Methylation: How can it be supported by nutrition?

As our understanding of gene regulation and metabolic processes continues to evolve, research is now investigating the links between biochemical methylation and the development of disease or dysfunction. The processes of methylation, or “one-carbon metabolism”, are the mechanisms through which methyl groups are transferred from one-carbon molecules to DNA or proteins that are required for fundamental physiological activity (98).

As with all processes of the body, a balance is required in methyl status for proper function. Several nutrients are involved in maintaining a balance between hypomethylated and hypermethylated states, including folate, vitamin B2, B6, B12, choline, betaine, and methionine (4). This article details the mechanisms of methylation, provides information on assessing the need for methylation support, and reviews evidence on dietary and supplement interventions that may support appropriate methylation.

What is methylation?

Biochemical methylation reactions have been widely studied with respect to their roles in gene expression, DNA/RNA synthesis, protein synthesis, central nervous system development, immune function, detoxification, neurotransmitter production and metabolism, hormone homeostasis, and cellular metabolism and structure (44).

Two important actions of methylation reactions include the recycling of homocysteine via folate metabolism and the methylation of DNA, hormones, neurotransmitters, and other compounds such as pharmaceuticals. The accumulation of homocysteine is associated with a plethora of conditions, while disrupted DNA methylation can increase the risk for developmental conditions in future generations, as well as the development of disorders from epigenetic modification (4).

The processes of methylation readily depend on an adequate supply of nutrients, most significantly B vitamins, folate in particular. Vitamin B6 and Vitamin B12 act as cofactors in the conversion of tetrahydrofolate (THF) to 5,10-methyleneTHF, and of 5-methylTHF to THF, respectively. Vitamin B12 simultaneously converts homocysteine to methionine using betaine. Subsequential production of S-adenosylmethionine (SAMe) also donates its methyl group to DNA via DNA methyltransferases (DNMT) (4). Depletions in the nutrients involved in methylation cycles may disrupt methylation activity and lead to reductions in metabolic and genetic methylation processes (190).

Several nutrients are involved in maintaining a balance between hypomethylated and hypermethylated states.

Assessing the need for methylation support

As methylation is involved in the development of a wide range of conditions and in preventing physiological dysregulation, it can be difficult to determine whether unbalanced methylation status is the cause of a disorder or dysfunction, or whether the pathophysiology should be attributed to another underlying factor. Disharmony in methylation processes in the body has been linked with conditions of birth, pregnancy, and fertility (96), as well as cancer, cardiometabolic conditions, and neurological conditions (76).

Nevertheless, there are several clues and tools that practitioners may use to identify the presence of impaired methylation status. This includes conducting genetic profiling, measuring metabolites of methylation, appraising inflammatory status and oxidative stress, and determining nutrient status. It is recommended that practitioners employ multiple techniques to gain a broader understanding of the potential implications of methylation status to avoid prognosis misinterpretations (44).

Genetic profiling

Genetic profiling can be used for the identification of polymorphisms in genes of enzymes that often lead to reductions in methylation activity. In general, states of DNA hypermethylation downregulates gene transcription while states of hypomethylation may upregulate genetic expression, though this can be specific to individual cell types. For example, reduced global methylation status is often observed in cancer and may lead to the upregulation of cellular proliferation, while tumor suppressor genes may be hypermethylated, resulting in reduced activity (181). 

Polymorphisms leading to altered methylation processes may include enzymes such as:

  • Adenosyl homocysteinase (AHCY) (41)
  • Betaine-homocysteine methyltransferase (BHMT) (89)
  • Catechol-O-methyltransferase (COMT) (79)
  • Cystathionine beta-synthase (CBS) (116)
  • Glycine-N-methyltransferase (GMNT) (68)
  • Methionine adenosyltransferase I, alpha (MAT1A) (14)
  • Methylenetetrahydrofolate reductase (MTHFR) (188)
  • Serine hydroxymethyl transferases (SHMT) (144)
  • 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR) / Methionine Synthase (MS) (148)

5-methyltetrahydrofolate-homocysteine methyltransferase reductase / Methionine synthase reductase (MTRR) (40)

Methylation metabolite status

The levels and proportions of metabolites involved in methylation reactions may be measured to provide an indication of potential imbalances in methylation cycles.

