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What is Methylation and Why Is It Important?

Methylation: What is it and Why It’s So Important For Your Health

You’ve probably heard of methylation, and how important it is for your health. But you may not know how powerful it really is—even though it is an amazingly simple biochemical action that takes place in every cell of your body. Put simply, methylation is the addition of a methyl group to a molecule. Demethylation is the opposite—the removal of a methyl group from a molecule. A methyl group is made of one carbon and three hydrogen atoms (CH3). That’s it!

Methylation is a basic cellular switch—a switch that keeps turning off and on billions of times a day and allows the biochemical gears of your body to turn smoothly.

You might think of methylation as the switch that changes everything.

Methylation helps regulate your response to stress, your brain chemistry, immune function, the ability to keep viruses in check (including latent viruses we harbor but suppress), the activity and expression of your genes, and your capacity to detoxify.[1] In the liver, methylating a toxin will transform it to a safer form that can be more easily processed and excreted.[2] Methylation also regulates the responses of genes to environmental factors and to diet. As you age, your ability to methylate can change.[3]

Methylation is the switch the body uses to help direct a baby’s development in the womb, so that the organs and tissue form properly and at the right time.[4] Methylation is so important that its actions in the womb or early life can lead to permanent, lifelong changes, changes that can even be passed down to the next generation. This was conclusively shown in a famous study of mice, where simply feeding mama mice vitamins important for methylation during pregnancy turned their usually fat, yellow-furred offspring into lean mice with brown fur. The vitamins—B12, folate, choline and betaine—switched off an important gene by adding methyl groups to it.[5] These methylation changes can be inherited by subsequent generations.

That’s not all. Methylation defects due to deficiencies of the B vitamin folate in papa mice decreases sperm counts and increases mortality in offspring.[6] And in humans, the impact of diet in mothers is equally potent—a study of babies who were conceived in the rainy or the dry season in rural Gambia in Africa, found methylation patterns were altered accordingly. The rainy season was linked to better nutrition, with higher levels of a methyl donor called SAMe (S-adenosyl-L-methionine), and higher concentration of methyl donors like folate, betaine and methionine. Rainy season moms also consumed higher levels of vitamins that assist methylation, such as B2 and B6. The rainy-season babies were born with naturally higher methylation activity that likely will influence many aspects of their health lifelong.[7] They had an advantage over the children conceived in the dry season. That’s pretty profound.

Methylation is the fundamental language of life. Through methylation, your internal and external environment can talk to each other.

When methylation is slowed (hypomethylation), we can have trouble suppressing viruses, processing toxins in the liver, controlling inflammation and oxidation, and generating sufficient neurotransmitters in the brain.

It’s important, then, that we have optimal methylation.


Why Balancing Methylation Is So Important for Detoxification

You’ve read a lot about the mother of all antioxidants, glutathione. It is our most potent endogenous antioxidant, and the glutathione supersystem (which includes enzymes and cofactors) is critical for binding to and neutralizing innumerable toxins generated in everyday life. But you may not know that every moment of every day, your body comes to a fork in a metabolic road and has to decide: Should I activate methylation, or should I make some more glutathione? Which one is more important right now, right this moment?

Here’s how it works. Methylation and glutathione are tightly linked and move in lockstep.

There is a critical fork in the road where cells get to make an important decision, again and again and again. That is: should I make more glutathione, or should I support more methylation? Optimal balance between these two choices is the bedrock of good health. Though there are many enzymes and cofactors that contribute to both methylation and the synthesis of glutathione, a short and simple version of this decision goes like this: Let’s say we need to methylate a gene or perhaps a latent virus to quiet it down. A methyl donor called methionine can give up its methyl group, and accomplish this for us. But then we are left with the metabolite of methionine, homocysteine. Some homocysteine is okay, but too much has been linked to cardiovascular disease.[12] And now the body has to decide, should homocysteine be methylated, and be transformed back into methionine, or should homocysteine be converted into cysteine, which is a building block for glutathione? Glutathione or methylation? This fundamental decision is made again and again by the body. If we make too little glutathione we end up with oxidative stress. But if we don’t methylate enough, many genes and viruses will not be properly regulated. A balance of both is the key to optimal health.

The B Vitamins That Matter for Methylation

Many B vitamins and methyl donors contribute to both methylation and detoxification, but at the center of the wheel spokes are two B vitamins. These are the active, methylated form of vitamin B12 (methyl B12) and the active, methylated form of folate (methylfolate). If we don’t make enough of these active forms, we will not be able to smoothly and fluidly shift between methylation and glutathione production. Vitamin B12 is found in abundance in animal-based foods like meat and eggs[13], and is extracted from our food and chaperoned into cells, where it is processed into the two active forms. (For those on vegan diets, or with gene variations that render this process less optimal, supplementation with active forms can help.)

