How Going Primal Can Help With 5 Common Genetic Mutations

Top x Genetic Variations finalAs I mentioned earlier this year, our personal ancestry can help determine how we respond to certain dietary, behavior, exercise, and lifestyle patterns. The big question remaining is this: does going Primal mesh with some of the more common polymorphisms? Yes. The Primal Blueprint is a living document. Its foundation rests on pre-agricultural human evolution, but by remaining flexible and offering ample room for personalization, it acknowledges the fact that evolution has continued to occur.

Let’s take a look at five genetic mutations and how the Primal way of eating, living, and moving can help mitigate their downsides.

1. Aerobic exercise “non-responder” genes

By now, you’ve likely heard of exercise “non-responders”—people who don’t respond to cardio the way they’re supposed to. Rather than experience health and fitness benefits, an exercise non-responder might see no changes, or even detrimental ones when they exercise. These non-responders seem to cluster in families, an indication of genetic influence.

Aerobic exercise non-responders are the most common. Whereas about 85% of the population experiences big improvements in VO2max after sustained endurance training, about 15% do not. They can work hard, about as hard as the others, and follow the same protocol yet experience almost no improvement to their oxygen consumption rates. In some people, endurance training can even degrade their health. They actually experience worsened insulin sensitivity, lower HDL, and elevated blood pressure when they train.

If a person is an aerobic non-responder, they do the work but see little benefit unless they really up the intensity and duration of their aerobic training. This means they have to lapse into chronic cardio territory just to get the “benefits,” and that carries its own set of problems as I’ve discussed many times before. Since animal studies suggest that exercise non-responders are more reliant on glucose for energy, that their blood sugar levels decline more rapidly and they can only run about half as long during endurance exercise, increasing the intensity and duration isn’t sustainable.

What does seem to work is high-intensity training. The experts claim that non-responders need high-intensity, high-volume training to see results, but when you examine the study designs you find they haven’t tested the kind of high-intensity, low-volume training I promote. For instance, sprint interval training works for exercise non-responders. They may have to increase the number of workouts they do, but at least they’re getting somewhere without having to spend several hours a day in that elevated HR zone.

There’s also a psychological component to movement that most training programs neglect: is it enjoyable? If you’re a non-responder with low blood sugar seeing very few results, you’re not going to keep plodding along the treadmill. But that same non-responder may have a blast playing Ultimate Frisbee, or learning a martial art, or breaking through the clouds to reveal a stunning sunrise on an early morning hike. Incorporating, or indeed focusing on play as the proximate goal of training and movement is a winning strategy for people with a genetic aversion to exercise.

2. Genes associated with soft tissue injuries

This is me. Based on my genetics, I have an increased risk of incurring soft tissue injuries like arthritis and the various tendinopathies.

But those genetic polymorphisms are linked to soft tissue injuries across the population. What’s the “population” doing?

They’re eating inflammatory diets. They’re not exercising or moving much at all, and when they do, they do it wrong. If they’re dedicated exercisers, they probably train too much. They’re not eating the whole animal. That’s how I used to be, and sure enough, I ended up with a steady stream of soft tissue injuries. When I went Primal, they stopped.

Going Primal helps in multiple ways:

By promoting correct movement patterns. Less sitting (so you don’t get so stiff and creaky), more full body compound movements (so you’re not isolating your tissues and placing undue stress on them), less chronic cardio (which increases inflammation and chronic loading patterns), more strength training (placing acute loads onto tissues with plenty of recovery time promotes stronger tissues).

By reducing systemic inflammation. Fewer unnecessary carbs, more anti-inflammatory plants and spices, better sleep, more omega-3s, and an increased awareness of stress and the danger of chronic inflammation lead to less of it.

More dietary collagen. Regular diets don’t provide enough dietary collagen to meet the body’s daily glycine requirements. Since glycine contributes to rebuilding and repairing collagen in the body (cartilage, tendons, ligaments, fascia), inadequate collagen can open you up to soft tissue injury. By promoting the consumption of bone broth, gelatinous meats, and collagen supplements, the Primal eating plan usually leads to greater collagen consumption.

3. PUFA metabolism variants

FADS1 controls elongation of shorter-chain polyunsaturated fats into their longer-chain counterparts. People with certain FADS1 mutations are bad at converting alpha-linolenic acid (ALA) into the longer-chained (and extremely important) omega-3s EPA and DHA. In pregnancy and nursing, these mutations can lead to impaired levels of omega-3 in the breastmilk and lower IQ in the fetus. To get enough of the physiologically relevant forms, they need to eat them directly.

