Methyl-donors:

Preventing & Reversing of the Atherosclerosis-Process

Children with homocystinuria,, regardless of the particular enzyme defect causing the elevated homocysteine level, develop arteriosclerosis, despite normal cholesterol levels. In 1933 an 8-year old boy was found to have dislocated lenses, some mild developmental abnormalities, and mental retardation. He was admitted to the hospital with symptoms and signs of a stroke and died of a stroke three days later. In the analysis of the case, the pathologist reported severe arteriosclerosis of the carotid arteries with thrombosis and cerebral infarction. This child appeared to have abnormalities of the arteries resembling the arteriosclerotic changes one ordinarily sees in an elderly individual.

Methyl Donor Summary:

TMG = Trimethylglycine = Gly (Glycine, amino acid) + 3 methyl groups (-CH3)

  • Converts to DMG on donation of first methyl group
  • Increases SAMe, dopamine, serotonin, and norepinepherine levels
  • Reduces Homocysteine levels by converting it to SAMe
  • Methylates DNA, providing a protective coating against genetic damage by free radicals
  • Elevates mood
  • Oxygenates tissue including brain in mental disorders
  • Improves immunity
  • Enhances energy and physical stamina

DMG = Dimethylglycine = Gly + 2 methyl groups

  • Relieves muscle spasms (heart and skeletal muscle)
  • Increases immunity

SAMe = S-Adenosyl-Methionine = Met (Methionine, amino acid) + 1 methyl group

  • Elevates mood
  • Normalizes high liver enzymes

Methionine is an amino acid that can donate a methyl group.

Vitamin B6

  • 30-40 percent of elderly get less than RDA level
  • RDA level is about half that needed to prevent atherosclerosis
  • Increase in the requirement in rheumatoid arthritis, associated with elevation of Homocysteine
  • Carbon monoxide in cigarette smoke inactivates Vitamin B6
  • 75 percent reduction in the risk of angina pectoris and myocardial infarction with supplementation of 50-200 mg/day

Vitamin B12

  • Pernicious anemia affects nervous system, blood formation
  • Deficiency more common among vegetarians and elderly

Folic Acid

  • The most commonly deficient vitamin in America
  • Prevents birth defects (neural-tube)

Choline

  • Another B-vitamin with the ability to donate a methyl-group.

Homocysteine = toxin; indicator of methyl group depletion

  • 1500 publications link homocysteine and vascular heart disease
  • Three-fold increase of the risk of a heart-attack with an elevation of the homocysteine-level (Harvard School of Public Health, 1992)
  • Blood levels correlate with cardiovascular disease much more strongly and independent of cholesterol levels (although LDL and cholesterol transport Homocysteine to the endothelial site of tissue damage and Homocysteine stimulates storage of cholesterol and fats in fibrolipid plaques)
  • Increases production of fibrous tissues of sulfated glycosaminoglycans and the destruction of elastin fibers in the artery wall leading to the formation of fibrous plaques
  • Cerebrospinal fluid (CSF) levels correlate with chronic fatigue and fibromyalgia
  • Interferes with cellular oxygen utilization
  • Promotes free radical generation and oxidation of cell components
  • Triggers endothelial cell damage and proliferation
  • Oxidation of low-density lipoproteins (LDL) produces oxycholesterols, oxidized fats and proteins in developing plaques
  • Stimulates growth of smooth muscle cells, deposition of extracellular matrix and collagen, and a thickening and hardening of artery walls.
  • Reactive form, homocysteine thiolactone increases platelet aggregation and clot formation (e.g. coronary thrombosis, myocardial infarction, stroke)
  • Even low levels cause fibrin to bind to lipoprotein (a) which is linked to thrombosis in coronary heart disease.
  • Affects protein C, factor 7, factor 12, and other clotting factors.
  • Malignant cells have a blockage in the conversion of homocysteine thiolactone to sulfate.
  • In healthy cells, homocysteine thiolactone combines with vitamin A acid (retinoic acid), forming thioretinamide. Thioretinamide combines with vitamin B-12, forming thioretinaco. These substances are anticarcinogenic and antineoplastic in animal studies. The activation of thioretinaco may be via ozone-oxidation of the sulfur atoms in homocysteine.
  • Elevation in rheumatoid arthritis, with immune lymphocytes reactive to a homocysteine-alteration of the HLA antigens
  • Increased by excess intake of protein as a source of methionine
  • Coronary heart disease associates with an increase in the production of Homocysteine with dietary methionine intake. (Drs. Bridget and David Wilcken of Australia, 1976)
  • Elevation of the risk of a neural-tube-defect is with the association of elevation of an increase in the homocysteine in the mother and in the amniotic fluid in a mother with a low-folate-level.
  • Converts with methyl donation to S-Adenosyl-Methionine (SAMe)
  • 12% of population requires especially high methyl donor levels to help an inefficient reductase enzyme keep homocysteine levels low.
  • Over age 60 homocysteine increases one micromole per liter for every ten years of age, contributing strongly to aging
  • Prior to menopause, women (6-10 micromoles per liter) benefit from an average of 2 micromoles less homocysteine than men (8-12) the same age
  • Levels are higher with low thyroid function
  • Cigarette smoke, alcoholism and the drugs methotrexate, nitrous oxide, and azaribine increase Homocysteine levels
  • Exercise decreases Homocysteine levels
Keywords:

