This crucial B-vitamin does battle with the villainous homocysteine in the heart, the brain, and throughout the body 

Don't be judgmental, people say - it's not nice. Well, the heck with nice. Some things deserve a kick in the butt, and one of them is homocysteine. It may be an amino acid and a natural component of all our cells, but it's a bad molecule. So there.

In this article, we'll see how bad a molecule homocysteine can be (really bad!), but we'll also see its counterpoint: a molecule, folic acid, so good that we should be sure to get plenty of it, because the good molecule helps keep the bad molecule from being so bad. It really is as simple as that. You'll see.

But first, some background. It has long been known that folic acid (which is a B vitamin without a number) is extremely important for preventing certain neurological disorders, called neural tube defects, in the developing embryos of pregnant women. Two examples are spina bifida (an imperfectly closed spinal column) and anencephaly (the congenital absence of most of the brain and spinal cord). With sufficient folic acid, the risk for these tragic conditions plummets.

Please, Sir, May I Have Some More Folic Acid in My Gruel?

The value to society of preventing maladies such as those is so great that folic acid is now routinely added to all refined cereal grains sold in the United States. This program, begun in 1998, was mandated by the FDA. The grains are fortified with 140 micrograms (mcg) of folic acid per 100 grams of product (1 microgram is 1/1000 of a milligram, so 100 mcg = 0.1 mg).

It is estimated that the FDA mandate has increased the American consumer's average daily consumption of folic acid by about 100 mcg over what it used to be. Nonetheless, folic acid deficiency is probably the most common vitamin deficiency in the United States, affecting about 10% of the population.*1 The FDA's Recommended Daily Allowance for folic acid is 400 mcg, so the balance has to be obtained through foods or supplements. Folic acid is found naturally in whole grains, citrus fruits, green vegetables, and beans (but cooking can destroy it).

*Most of the information on folic acid and homocysteine in this article is taken from the paper cited here, a review of the literature in the field by Dr. Mark P. Mattson et al. of the Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, and the Department of Neuroscience, The Johns Hopkins University School of Medicine.

Folic Acid Protects Your Vascular System

Well, fine, you say, but if I don't happen to be a pregnant woman, what can folic acid do for me? A lot, as it turns out. It has also been known for a long time that folic acid has a strong protective action against heart disease, by suppressing blood levels of homocysteine, one of the many chemical compounds whose levels increase - to our disadvantage - as we age. Elevated homocysteine levels are strongly linked to an increased risk of vascular disease - cardiovascular disease in particular, but also cerebrovascular disease and peripheral vascular disease (including deep venous thrombosis).

Excess homocysteine is so harmful, in fact, that it is thought to be as important as cholesterol, if not more so, as a cause of atherosclerosis, and thus of coronary heart disease and stroke. But . . . folic acid to the rescue! Mattson et al. say, "Dietary supplementation with folate can normalize plasma homocysteine levels and may thereby reduce the risk of cardiovascular disease. . . . Indeed, the available data on dietary folate intake and coronary heart disease risk suggest that the current recommended daily intake of folate may be suboptimal." (Folate is the chemical form in which folic acid is most commonly found in the body; for all practical purposes, the two terms are synonymous.)

More Folic Acid Is Better

"May be suboptimal" is a polite way of saying "inadequate." A more hard-nosed approach to the question of how much folate we ought to be ingesting every day was taken by a group of researchers from the United States and the Netherlands, who did a detailed cost-benefit analysis in terms of the coronary heart disease it could reduce or prevent, and the lives it could improve or save.2 Their conclusion was that, beyond the grain fortification imposed by the FDA, we should all be taking 1000 mcg (1 mg) of supplemental folate per day, as well as 500 mcg (0.5 mg) of supplemental vitamin B12.*(For a detailed discussion of this study, see "Fight Alzheimer's and Heart Disease with B-Vitamins" in Life Enhancement, December 2001.)

*In its action against elevated homocysteine levels, folic acid works in concert with vitamins B12 and B6. Both are very important for this purpose, in addition to the countless other vital roles they play in human physiology. Getting sufficient B12 daily becomes more difficult as we grow older, because our ability to absorb it diminishes with age. Hence the recommendation for a lot more B12 along with a lot more folate.

