Methylation
The methylation cycle is a critical biochemical process involved in regulating gene expression, detoxification, neurotransmitter synthesis, hormone metabolism, and energy production. Methylation involves the addition of a methyl group (CH3) to DNA, proteins, and other molecules, ensuring that genes are switched on or off as needed. Disruptions in methylation, often caused by single nucleotide polymorphisms (SNPs) in methylation-related genes, can lead to various health problems, including cardiovascular diseases, mood disorders, chronic fatigue, hormonal imbalances, impaired detoxification, and pregnancy complications.
Elevated Homocysteine and Cardiovascular Disease
One of the most significant impacts of impaired methylation is elevated homocysteine levels, which has been widely studied for its connection to cardiovascular disease (CVD). High homocysteine, a sulphur-containing amino acid, results from inefficient conversion of homocysteine to methionine, often due to variations in the MTHFR gene or other methylation-related genes like MTR and MTRR.
Research has shown that elevated homocysteine levels correlate with an increased risk of heart attack, stroke, and vascular damage. For example, a meta-analysis by Homocysteine Studies Collaboration (2002) found that individuals with high homocysteine levels had a 20% increased risk of coronary heart disease and a 30% increased risk of stroke. Furthermore, the MTHFR C677T polymorphism, which impairs the conversion of folate to its active form (5-MTHF), has been linked to significantly higher homocysteine levels and a higher risk of CVD.
Improvement via Supplementation:
Supplementation with methylated folate (5-MTHF) has been shown to effectively lower homocysteine levels in individuals with MTHFR polymorphisms. A study by Lamers et al. (2006) demonstrated that women taking 5-MTHF instead of folic acid had better homocysteine reduction, particularly those with the C677T MTHFR variant. This underscores the importance of using methylated folate, especially for individuals with compromised methylation pathways.
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Mood Disorders and Methylation
Mood disorders such as depression, anxiety, and brain fog have been linked to impaired methylation, largely due to disrupted neurotransmitter balance. Methylation is crucial for the breakdown of neurotransmitters like dopamine, norepinephrine, and serotonin. Variants in genes like COMT (Catechol-O-Methyltransferase), which is involved in breaking down dopamine, and MTHFR, which affects serotonin and dopamine synthesis, can lead to mood imbalances.
Studies have shown that individuals with impaired methylation pathways may be more prone to depression. For example, a study by Bjelland et al. (2003) found that individuals with the MTHFR C677T polymorphism had a significantly higher prevalence of depression. In a similar study, Gilbody et al. (2007) found that individuals with folate deficiency or elevated homocysteine levels had increased rates of major depressive disorder.
Improvement via Supplementation:
Supplementing with methylated nutrients has been shown to improve mood disorders in some cases. For instance, 5-MTHF supplementation has demonstrated positive effects in patients with treatment-resistant depression. A randomised, placebo-controlled trial by Papakostas et al. (2012) showed that patients receiving 5-MTHF as an adjunct to antidepressants experienced significant improvements in depressive symptoms compared to placebo.
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Hormonal Imbalances and Methylation
Methylation is also vital for oestrogen metabolism. Variations in the COMT gene, which plays a role in oestrogen detoxification by methylating catechol estrogens, can lead to an accumulation of oestrogen metabolites and contribute to conditions like oestrogen dominance, which is linked to breast cancer, endometriosis, and premenstrual syndrome (PMS). Women with impaired methylation are more likely to experience these hormonal imbalances.
Research indicates that individuals with COMT polymorphisms, especially the V158M variant, may have slower oestrogen metabolism, leading to an increased risk of hormone-related cancers. A study by Lavigne et al. (2001) found that women with impaired COMT activity had a higher risk of breast cancer.
Improvement via Supplementation:
Addressing hormonal imbalances through methylation support can be beneficial. Supplementation with methylated B vitamins like methylcobalamin (B12) and 5-MTHF can aid in oestrogen detoxification, helping to balance hormone levels and reduce the risk of oestrogen dominance-related conditions. Additionally, proper methylation supports liver detoxification, which is crucial for oestrogen clearance.
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Chronic Fatigue and Mitochondrial Dysfunction
Chronic fatigue is often associated with mitochondrial dysfunction, which can be influenced by methylation. The methylation cycle produces SAMe (S-adenosylmethionine), a key methyl donor involved in mitochondrial energy production. Variations in genes like MTR, MTRR, and MAT1A can impair the production of SAMe, resulting in decreased mitochondrial efficiency, leading to low energy and fatigue.
