The MTHFR Gene

In today’s world of hyper-targeted health advice and genetic testing, the MTHFR gene has been framed as a major culprit behind countless chronic conditions from fatigue and anxiety to infertility and autism. But this view is overly simplistic and often misleading. The truth is far more nuanced. Our genes are not fixed determinants of disease; they are responsive to the environments we live in, especially light, magnetism, and mitochondrial health. As Dr. Douglas Wallace, pioneer of mitochondrial genetics, emphasizes over 80% of chronic disease originates not in our nuclear DNA, but in our mitochondrial DNA. In this article, we’ll explore the real science behind MTHFR mutations, methylation, and vitamin B12 and folate metabolism, what actually matters, how to test effectively, how to correct dysfunction, and why your environment, especially light exposure, may be more important than any gene variant. You’ll also discover how evolutionary biology, circadian medicine, and decentralized approaches to health give us powerful tools to override genetic limitations, often without needing supplements at all.

The Common misunderstanding of MTHFR

Let’s begin with the fact that genes generally do not control your chronic disease outcome, your metabolism and mitochondrial genome does. This was put to us by Dr. Douglas Wallace of the Children’s Hospital of Philadelphia. He states that 80%-90% of all chronic diseases are mitochondrial DNA based rather than nuclear DNA based. SO, the real reason why centralized medicine is kicking up a fuss about MTHRF is because they don’t understand metabolism and the mitochondrial genome.

Introduction: If someone has a genetic mutation on their MTHFR genes this results in reduced methylation.

Having an MTHFR mutation is very common. 20% of the genetically tested population in the USA have this allele and live perfectly normal lives. So, if you do have this allele, it’s not necessary to assume that you need to take extensive methylated folate or vitamin B12 for the rest of your life. Sometimes people do benefit from this but not enough to warrant it as a certainty. Therefore, you could spend all this time testing and spending money on expensive methylated folate and it’s possible that it does absolutely no benefit. So how do you know?

The best test for this is not to test the gene, but to measure Vitamin B12 levels, folate levels and then homocysteine and methylmalonic acid. If all of these are normal within range, you do not have a problem with 1 carbon metabolism weather you have the MTHRF genetic variant or not. On the other hand, if you have elevated homocysteine and methylmalonic acid, then it does strongly indicate that you do have a problem and in fact this may indicate you have a problem with methylation whether you have the gene mutation or not, and you might benefit from more thorough workup clinically and future supplementation. In this case before rushing to supplement there may be other things going on such as an autoimmune condition called ‘intrinsic factor deficiency’, which stops the absorption of Vitamin B12. The clinician will then decide if you need B12 injections, methylated folate, or some need to just supplement vitamin B12. So, the key is figure out what the problem is and then find an expert who knows how to address it.

Blood Tests which are better indicators of methylation issues:

• Methylmalonic Acid

• Homocysteine

• Vitamin B12

• Folate

Folate, MTHFR and Vitamin B12: Why is B12 so important?

Vitamin B12, crucial for nerve function, red blood cell synthesis, and DNA production, plays a key role in cellular regeneration by being a limiting factor for methylation. Deficiency in B12 is linked to inflammation, oxidative stress, and various symptoms, and recent research suggests its potential in tissue repair, including conditions like ulcerative colitis. Additionally, B12 supplementation has shown promise in treating radiodermatitis and may play a role in addressing non-alcoholic steatohepatitis (NASH). B vitamins, including B12, are essential for a healthy immune system, and their supplementation is proposed as an adjunct in managing COVID-19 symptoms. Advancing age and certain health conditions may increase the need for B12 supplementation, and various sources, including animal foods, nutritional yeast, sublingual sprays, or injections, are recommended to maintain optimal B12 levels.

Folate and vitamin B12 are the most important cofactors working with enzymes in the methylation cycle. The methylation cycles begin with folate. Folate is converted into its active form (5-methyltetrahydrofolate) through the folate cycle, and MTHFR is directly responsible for the creation of folates active form. MTHFR deficiencies lead to a shortage of the active form of folate within the body and negatively impacts the conversion of homocysteine to methionine. Low active folate levels can lead to a buildup of homocysteine and lack of methionine in the body and can lead to several health problems.