If there’s one thing the Primal way of eating does well, it’s promote the consumption of healthy animal fats containing long-chain PUFAs. Indeed, certain people simply need to eat more fatty fish to be healthy. I’m one of them, likely owing to my Scandinavian ancestors coastal living and heavy reliance on marine foods.

Other PUFA metabolism variants affect the conversion of linoleic acid into inflammatory compounds. If you have these variants, higher intakes of linoleic acid (around 17 grams per day in one study, which is typical for people eating regular modern diets) are associated with breast and prostate cancer.

In the end, no one benefits from excessive intakes of omega-6 PUFAs and some are harmed. On the other hand, eating adequate amounts of omega-3s through marine foods and pastured eggs is safe for everyone and especially crucial for some. Going Primal takes care of all that by eliminating the most concentrated source of linoleic acid (processed seed oils) and emphasizing regular fatty fish consumption. The modern western model of high omega-6 intake through seed oils and low omega-3 intake is bad for every polymorphism; going Primal reverses that.

4. Glutathione synthesis genes

Whether it’s countering airborne pollution, detoxifying toxins like ethanol, or regenerating immune cells, glutathione is the premier antioxidant in our bodies. Unfortunately, some people just don’t make enough glutathione to deal with modern insults. Multiple genes determine how much glutathione we synthesize. Among them, GCLC is the gene regulating the cysteine-to-glutathione conversion pathway. GCLC-knockout mice with the cysteine-to-glutathione pathway severed normally develop severe steatosis and die from total liver failure within a month. Giving them a concentrated source of n-acetylcysteine (NAC), a widely available and inexpensive supplement, restores some glutathione synthesis by providing the necessary building block and rescues them from liver failure. They’re not rescued from death—the mice do end up with chronic cirrhosis of the liver—but they live longer.

The Primal eating plan includes many of the richest sources of cysteine and other glutathione-boosting foods, like whey protein and dietary flavonoids found in colorful fruits and vegetables.

5. MTHFR mutations

Forget any other diet. With its forests of broccoli, spinach, and asparagus and the acknowledgment of liver’s nutritional supremacy, the Primal way of eating can be exceedingly rich in folate. This makes it a great choice for MTHFR mutation carriers with an impaired ability to convert folic acid to folate. Folic acid, the most common supplemental form of the vitamin, can work for folks without a MTHFR mutation, but the form of folate found in food is the most helpful for people with a mutation.

What about veganism, Sisson? Isn’t that going to be ideal? Sure, vegans—at least the ones who actually eat vegetables—have the biggest folate intakes of anyone. But there’s another nutrient whose requirements are often elevated in MTHFR people: B12. And because B12 is only found in animal foods, vegans are almost guaranteed to be deficient without supplementation. So when it comes to correcting the common deficiencies inherent to MTHFR polymorphisms, going Primal helps.

There are other polymorphisms—too many to cover. But these were five that jumped out at me. What about you, folks? Got any questions or comments about these or other genetic variants that interact with your Primal lifestyle?

Thanks for reading.

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About the Author

Mark Sisson is the founder of Mark’s Daily Apple, godfather to the Primal food and lifestyle movement, and the New York Times bestselling author of The Keto Reset Diet. His latest book is Keto for Life, where he discusses how he combines the keto diet with a Primal lifestyle for optimal health and longevity. Mark is the author of numerous other books as well, including The Primal Blueprint, which was credited with turbocharging the growth of the primal/paleo movement back in 2009. After spending three decades researching and educating folks on why food is the key component to achieving and maintaining optimal wellness, Mark launched Primal Kitchen, a real-food company that creates Primal/paleo, keto, and Whole30-friendly kitchen staples.

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27 thoughts on “How Going Primal Can Help With 5 Common Genetic Mutations”

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    1. Interesting, it’s hard to find studies showing vegetarian diet increase those chronic diseases. I do know the PCRM is responsible for most of the vegan propaganda. I tried a vegan diet once and didn’t last two years. I ate vegetables and fruit too, I wasn’t a vegan that simply ate pasta an veggie junk food. I didn’t develop a serious disease but I may have been well on my way.
      I started to get extreme anxiety attacks and even had to go to the hospital a couple times. Felt really bad when they would hit, my blood pressure would shoot sky high and my heart rate would substantially rise. At any rate I wasn’t vegan for ethical reasons I just got scooped into think it was healthier, I later found primal blueprint and have been fine since. I’m thinking it was definitely a nutritional deficiency of some kind. Glad to see a actual study like that, thanks.