Homocysteine Wreaks Havoc on Blood Vessels

Excess homocysteine is believed to harm our blood vessels by damaging the endothelium, the thin layer of smooth, tightly packed cells that line the vessels' inside walls. The damage makes these cells more hospitable to the formation of atherosclerotic plaque, which clogs the vessels. Endothelial cells play a vital role in the expansion or contraction (as conditions warrant) of our blood vessels, and dysfunction of these cells can contribute not only to atherosclerosis but also to hypertension (high blood pressure), by preventing blood vessels from expanding when necessary to allow the freer flow of blood. It is believed that excess homocysteine impairs the function of endothelial cells by several different mechanisms and that, under some circumstances, it may even kill them.


Folic Acid, Vitamin B12, & Vitamin B6 - A Versatile Trio

Folic acid, in addition to its role in suppressing homocysteine levels (with the help of vitamins B12 and B6), is important in the formation of red blood cells (with the help of vitamin B12) and the metabolism and utilization of proteins and amino acids. It is vital for all processes involving cell division, and, like B12, it plays a critical role in the production of DNA and RNA. Folic acid should always be taken in conjunction with B12, because too much of one can mask a deficiency in the other.

Vitamin B12 (cyanocobalamin) was the last vitamin to be discovered, in 1948, and its functions are still not entirely understood. It is essential for cell replication and plays a critical role in the production of DNA and RNA. It supports growth, appetite, and the formation of red blood cells and myelin sheaths (the insulating sheaths on nerve fibers). It may also be involved in the production of brain neurotransmitters, and it is used in the treatment of various mental disorders.

Vitamin B6 (pyridoxine) figures in so many life-supporting functions in metabolic reactions in our bodies - more than any other vitamin or mineral - that it is regarded as the most important of the B vitamins. It is necessary for the production of red blood cells, for protein metabolism, for energy production from food, and for maintaining a healthy nervous system, among others. In general, it can be viewed as the "feel-good" vitamin. It is helpful in preventing heart disease and alleviating the symptoms of PMS, asthma, and even carpal tunnel syndrome.

In addition to facilitating the formation of atherosclerotic plaque and contributing to hypertension, there is evidence that excess homocysteine may also facilitate the formation of blood clots that can lead to cardiovascular or cerebrovascular "events" (as in "fatal"). And as if all that weren't enough, homocysteine also inhibits angiogenesis,the formation of new blood vessels where they are needed, such as for healing wounds and for restoring blood flow to tissues that have been injured in some way.

Folate Reduces the Risk of Cancer

Angiogenesis of the kinds just described is obviously desirable. But this process is a double-edged sword, and the other edge cuts the wrong way. When angiogenesis occurs in or around tumors, it promotes their growth and facilitates their metastasis (spread) to other parts of the body. But wait - by inhibiting angiogenesis, therefore, homocysteine should have some value in combating cancer, right? Perhaps it does, but it's not enough to matter, because elevated homocysteine levels, not content with wreaking all the vascular havoc outlined above, are linked to an increased risk for several cancers, colorectal in particular.

Here again, it's folate to the rescue, because studies have shown that when folate levels go up, homocysteine levels go down, and so does the risk of those cancers. Another way to put it is that low levels of folate are associated with an increased risk of cancer - as well as the other diseases discussed above.

Homocysteine Gets on Your Nerves - and Kills Them

But does the bad in homocysteine - and thus the good in folate - stop there, finally? Not on your life (and your life does depend, to a degree, on your having enough folate in your system to keep the homocysteine in check). Remember the link between low folate and neural tube defects, mentioned above? The villain there was homocysteine. If this malevolent molecule can disrupt neural function at the outset of life, can it do so nearer the end of life as well?