High homocysteine levels can also be caused by low vitamin B12 levels because vitamin B12 is the cofactor needed by the enzyme responsible for converting homocysteine to methionine. Without adequate vitamin B12 levels a build of homocysteine begins occurring and can be made even worse in combination with harmful MTHFR mutations.

A healthy vitamin B12 level is between 500-800 µmol. MTHFR SNP’s can be present, and labs can still show up normal levels of B12. The answer is to measure homocysteine and metabolomics acid instead. Always Check mutations in C677T and A129C to determine how much folate you need to eat or supplement.

• Hydroxocobalamin

• Hydroxocobalamin is more bioavailable than cyanocobalamin and does not require extra reactions occurring in the liver before the body can use it. For this reason, hydroxocobalamin is recommended for people with MTHFR mutations, known methylation issues, and is the best supplement for anyone living with low blood pressure. Hydroxocobalamin should be taken as a preventative measure against complications that arise from vitamin b12 deficiencies, high homocysteine levels, and methylation issues.

• Adenosylcobalamin

• Adenosylcobalamin is great to take alongside hydroxocobalamin to obtain the full spectrum of benefits that can be derived from vitamin B12 supplementation. Adenosylcobalamin is the form of vitamin B12 associated most closely with improving energy levels in people who are deficient in vitamin B12. 

• Methylcobalamin

• Methylcobalamin is another form of vitamin B12 that does not require extra processing in the liver, making it a great alternative to taking cyanocobalamin. Methylcobalamin is often taken to improve cardiovascular problems, cognitive impairments, behavioural issues associated with autism, and circadian rhythm disturbances.

MTHFR mutations impact the body’s ability to use vitamin B12. This happens because certain MTHFR mutations (C667T and A129C) lower the amount of active folate being produced in the body, and the use of vitamin B12 requires the active form of folate. If you don’t want to override these methylation issues by moving closer to the equator you can increase your folate intake through supplementation and eating more folate containing foods. But note: The former is the best solution with the latter being the next best.

MTHFR mutations and vitamin B12 deficiencies commonly work together to produce elevated homocysteine levels which can damage the nervous system, leading to cognitive impairment, and increased risk of Alzheimer’s Disease and dementia. Elevated homocysteine levels are also associated with increased risk for cardiovascular issues such as strokes and heart attacks.

Symptoms of vitamin B12 deficiency include fatigue, irritability, anxiety, low energy, depression, forgetfulness, constipation, new food sensitivities, hot and cold flashes, sore muscles, pale skin, numbness, tingling, and dermatitis.

MTHFR: Helps You Use Folic Acid, an Essential B Vitamin for Health

Folate is a B vitamin that must be activated (methylated) to be used by our bodies. This activation is done by an enzyme (protein) named MTHFR (methylenetetrahydrofolate reductase). All of us have this enzyme. If MTHFR is working properly, it activates 100% of folic acid. This is the dominant form. Half of all people have a combination of MTHFR that does not completely activate folic acid. These two forms are called heterozygous and homozygous. If you are heterozygous, you activate folate at 60-70% efficiency. If you are homozygous, you only activate 10% of folic acid. There are two main types of MTHFR that we check for, MTHFR C677T and MTHFR A1298C.

So, what if you cannot activate folic acid well and your body cannot use the folic acid you get in your diet or through supplements? We are now learning that many medical conditions are helped by adding activated Methylfolate.

Conditions helped:

1. Depression, Anxiety, ADD, Autism and Dementia: Methylfolate helps make up three of our four main neurotransmitters (dopamine, serotonin, and norepinephrine). It also helps with peripheral neuropathy, even in people with diabetes.

2. Peripheral Vascular Disease: Methylfolate helps in nitric oxide formation which relaxes blood vessels.

3. Uric Acid Metabolism (Gout): Methylfolate is connected to the normal metabolism of uric acid. (rising homocysteine = increase uric acid = lower nitric oxide = rising heteroplasmy = lower redox/energy production)

4. Detoxifications: Methylfolate can eventually influence downstream formation of compounds that help clear toxins.

5. Lowering Homocysteine: Methylfolate is required to metabolize and decrease homocysteine levels.

6. DNA Repair (decreases cancer risk): Methylfolate helps provide methyl groups for DNA repair and eventually decreases the risk of abnormal DNA and cancer.
   
   

Miscarriage Frequency: Methylfolate is integral for maintaining pregnancy.