    2. Nice study, thanks. I tried a vegan diet once and it hurt me. My blood pressure would shoot up and my heart rate would increase, felt like an anxiety attack. Went primal and have been fine since, I’m now thinking it was a nutritional deficiency of some kind. You should look up the PCRM, they are at the center of all vegan propaganda.

      1. As far as I know I don’t have any of these genetic mutations. But I can say that after many (30+) years of being a pretty good vegetarian (few fake meats, etc) and a short time as a mostly raw vegan, I feel my absolute best going Primal/Paleo/whole foods. I don’t like to give myself a label, but can say that adding pastured meats and eggs, and eliminating grains and dairy, as well as consuming tons of fresh veggies, has me feeling better than ever! I really did it to clear up my skin, but saw the added benefits of more energy, no more crazy anxiety, and much better digestion.

    3. Sorry for the second post, my computer was lagging and I thought my comment was too long so I shortened it only to see both got loaded lol.

  1. Very interesting post! I’ve been looking into MTHFR mutations. My twins both had tongue and lip ties and I heard that could be related to these “midline” mutations. I kind of stopped researching it, because I was starting to feel guilty – like I didn’t get enough folate and caused it or something. I took prenatals with folate (not folic acid) and ate mostly primal throughout my pregnancy and preconception time period. I guess maybe there are times when you can’t prevent this stuff!

    1. Ashley, there ARE times when you can’t prevent things from happening. Don’t beat yourself up over something that in all probability had nothing to do with what you ate.

    2. There also isn’t (or wasn’t a few years ago) research that causally ties MTHFR mutations with “midline defects.” My son also had tongue and lip ties, DH and I both had lip ties. Theirs were laser-corrected, mine was “corrected” when I fell hard enough to chip a permanent tooth as a child. All three of us are heterozygous for MTHFR mutations. I’m just glad our son got lucky and didn’t get a bad allele from both of us.

      That being said, learning about my various defective methyl-cycle alleles has allowed me to supplement in ways that have noticeably improved my overall health and specifically my energy levels. I find that supplementing with L-5 methyltetrahydrofolate works better than supplementing with regular folate because it’s already in its usable form.

  2. The Primal Blueprint is a living document. Its foundation rests on pre-agricultural human evolution, but by remaining flexible and offering ample room for personalization, it acknowledges the fact that evolution has continued to occur.

    THIS! Especially that remaining flexible part. I have so many conversations with people who either think that Primal (or more usually Paleo) should ONLY contain foods that were available in ‘caveman days’, or who think it is akin to a religion and should be followed to the letter with no room for individual needs.

    We as a species continue to evolve and change. We as individuals change and ‘evolve’ throughout our lives. Both of those facts should inform our decisions regarding what we eat, how we move, and how we live.

    Since going Primarily Primal –that’s how I refer to 80/20–I look better, feel better, sleep a bit better, and most importantly I’m not on ANY medication, which for a 47 year old woman in the US is HUGE!

  3. Great article – not sure if this has been studied, but since going primal I have seen significant improvement in my cholesterol numbers, including and increase in HDL (good cholesterol) after trying for many years through exercise and medication to bring it up. Also significant decreases in LDL. I have a genetic form of high cholesterol (hyperlipidemia).

  4. Interesting on a couple of levels, I thought polymorphism was a term only we computer science types used. 🙂

  5. I did the 23andme DNA test. Do you happen to know which genes specifically which genes I can look for in my results that pertain to these things that you discuss in this article?

    1. I just read yesterday in site that 23andMe no longer analyzes the results, but you can input your data into GeneticGenie adn get a free pdf showing your methylation and detox results. This info is in the article “Is Your B-Complex Vitamin doing More Harm Than Good?”on page 7 under MTHFR and Methylation Issues.

      1. I did the 23andme before they got in trouble with the FDA. I have a lot of my genetic disposition type stuff (e.g., yeah, red hair, blue eyes, not lactose intolerant, don’t have the breast cancer genes…), but they’ve since been approved. Of course, now the test costs twice as much as what I paid. Thanks, FDA!

        Thanks for the article!

      2. No 23andme do not tell you pr no longer break down your % of health issues you MAY get from having certain mutations, but you can run your program of raw data in many different programs that will tell you what mutations you have and you can look up the mutations on the web, many diff gene dictionaries.. best of luck.