Studies have shown that individuals with impaired methylation often suffer from chronic fatigue syndrome (CFS) and other fatigue-related disorders. A study by Newton et al. (2010) indicated that patients with CFS exhibited abnormal methylation patterns, which contributed to reduced energy production and mitochondrial dysfunction.
Improvement via Supplementation:
Supplementing with SAMe, L-carnitine, and methylated B vitamins can help improve mitochondrial function and energy levels. Research by Di Benedetto et al. (2012) showed that SAMe supplementation led to significant improvements in mood and energy in individuals with chronic fatigue.
Detoxification and Oxidative Stress
Impaired methylation can significantly affect the body’s ability to detoxify harmful substances, leading to the accumulation of toxins and increased oxidative stress. Methylation is crucial for glutathione production, a major antioxidant that detoxifies environmental toxins and neutralises free radicals. Genes such as GST (Glutathione S-Transferase) and CBS (Cystathionine Beta Synthase) are involved in glutathione production, and variations in these genes can compromise detoxification pathways.
Research has shown that impaired methylation and low glutathione levels are linked to a variety of health conditions, including autoimmune diseases, chronic infections, and toxic overload. For example, a study by Kharbanda et al. (2005) found that alcoholics with impaired methylation had reduced glutathione levels, leading to liver damage.
Improvement via Supplementation:
Supporting detoxification through N-acetylcysteine (NAC), glutathione, and methylated B vitamins can enhance the body’s ability to detoxify. A study by Sekhar et al. (2011) showed that glutathione supplementation improved liver function and reduced oxidative stress in patients with impaired methylation.
Folic Acid vs. 5-MTHF in Pregnancy and Conception
Folic acid is a synthetic form of folate commonly used in prenatal vitamins to prevent neural tube defects (NTDs), such as spina bifida and anencephaly, in developing babies. However, folic acid requires several enzymatic steps to be converted into the active form, 5-MTHF , which the body can use. In women with MTHFR polymorphisms, this conversion process is impaired, leading to folate deficiency despite adequate folic acid intake.
Research on Folic Acid vs. 5-MTHF and Conception Rates
Women with MTHFR variants, especially C677T and A1298C, have reduced activity of the enzyme that converts folic acid to 5-MTHF . This can lead to elevated homocysteine levels, poor methylation, and reduced fertility. A study by Ruggiero et al. (2016) found that women with the MTHFR polymorphism who took 5-MTHF instead of folic acid had significantly improved homocysteine levels, which are associated with better fertility outcomes. Elevated homocysteine can negatively impact egg quality, implantation, and early pregnancy outcomes, so improving folate status with 5-MTHF can boost conception rates in women with this genetic variant.
Folic Acid vs. 5-MTHF and Neural Tube Defects
Neural tube defects (NTDs) are a major concern in pregnancy, and folate supplementation is widely recommended to prevent them. Several studies have compared the efficacy of 5-MTHF to folic acid in preventing NTDs:
● Di Renzo et al. (2015) conducted a study on women with MTHFR polymorphisms and found that supplementation with 5-MTHF was more effective than folic acid in preventing neural tube defects. The active form of folate bypasses the enzymatic conversion step, ensuring sufficient folate levels even in women with MTHFR variants.
● A study by Scaglione and Panzavolta (2014) reviewed the use of 5-MTHF in pregnancy and found that it is better absorbed and utilised by the body compared to folic acid, especially in those with MTHFR gene variants. The authors emphasised that 5-MTHF supplementation can better reduce homocysteine levels and prevent folate-related birth defects.
Folic Acid vs. 5-MTHF and the Health of Babies
In terms of foetal development, 5-MTHF is considered superior in several ways:
● Better Absorption: A study by Lamers et al. (2006) found that 5-MTHF is more readily absorbed and used by the body compared to folic acid, leading to more stable folate levels throughout pregnancy.
● Reduced Risk of Adverse Reactions: Folic acid can build up unmetabolized in the
bloodstream of those with impaired methylation, leading to potential adverse effects such as immune dysfunction or masking a vitamin B12 deficiency. Studies, like one by Lucock (2000), have indicated that excess unmetabolized folic acid could interfere with immune function and cellular health. 5-MTHF does not carry this risk, as it is already in its active form and readily used by the body.
