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Homocysteine’s Rap Sheet
But look to folic acid and vitamin B12 as the
good guys who kick homocysteine’s butt
By Will Block
itting someone on the head with a baseball bat is assault with a deadly weapon, and you (well, not you, but whoever did it) could go up the river for a long time. Seeing the assailant behind bars might be small comfort, however, if the victim suffered lasting effects from the attack, such as impairment of memory or other cognitive functions. Brain injury can have many kinds of consequences, all of them bad. That’s why Mother Nature saw fit to encase our precious brains in a fortress of bone: the skull. All jokes aside, the thicker, the better when it comes to skulls.
But what if an attack came from within the skull? Is there a “weapon” that can do that? Indeed there is—it’s tiny, but effective, and everyone has it. It’s a chemical compound called homocysteine, an amino acid that’s found in every cell of our bodies. It does not come from food; instead, it’s produced from another amino acid, methionine, which is found in food. Methionine is required for protein synthesis and other vital metabolic processes. (For more on this, see the sidebar “The Importance of a Single Carbon Atom.”)
The Importance of a Single Carbon Atom
Homocysteine is produced in our cells by a type of chemical reaction, single-carbon transfer, that has profound effects on cellular metabolism, especially in the brain, where it plays a central role in DNA synthesis, gene regulation, cell-membrane fluidity, synaptic function, and neurotransmitter synthesis. Any dysfunction in single-carbon metabolism can have highly complex and unforeseeable consequences.
The most common form of single-carbon transfer is methylation, which entails the transfer of a methyl group (–CH3) from one molecule to another. In many of these enzyme-catalyzed reactions, folic acid (in the form of its anion, folate) serves as a coenzyme, or “enzyme helper.” This is, in fact, folic acid’s only known physiological function, and it plays a key role in the metabolism of amino acids and nucleic acids.
When the amino acid methionine donates a methyl group to some other compound, it becomes a molecule of homocysteine; this, however, is not one of the methylation reactions facilitated by folate. Rather, folate facilitates the opposite reaction, in which homocysteine is methylated by some other compound, converting it back to methionine; this tends to preserve the delicate balance between these two amino acids. If, however, there is insufficient folate for this purpose—or insufficient vitamin B12, which is also required—homocysteine levels will rise, to our great detriment.
Another metabolic pathway that homocysteine can take is the enzyme-catalyzed conversion to the amino acid cysteine. This process does not require folate or vitamin B12 as coenzymes, but it does require vitamin B6. Thus the homocysteine levels in our blood are regulated by all three of these B-vitamins.
With regard to brain function, much evidence suggests that any dysfunction in single-carbon metabolism, such as an imbalance in the methionine-homocysteine equilibrium, may result in neuropsychiatric disorders of many kinds, from chronic fatigue and depression to psychosis and dementia and, perhaps, schizophrenia. Oxidative stress may also play a role: homocysteine’s conversion back to methionine can be impaired by reactive oxygen species, and folate itself can undergo irreversible oxidation.
In a recent study of schizophrenia patients in Sweden, a researcher found evidence of a dysfunction in single-carbon metabolism: the majority of the patients had elevated levels of methionine in their cerebrospinal fluid, and a smaller subgroup had elevated levels of homocysteine. The author stated,
A most encouraging feature of single-carbon metabolism is its potential modification by natural means, such as B-vitamins and antioxidants. Our findings in this field point to a new area of schizophrenia research: the role of nutrients and antioxidants for rational prevention and treatment.
- Regland B. Schizophrenia and single-carbon metabolism. Prog Neuro-Psychopharmacol Biol Psychiatry 2005;29:1124-32.
Why We Need Our B-Vitamins
Thus, homocysteine is actually an OK molecule—as long as its levels remain within the normal range. If they become elevated, however, as is common with advancing age, there’s hell to pay in terms of our health—unless
we fight back with homocysteine’s natural enemy, folic acid. This water-soluble B-vitamin is found in various foods, notably whole grains, citrus fruits, green vegetables, and beans (but cooking can destroy it). As with many other nutrients, folic acid levels tend to decline with age, so supplementation becomes increasingly important. (See the sidebar “How Much Folic Acid Do We Need?” See also the article
“Folic Acid to the Rescue!” in the September 2002 issue.)
How Much Folic Acid Do We Need?