    2. You’ll need to download the “raw data” to do any of this (it’s a huge plain text file). Third parties to consider, that have come to my attention, include (alphabetical, not priority order):
      Enlis Genomics (I haven’t tried them yet)
      GeneticGenie (free, but MTHFR & “detox” only)
      MthfrSupport (I haven’t tried them yet)
      Promethease (US$5 or $10, deep, perhaps too deep)

      23andme does again provide some Carrier Reports, but thanks to FDA meddling, they aren’t the reports that most people are looking for, and they are watered down. The ancestry stuff is still valuable (with some risk of discovering that your close relatives aren’t, actually).

      The list of metabolism-related polymorphisms is a lot longer than the article here might imply. Some, such as those for ApoE and Lp(a), don’t necessarily have trivial dietary fixes.

      1. I downloaded my raw data on and then jumped to MTHFR. There are a page full of hits for that. Such as:
        LOC100506310, MTHFR 11846198 rs15854 A or G AA
        MTHFR 11850365 rs4846049 G or T GG

        etc. when I have time, I’ll delve deeper. Interesting stuff!

        1. Well I have don’t have these issues, so I guess I don’t have to worry about MTHFR: increase the risk for neural tube defects and vascular disease

  6. I’ve been wondering this for quite as while, can we turn off MTHFR via epigenetic? Or is it something set in stone? Thanks all!

    1. Your mthfr just may not be bothering you if your life style and environment have been good to you.. having some MTHFR mutations make it hard to detox so getting many vaccines can harm some of us.. no matter what the media says!!!! Lots to learn once you do get your raw data ran in a program, many free ones out there too, but to get a complete run of 50 plus pages best to go to MTHFR support program. best of luck

  7. I have two heterozygous MTHFR mutations that were causing high homocysteine levels, a risk factor for heart disease. The Primal/Paleo diet that I was eating (and still eat) had no effect. Now I take a daily supplement of bioavailable methylfolate and that has done the trick.

  8. What a great article Mark, with other great comments from the gallery, so to speak. It is interesting to note after practicing Functional Medicine for awhile that many of these Polymorphisms are actually being brought out by our SAD or Standard American Diet. Here’s what I mean, I see many B Vitamin deficiencies now and you would never expect that in our modern society, but remember, a high carbohydrate diet burns right through our Vitamin B stores. Also, Magnesium and Zinc deficiencies are more and more common as well as Sulfur. All of these are key in Energy metabolism, Detoxification, Neurotransmitter metabolism and maintaining the integrity of connective tissue as well as bone. It is also interesting to note that the body will ‘scavenge’ any mineral it needs for primary functions and will sacrifice secondary tissues, as in bone and cartilage. (The musculoskeletal system is not a primary system) I noticed when a patient is dealing with a recurring injury or poor joint health, they are invariably low in Sulfur, Zinc and Magnesium as well as B Vitamins. My point is all of these nutrients are well supplied by a Primal Diet. Quality meat, eggs, seeds and vegetables! This can overcome most SNPs in and of itself although I always recommend a quality Multi-Vitamin and Mineral supplement since food quality is always suspect today and we all have individual bodily demands. Keep up the great work!!

  9. I have the HLA B27 gene. It predisposes me to reactive arthritis, an autoimmune thing – kinda like rheumatoid arthritis, but was triggered in my case (and my brother’s) by food poisoning, and also only lasts for a few months (in my case, 8), rather than for your entire life (but it can recur multiple times).

    I have followed the primal way of eating for many years, now going to try the autoimmune version. I already avoid dairy and white potatoes, so hopefully it won’t be too much of a stretch.

    Many of these genetic variants have persisted in the population because they offer some advantage; e.g., “HLA-B27 is associated with low viral load and long-term nonprogression in HIV infection as well as spontaneous clearance of hepatitis C virus (HCV) infection. ” — from

  10. Hi Mark, Can you consider changing your multivitamin to have methyl folate instead of folic acid?

  11. Since you wrote this article, my husband found out he is Heterozygous for C677T and A1298c and my daughter is homozygous for C677T. Did you have a particular website or person you got your information from regarding the MTHFR gene mutation?
    I have not been tested but obviously passed the C677T gene to my daughter. I don’t think I am so much affected since I do Paleo and take supplements.

  12. HI Mark, thanks for your great article on genetic polymorphisms. Going primal has been key to up-regulating my health and dealing with the challenges of being homozygous for several SNPs including MTHFR and COMT. What are your ideas around supplementing with SAMe for those with difficulty clearing catecholamines, when already leading a devoted Primal lifestyle?
    Thanks for your stellar work!!
    Live Awesome,
    Best always,