Aging
Arteriosclerosis
Artery wall thickening
Brain
Cancer
Cardiovascular disease
Chronic fatigue (CFIDS)
Coronary thrombosis
Depression
DNA-protection
Fibromyalgia
Fibrous and fibrocalcific plaques
Gangrene
Heart disease
Homocystinuria
Liver disease
Mental disorders
Myocardial infarction (MI)
Neurological disease
Peripheral vascular disease
Rheumatoid arthritis
Stroke
Vascular events (reduced 2/3 by supplementation)

Dosages:

Supplement: Optimum-Dosage-Range: Frequency: Timing:
TMG 1500-2500 milligrams Divide-dose Best with an empty-stomach.
Vitamin B6 3.5 - 200 milligrams Divide-dose Best with an empty-stomach.
Folic acid 350-1000 micrograms Divide-dose Best with an empty-stomach.
Vitamin B12 5 - 1000 micrograms Divide-dose Best with an empty-stomach.

The Homocysteine-Theory

Dr. Kilmer McCully, author of "The Homocysteine Revolution" (Keats Publishing, 1997) is a graduate of Harvard College in 1955 and Harvard Medical School in 1959, where he received degrees in chemistry, biochemistry and medicine. Following his internship in internal medicine at Massachusetts General Hospital, he received fellowship training in biochemistry, molecular biology, and genetics at National Institutes of Health, Massachusetts General Hospital, Glasgow University in Scotland and Harvard University. Following his residency in pathology at Massachusetts General Hospital, he became Associate Pathologist and Assistant Professor of Pathology at Harvard Medical School. Additional appointments were Visiting Professor of Laboratory Medicine at University of Connecticut and Associate Professor of Pathology at Brown University. He has served as a pathologist at the Veterans Affairs Medical Center in Providence since 1981.

In an interview with Richard A. Passwater, Ph.D. in Whole Foods magazine (WFC Inc.), Dr. McCully says: �The majority of patients who have severe coronary heart disease and arteriosclerosis have cholesterol levels in the normal range. I did a study of our Providence Veterans population in 1990 and I analyzed just this point. In a consecutive series of 194 autopsies, the degree of arteriosclerosis was carefully assessed based on the autopsy findings. The records were then examined for the cholesterol levels in these veterans who had died. It was very surprising to me to find that in the group with the most severe coronary heart disease about 85 percent of these veterans had levels lower than 250 milligrams per deciliter. Only about 15 percent had distinctly elevated cholesterol levels above 250, and the mean level for that group was 186 milligrams per deciliter, well within the recommended guidelines of several of the major agencies. In looking at the group as a whole, among those with severe arteriosclerosis, about two-thirds of the veterans had no evidence of elevated cholesterol, diabetes, or elevated blood pressure.�

�The normal level of homocysteine in the blood for a middle aged man is about 8 to 12 micromoles per liter, so a 50 percent increase in this would be up to 17 micromoles per liter. In different human studies, this level of homocysteine in the blood has been shown to be associated with an increased risk of development of myocardial infarction, as shown by the Physicians Health Study, and for thickening of the carotid arteries, as shown by the Tufts Nutrition Center and Framingham Heart study, and also for increased risk of coronary cerebral and peripheral vascular disease throughout the body.�

�I was able to publish the basic elements of the theory until about 1975, when the chairman of my department retired. The new chairman informed me that I would have to support my work in some way but no he made no effort to help obtain this support. My laboratory was removed from the department to another part of the hospital. It was made clear to me that I should look elsewhere for support. The Director of the hospital told me that Harvard Medical School believed that I hadn't proven my theory.�

 

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