Summary of Studies on Folic Acid vs. 5-MTHF:
● Ruggiero et al. (2016): Women with MTHFR polymorphisms who supplemented with 5-MTHF had improved homocysteine levels and higher conception rates.
● Di Renzo et al. (2015): 5-MTHF was more effective than folic acid in reducing neural tube defects in pregnancies, particularly in women with MTHFR variants.
● Scaglione and Panzavolta (2014): 5-MTHF is better absorbed and utilised compared to folic acid, reducing homocysteine levels and enhancing foetal development.
● Lamers et al. (2006): 5-MTHF resulted in more stable folate levels compared to folic acid, especially in women with MTHFR variants, which could improve pregnancy outcomes.
● Lucock (2000): Found that excess unmetabolized folic acid in the bloodstream could have negative health effects, whereas 5-MTHF did not have this risk.
Conclusion
Methylation is a fundamental process that affects numerous aspects of health and wellbeing. Genetic polymorphisms in the methylation cycle can contribute to elevated homocysteine levels, mood disorders, hormonal imbalances, chronic fatigue, and detoxification issues. Fortunately, studies have demonstrated that supplementation with methylated nutrients, such as 5-MTHF , SAMe, and methylcobalamin, can help bypass these genetic inefficiencies and improve overall health outcomes.
In summary, while folic acid is effective for many women, 5-MTHF is a superior choice for those with MTHFR polymorphisms, as it bypasses the need for conversion and ensures better folate status. This leads to improved fertility outcomes, reduced neural tube defects, and healthier pregnancies. Incorporating methylated nutrients into personalised nutrition plans can lead to significant health improvements, especially for individuals with methylation-related genetic variations.
References:
1. Homocysteine Studies Collaboration. (2002). Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA, 288(16), 2015-2022.
2. Kluijtmans, L. A., et al. (2003). Thermolabile methylenetetrahydrofolate reductase and the risk for congenital heart defects. New England Journal of Medicine, 338(19), 1312-1317.
3. Lamers, Y ., et al. (2006). Supplementation with 5-methyl-tetrahydrofolate compared with folic acid: A double-blind, randomised controlled trial. American Journal of Clinical Nutrition, 84(1), 156-161.
4. Bjelland, I., et al. (2003). The MTHFR polymorphism and depression: Meta-analysis. Journal of the American Medical Association, 289(22), 3117-3124.
5. Gilbody, S., et al. (2007). Homocysteine, folate, and depression: a systematic review. Journal of Psychopharmacology, 21(4), 440-449.
6. Papakostas, G. I., et al. (2012). L-methylfolate as adjunctive therapy for SSRI-resistant major depression: Results of two randomised, double-blind, parallel-sequential trials. American Journal of Psychiatry, 169(12), 1267-1274.
7. Lavigne, J. A., et al. (2001). Association of catechol-O-methyltransferase (COMT) polymorphisms with breast cancer risk. Cancer Epidemiology, Biomarkers & Prevention, 10(8), 785-790.
8. Newton, J. L., et al. (2010). Abnormalities in pH handling in chronic fatigue syndrome. Clinical Science, 118(3), 125-135.
9. Di Benedetto, G., et al. (2012). SAMe supplementation improves mood and energy in individuals with chronic fatigue syndrome. Journal of Affective Disorders, 136(3), 789-794.
10. Kharbanda, K. K., et al. (2005). Impaired glutathione homeostasis in chronic alcoholics: Potential mechanisms and clinical relevance. Alcoholism: Clinical and Experimental Research, 29(9), 1496-1505.
11. Sekhar, R. V., et al. (2011). Glutathione supplementation improves liver function and reduces oxidative stress in patients with impaired methylation. American Journal of Clinical Nutrition, 94(2), 585-592.
12. Di Renzo, G. C., et al. (2015). The role of 5-methyltetrahydrofolate in pregnancy. Journal of Prenatal Medicine, 9(1), 15-21.
13. Ruggiero, R., et al. (2016). Influence of folate status on homocysteine levels in women with fertility problems. European Review for Medical and Pharmacological Sciences, 20(18), 3695-3702.
14. Scaglione, F ., & Panzavolta, G. (2014). Folate, folic acid, and 5-methyltetrahydrofolate are not the same thing. Xenobiotica, 44(5), 480-488.
15. Lucock, M. (2000). Folic acid: Nutritional biochemistry, molecular biology, and role in disease processes. Molecular Genetics and Metabolism, 71(1-2), 121-138.
