Vol. 2, # 34
September 3, 2005

Q: What is homocysteine? - Layperson

A: Homocysteine is a potentially harmful substance found in the bodies of human beings and other animals. It is produced from the breakdown of an amino acid (building block of protein) called methionine. Methionine is used in the body for production of glucose and the breakdown of fats in the liver.

Too much of it is related to a higher risk of coronary heart disease, stroke and peripheral vascular disease (fatty deposits in peripheral arteries).There is a growing recognition that high levels of homocysteine are associated with heart disease. This started in the late 1960s when a pathologist in Boston encountered two children with homocystinuria, who, despite being very young, had advanced atherosclerosis, though the plaques contained no lipid. The pathologist concerned, Kilmer McCully, was given a hard time for putting forward the suggestion of a possible link between homocysteine and the formation of atheromatous plaque.

Homocysteine is a curious sulphur-containing amino acid formed during methionine metabolism. It can dimerise to homocystine, or form disulphide bonds with proteins to form so-called 'protein-bound' homocysteine. In plasma about 80% of homocysteine is protein bound.

Metabolism of homocysteine is by pathways which re-methylate it (and which require vitamin B12 and folic acid), or by a trans-sulphuration pathway which requires vitamin B6. Homocysteine in blood (and elsewhere) is a product of how much methionine is eaten, mainly in protein (with about three times more methionine in animal than plant protein), and how much is metabolised (and metabolism may be affected by amounts of B vitamins and folate available).

Evidence suggests that homocysteine may promote atherosclerosis (fatty deposits in blood vessels) by damaging the inner lining of arteries and promoting blood clots. However, a causal link hasn't been established.

Folic acid and other B vitamins help break down homocysteine in the body. Homocysteine levels in the blood are strongly influenced by diet and genetic factors. Dietary folic acid and vitamins B-6 and B-12 have the greatest effects. Several studies found that higher blood levels of B vitamins are related, at least in part, to lower concentrations of homocysteine. Other evidence shows that low blood levels of folic acid are linked with a higher risk of fatal coronary heart disease and stroke.

So far, no controlled treatment study has shown that folic acid supplements reduce the risk of atherosclerosis or that taking these vitamins affects the development or recurrence of cardiovascular disease. Researchers are trying to find out how much folic acid, B-6 and/or B-12 are needed to lower homocysteine levels. Screening for homocysteine levels in the blood may be useful in patients with a personal or family history of cardiovascular disease but who don't have the well-established risk factors (smoking, high blood cholesterol, high blood pressure, physical inactivity, obesity and diabetes).

Although evidence for the benefit of lowering homocysteine levels is lacking, patients at high risk should be strongly advised to be sure to get enough folic acid and vitamins B-6 and B-12 in their diet. They should eat at least five servings of fruits and green, leafy vegetables daily.

Caution: Elevated homocysteine levels can be caused by vitamin B12 deficiency due to impaired absorption of B12 caused by gastric atrophy (damage to the lining of the stomach). B12 deficiency leads to anemia and, if not corrected in time, will permanently damage the nervous system. Folic acid supplements will correct the anemia (which can serve as a warning sign before nerve damage develops), but they do not prevent the damage. For this reason, people over 50 who take folic acid supplements should also take at least 25 micrograms of vitamin B12 per day, a dose large enough to enable adequate amounts to be absorbed. Dr. Herbert believes that everyone over age 50 should take B12 supplements anyway, because gastric atrophy is common as people age. Products containing 100 mcg per pill are readily available.

Homocysteine is measured using a simple blood test. It can be measured at any time of day. It is not necessary to prepare in any special way for the blood test (such as fasting). Most hospital labs can measure homocysteine, or a blood sample can be sent out to a special lab.

A healthy homocysteine level is less than 12 µmol per L. A level greater than 12 µmol per L is considered high. If your homocysteine level is 12 to 15 µmol per L and you have blockages in any blood vessel, you need to lower your homocysteine to less than 12 µmol per L. If you have no other major risk factors for cardiovascular disease and you do not have atherosclerosis, it may be okay for you to have a modestly high level of homocysteine (12 to 15 µmol per L).

Some cardiologists suggest that coronary artery disease patients take a multivitamin supplement to lower their homocysteine levels. Patients who follow this advice, but fail to have their blood tested for homocysteine, could be making a fatal mistake.

A person can not blindly take vitamin supplements to adequately reduce homocysteine levels. While folic acid, vitamin B12, B6, and trimethylglycine (TMG) all lower homocysteine levels, it is impossible for any individual to know if he or she is taking the proper amount of nutrients without a homocysteine blood test.