Most commonly, this includes (44):

  • Elevated homocysteine, which may lead to reduced DNA methylation (67)
  • Elevated S-adenosyl homocysteine (SAH) (202)
  • Elevated cystathionine as a result of disrupted remethylation (163)
  • Reduced SAMe, which provides an indication of reduced methylation potential (142)
  • Reduced SAMe:SAH ratio, which may indicate reduced methylation potential (38)

Inflammatory status

Inflammatory markers can play a role in DNA methylation leading to inflammatory conditions. 

Examples include (64):

  • DNA hypomethylation from high fat, inflammatory diets, which may increase TNF-α, IL-6 and IL-1β
  • DNA hypomethylation from upregulated toll-like receptors, which facilitate inflammation in obesity and other conditions such as cystic fibrosis
  • DNA methylation may be inversely associated with CRP, ICAM-1 and VCAM-1 after exposure to polluted air
  • DNA hypomethylation of genes associated with inflammation in rheumatoid arthritis
woman and doctor chatting in the doctor's office
There are several clues and tools that practitioners may use to identify the presence of impaired methylation status.

Oxidative stress

Metabolites associated with oxidative stress can be measured as an indication of disrupted methylation status. To manage oxidative stress, the body increases glutathione synthesis, which requires deferral of the supply of homocysteine from methylation. Oxidative stress can also cause DNA damage and hypomethylation (32).

Examples of commonly measured markers of oxidative stress include:

  • 8-OHdG (marks DNA damage) (146)
  • Alpha-hydroxybutyrate (marks glutathione status) (95)
  • F2-isoprostanes (marks activity of free radicals on arachidonic acid) (191)
  • Lipid peroxides (marks activity of free radicals on lipids) (12)

Nutrient status

The identification of nutrient levels may provide information on the underlying causes of altered methylation capacity. Table 1 provides a summary of nutrients involved in methylation and contains clinical information to support methylation processes.

It is important to note that while evidence is primarily presented for the nutrients in isolation, varying combinations of these ingredients, especially the B vitamins, may provide additional benefit in supporting methylation outcomes (31, 87).

Pathologies linked to methylation disorders

Alzheimer’s disease: While research is inconclusive, cerebral and cellular specific alteration in DNA methylation may lead to synapse loss, cerebral and hippocampal atrophy, reduced amyloid Aβ degradation and increased secretion, increased neuroinflammation (IL-1β and IL-6), and reduced BDNF (205).

Autism spectrum disorders: Reduced SAMe and increased SAH leading to DNA methylation disruptions may alter the expression of genes such as MeCP2 and oxytocin receptor genes. Impaired GSH status may lead to compromised brain cell development and connectivity from oxidative stress (110).

Cancer: DNA hypermethylation of tumor suppressor genes may reduce transcription of proteins that inhibit tumor growth, while hypomethylation of proto-oncogene promoters can increase oncogenesis. Hypermethylation can also lead to a higher risk of somatic mutations that cause cancers, while reduced methylation may lead to decreased transposon activity (105).

Cardiovascular disease: Hyperhomocysteinemia may lead to atherosclerosis, reduce vascular elasticity and NO, and increase platelet coagulation, vascular smooth cell proliferation, collagen synthesis, and oxidative stress leading to endothelial dysfunction (49).

Chronic liver diseases: Reduced production of SAMe may lead to the release of hepatic cytokines, impaired GSH synthesis from oxidative stress may impair detoxification pathways, and increased homocysteine (Hcy) may lead to necrosis and fibrogenesis (43).

Coronary artery disease: Increased Hcy may reduce NO leading to endothelial dysfunction, and increase platelet coagulation and vascular smooth cell proliferation (159).

Depression: Increased Hcy may over-activate NMDA receptors leading to neurotoxicity, reduce dopamine and serotonin, alter neural plasticity, cause oxidative stress, and impair cerebral vascular function (118).

Diabetic neuropathy: Elevated Hcy may lead to vasoconstriction via reduced NO, limiting blood flow to nerves. The use of metformin therapy may lead to increases in Hcy (113).

Dyslipidemia: Reductions in SAMe from raised Hcy may lead to reduced synthesis of phospholipids, ultimately causing a build-up of hepatic cholesterol and lipids (136).

Fat mass and homocysteine management: Increased Hcy may lead to increased lipid storage through altered DNA methylation mechanisms (47).

