Link between hypomethylation, gene expression, and pathologies
Hypomethylation, by altering gene expression and metabolic balance, is associated with numerous pathologies. This alteration is due to epigenetic changes affecting gene regulation and causing imbalances in several biological processes. The causes of these deficits, summarized below, often lead to hyperhomocysteinemia, a major risk factor for vascular and neurodegenerative diseases.
Origins of hypomethylations
The origins of methylation deficits can be multiple and include nutritional deficiencies, genetic factors such as enzymatic polymorphisms, and environmental factors like exposure to toxins or poor lifestyle habits. These elements disrupt the biochemical cycles involved in remethylation and promote the accumulation of homocysteine, a key factor in metabolic imbalances.
This table summarizes the main causes of methylation deficits, including nutritional deficiencies, genetic factors, and environmental influences. These well-documented causes play a crucial role in the development of pathologies associated with hyperhomocysteinemia.
1. Nutritional deficits
- Alterations in CH3 transfers are often linked to deficiencies in key nutrients such as folates, B vitamins (B6, B9, B12), choline, and betaine. These elements play a central role in the biochemical cycles of methylation.
- A significant correlation exists between nutritional deficiencies and DNA methylation, directly impacting cellular functions and overall health.
2. Genetic polymorphisms
- Enzyme anomalies involved in transsulfuration and remethylation, such as MTHFR, affect up to 40% of the population.
- The MTHFR677C-T polymorphism reduces the conversion of folic acid into CH3THF, required for the remethylation of homocysteine into methionine, thereby disrupting the methylation cycle.
3. Environmental factors
Air pollution, benzene, pesticides, alcohol, tobacco, overweight, and coffee are among the main risks. These external agents disrupt metabolic cycles, increasing the risk of hypomethylation.
Pathologies associated with hypomethylation
Methylation deficits are directly linked to severe pathologies affecting multiple biological systems. From cancer cell proliferation to increased cardiovascular and neurodegenerative risks, these anomalies highlight the importance of methylation cycles in maintaining cellular and systemic health.
This chapter details the clinical consequences of hypomethylation, particularly in cancers, cardiovascular diseases, cognitive disorders, and liver dysfunctions. The mechanisms involved emphasize the importance of a proper methylation balance for maintaining health.
1. Cancers
- DNA methylation, through the addition of a CH3 group to cytosine, is essential for regulating gene expression. Hypomethylation increases the expression of oncogenes, promoting tumor development.
- A negative correlation between the level of 5-CH3-cytosine and cancer incidence has been demonstrated, highlighting the importance of maintaining optimal methylation levels to prevent these pathologies.
2. Cardiovascular and cognitive risks
- Homocysteine, whose levels increase during methylation deficits, is a risk factor for thrombosis, coronary artery disease, and stroke. It promotes oxidative stress, inflammation, and vascular disorders.
- Recent studies highlight the link between hyperhomocysteinemia and neurodegenerative disorders such as Alzheimer’s, as well as severe depression.
3. Liver dysfunctions
- Hypomethylation disrupts phase II of hepatic detoxification, a crucial role of the liver in toxin elimination.
- Deficiencies in choline and betaine, combined with environmental factors (alcohol, pesticides, tobacco), increase the risks of steatosis and liver cancers.
4. Energy and muscle disorders
- Methylation is essential for energy metabolism through the conversion of lysine into carnitine (fatty acid transport) and arginine into creatine (muscle contraction).
- Patients with chronic fatigue often exhibit a methylation deficit measured in their DNA.
What supplementation strategy ?
To restore an optimal methylated balance and lower homocysteine levels, it is essential to target nutritional intake of indispensable nutrients. A comprehensive approach includes active folates, B-group vitamins, as well as natural sources of betaine and choline. These interventions promote efficient enzymatic function and mitigate the harmful effects of hypomethylation.
This section explores various nutritional solutions to restore methylation potential. It highlights the importance of folates, B vitamins, betaine, and choline, emphasizing their synergies and combined effects in reducing homocysteine and preventing associated pathologies.
1. Folates and B vitamins
- Folate requirements (400 µg/day) are rarely met through diet alone. Age, overweight, and digestive disorders reduce the efficiency of their absorption.
- Supplementation with active forms such as CH3-folate is particularly useful to bypass genetic and metabolic limitations.
- Vitamins B2, B6, and B12 work synergistically to support CH3 transfers, methionine synthesis, and glutathione regeneration.
2. Betaine, choline, and di-CH3-glycine
- These molecules, provided through diet (beets, eggs, liver), support methylation via the remethylation of homocysteine.
- Betaine, triply methylated, acts primarily in the liver and kidneys, complementing the folate cycle. It is particularly effective in alcoholic patients or those with liver deficits.
- A combination of folates and betaine maximizes the effectiveness of supplementation. Studies show improved remethylation and a significant reduction in homocysteine.
3. Nutrient synergy
Betaine, by stimulating BHMT (betaine-homocysteine methyltransferase), promotes hepatic methylation and reduces the risk of steatosis.
Choline, although synthesized by the body, is essential and must be supplemented through diet (red meat, dairy products, eggs). It prevents fat accumulation in the liver and supports acetylcholine production.
Summary
Hypomethylation is a key factor in many pathologies, including cancers, cardiovascular diseases, cognitive disorders, and depression. Proper supplementation with folates, B vitamins, betaine, and choline is essential to prevent these risks and restore an optimal methylation balance. Serum homocysteine assessment can serve as a predictive marker to precisely tailor individual needs.
Scientific References
Folate, DNA methylation and colo-rectal cancer. Proc Nutr Soc. 2003 May;62(2):437-45