Neural Tube Defect in Newborns: Methylfolate can help prevent these defects by adequate B12 and Methylfolate levels.

Post miscarriage to bring periods back into balance = Papaya, Pennyroyal tea, evening primrose oil = brings on a period and uterine contractions.

MTHFR can be checked by a simple blood sample if you have any of the above conditions, or you have a medical/family history that includes any of these conditions. There are other B vitamins that are also an important key part of metabolism called methylation. These B vitamins include, methyl B12 and activated B6 or Pyridoxine 5 Phosphate.

The Evolutionary Biophysics interpretation of the MTHFR Gene

Our SNP’s become a problem if our environment is chronically toxic, we are living in a circadian mismatch or if our mitochondria are sick and thus cannot thrive. Unfortunately, many people today are living in locations in which their mtDNA is not designed to live which will signal to the genome within the nucleus to express our DNA template containing mutations which can lead to ‘genetically predisposed diseases’; but only if the environment is poor. If this happens, our mutated SNPs involved in methylation and Regulation of folate, sulfate, methionine, biopterin or histamine cycles and pathways become problematic; leading to the wide variety of diseases we see today. This can be almost certainly avoided if you recognise the mismatch in the environment, remove the environmental stressor(s), biohack the environment, fix your decision-making process (beliefs, conditioning and choices) or move to a more optimal environment. You can overcome any MTHFR Single Nucleotide Polymorphism (SNP) with lifestyle and dietary adjustments/choices.

All SNPs are a result of a change in the local zip code to optimize mitochondrial heteroplasmy. Extreme equatorial sunlight is well known to reduce folate in tissues. Normally this will reduce the amount of RBCs in equatorial humans because we need folate to maintain them. RBCs contain both porphyrins and haemoglobin. Both proteins absorb UV light and Infrared light. When the body absorbs a great deal of UV light delivered from the full spectrum of sunlight, venous oxygen saturation rises, so not as much oxygen carrying capacity from haemoglobin is needed. Oxygen levels are ideal temperature sensors for a quantum biologist. More sunlight = More Oxygen so you don’t need as many RBCs.

The environment dictates how mitochondria work and SNPs are fine tuners for the local environment you are inhabiting. Today, humans go to places their genome is not adapted too. If you have a SNP, you likely are one of those people. So, as we migrated away from environments in which we evolved out genome developed mutations over many generations. However, these days we can move across the globe to a completely altered environment to what we are used to, and our genome has relatively 0 time to adapt to this new light, water and magnetic environment. Not to mention the radical introduction of artificial light, magnetism and chemicals in water which have been introduced to all our environments in evolutionary the blink of an eye with our biology having no time to adapt.

SNPs like the MTHFR gene mutations only cause disease when we live where we should not be because SNP's link to our maternal mitochondrial DNA lineage. Note, the tropics are where humans evolved, and we developed gene mutation s when we migrated away from the tropics. So, what does this tell you about reversing a perceived MTHFR problem? It might be time to make a plan to override your DNA mutations if you are diagnosed with a chronic disease above the 23-5 North latitude or below the 23.5-degree South latitude? Nature’s message could not be clearer.

The most important methylation genes:

1. MTHRF1298C

1. A1298C: Arose this SNP is an epigenetic modification for the environment your mitochondria come from. All mitochondrial DNA comes from mom. Where mom comes from is coded for in your % heteroplasmy.

2. Being in a low quantum yield environment and thus, lower intake of folic acid and less exposure to sunlight increase the risk of diseases arising from these surviving prehistoric polymorphisms. A1298C a C is replacing the normal A at location 1298 on the MTHFR gene. This gene encodes the enzyme methyl-enetetrahydrofolate reductase. Reduces 5-10 methylene THF to,5 methyl-THF for methionine biosynthesis.

3. RBCs contain both porphyrins and haemoglobin. Both proteins absorb UV light. When you absorb a lot of UV light you also raise venous oxygen saturation, so you do not need as much oxygen carrying capacity from haemoglobin. In this way the homozygous defect (-/-) of A1298C is a key "fuse switch" for an environment who has a lot of UV light and a lot of oxygen. This local environment would be close to the equator and at sea level next to a large amount of plants who provide an excellent photosynthetic yield. This ideal environment was found in human history from the East African rift zone and the exodus out of Africa to the Mediterranean basin.