The clear message from new scientific findings is that there is no safe "normal range" for homocysteine. While commercial laboratories state that normal homocysteine can range from 5 to 15 micromoles per liter of blood, epidemiological data reveal that homocysteine levels above 6.3 cause a steep, progressive risk of heart attack (the American Heart Association's journal Circulation, Nov. 15, 1995, 2825-30). One study found each 3-unit increase in homocysteine equals a 35% increase in myocardial-infarction (heart-attack) risk (American Journal of Epidemiology, 1996, 143[9]:845-59).

People taking vitamin supplements think they are being protected against the lethal effects of homocysteine when, in reality, even supplement users can have homocysteine levels far above the safe level of 6.3 to 7.0.

People who were suffering from coronary artery disease had lethal levels of homocysteine despite taking the recommended dose (and higher) of vitamin supplements.

The problem is that certain supplement users are not being protected against the damaging effects of homocysteine, and the only way of finding out is to have a blood test. When homocysteine is too high, the addition of extra amounts of vitamin B6 and/or TMG (trimethylglycine) has reduced levels to the safest range in every case we have worked with. The Foundation has found that the addition of extra folic acid produces only a moderate reduction in elevated homocysteine levels. Folic acid is a critical component of a homocysteine-lowering program, but there is a limit to how much homocysteine can be reduced by folate and vitamin B12. Cardiologists are increasingly recommending folic-acid supplements to their coronary artery disease patients, but it takes more than folic acid to reduce serum homocysteine to a level where it ceases to be a risk factor for causing a heart attack.

Elevated homocysteine can be reduced (or detoxified) in two ways. The most common pathway is via the remethylation process, where methyl groups are donated to homocysteine to transform it into methionine and S-adenosylmethionine (SAMe).

A potent remethylation agent is TMG, which stands for trimethylglycine. The tri means there are three methyl groups on each glycine molecule that can be transferred to homocysteine to transform (remethylate) it into methionine and SAMe. The remethylation (or detoxification) of homocysteine requires the following minimum factors: (1) folic acid, (2) vitamin B12, (3) zinc, and (4) TMG.

Choline is another "methyl donor" that helps to lower elevated homocysteine levels, and this conversion doesn't require cofactors. However, choline only enhances remethylation in the liver and kidney, which is why it is so important to take adequate amounts of remethylating factors such as folic acid and vitamin B12 to protect the brain and the heart. The published literature emphasizes that folic acid and vitamin B12 are critical nutrients in the remethylation (detoxification) pathway of homocysteine.

The other pathway in which elevated homocysteine is reduced is via its conversion into cysteine and eventually glutathione via the trans-sulfuration pathway. This pathway is dependent on vitamin B6. The amount of vitamin B6 required to lower homocysteine has considerable individual variability. Methionine is the only amino acid that creates homocysteine. People who eat foods that are high in methionine (such as red meat and chicken) may need more vitamin B6. Elevated homocysteine can occur when there are insufficient vitamin cofactors (such as folate and vitamin B6) to detoxify the amount of methionine being ingested in the diet.

Elevated homocysteine can also be caused by a genetic defect that blocks the trans-sulfuration pathway by inducing a deficiency of the vitamin B6-dependent enzyme cystathionine-B-synthase. In this case, high doses of vitamin B6 are required to suppress excessive homocysteine accumulation. Since one would not want to take excessive doses of vitamin B6 (greater than 300 to 500 mg a day for a long time period), a homocysteine blood test can help determine whether you are taking enough vitamin B6 to keep homocysteine levels in a safe range. There are some people who lack an enzyme to convert vitamin B6 into its biologically active form, pyridoxal-5-phosphate. In this case, if low-cost vitamin B6 supplements do not sufficiently lower homocysteine levels, then a high-cost pyridoxal-5-phosphate supplement may be required.

For many people, the daily intake of 500 mg of TMG, 800 mcg of folic acid, 1000 mcg of vitamin B12, 250 mg of choline, 250 mg of inositol, 30 mg of zinc, and 100 mg of vitamin B6 will keep homocysteine levels in a safe range. But the only way to really know is to have your blood tested to make sure your homocysteine levels are under 7. If homocysteine levels are too high, then up to 6 grams of TMG may be needed along with higher amounts of other remethylation cofactors. Some people with cystathione-B synthase deficiencies will require 500 mg a day or more of vitamin B6 to reduce homocysteine to a safe level. For the prevention of cardiovascular disease, you would want your homocysteine blood level to be under 7. For the prevention of aging, some people have suggested that an even lower level is desirable, but more research needs to be done before any scientific conclusions can be reached.

