What Is The Process of Methylation

Methylation is the process of putting a methyl group (one carbon atom and three hydrogen atoms), on proteins, enzymes, chemicals, DNA, or amino acids like homocysteine. Methylation is a process necessary for many biological functions.

Methylation is involved in maintaining DNA integrity, processing fats, improving neurological function, detoxifying the liver, and is connected to nearly every biochemical process in the body. Several scientific peer-reviewed articles have demonstrated that this methylation process degrades with age which is associated with a large variety of age-related diseases.

Usually, this methylation process occurs through a chemical called s-adenosylmethionine (SAM). SAM, increased by the dietary methyl donors, requires proper mineral balance. As a result, many researchers suggest additional minerals to help the body maintain proper methylation. lencopyrighted lencopyrighted

What Is Homocysteine

Homocysteine is a toxic amino acid that is present in everyone. As a non-essential amino acid, the research on homocysteine got off to a late start, beginning in earnest in the 1960's. Several cases of children dying of vascular damage usually reserved for older people were noted in the medical literature. In 1968-69, Dr. Kilmer McCully studied the cases and noted that the only known problem was a genetic defect in the children's ability to lower homocysteine. He theorized that homocysteine must be able to cause vascular disease, and given the weakness in the current theories, proposed homocysteine as a cause of vascular disease in the general population.

Dr. McCully performed a variety of animal experiments confirming his hypothesis, but it would take a large scale human epidemiological study before his hypthesis would be accepted. That study was finally completed in 1994 and published in the Journal of the American Medical Association, authored by another Harvard researcher. Dr. Meir Stampfer (oddly, Dr. McCully was denied tenure at Harvard decades earlier). Since the 1994 study, many studies have confirmed homocysteine's role in vascular disease, from stroke, to myocardial infarction (heart attack) to carotid artery damage and more! Now homocysteine is the most talked about risk factor for vascular disease. lencopyrighted lencopyrighted

One of the saddest aspects of this history is that for decades the research not only pointed to homocysteine's damaging effect on the vascular system, but it also clearly demonstrated how to control this risk factor. Proper application of nutrition and nutritional supplementation could have saved thousands, if not millions of lives. Today, homocysteine is starting to get the attention it deserves, but still only a small fraction of the population are aware of its role in vascular disease. This is particularly surprising since a recent report in the medical literature demonstrated a greater than 60% decrease in vascular disease among users of nutritional supplements containing some of the nutrients required to lower homocysteine,

With proper nutritional supplementation nearly all cases of elevated homocysteine can be resolved and dramatically improved. Even people with previously diagnosed vascular disease have survival dependent on their homocysteine levels.

Even though homocysteine's role in heart and vascular disease has now been accepted, the field is still in its infancy. Homocysteine can be found in several forms in the blood. Some forms, like homocysteine thiolactone, are thought to be more damaging than other forms. In addition, homocysteine seems to increase the damaging efffects of fibrinogen and lipoprtoein-a, thereby increasing clotting while decreasing the ability of the blood vessels to contract and expand. These damaging effects appear to be
separate from the direct damage to the blood vessels by the irritant, homocysteine.

Methylation and Homocysteine

While there is a considerable amount we do not know about homocysteine (like why exercise reduces it), we do know how to use nutritional supplements to reduce homocysteine levels. This is done through three independent routes: (1) using folic acid with vitamin B-12, (2) using trimethylglycine (TMG), and (3) through B-6. The first two are called methylation, and the last is called transsulfuration.

Methylation is the process of putting a methyl group (one carbon atom and three hydrogen atoms), on proteins, enzymes, chemicals, DNA, or amino acids like homocysteine. When a methyl group is transferred from folic acid to homocysteine, the homocystein is converted to the essential amino acid, methionine. When a methy group is transferred from TMG to homocysteine, the homocysteine is similarly converted to methionine (and TMG is converted to dimethylglycine). This process of methylation results in lower homocysteine and an increase in methionine. In fact, nearly twice the dietary level of methionine is produced during this conversion process. lencopyrighted lencopyrighted

Both folic acid and TMG have been used for nearly two decades to lower homocysteine. These two pathways are independent. Some people are better at using TMG to lower homocysteine and others are better at utilizing folic acid. That is why the literature suggests using both TMG and folic acid to lower homocysteine (folic acid requires B-12 for this activity). Such a combined approch, in conjunction with vitamin B-6, can normalize homocysteine in 95% of the people studied (Choline is also used as a methyl donor, as has been noted in JAMA, although its role is secondary to TMG).