4. During human evolution, high dietary levels of folic acid and regular exposure to sunlight (catalysing the production of vitamin D in our skin) likely saturated genetic and biochemical pathways and compensated for any deleterious effect of these polymorphisms.

5. Folic Acid Metabolism

6. The aim is to lower folic acid and increase venous O2 from strong sunlight. If you live in a strong solar environment, you have a lot of venous oxygen. This regulates the venous O2 by blocking folic acid.

7. This mutation occurred in area with abundant sunlight to regulate the venous O2 in the system using folic acid metabolism.

8. -/- = Equatorial origins. This evolved in the Mediterranean where dietary folic acid was low. Sunlight breaks down folic acid naturally. Therefore, this non-mutated require sunlight to increase venous O2 to remain optimal.

9. +/+ = Not equatorial. The environment away from the equator required a diet high in folic acid and therefore a requirement for the body to methylate this folic acid to increase oxygen tensions in the blood and keep it at optimal levels.

10. +/- = Heterozygous, requires sun but doesn’t have to be in strong solar all the time, unless VDR’s dictate doing so.

11. If you have a problem with homocysteine or methylation, you may need a folic acid supplement such as methyl folate and go in the sun.

12. If you cannot activate/methylate folic acid, this decreases venous oxygen. If you can methylate folic acid, this increases oxygen tensions. Depending on the methylation of folic acid, the venous oxygen goes up or down.

13. Methylation of folic acid = Increased venous oxygen tensions.

2. MTHRF C677T

1. It is currently theorized that the C677T impacts the methionine cycle more significantly while the A1298 impacts the BH4 cycle. If this theory is correct, those with C677 would need more support in reducing Homocysteine while A1298C may need more support with creating BH4 and preventing NOS uncoupling. Nonetheless, there is usually a need for folate with these variants. However, to be sure, checking the urine organic acids can confirm, and can also be used as a measure when adequate levels are reached when supplementing.

2. Remember you don’t need to supplement your way out of this gene mutation; you can ground and connect to strong sunlight as a first option or eat a keto/paleo seafood-based diet and experience cold exposure if living at a high latitude as a backup option with no need for supplements whatsoever.

3. +/+ = Non-equatorial environmental evolution = Nutrition, Cold, Grounding

4. +/- = 25-45 latitude over time created this 1 mutation so you can use a combination of cold/food and sunlight to overcome this 1 mutation.

5. -/- = Equatorial environmental evolution = Sunlight

With 1 heterozygous MTHFR variant, there is a possible need for folate, methylation, and possibly circulation support. Folate production may be about 70%. However, doing the Genova Urine Organic Acid test will verify if there is a need for folate. In some instances, people compensate OK.

With 6 folate production variants, folate supplementation (Methylfolate) or increased intake in diet may be extremely important. Otherwise just move into the tropics to allow the sun to correctly methylate genes. YES, you read that right. Methylation and acetylation generally take place as they should when you are connected to a natural environment and have access to strong full spectrum sunlight. The only exception to this are chimeras (people with heavily mutated vitamin D receptors with dozens of generations originating from very high latitudes like Iceland or Finland, this can include those with like people with red hair and pale white Fitzpatrick type 1 skin and these can use cold, grounding and a good keto/paleo seasonal seafood-based diet.

Methylation

Methylation is not just one specific enzymatic reaction. There are hundreds of methylation reactions in all cells of the body. Methylation is simply the adding or removal of the methyl group (CH3) to a compound or other moiety. When some compounds receive a methyl group, this begins a reaction such as turning a gene on or activating an enzyme. When the methyl group is donated or removed, the reaction stops, or a gene or enzyme is turned deactivated. Some key methylation reactions would be:

1. Detoxification of dietary phenols from fruits

2. Methyl transfers turn on production of serotonin and melatonin

3. DNA methylation altering epigenetic signalling.

4. Cancer cells are characterized by a generalized disruption of the DNA methylation pattern involving an overall decrease in the level of 5-methylcytosine together with regional hypermethylation of particular CpG (cytosine-phosphate-guanine sites) islands.

1. The extent of both DNA hypomethylation and hypermethylation in the tumour cell is likely to reflect distinctive biological and clinical features of the cancer in question.