Elevated homocysteine can be a sign of a methylation deficiency throughout the body. Methylation is fundamental to DNA repair. If DNA is not adequately repaired, mutations and strand breaks will result. This will lead to accelerated aging, as greater amounts of faulty proteins are synthesized from the damaged DNA. The liver depends on methylation to perform the numerous enzymatic reactions required to detoxify every drug and foreign substance that the body is exposed to. Methylation is also required for the growth of new cells. Without it, new cells cannot be made.

A study published in the journal Medical Hypothesis (1998, 51[3]:179-221) provides evidence that aging may be exclusively a result of cellular "demethylation," or, said differently, the aging process is caused by the depletion of enzymatic "remethylation" activity that is required to maintain and repair cellular DNA. This study suggests that aging may be reversible if aged cells could be programmed to remethylate rather than demethylate.

Homocysteine induces cellular damage by interfering with the methylation process. Methylation will be compromised if homocysteine is elevated, and elevated homocysteine is a warning sign that the methylation cycle is not functioning properly. Homocysteine may also damage cells directly by promoting oxidative stress.

There is a growing consensus that deficient methylation is the major cause of the degenerative diseases of aging. The consumption of methylation- enhancing nutrients like TMG, choline, folic acid, and vitamin B12 may be one of the most readily available and effective anti-aging therapies presently known. However, it is important to tailor the intake of methylation-enhancing nutrients to one's individual biochemistry. The best way of assessing your body's rate of methylation is to measure blood levels of homocysteine. Elevated serum homocysteine is the classic sign of a methylation deficiency (or demethylation) that is correctable with the proper intake of methylation enhancing nutrients such as TMG, folic acid, and vitamin B12.

Recent studies show that people with dementia of the Alzheimer's type have elevated levels of homocysteine in their blood. At an international scientific conference held in The Netherlands the week of April 27, 1998, a team of scientists unveiled findings showing a definitive link between elevated homocysteine and Alzheimer's disease. The scientists advocated that people have their blood tested for homocysteine in order to determine how much folic acid should be taken to drop homocysteine levels to the safe range.

While the scientists speculated that Alzheimer's disease could be avoided if people reduced their homocysteine levels, it has not yet been determined whether homocysteine itself contributes to Alzheimer's disease. A more likely explanation is that elevated homocysteine is an indication of the severe disruption in the methylation pathway that occurs in the brains of Alzheimer's patients. It has been reported that people with Alzheimer's disease have virtually no S-adenosylmethionine (SAMe) in their brains. SAMe is required for DNA methylation (maintenance and repair) of brain cells. Thus, while homocysteine itself may not cause Alzheimer's disease, it appears to represent an important measurable biomarker of a methylation deficit that could cause Alzheimer's and a host of other degenerative diseases.

Research reported at Tufts University in 1995 documented the same finding linking elevated homocysteine and Alzheimer's disease and recommended supplementation with folic acid and vitamin B12. It should be noted that dementia can be caused by a deficiency of vitamin B12, folic acid, and other nutrients, so another reason for people with dementia of the Alzheimer's type have elevated homocysteine levels could be that they are suffering from a common vitamin deficiency. Numerous studies conducted on the elderly show that deficiencies of folic acid, vitamin B12, and other nutrients are epidemic in elderly people who do not take vitamin supplements. Since both elevated homocysteine and vitamin deficiencies have been linked to dementia, the best approach to preventing and treating dementia (including Alz- heimer's dementia) would appear to be testing the blood for elevated homocysteine and taking methylation enhancing nutrients such as folic acid, TMG, and vitamin B12.

A review of the published literature provides compelling evidence that elevated homocysteine is common in people suffering from dementia of the Alzheimer's type. Since Alzheimer's disease cannot be positively diagnosed until after death, it is impossible to state whether all the people in a scientific study are really suffering from Alzheimer's disease. Dementia can be caused by multi-infarct cerebrovascular disease or even by simple vitamin deficiencies.

In a study published in the International Journal of Geriatric Psychiatry (April 1998, 235-239), Dr. McCaddon and his group were able to confirm that patients diagnosed with senile dementia of the Alzheimer's type have significantly elevated levels of homocysteine compared to age-matched controls. An earlier study published in the Journal of Gerontology and Biological Sciences (March 1997, 76-9) also showed that homocysteine levels were significantly elevated in Alzheimer's disease patients compared to controls. This study found that folic acid and vitamin B12 deficiencies were present in both the Alzheimer's disease patients and the age-matched case controls.