Vitamin B-6 and Transsulfuration

The remaining method of lowering homocysteine is through a process using vitamin B-6. This is a separate process from methylation. Using B-6, the cells convert homocysteine to cystathionine and then to cysteine where it is either further processed and excreatedk or used in protein metabolism. This important method of lowering homocysteine is particularly relevant in the U.S. because B-6 is very unstable, and in today's diet of processed foods B-6 is destroyed and usually needs to be supplemented. In addition, B-6 is destroyed by smoking or birth control pills, which can explain the recent rise in vascular disease in women (remember vascular disease is cumulative, so women who started the pill in the 60's are now showing the results).

Supplemental B-6 is usually supplied in the form of pyridoxine HCL, even though the body uses B-6 in the form of pyridoxal 5' phosphate. Some people are not as efficient in converting pyridoxine HCL to pyridoxal 5' phophate, so a combined formulation is often suggested to insure that the B-6 is utilized.

Who's at Risk for Disorders Related to Homocysteine and Poor Methylation

1. Do you excercise less than three times a week? While excercise has long been known to help prevent many diseases including cardiovascular disease, there was no biological explanation until recently, when it was discovered that the risk factor known as homocysteine is reduced during exercise. lencopyrighted lencopyrighted
   
   
2. Is a significant amount of your diet derived from a box, a can, a bag, a freezer, or fast food? Processing foods removes vital nutrients required to maintain health. Processed foods contain a fraction of the critical vitamins, B-6, B-12, and folic acid. These nutrients are required to lower homocysteine and prevent cardiovascular disease. In addition, lack of these nutrients is related to carpal tunnel syndrome, anemia, polyp formation, rickets, and a variety of neurological and developmental conditions.
   
   
3. Did anyone in your family suffer from vascular disease? Recently, a genetic weakness in the body's ability to lower homocysteine has been linked to premature vascular disease. If your parents, grandparents, aunts, or uncles suffered from strokes, heart attack, angina, or any vascular disease, you are at an increased risk for vascular disease even if all your standard risk factors are normal. Fortunately, researchers have discovered that betain (TMG), combined with B-6, B12, and folic acid, can prevent much of the damage created by this silent genetic defect.
   
   
4. Do you eat less than three courses of vegetables and fruits per day, or consume a typical high protein diet? While the benefits of moderate protein intake and an abundance of fruits and vegetables have long been advocated by health professionals, it is often unrealistic. Recently, the government reduced the reccommended daily allowance (RDA) for folic acid simply because so few people were obtaining the required amount for proper health -- not because the body suddenly rrquired less vitamins. Only a diet high in fresh vegetables and fruits combined with moderate protein can keep our homocysteine levels low and allow for optimal health and longevity. In response to the reality of the American diet, the government has advocated using supplements in many foods, especially the methyl donor folic acid and B-6. lencopyright
   
   
5. Do You eat commercial non-organic vegetables and fail to eat foods high in minerals? Foods high in minerals include organic vegetables and sea vegetables. Both are common in Japan where both vascular disease and many of the types of cancer found in the U.S. are significantly less common. Minerals such as Zinc, Copper, and Magnesium are required to allow the enzymes that lower homocysteine to function properly and maintain proper DNA methylation (described later).
   
   
6. Is there a history of depression, neurological disease, fatty-liver, or "weak" liver in your family? Often, depression and neurological disease are related to low S-adenosylmethionine levels (SAM), which are directly related to high homocysteine levels and poor methlation. Research journals have shown that the nutritional supplement betaine and the other methyl donors can significantly elevate the level of SAM. SAM is beneficial not only for depression, but has proven useful for some liver problems as well.
   