Methyl B 12 is constantly recycled. It donates a methyl group to homocysteine, which then turns homocysteine back into methionine. Once B12 has lost its methyl group, it needs to acquire a new one. Methylfolate is the sole molecule than can donate a methyl group to B12. Once it does that, the rest of the folate can go support many other actions and reactions in the body that need folate.[14]

Methyl B12 helps your body synthesize new DNA and RNA as well as new red blood cells and it is important for optimal neurological function, mood and memory, and bone and heart health.[15]

Which B Vitamins Are Important If You’re A Slow Methylator?

One of the most famous gene variations discussed when addressing issues of methylation, is a variant in the MTHFR (methylenetetrahydrofolate reductase) gene, which can lead to less than ideal methylation activity.[16],[17]  About 30 to 40 percent of the American population may have a mutation at gene position C677T. Another common gene position is A1298C. One can even harbor variants of both genes, though that’s uncommon. These mutations can lead to a greater chance of high homocysteine, as well other issues such as migraines or miscarriages.[18]

Vitamin B2 is especially significant for those with less than optimal MTHFR variants, since MTHFR is a vitamin B-2 containing enzyme and is thus dependent on adequate B2 levels for full activity.[19] B2 deficiency can also lead to lower levels of reduced glutathione (GSH).[20] Supplementing with generous amounts of B2 may offer support to MTHFR. Also for those with variants in this gene, betaine, or trimethylglycine (TMG), offers a safe source of methyl donors that supports methylation without driving it too fast or too hard.

Both vitamin B6, and folinic acid—an intermediate, active form of folate—are also important for optimal methylation, especially in those with MTHFR issues.[21],[22] Vitamin B6 helps the body convert homocysteine to cysteine.

What Common Conditions Can Be Impacted by Methylation?

Abnormalities in methylation have been found in a whole host of conditions, from Alzheimer’s disease to cardiovascular disease to autoimmune illnesses such as rheumatoid arthritis and lupus. [23],[24] Poor methylation can also affect neurotransmitters, leading to mood changes and depression. Both folate and vitamin B12 deficiency can lead to depression and dementia, likely through a defect in methylation processes.[25],[26] In fact, methyl donor S-adenosylmethionine (SAMe) has known antidepressant properties.[27] Proper DNA methylation has been shown to help suppress cancer and tumor growth.[28]

There is an intriguing connection between histamine—the neurotransmitter implicated in allergies and in mast cell disorders—and methylation. Histamine is important for dilating blood vessels, sneezing, nasal congestion, sexual function and erection, and even the secretion of hydrochloric acid in the stomach. Histamine is implicated in allergic responses, as it is released by mast cells in response to allergens, leading to the familiar symptoms of sneezing, wheezing, itchy eyes, rashes and more. Proper release and levels of histamine require adequate methylation. There are variations among individuals in the genes that regulate methylation of histamine.[29],[30] In addition, new research suggests that folate metabolism may also be linked to allergic disorders, adding another possible connection to methylation.[31]

Can Optimal Methylation Help Maintain Youthful Vitality?

Everybody seeks that proverbial fountain of youth—not only to live a long life but to do so with energy and youthful vitality. Changes in DNA methylation occur during aging and may actually contribute to the aging process.[32] One molecule that has been of tremendous interest lately is NAD+ (nicotinamide adenine dinucleotide). It has been called a true ‘anti-aging’ molecule naturally present in every cell and critical for DNA repair, cellular bioenergetics, genomic signaling and cell survival.[33],[34]  As we age, we experience a steady decrease in NAD+ levels in our body. Higher levels of NAD+ have been shown to increase the body’s resilience to the diseases of aging, possibly extending healthy human lifespan.[35]

As our body synthesizes NAD+, methylation activity increases and methyl donors are consumed at a higher rate. In fact, NAD+ and methylation are closely linked.1,[36],[37],[38],[39],[40]  For optimum health, the two cycles must be balanced.

There is much still to learn about methylation, and there has been an explosion in research in recent years, accompanied by a huge increase in knowledge. Scientists predict that great strides will be made in methylation research over the next decade as well, which may revolutionize how we think about and treat health and disease. Until then, a basic understanding of the delicate choreography of methylation, and the importance of adequate methyl donors and B vitamins, can help us make decisions that ensure optimal health.