Elevated homocysteine levels occur in various conditions, including certain genetic disorders, nutritional deficiencies, chronic diseases, and just plain aging. The levels are generally higher in men, but they increase sharply in women after menopause. This is believed to be one reason for the increased incidence of cardiovascular disease, cancer, and osteoporosis in postmenopausal women.
The antidote to homocysteine, as we have seen in the accompanying article, is the combination of folic acid and vitamin B12. It’s important for the elderly to supplement generously with vitamin B12, because the body’s ability to absorb this compound declines sharply with age. Folic acid supplementation is also important, because it’s difficult to obtain adequate amounts of this vitamin from foods. Furthermore, despite the FDA-mandated addition of folic acid to all refined cereal grains in the United States starting in 1998, folic acid still represents probably the most common vitamin deficiency in our society, affecting about 10% of the population.
The FDA’s typically conservative RDA for folic acid is 400 mcg. However, 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, concluded that, beyond the grain fortification imposed by the FDA, we should all be taking 1000 mcg (1 mg) of supplemental folic acid per day, as well as 500 mcg (0.5 mg) of supplemental vitamin B12. (For a discussion of this study, see
“Fight Alzheimer’s and Heart Disease with B-Vitamins” in the December 2001 issue.)
- Mattson MP, Kruman II, Duan W. Folic acid and homocysteine in age-related disease. Ageing Res Rev 2002;1:95-111.
- 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.
Another vitamin that declines with age (often sharply) is vitamin B12, for which supplementation is very important, especially if folic acid is being taken. This is because folic acid supplementation can mask a B12 deficiency (and vice versa). It’s therefore essential to take the two together—not just for that reason, but also because folic acid’s biological effectiveness depends critically on the presence of vitamin B12 as a cofactor.*
Homocysteine Is Bad
There is abundant scientific evidence demonstrating the effectiveness of both folic acid and vitamin B12 in combating the effects of excessive homocysteine, whose “rap sheet” would put those of most career criminals to shame. For example, elevated homocysteine levels are very strongly implicated in:
Elevated homocysteine levels are also implicated (but less strongly) in:
- Neural tube defects – These are pathologies of the developing spinal cord and brain in embryos. Two examples of the resulting birth defects are spina bifida (incomplete closure of the spinal column) and anencephaly (absence of much of the brain). To minimize the risk of such tragedies, it’s vital that pregnant women keep their homocysteine levels down by taking folic acid.
- Vascular diseases – These include cardiovascular disease, cerebrovascular disease, and peripheral vascular disease (including deep vein thrombosis), which can lead to injury or death due to heart attack, stroke, or pulmonary embolism. Homocysteine rivals smoking as a risk factor for vascular disease. It is believed to damage our blood vessels’ endothelial cells, inviting hypertension and atherosclerosis (it may be as important as cholesterol, if not more so, as a cause of the latter). It also accelerates the oxidation of lipoproteins, promotes the formation of blood clots, and inhibits angiogenesis, the formation of new blood vessels where they’re needed, such as for healing wounds and restoring blood flow to injured tissues.
- Cancer – The primary link is with colorectal cancer. (Although homocysteine’s inhibition of angiogenesis is presumably beneficial against tumors, which need new blood vessels to allow them to grow, this is apparently not enough to offset its tendency to promote the cancer in the first place.)
- Depression – This affliction becomes more prevalent with age, just as increased homocysteine levels do. The correlation between the two is well established, and there appears to be a causal link.
- Schizophrenia – There is evidence that homocysteine may be involved in the development of this disease. (See the “Single Carbon Atom” sidebar above for more on this.)
- Alcoholism – It’s likely that high homocysteine levels contribute to the various pathologies associated with alcohol, including liver disease and cognitive and motor dysfunctions.
- Type 2 diabetes
- Rheumatoid arthritis
- Inflammatory bowel disease (Crohn’s disease and ulcerative colitis)
It Gets Even Worse
You’ll notice that several of the above “crimes” involve the brain in one way or another, so it’s apparent that homocysteine can do damage upstairs. But there’s more—much more. Homocysteine is also strongly implicated in neurodegenerative diseases, including dementias, such as Alzheimer’s disease and vascular dementia, in which elevated levels of this compound occur more frequently than in age-matched controls. Elevated levels are also associated with a more rapid progression of dementia.
A study published in 2002 found that elevated homocysteine levels up to 11 years before a diagnosis of dementia are associated with an increased risk for this terrible affliction. This strongly suggests that homocysteine may also be implicated in the age-related cognitive decline that precedes dementia, and it naturally raises the question of whether dementia could be prevented by reducing homocysteine levels.