2. Hypermethylation of the brainstem can impair proton tunnelling in the trigeminal motor nucleus, disrupting function in nearby regions and contributing to TMJ dysfunction and dental issues like bruxism. This nucleus, which sits deep in the brainstem, governs motor control for the jaw and mouth, and when methylation is excessive, it can alter signalling pathways critical for jaw mechanics.

1. Photobiomodulation (PBM) through the eyes—open or closed—can help demethylate the brainstem, improving neural communication. Cooling the carotid arteries, upper neck, and back of the head with 1-gallon zip lock bags during PBM amplifies the effect.

2. Do this for 20 minutes, 3–4 times per day.

3. Apply infrared or red light directly to the TMJ area.

4. Use for 20 minutes, 2 times per day.

5. Medical option: A polyethylene dental tray (night guard) can help prevent teeth from coming together and reduce further stress on the TMJ.

6. Bruxism (chronic jaw clenching or teeth grinding) often stems from these deeper neurological and biophysical imbalances, not just stress or bite alignment.

Not all people or cancers have the same methylation rates. Humans can be hyper methylators or hypomethylates. Some genetic diseases even show a pattern of hyper or hypo methylation, such as autism spectrum disorder and Cancer. Neoplasia is characterized by “methylation imbalance” where genome-wide hypomethylation is accompanied by localized hypermethylation and an increase in expression of DNA methyltransferase.

Research in humans has shown that repeated high-level activation of the body’s stress system, especially in early childhood, can alter methylation processes and lead to changes in the chemistry of the individual’s DNA. The chemical changes can disable genes and prevent the brain from properly regulating its response to any type of biologic stress. Researchers and clinicians have drawn a link between this neurochemical dysregulation and the development of chronic health problems such as depression, obesity, diabetes, hypertension, and coronary artery disease as the child ages.

Hypermethylation

• This is a pro-growth state Hydrogen bonding networks in water. Methyl groups have 3 protons which unfold the information in DNA.

• This is an indication that your environment is bad, and your nuclear genetics are in control and expression of these including disease states occurs. The more your genetics are in control, the more methylated your genome and brain stem are.

Hypomethylation

• No growth status. Where the body is not unfolding DNA signals correctly.

• It is more advantageous to be hypomethylated when you are in an unwell state. This will result in slow growth of cancer and allow you to live longer.

• Autism Spectrum Disorder (ASD) are usually hypomethylates.

Geeks Detail about Methylation (Proteins and Epigenetics)

DNA methylation in vertebrates typically occurs at CpG sites. CpG sites are cytosine-phosphate-guanine sites, where a cytosine is directly followed by a guanine in the DNA sequence. This methylation results in the conversion of the cytosine to 5-methylcytosine. The formation of Me-CpG is catalysed by the enzyme DNA methyltransferase. Human DNA has about 80 of CpG sites methylated, but there are certain areas, known as CpG islands, that are GC-rich (made up of about 65 CG residues), wherein none are methylated. These are associated with the promoters of 56 mammalian genes, including all ubiquitously expressed genes. One to two percent of the human genome are CpG clusters, and there is an inverse relationship between CpG methylation and transcriptional activity.

Protein methylation typically takes place on arginine or lysine amino acid residues in the protein sequence. Arginine can be methylated once or twice, with either both methyl groups on one terminal nitrogen or one on both nitrogens by peptidyl arginine methyltransferases (PRMTs).

• Lysine can be methylated once, twice, or three times by lysine methyltransferases. Protein methylation has been most studied in the histones. Histones directly control DNA/RNA binding sites for control of the epigenetic switches or for gene translation. The transfer of methyl groups from S-adenosyl methionine to histones is catalysed by enzymes known as histone methyltransferases. Histones that are methylated on certain residues can act epigenetically to repress or activate gene expression. Protein methylation is an example of one type of post-translational modification.

Appendix 1: Sex Hormones and Methylation

Figure 1: Nutritional Influences on Estrogen Metabolism
This complex biochemical pathway map outlines how various nutrients and hormones including cholesterol, pregnenolone, DHEA, progesterone, and testosterone feed into estrogen metabolism, with a specific focus on the conversion and detoxification of estrogenic compounds. It highlights the critical role of methylation (via SAM/SAH cycles), hydroxylation, and conjugation in modulating the effects of endogenous estrogens and xenobiotic estrogen mimics (xenoestrogens). Key enzymes such as COMT, CYP450 variants, and glucuronosyltransferases are regulated by nutritional inputs including B vitamins, magnesium, and antioxidants. The diagram also shows how estrogens interact with receptor sites in various tissues, influencing gene expression and physiological effects, and underlines how imbalances in detoxification pathways can lead to carcinogenic estrogen metabolites (e.g., 4-OH and 16α-OH estrogens).

