hardening of the arteries
  • Preeclampsia in pregnancy (this is also a risk with MTHFR alone).
  • Family or personal history of Alzheimer’s disease.

Supporting a NOS3 Polymorphism

There are many ways you can support nitric oxide synthesis in your body, with or without a NOS3 gene SNP. Here are just a few:

  • Eliminate Folic Acid – folic acid causes a decrease in BH4, which is bad for your nitric oxide synthesis and your neurotransmitter production (also, your methylation).
  • Hum! – eNOS is highly expressed in your sinuses, and humming causes a 15-20 x increase in nitric oxide synthesis in those tissues. This is part of why breathing through your nose at night is so important for tissue oxygenation. A wonderful study published in the journal Medical Hypothesis showed that not only will strong humming for an hour every evening clear up nasal blockages and sinus infections, it also increases your functional nitric oxide.
  • Eat a low glycemic index diet – lowering your blood sugar fluctuations as well as your blood sugar in general will help your NOS, your heart, and your risk of diabetes in the long term. This means that every meal and snack should have a balance of proteins, good fats, fiber, complex carbs and sugars. A big pop or candy bar in the middle of the afternoon with no real food to back it up is the opposite of this.
  • Breathe through your nose– talk with your doctor about mouth breathing (Especially at night), try mouth taping, and make sure any larger issues like deviated septum get addressed. Deep breathing exercises for one minute three times per day can really help as well.
  • Exercise – exercise is great for everything and a healthy NOS3 is no exception.
  • Stop smoking and stay away from chemicals – chemicals in your environment can impair your NOS function by reducing the amount of BH4 produced, as well as impacting glutathione levels and NOS needs support from glutathione so it doesn’t get into the uncoupling situation.
  • Good dietary sources of arginine, calcium, and B2. Arginine comes from high protein foods like meat, dairy, and legumes which you will be eating more of with a low glycemic index diet. Calcium also comes from dairy, dark ark leafy greens, and broccoli. Riboflavin can be found in eggs, liver, lamb, mushrooms, spinach and almonds.

Whether you have a NOS3 polymorphisms or not, supporting a healthy nitric oxide function is crucial for a healthy heart, brain, and sinuses. It is especially important if you have an MTHFR polymorphism because we do have tendencies toward compromise in this area. Plus, most of the steps here overlap with the MTHFR lifestyle – so if you do the MTHFR lifestyle plus some deep breathing or humming, you’re there.

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S2E16: Hydration and MTHFR

Water is so talked about that it’s incredibly easy to ignore. Like everyone knows we need a ton of water, so that can’t be the key to anything, it’s just too common. Too simple, too “normal.” I get that. We talk about it so much in every health format, that people just skim right over it because they’ve heard it before. It’s easy to wear-out an idea in this way so that the value of the thing gets lost, and unfortunately that has happened to many of the pillars of health. Things like eating your greens, drinking enough water, exercising regularly, and even mindfulness. Yeah, yeah, we’ve heard all of that.

I know. I do understand and I can be guilty of disregarding the simple things too. But I want to emphasize a point here – it isn’t just water, it’s hydration. Hydration matters for MTHFR, in fact, hydration matters for humans, MTHFR or not.

Why Are Hydration and Water Not The Same Thing?

Hydration, the way I’m using it here, doesn’t mean how much water you drink. It doesn’t even mean how much water you absorb. In its most important context, it means how much water gets into your cells.

This might seem like an odd benchmark, so let’s talk it through.

First off, I have seen many, many people who drink a ton of water, but who are still chronically dehydrated. That seems like a thing that shouldn’t happen but it does, and frequently.

Do you remember in chemistry class in high school learning about osmosis? I’ll put a picture of it here to jog your memory.

Osmosis is the diffusion of water through a semipermeable membrane down its concentration gradient. This file is generously licensed under creative commons and is from OpenStax online Anatomy and Physiology Text.

The osmosis experiment shows water moving across a semi-permeable membrane (which is most of what humans are made of, but certainly cell membranes qualify). The water moves so that the concentration of salts, minerals and solutes in general (which means things dissolved in the water) is equal on both sides of the membrane. To say it a different way, it shows water following salt and minerals through a semi permeable membrane.

This is exactly what happens in real life, too. Not just in high school chemistry or biology. Water follows salt and minerals and goes where those concentrations are the highest.

Great! So What Does This Have To Do With Hydration?

Well, everything. The goal is not just getting water in, but getting it into your cells. This means that salt, minerals, or some other good things that your body likes to pull into your cells could actually pull water with it.

Let’s say, for the sake of a vivid argument, that you drink distilled water all day long. Distilled water has no or extremely little of anything other than water in it – it is very pure and free from mineral contamination. That sounds good, and as you drink it, your body absorbs it into your bloodstream. Also good.

Now it’s in your bloodstream diluting your blood so your body pushes some of it into your cells. This seems good – it’s all going according to plan. Except, as you continue to drink more, the balance is getting too watery on the bloodstream side so your body does something that most semi-permeable membranes can’t do. It pushes salts into your blood to help balance things out because our cell membranes have active transporters as well. That wasn’t in the chemistry experiment.

So now salt is going out of the cells, and that’s not great. That means the cell won’t draw in as much water in the near future until it gets its salts and minerals back.

What are these salts and minerals of which we speak? They’re electrolytes, and the reason why most sports drinks have them is that they do actually help to push water into cells because your cells are hungry for them so they grab them up, then water follows along behind.

The Key to Hydration is Electrolytes.

Electrolytes are irresistible to cells and the higher quality the electrolytes, the better. Every time you drink water, try to remember to put a dash of electrolytes into it. You’ve got a few options.

  • Himalayan pink salt or good quality sea salt. These are rich in sodium, but also balanced with other minerals including the trace minerals your body might be lacking the most. Just a pinch in a 16 oz glass will do. The water shouldn’t taste salty like sea water, it’s just a small amount to help absorption.
  • A squeeze of lemon or lime juice. Hydrating and yummy at the same time. Total bonus. Lemons and limes are rich in minerals, have small amounts of fruit sugars (which your cells also gobble up) and will also help that water get to the right places in your body.
  • A splash of organic apple cider vinegar. Again, this doesn’t have to be enough to make your throat burn like hellfire, just enough to add a good healthy dose of minerals and yeasts from apples.
  • “Half-salt” or “No-salt.” This is actually a potassium-sodium blend (or potassium only) and is great for those on a sodium-restricted diet.
  • Powdered Magnesium. There are a number of magnesium powders you can add to your water and these are perfect if you tend to be tense or anxious. Remember, we’re not looking for the dose on the package here, we’re just adding a pinch to make your water more hydrating.

Now, I know you’re thinking that there are sports drinks for this type of thing. That is true, but anybody who drinks 64 ounces of sports drink daily isn’t going to be in good health. Sports drinks are pretty good for during or after activity in which there is a lot of sweating and burning of calories, but for sitting behind a computer they’re pretty much the salty equivalent of a big gulp.

Sports drinks are meant to replenish a large amount of electrolytes in a short amount of time and aren’t appropriate for all-day drinking. We’re looking for much smaller doses spread through a lot more water.

Just remember, it isn’t how much you drink, it’s how much you get into your cells that matters. Keep your cells nice and plump and watery with simple additions to your drinking water.

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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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