Apparently yes. Elevated homocysteine levels (low folate levels) are associated with an increased risk of both Alzheimer's disease and Parkinson's disease, and there is evidence that they may also be implicated in Huntington's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), and epilepsy. Furthermore, deficiencies in folate and vitamin B12 are associated with cognitive and other neurological functions that commonly occur with aging. The homocysteine link in all of these apparently has to do with this bad molecule's propensity to damage and even kill neurons (nerve cells) by doing certain kinds of damage to DNA molecules.

Homocysteine Is Depressing

If all this damning information about homocysteine (which should probably get some kind of booby prize for biological destructiveness) is depressing, wait until you hear what's next in the litany of its offenses. Homocysteine, whose levels increase with age, is also implicated in . . . depression, an affliction that becomes ever more prevalent with age. Coincidence? Apparently not. There is a well-established correlation between the two, and correcting the low levels of folate and vitamin B12 commonly found in depressed individuals alleviates the incidence and severity of depression.



The Homocysteine-Thyroid Connection

It may not be coincidental that two of the common consequences of aging are declining levels of thyroid hormones (a condition called hypothyroidism, or low thyroid) and increasing levels of homocysteine. These two phenomena are apparently related, as it has been found that restoring thyroid levels to normal through supplementation with thyroid hormones significantly reduces serum homocysteine levels - a desirable outcome.

In one study, for example, it was found that normalizing thyroid hormone levels in 14 hypothyroid patients sharply reduced their homocysteine levels, with a median drop of 44%.1 (Further evidence of the benefits of thyroid hormone therapy in this regard can be found in the article "Another Way to Help Your Heart" in Life Enhancement, August 2000.)

With respect to heart disease, the association between thyroid deficiency and elevated homocysteine levels is one-half of a double whammy, the other half being the association between low thyroid and elevated cholesterol levels. (For more on the latter subject, see "Help Your Heart With Thyroid Hormones" in this issue.)

  1. Hussein WI, Green R, Jacobsen DW, Faiman C. Normalization of hyperhomocysteinemia with L-thyroxine in hypothyroidism. Ann Intern Med 1999 Sep 7;131(5):348-51.

Homocysteine Is Two-Faced

We're not done with homocysteine yet, because there is still . . . schizophrenia. When homocysteine levels are high and folate levels are low, there is an increased risk of this disease, but when homocysteine levels are normal and folate levels are low, there is noincreased risk. This suggests that homocysteine is involved in the pathogenesis of schizophrenia.

It's enough to drive you to drink. Uh-oh, better not, because homocysteine is even linked with . . . alcoholism! Yes, alcoholics have very low folate and vitamin B12 levels, and it's likely that the associated high homocysteine levels contribute to the various pathologies associated with alcohol, including liver disease and cognitive and motor dysfunctions.

Will It Never End?

Did we mention type 2 diabetes? And rheumatoid arthritis? And more? It's all there in the paper by Mattson et al., who conclude by saying:

As can be appreciated from this brief review of the literature, elevated homocysteine levels are associated with a broad array of age-related diseases. There are a number of approaches that can be taken to lower homocysteine levels and that would, therefore, be expected to reduce the risk of various disorders during aging. The major approach already in use is dietary supplementation with folate (typically 400 mcg per day). Dietary supplementation with vitamins B12 and B6 can also lower homocysteine levels, and may enhance the effect of folate.

They go on to say that other ways of reducing homocysteine levels may include caloric restriction (eating a lot less), vegetarianism, and physical exercise.

A Good Ending

Oh, by the way, you must be wondering - is there anything good about homocysteine? Yes - it's used by the body in cellular metabolism and the manufacture of proteins. And as long as its levels are held in check, it's actually an OK molecule. So you can do just about every aspect of your health a favor by taking plenty of folate and vitamins B12 and B6. May the good guys always win!


  1. Mattson MP, Kruman II, Duan W. Folic acid and homocysteine in age-related disease. Ageing Res Rev 2002;1:95-111.
  2. Tice JA, Ross E, Coxson PG, Rosenberg I, Weinstein MC, Hunink MGM, Goldman PA, Williams L, Goldman L. Cost-effectiveness of vitamin therapy to lower plasma homocysteine levels for the prevention of coronary heart disease. JAMA 2001;286(8):936-43.