   
7. Do you smoke, or use birth control pills? Both smoking and birth controls pills elevate homocysteine levels.

If you answer 'YES" to ANY of the questions above, you are at risk for disorders related to homocysteine and poor methylation.

Scientific References

1. JAMA¹ (vol. 277, No. 22, pg. 1776-1781, 1997)"In this study, users of vitamin preparations containing these nutrients appear to experience substantial protection from vascular disease, with a relative risk of 0.38 (95% CI 0.2-0.72) compared with nonusers of vitamins." [Interpretation: If a group of nonusers of vitamins contained 100 people with vascular disease, the same size group of vitamin users would expect only 38 people with vascular disease.]
   
   
2. Lancet² (vol. 349, pg. 397. Feb 8, 1997) The present data extend the previous view that an increased level of plasma Hcy (homocysteine) may be a risk factor for CVD (cardiovascular disease)."
   
   
3. JAMA³ (vol. 268, pg. 877-881. Aug. 12, 1992) "Moderately high levels of plasma homocyst(e)ine are associated with subsequent risk of MI (myrocardial infarction) independent of other coronary risk factors. Because high levels can often be easily treated with vitamin supplements, homocyst(e)ine may be an independent, modifiable, risk factor." "Elevated homocyst(e)ine levels can often be normalized by modest doses of folate (1 to 5 mg/d). For cases that are resistant to this therapy, the addition of vitamin B6, choline, or betaine, is often effective. These supplements at the recommended dosages have few or no side effects under most circumstances."
   
   
4. Journal of Nutrition⁴ (vol. 126, pg. 1295s-1300s, 1996) "Long-term betain (TMG) supplementation of 10 patients, who had pyridoxine-resistant homocystinuria and gross hyperhomocysteinemia due to a deficiency of cystathionine ß-synthase activity, caused a substantial lowering of plasma homocysteine, which has now been maintained for periods of up to 13 years...We have found that prolonged betaine treatment, taken with concurrent vitamin B-6 and folic acid therapy, maintained its initial promise of lowering plasma homocysteine concentrations substantially in all patients."
   
   
5. JAMA⁵ (vol. 274, No. 19, pg. 1532, 1995) "(the data suggest) that exercise, especially heavy physical activity exerts its most favorable effect in subjects with hyperhomocysteinemia. Several studies have shown that there is a dose-dependent reduction in risk for coronary heart disease with physical activity, and a greater benefit has been demonstrated in older age groups. Since this effect cannot be fully explained by changes in other established risk factors, decreased plasma tHcy (total homocysteine) level may contribute to the beneficial effect of physical activity on coronary risk." "...in patients with homocystinuria, the risk of a fatal thromboembolic event is substantially reduced after Hcy-lowering therapy." lencopyright
   
   
6. Lancet⁶ (vol. 346, pg. 1395-98, 1995) "These findings suggest that tHcy (homocysteine) is a strong and independent risk factor for stroke." "Moderately elevated Hcy concentrations, reflecting less severe genetic defects and deficiency of nutritional factors required for Hcy metabolism (folic acid, vitamin B12, vitamin B6) are common in the general population. There are consistent data from more than 20 cross-sectional and case-control studies linking moderate hyperhomocysteinaemia with vascular disease, including peripheral vascular disease, ischaemic heart disease and stroke."
   
   
7. Lancet⁷ (vol. 349, pg. 1102-1103, April, 1997) "Conversely, macroangiopathy at the level of the heart and legs is associated with clinical signs of microangiopathy, such as retinopathy and kidney disease. Thus, moderate hyperhomocysteinaemia may represent a mechanism that accounts for the concomitant presence of the two conditions in patients with insulin-dependent diabetes."
   
   
8. New England Journal of Medicine⁸ (vol. 337, pg. 230, July 24, 1997) "Plasma total homocysteine levels are a strong predictor of mortality in patients with angiographically confirmed coronary artery disease."
   
   
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