[1]Moore LD et al. DNA methylation and its basic function. Neuropsychopharmacology. 2013 Jan;38(1):23-38. View Full Paper

[2]Krajka-Kuźniak V et al. Betanin, a beetroot component, induces nuclear factor erythroid-2-related factor 2-mediated expression of detoxifying/antioxidant enzymes in human liver cell lines.Br J Nutr. 2013 Dec;110(12):2138-49. View Abstract

[3]Zampieri M. Reconfiguration of DNA methylation in aging. Mech Ageing Dev. 2015 Nov;151:60-70. View Abstract

[4]Slieker RC et al. DNA Methylation Landscapes of Human Fetal Development. PLoS Genet. 2015;11(10):e1005583. View Full Paper

[5]Waterland RA et al. Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Molecular and Cell Biology, 2003;23: 5293–5300 View Full Paper

[6]Ly L et al. Intergenerational impact of paternal lifetime exposures to both folic acid deficiency and supplementation on reproductive outcomes and imprinted gene methylation.Mol Hum Reprod. 2017 Jul 1;23(7):461-477.  View Abstract

[7] Dominguez-Salas, P; Developmental epigenetics in humans: Can maternal nutritional status mediate DNA methylation in their offspring? PhD (research paper style) thesis, London School of Hygiene & Tropical Medicine, 2013. View Abstract

[8]Shames DS, Minna JD et al. DNA methylation in health, disease, and cancer. Curr Mol Med 7: 85-102View Full Paper

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[10]Ligthart S et al.  DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases. Genome Biol. 2016 Dec 12;17(1):255 View Full Paper

[11]Lertratanangkoon K Alterations of DNA methylation by glutathione depletion.Cancer Lett. 1997 Dec 9;120(2):149-56 View Abstract

[12]Ganguly P et al. Role of homocysteine in the development of cardiovascular disease. Nutr J. 2015;14:6. View Full Paper

[13]Obeid R et alM. Vitamin B12 intake from animal foods, biomarkers and health aspects. Front Nutr 2019;6:93. View Full Paper

[14]Sauer H et al. Br J Haematol. Cobalamin dependent methionine synthesis and methyl-folate-trap in human vitamin B12 deficiency 1977 Jun;36(2):189-98 View Abstract

[15]O’Leary F. Vitamin B12 in health and disease Nutrients. 2010 Mar;2(3):299-316. View Full Paper

[16]NIH U.S. National Library of Medicine, MTHFR gene. Genetics Home Reference Available at: https://ghr.nlm.nih.gov/gene/MTHFR Accessed 1-4-2020

[17]Castro R et al. 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C→T and 1298A→C mutations are associated with DNA hypomethylation. Journal of Medical Genetics 2004;41:454-458View Full Paper

[18]Sah AK et al. Association of parental methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism in couples with unexplained recurrent pregnancy loss. BMC Res Notes. 2018;11(1):233. View Full Paper

[19]Hustad S et al. Riboflavin and methylenetetrahydrofolate reductase. Madame Curie Bioscience Database [Internet]. View Full Paper

[20]Pinto JT et al. Riboflavin. Advances in Nutrition 2016 (5):5;973-975 View Full Paper

[21]Belardo A et al. The concomitant lower concentrations of vitamins B6, B9 and B12 may cause methylation deficiency in autistic children J Nutr Biochem. 2019 Aug;70:38-46.  View Abstract

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[25]Miller AL. The methylation, neurotransmitter, and antioxidant connections between folate and depression. Altern Med Rev. 2008 Sep;13(3):216-26. View Abstract

[26]Bottiglieri T. Folate, vitamin B12, and neuropsychiatric disorders. Nutr Rev. 1996 Dec;54(12):382-90. View Abstract

[27]Reynolds EH. Methylation and mood. Lancet. 1984 Jul 28;2(8396):196-8 View Abstract

[28]Kulis M. DNA methylation and cancer. Adv Genet. 2010;70:27-56. View Abstract

[29]White MV. The role of histamine in allergic diseases. The Journal of Allergy and Clinical Immunology, 1990 86, 4, 599-605 View Full Paper

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[31]Keagy CD. The potential role of folate metabolism in interstitial cystitis.Int Urogynecol J. 2019 Mar;30(3):363-370. View Abstract

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[33]Longo VD et al. Interventions to Slow Aging in Humans: Are We Ready? Aging Cell 14 (4): 497-510. View Abstract

[34]Fang EF et al. NAD (+) in aging: molecular mechanisms and translational implications. Trends Mol Med. 2017;23(10):899–916 View Abstract

[35]Hershberger KA et al. Role of NAD+ and mitochondrial sirtuins in cardiac and renal diseases. Nat Rev Nephrol. 2017 Apr;13(4):213-225. View Full Paper

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[37]Aguilar-Arnal L et al. NAD(+)-SIRT1 control of H3K4 trimethylation through circadian deacetylation of MLL1.Nat Struct Mol Biol. 2015 Apr;22(4):312-8. View Full Paper

[38]Cantó C et al. NAD+ metabolism and the control of energy homeostasis: a balancing act between mitochondria and the nucleus. Cell Metab. 2015 Jul 7;22(1):31-53. View Full Paper

[39]Kang-Lee YA et al. Metabolic effects of nicotinamide administration in rats.  J Nutr. 1983 Feb;113(2):215-21. View Abstract

[40]Aksoy S et al.  Human liver nicotinamide N-methyltransferase. cDNA cloning, expression, and biochemical characterization. J. Biol. Chem. 1994 269, 14835–14840.

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