Elderly Norwegians Are Put to the Test
New evidence in this matter comes from a study by British and Norwegian researchers, who cite many previous studies demonstrating a link between homocysteine and cognitive decline, as well as many studies demonstrating a positive association between cognitive function and blood levels of B-vitamins. The authors state,
Vitamin deficiency may lead to memory problems, cognitive decline, and even dementia, and there is evidence that Alzheimer’s disease and vascular dementia are related to blood concentrations of B vitamins, as well as total homocysteine.
The new study entailed an analysis of data gathered during the 1990s on 2189 community-dwelling men and women in Norway whose average age was 66 at baseline (the outset of the study). All were required to give detailed health and lifestyle information. The researchers also measured their blood levels of homocysteine, folate (the chemical form in which folic acid is found in our bodies), vitamin B12, and genetic markers associated with Alzheimer’s disease and folate dysfunction. Six years later, the subjects were retested for the above factors and were also given a standardized cognitive function test designed to assess episodic memory among noninstitutionalized elderly people.
Men Won’t Like This One
An intriguing—but not uncommon—finding was that the cognitive test scores for men were consistently lower than those for women (insert your own joke here). The prevalence of moderate to severe memory impairment, in fact, was twice as high in men as in women. This was true even after correcting for many potentially confounding factors, such as educational level, history of heart disease or hypertension, the genetic factors mentioned above, depression status, smoking, coffee consumption, and intake of supplemental B-vitamins. Nonetheless, the observed patterns of association between the test scores and blood levels of homocysteine, folate, and vitamin B12 were similar in both sexes.
A Clear Link Between Low Folate and Memory Decline
And what were those patterns? An increase in homocysteine levels over the 6-year period was strongly associated with declining test scores, and vice versa: declining homocysteine levels were associated with improved test scores. For folate, these trends were reversed: increasing folate levels correlated with increasing test scores, and vice versa. For vitamin B12, however, no statistically significant trends in either direction were observed.
The fact that the risk for memory impairment appears to increase significantly with increasing homocysteine levels, independently of other relevant risk factors, suggests, according to the authors, that elevated homocysteine levels precede or appear at an early stage of memory decline; this conclusion is in agreement with earlier reports on a variety of cognitive tests. The authors also speculated that homocysteine as a risk factor for memory decline may become stronger with increasing age. Their study confirmed that low folate levels were associated with memory decline.
B-Vitamin Supplements May Be the Answer
Although, as the authors pointed out, there is still no conclusive evidence that B-vitamin deficiency is a common cause of dementia or that supplementing with B-vitamins can prevent it, they were optimistic about the latter and concluded on a positive note:
Altogether, these findings are consistent with the hypothesis that reducing total homocysteine levels by changes in lifestyle, or by using B-vitamin supplements, may protect against memory decline in elderly people.
- Smith AD. Homocysteine, B vitamins, and cognitive deficit in the elderly. Am J Clin Nutr 2002;75:785-6.
- Morris MS. Homocysteine and Alzheimer’s disease. Lancet Neurol 2003;2:425-8.
- Clarke R, Smith AD, Jobst KA, et al. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol 1998;55:
- Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. NEJM 2002;346:476-83.
- Nurk E, Refsum H, Tell GS, Engedal K, Vollset SE, Ueland PM, Nygaard HA, Smith AD. Plasma total homocysteine and memory in the elderly: the Hordaland Homocysteine Study. Ann Neurol 2005;58:847-57.
Folic Acid and Vitamin B12 for Brain Balance
For those who wish to preserve and protect their mental health, as well as other aspects of their health, such as proper cardiovascular function, a formulation containing both folic acid and vitamin B12 (which should always be taken together) is a good idea. However, as we grow older: vitamin B12 is so poorly absorbed that much of it is excreted unused.
Thus, a liposomal technology to encapsulate vitamin B12 in microscopic spheres consisting of lipid bilayers that are similar to natural cell membranes can improve bioavailability. The resulting liquid suspension can penetrate readily into the system via the buccal membranes in the mouth, thus bypassing the gastrointestinal tract.
Another compound known to reduce homocysteine levels is choline (see
“Choline Battles Homocysteine” in the April 2005 issue), which is a precursor to several vital brain constituents, including the neurotransmitter acetylcholine.
Will Block is the publisher and editorial director of Life Enhancement magazine.