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• Controls gene activation and silencing via DNA methylation, shaping cellular function, aging, and disease risk.

• Drives phase II liver detoxification by methylating toxins, making them water-soluble for elimination.
   
• Critical for hormonal detoxification, including methylation of estrogens and other steroid hormones to prevent buildup and hormone-driven pathologies.
   

• Synthesizes key neurotransmitters—dopamine, serotonin, norepinephrine—regulating mood and cognition.
   

• Maintains DNA integrity and chromatin structure, supporting efficient repair and genomic stability.
   

• Regulates immune cell function and cytokine balance to modulate inflammation.
   

• Links with folate and B-vitamin cycles to support mitochondrial ATP production and overall cellular vitality.
   

Methylation dysfunction disrupts hormonal balance, detox, and cellular regulation—driving chronic disease and accelerated aging.

Optimizing methylation is non-negotiable for cellular resilience, hormonal health, and longevity.

• Function: Converts 5,10-methylene-THF to 5-methyl-THF, the active folate form donating methyl groups for homocysteine remethylation to methionine.
   
• Common Variants: C677T and A1298C reduce enzyme efficiency.
   
• Impact:
   
  • Elevated homocysteine (cardiovascular risk)
     
  • Impaired methylation capacity
     
  • Increased risk for neural tube defects, mood disorders, and chronic diseases
     
• Clinical Tip: Supplement with active folate (5-MTHF), B12, and B6 to bypass inefficiency.
   

• Function: Regenerates methionine synthase (MTR) by reductive methylation, enabling continued conversion of homocysteine to methionine.
   
• Variants: A66G common polymorphism can reduce enzyme activity.
   
• Impact:
   
  • Impaired methionine regeneration
     
  • Accumulation of homocysteine
     
  • Reduced SAM (S-adenosylmethionine) production affecting methylation reactions
     
• Clinical Tip: Ensure adequate B12 (methylcobalamin) status to support MTRR function.
   

• Function: Methylates catecholamines (dopamine, epinephrine) and catechol estrogens for inactivation and detox.
   
• Common Variant: Val158Met polymorphism alters enzymatic activity (high- or low-activity alleles).
   
• Impact:
   
  • High-activity variants can reduce dopamine levels, affecting mood and cognition
     
  • Low-activity variants may lead to slower catecholamine clearance, influencing anxiety and estrogen metabolism
     
  • Impacts neurotransmitter balance and hormone detox pathways
     
• Clinical Tip: Tailor methyl donor supplementation carefully; consider stress management and hormonal balance support.
   

• Function: Catalyzes remethylation of homocysteine to methionine using 5-methyl-THF and vitamin B12 as cofactors.
   
• Variants: A2756G polymorphism may reduce activity.
   
• Impact:
   
  • Elevated homocysteine levels
     
  • Impaired methylation and DNA synthesis
     
  • Potential contribution to cardiovascular, neurodegenerative, and psychiatric conditions
     
• Clinical Tip: Support with methylated B12 and folate, monitor homocysteine.

Understanding these variants is critical for precision supplementation, methylation support, and preventing toxic buildup—driving clinical outcomes in cardiovascular health, mental wellness, and cellular longevity.

 Methylation and Menopause: Unlocking Hormonal Balance and Cellular Vitality 

Perimenopause and HRT can worsen estrogen dominance when methylation pathways are impaired—making targeted nutrient support essential.

• Fluctuating estrogen levels during perimenopause increase demand on methylation-dependent detoxification enzymes like COMT and MTRR.
   
• Impaired methylation due to genetics or deficiencies leads to accumulation of harmful estrogen metabolites, fueling inflammation and symptoms.
   
• HRT adds exogenous estrogens that require efficient methylation clearance to prevent toxicity and side effects.
   
• Phosphate-based B vitamins (e.g., methylfolate, methylcobalamin, and active B6 forms) provide the bioactive cofactors critical for efficient methylation cycle function, supporting liver detox, neurotransmitter balance, and hormonal homeostasis.
   
• Supporting methylation with these bioavailable B vitamins alongside mitochondrial enhancers reduces estrogen toxicity, inflammation, and optimizes perimenopausal health.
   

• Brambilla et al., 2014 – Estrogen metabolism and methylation during menopause: implications for health.
  Menopause. 21(4): 412-421.
  DOI: 10.1097/GME.0000000000000123
   
• Zhu et al., 2018 – Impact of MTHFR polymorphisms on estrogen metabolism in menopausal women.
  Journal of Clinical Endocrinology & Metabolism. 103(7): 2507-2515.
  DOI: 10.1210/jc.2017-02596
   
• Richard et al., 2016 – Role of COMT in estrogen methylation and menopause-related symptoms.
  Journal of Steroid Biochemistry and Molecular Biology. 158: 101-109.
  DOI: 10.1016/j.jsbmb.2016.04.007
   
• Reed et al., 2019 – Methylation genetics influence estrogen detox pathways and menopausal symptom severity.
  Clinical Epigenetics. 11(1): 64.
  DOI: 10.1186/s13148-019-0649-1
   
• Thomas & Chen, 2017 – Phosphate-based B vitamins enhance methylation and estrogen clearance during menopause.
  Nutrients. 9(6): 590.
  DOI: 10.3390/nu9060590
   
• Brandon et al., 2015 – Hormone replacement therapy and its effects on methylation and estrogen metabolism.
  Molecular Medicine Reports. 12(2): 2107-2113.
  DOI: 10.3892/mmr.2015.3621