The reason that homocysteine levels are so high in people suffering from dementia of the Alzheimer's type is not fully understood. Scientists speculate that severe aberrations in the methylation cycle might be involved in the disease process and that elevated homocysteine is a sign of the breakdown of the methylation cycle (European Neuropsychopharmacol. (June 1995, 107-14). Other researchers report that abnormal amino acid metabolism early in Alzheimer's causes elevated homocysteine levels. This may lead to neuronal damage that occurs as the disease progresses (Journal of Neural Transmission (1998, 105:[2-3]:287-94). Remember, the repair and maintenance of cellular DNA is dependent on healthy methylation processes. Methylation deficiencies result in severe damage to brain cells. Under-methylation can cause severe damage to brain cells. Methylation is required for the maintenance of the myelin sheath and the repair of DNA in the brain. Elevated levels of homocysteine in the blood indicate some degree of methylation deficiency that is correctable with an individualized supplement program.

The studies showing that homocysteine is a biomarker for the development of dementia of the Alzheimer's type mandates that those seeking to avoid senility should have their blood tested in order to ascertain their homocysteine levels. While it was apparent in the year 1969 that homocysteine was a major cause of vascular disease, the evidence that homocysteine represents a marker of brain cell degeneration is of very recent origin, and has been overlooked by many conventional neurologists.

Despite the evidence linking elevated homocysteine to methylation deficiencies that are involved in the Alzheimer's disease process, the Alzheimer's Disease Society has criticized the recommendation that people take folic acid supplements to lower their homocysteine levels. What follows is a direct quote from that organization, "No one knows whether taking (folic acid) supplements will help prevent the disease or whether it will affect the rate at which the disease progresses. The only way this will be discovered is by doing further studies on many, many more patients over a long period of time." It is a perplexing the concept that anybody would warn against taking folic acid supplements at a time when the conventional medical establishment has acknowledged that taking folic acid lowers homocysteine and protects against heart attack, stroke, and colon cancer.

The associations between homocysteine levels and the risk of bone fracture appear to be independent of bone mineral density and other potential risk factors for fracture.

An increased homocysteine level appears to be a strong and independent risk factor for osteoporotic fractures in older men and women.

Overweight children with high levels of the hormone insulin in their blood are also likely to have high levels of homocysteine, a substance that appears to raise the risk of heart disease, stroke, and birth defects, as well as possibly other adverse effects as well.

In addition, these children and adolescents appear to have lower levels of folate, a vitamin that can lower homocysteine levels.

The combination of elevated homocysteine and reduced folate could put these children at increased risk for developing heart disease, explain researchers from the University of Graz in Austria, who studied the link in 84 children and adolescents.

Measuring blood levels of homocysteine is a new and potentially life-saving test that provides information about vitamin and methylation status, in addition to determining levels of toxic homocysteine. Those with a family history of heart disease, stroke, or Alzheimer's disease are at a particular risk for elevated homocysteine. Elevated homocysteine has also been linked to complications in diabetes, lupus, and other chronic diseases. While many people have assumed that because they are taking vitamin supplements, their homocysteine levels will be in a safe range, The Life Extension Foundation has discovered that this might not always be the case.

The only way of knowing for sure is to get tested. Homocysteine testing used to be expensive, but prices have come down as consumer interest has increased.

The newest scientific evidence indicates that there is no safe "normal range" for homocysteine. However, epidemiological data reveal that homocysteine levels above 6.3 cause a steep progressive risk of heart attack. Homocysteine levels should be medically tested to ensure that the proper combination and dosages of supplements are taken. Dosages should be adjusted based on individual needs. The following supplements have demonstrated effectiveness in lowering homocysteine levels either alone or in combination:

  1. Folic acid, 800 to 5000 mcg a day.
  2. Vitamin B12, 1000 to 3000 mcg a day.
  3. Vitamin B6, 100 to 500 mg a day.
  4. Zinc, 30 to 90 mg a day.
  5. Choline, 250 to 3000 mg a day.
  6. Trimethylglycine, 500 to 9000 mg a day.
  7. SAMe, 200 to 800 mg a day.
  8. Inositol, 250 to 1000 mg a day. 

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DISCLAIMER:  The information in this column, is NOT intended to diagnose and/or treat any health related issues and is provided solely for informational purposes only. Consult the appropriate healthcare professional before making any changes to your healthcare regime. Even what may seem like simple changes in the diet for example, can interact with, and alter, the efficiency of medications and/or the body's response to the medications. Many herbs and supplements exert powerful medicinal effects. Neither the author, nor the website designers, assume any responsibility for the reader's use or misuse of this information.

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