Fetal alcohol spectrum disorder: Alcohol may reduce maternal folate status, reduce the production of SAMe, increase SAH, deplete GSH to shift homocysteine to transsulfuration rather than methylation pathways causing DNA hypomethylation, increase oxidative stress, and inhibit MS, MATs, and DMNTs (99).

Fibromyalgia: Reduced DNA methylation may lead to increased gene expression for IL-10 increasing pain threshold, IL-25 increasing Th2 cytokine responses, SLC1A5 and SLC25A22 increasing CNS glutamate receptors, and GRM6 increasing the group III G protein-coupled receptor expression to inhibit cAMP cascade in neuropathic pain (23).

Hypertension: Elevated Hcy may reduce NO and increase asymmetric dimethylarginine and inflammation, leading to endothelial dysfunction. It may also increase metalloproteinase activity, collagen synthesis, and ACE activity (200).

Hypertension with MTHFR 677TT polymorphism: MTHFR polymorphism increases carotid intima-media thickness, carotid plaque, vascular wall thickness and surface area. Increased Hcy and decreased folate, may also lead to higher carotid resistance, endothelial oxidative stress and reduced NO (84, 93, 139, 149).

Male infertility: Hyperhomocysteinemia may lead to increased testicular or spermatic inflammation via MCP-1 and IL-8, while reductions in NO may impair erectile function, spermatogenesis and maturation, sperm motility and fertilization. Increased oxidative stress may cause sperm DNA damage. Reductions in SAMe may reduce testosterone synthesis (45).

man holding his head in pain
Disharmony in methylation processes in the body has been linked with numerous conditions, such as migraines.

Migraine: Elevations in Hcy may cause cerebral vasodilation, or temporary thrombosis and increased coagulation. Associated increases in oxidative stress may impair cerebral vascular endothelial function (11).

Neural tube defects: Reductions in folate status may lead to impaired DNA methylation and nucleotide synthesis, which may be required for adequate neural folding and closure (70).

Osteoporosis: Altered DNA methylation of chondrocytes can lead to imbalances in the synthesis and degradation of cartilage, as well as alterations in extracellular matrix protein compositions. DNA methylation may be influenced by the increased presence of inflammatory cytokines such as IL-1β, TNF-α, or leptin, and reactive oxygen species (112).

Parkinson’s disease: L-Dopa treatments for PD often increase Hcy, which can reduce B vitamin status and possibly compromise dopamine-producing cells via alterations in DNA synthesis or repair, neurotransmitter and protein synthesis, and cellular signaling processes (120).

Polycystic ovarian syndrome: Hypomethylation of genes required for lipid and steroid synthesis may lead to lipid accumulation and hyperandrogenism (141).

Pre-eclampsia: Hyperhomocysteinemia may lead to eNOS inhibition and reduced NO, as well as oxidative stress-related endothelial dysfunction (endothelial cell lesions, vascular fibrosis, altered coagulation, platelet activation, thrombogenesis) (35).

Recurrent pregnancy loss: Hyperhomocysteinemia may lead to embryonic hypomethylation, increased oxidative stress and apoptosis, and reduced embryonic vascularity and cellular proliferation (45).

Renal disease: Elevated Hcy is associated with increased microalbuminuria. Associated increases in oxidative stress, inflammation and DNA hypomethylation may lead to endothelial and mesangial cell dysfunction and renal damage from higher intraglomerular pressure and/or reduced glomerular charge and size selectivity (94).

Schizophrenia: Increased Hcy may over-activate NMDA receptors leading to neurotoxicity, reduce dopamine and serotonin, alter neural plasticity, cause oxidative stress and impair cerebral vascular function (118).

Tardive dyskinesia (anti-psychotic side-effect): Increased DNA methylation of the DLGAP2 gene has been found in both schizophrenia and TD. DLGAP2 plays a role in the organization of synapses and neural signaling (92).

Key nutrients involved in methylation

Several nutrients are involved in maintaining a balance between hypomethylated and hypermethylated states.

Educational in partnership

If you are seeking further education on methylation support, please refer to Dr. Kara Fitzgerald’s Functional Medicine Clinical Immersion. Dr. Fitzgerald’s team provides several high quality educational experiences to further clinical skills in functional medicine and nutrition, including live mentorship and nutritional residency programs.

Dr. Fitzgerald’s team has also produced an excellent resource on supporting methylation processes, titled Methylation Diet & Lifestyle: Whole Being Support for Healthy Methylation and Epigenetic Expression.

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