Figure 2: MTHFR Intervention and the Folate-Methylation Cycle
This simplified diagram presents the one-carbon methylation cycle with a focus on the MTHFR (methylenetetrahydrofolate reductase) enzyme and its role in converting dietary folic acid into 5-methyl-THF the bioactive form of folate required for methylation. The figure highlights cofactors such as vitamin B2 (riboflavin), B3 (niacin), B6 (pyridoxine), B12 (cobalamin), and TMG (trimethylglycine) that support this pathway. Key intermediates such as THF, SAM, SAH, homocysteine, and methionine are shown in sequence, emphasizing the importance of proper enzyme function and nutrient status to prevent homocysteine accumulation and support DNA synthesis, detoxification, neurotransmitter production, and epigenetic gene regulation.

Appendix 2: Mobile Phone Hazards: The Risks of Modern Wireless Technology

Myelination and Brain Development

• nnEMF Impact: Non-native electromagnetic fields (nnEMF) reduce myelination in babies, children, and adolescents, hypermethylated genes, and lower Vitamin C levels.

• Radiation Penetration: Cell phone radiation penetrates the blood-brain barrier, affecting myelination and slowing brain maturation. Vitamin B12 and folate, essential for brain development, are best sourced from liver and seafood.
  
  

Safety Standards and Usage

• Outdated Standards: Safety standards did not anticipate extensive phone use by young children or prolonged close contact with devices. 3G radiation was shown to cause cancer in rats in the National Toxicology Program (NTP) 2018 study. What about 4G and 5G?

• Rapid Technological Advancements: The rapid growth of technology and consumer demand have outpaced safety regulations. Modern devices and increased data usage contribute to faster onset of chronic illnesses, now appearing in younger individuals.
  
  

High-Risk Situations

• Travel: Phones may increase power output to connect to new towers, especially in vehicles.

• Low Reception Areas: Phones work harder to connect, raising power output and radiation levels.
  
  

5G Technology

• Infrastructure: 5G requires numerous antennas per city block, leading to significant environmental changes, including tree removal for better signal reception.

• Fibre Optics: Essential for 5G, fibre optic cables support the high data transmission needs.

• Health Risks: 5G frequencies, particularly 60GHz, can affect oxygen binding in haemoglobin, impacting overall health.
  
  

Mitigation and Solutions

• Optimal Environments: Living in wooded areas, underground, or in shielded homes can reduce exposure.

• Health Practices: Grounding, exposure to natural light, and avoiding metal objects can mitigate nnEMF effects.
  
  

Biological Impact

• Cellular Health: nnEMF affects cell membranes and lipid rafts, requiring regular DHA replacement. It also disrupts calcium e-flux and creates reactive oxygen species (ROS). It destroys melanopsin photoreceptors disregualting circadian rhythms and heme proteins like hemaglobin in blood and CYP enzymes so sex steroid homrones cannot be made very well in the mitochondria. It also causes hypoxia as a result of these destroyed heme proteins slowing electron transport chain (ETC) speeds in the mitochondiria and leading to a Warburg shift in metabolism away frm using the TCA cycle and towards glycolysis.

• Blood Glucose and AMPK Pathways: Exposure to 5G can increase blood glucose and activate AMPK pathways, influencing metabolism and health.
  
  

Environmental and Biological Observations

• Magnetic Fields: Earth's magnetic field is stronger at night, aiding regeneration processes like autophagy.

• Population Density: Higher population density correlates with increased technology use, leading to higher Blood Urea Nitrogen (BUN) levels and impaired metabolic cycles.
  
  

Key Takeaways

• Observation: Being aware of environmental changes, such as new antenna installations or tree removal, can indicate increasing nnEMF exposure.

• Testing: Monitoring BUN/creatinine levels can help assess environmental quality and its impact on health.
  
