Conditions as far-ranging as cardiovascular disease and arthritis may be treated through the use of nutrients that improve the process of methylation. Dr Christine Kraus, Dr Robert Faurie and Dr Lutz Thomas investigate
Methylation is the biochemical process in which certain molecules transfer or donate a methyl group (-CH3) to other molecules. This donation of the one carbon molecule comes from other larger molecules called methyl donors, such as methionine, S-adenosylmethionine (SAMe) and betaine. They transfer this molecule to other ?methyl acceptors? with the help of ?methyl carriers? that are primarily supplied as folates or vitamin B12. Important acceptors include nucleic acids/DNA, proteins, phospholipids and biological amines.
Without this methylation process, these methyl acceptors do not function optimally and damage to cellular structures can occur. Studies have demonstrated that impaired methylation can be detrimental to many functions in the human body, contribute to cardiovascular disease and arthritis, and potentially be the genesis of cancer.
This article discusses how the molecular key for a sufficient methylation process can be supported by oral administration of several methylation factors, including betaine, vitamins B6 and B12, and folates.
Vitamins B6 and B12, folates, and betaine are called methylation factors because they are needed to produce SAMe, a ubiquitous methyl donor in the human body involved in a broad variety of biological methylation reactions. A deficiency of methylation factors leads to a decrease of SAMe and, consequently, a decrease of methylation. Similarly, a deficiency or defect of the enzymes involved results in impaired methylation.
Because methylation occurs in every cell of the human body, insufficient methylation can affect many bodily functions. Three areas in particular are cardiovascular health, arthritis and cancerogenesis.
The Cardiovascular Connection
The key to understanding the importance of methylation for cardiovascular health is the correlation of methylation factors and plasma homocysteine levels. A lack of dietary methylation factors—vitamins B6 and B12, betaine, and folate—or corresponding enzyme deficiency or defect result in elevated blood homocysteine levels.
In turn, an elevated homocysteine level—hyperhomocysteinaemia—is a risk factor for cardiovascular diseases. At least 10 per cent of coronary artery disease cases in the US may be caused by hyperhomocysteinaemia.1 Typical clinical manifestations of hyperhomocysteinaemia concerning cardiovascular health can include coronary artery disease, renovascular hypertension,2 and thrombotic and embolic events.3,4
Hyperhomocysteinaemia is also a causative factor in atherosclerosis.5,6,7 Homocysteine accumulates when the conversion of homocysteine to methionine is impaired. This is the case when the involved enzymes are functioning sub-optimally, which—depending on the seriousness of the enzyme defect—can result from anything from mild clinical pictures up to life-threatening conditions. However, a deficiency of the dietary methylation factors such as folate, vitamins B6 and B12, or betaine can also lead to elevated homocysteine levels.8 Numerous studies have shown that supplementation with folate, vitamin B6 and B12, and/or betaine is effective in lowering homocysteine levels by making the sub-optimally functioning enzyme work more efficiently.9,10 According to estimations, in the US, about 50,000 coronary artery disease deaths annually may by avoided by supplementation with folate.1
Increased methylation seems to benefit those with osteoarthritis. According to clinical studies involving more than 20,000 osteoarthritis patients, SAMe, applied in higher doses (400?1,200mg/day), exerts analgesic and anti-inflammatory activities. Concerning pain relief and improvement of functional limitations, the efficacy of SAMe is comparable to the efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs). And, in contrast to NSAIDs, SAMe has no or only minimal side effects on the gastrointestinal tract and other organs.11,12
Studies with human chondrocyte cultures of the cartilage from osteoarthritis patients suggest that SAMe stimulates the synthesis of native proteoglycans.13,14 In this particular aspect, SAMe could be superior to NSAIDs, which are known to inhibit the formation of new cartilage.
DNA Methylation And Cancer
An important and intensively discussed aspect of methylation reactions is their role in DNA methylation and carcinogenesis.
An excess of DNA damage or incorrect expression of certain genes is, in a very simplistic view, thought to be a cause of cancer development. Abnormal methylation can lead to these states and is therefore most likely involved in carcinogenesis. In the formation of cancer, abnormal methylation, resulting in both hypomethylation and hypermethylation, has been observed.15
Folate deficiency is a major cause of impaired methylation, because it leads to a decrease in the levels of SAMe and hence to impaired methylation. Folate deficiency is linked to carcinogenesis of various tissues, the most intensively studied being cervix and colorectum.16
A very early finding in cancerogenesis, before mutation and deletion events occur, is a decreased level of genomic methylation.16,17 Besides this global hypomethylation, which is the overall decrease in methylation status of the total genome, site-specific methylation aberrations—hypo- and hypermethylation—in the DNA of specific genes have been reported in neoplastic tissues.18 Site-specific hypo- or hypermethylation is thought to be more of a determining factor than global hypo-methylation. Cancer-promoting proto-oncogenes are activated due to insufficient methylation. On the other hand, hypermethylation silences tumor-suppressor or anti-oncogenes.15 Paradoxically, a methyl-deficient diet in rats produced first a site-specific hypomethylation and then, when pre-neoplastic nodules became histologically evident, hypermethylation was reported.19 This shows that the effects of dietary methyl group deficiency might play a role that goes beyond only causing global DNA hypomethylation. Low methylation is also associated with an increase of DNA strand break. In folate- deficient humans, elevated DNA uracil content and increased numbers of chromosomal breaks have been reported. This state could be normalised by folate administration.20 Studies with cell cultures show that DNA repair is impaired by folate deficiency.21
At this point, it is not known for certain that methyl supplementation can treat cancer patients. Therefore, based on the current level of knowledge, cancer patients should ask their physicians if methyl supplements are suitable for them.
However, numerous studies give evidence that methylating factors could be useful for the prevention of cancer. For example, folate-deficient people who supplement with folic acid show significantly less DNA damage.22 Folic acid might protect from cancer. The relationship of folate to colorectal cancer has been intensively studied and is well documented.23 A large prospective cohort study in the Netherlands comprising more than 120,000 people showed clearly that dietary folate intake was related inversely to colon and male rectal carcinoma risk.24 SAMe has been demonstrated to help protect rats from liver cancer.25 These examples demonstrate the protective role of methylation in the prevention of oncogenesis caused by deficient DNA methylation.
Only The Beginning?
As the results from many independent studies in the fields of cardiovascular health, arthritis and even cancer attest, the influence of impaired methylation on human health may be considered profound in those areas. But on top of these findings, numerous other conditions or diseases have been attributed to methylation defects. For example, the methylation system is likely to be suboptimal in some patients with chronic fatigue syndrome or fibromyalgia.26 In addition, methylation factors have been demonstrated to reverse damage caused by free radicals and may therefore play a role in delaying the ageing process.27 Even a beneficial effect of methyl supplements for relieving PMS symptoms has been discussed.27
The molecular key for a sufficient methylation process, the production of SAMe, can be supported by dietary supplements. Moreover, besides supplementation with SAMe itself, it has been shown that methylation can readily be promoted by oral administration of the methylation factors betaine, vitamins B6 and B12, and folates.
Just how extensive the influence of methylation supplements can be on the maintenance of human health remains to be seen. But if the extensive research findings already achieved are any indication, the future of these supplements looks good.
Dr. Christine Kraus (scientist), Dr. Robert Faurie (head of R&D and quality control,) and Dr. Lutz Thomas (head of sales and Marketing) work for Amino GmbH, Frellstedt, Germany.
Respond: [email protected]
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