  

By understanding and mitigating the effects of nnEMF, particularly from modern wireless technology, individuals can protect their health and enhance biological resilience.

Appendix 3: Folate Metabolism and Genetic Variations

Folic acid undergoes initial reduction by the enzyme dihydrofolate reductase (DHFR) to become dihydrofolate, and subsequently tetrahydrofolate (THF), before entering the one-carbon metabolism pathway. In humans, DHFR activity is relatively slow and can become saturated at higher folic acid intakes, leading to unmetabolized folic acid circulating in the bloodstream. This unmetabolized folic acid has been associated with potential adverse effects, including interference with natural folate metabolism and immune function.

A common genetic variation, the MTHFR C677T polymorphism, affects the enzyme methylenetetrahydrofolate reductase (MTHFR), which converts 5,10-methylene-THF to 5-methyl-THF, the active form used in homocysteine demethylation to methionine. Individuals with this polymorphism have reduced MTHFR activity, leading to elevated homocysteine levels and potential health risks.

Health Implications of Folic Acid Supplementation

Neural Tube Defects

Folic acid supplementation before conception and during early pregnancy has been proven to reduce the risk of neural tube defects (NTDs) in offspring. This has led to public health policies mandating folic acid fortification in certain food products.

Autism Spectrum Disorders

Research on the relationship between maternal folic acid intake and autism spectrum disorders (ASD) in children has yielded mixed results. Some studies suggest that appropriate folic acid supplementation may reduce the risk of ASD, while others indicate that excessive folic acid levels could be associated with increased risk. These conflicting findings underscore the need for further research to determine optimal folic acid intake levels during pregnancy.

Metabolic Effects

High folic acid intake, especially in the presence of low vitamin B12 levels, has been linked to insulin resistance and metabolic disturbances in offspring. This highlights the importance of balanced nutrient intake during pregnancy to prevent long-term health issues in children.

Immune Function

Excessive folic acid supplementation may impact immune function. Some studies have observed that high folic acid intake can alter immune responses, potentially leading to increased susceptibility to infections or autoimmune conditions.

Environmental and Evolutionary Considerations

Folate is sensitive to ultraviolet (UV) radiation, which can degrade folate levels in the body. This has evolutionary implications, as higher melanin levels in the skin protect against folate degradation in regions with intense sunlight. Conversely, in areas with lower UV exposure, lighter skin facilitates vitamin D synthesis. These adaptations reflect a balance between protecting folate levels and ensuring adequate vitamin D production.

Some Suggestions

• Natural Sources: Prioritize obtaining folate from natural food sources that are really high in folate such as leafy greens, and organ meats.

• Supplementation: For individuals with increased folate needs, such as pregnant women, supplementation should be approached with caution, ensuring doses are within recommended limits to avoid potential adverse effects.

• Balanced Nutrient Intake: Maintain adequate levels of vitamin B12 to support proper folate metabolism and prevent metabolic complications.

• Genetic Testing: Consider genetic testing if you do not live a healthy lifestyle or eat plant based for MTHFR polymorphisms to personalize folate intake recommendations.

References

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2. Troen AM, et al. Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women. The American Journal of Clinical Nutrition. 2006;83(4):835-841. Link

3. Smith AD, et al. Is folic acid good for everyone? The American Journal of Clinical Nutrition. 2008;87(3):517-533. Link

4. Valencia-Vera E, et al. Association between seasonal serum folate levels and ultraviolet radiation. Journal of Photochemistry and Photobiology B: Biology. 2018;190:66-71. Link

5. Berry RJ, et al. Maternal prenatal folic acid supplementation and risk for autism spectrum disorders. Centers for Disease Control and Prevention. Link

6. Surén P, et al. Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children. JAMA. 2013;309(6):570-577. Link

7. Yajnik CS, et al. Maternal homocysteine concentrations and offspring birthweight and insulin resistance. Diabetologia. 2008;51(1):29-38. Link

8. Fatahi S, et al. Effects of folic acid supplementation on inflammatory markers: a systematic review and meta-analysis of randomized controlled trials. Journal of Nutrition. 2021;151(1):1-10. Link

9. Meador KJ, et al. Folic acid supplementation and child development: a randomized controlled trial. New York Post. 2025. Link

10. Fallin MD, et al. Elevated maternal folate levels and risk of autism spectrum disorders. Time Magazine. 2016. Link