Homocysteine excess in the blood is widely recognized today as a primary risk factor for cardiovascular disease. While not yet as well appreciated by mainstream medicine as cholesterol, high blood pressure, obesity, smoking, and "couch potato-itis," high levels of the amino acid homocysteine appear to be at least as great a danger for causing heart attacks and strokes.
Less well known, but just as important, new research is consistently showing that high homocysteine levels in the blood (a condition called hyperhomocysteinemia) can also take its toll on our cognitive lives. One recent study, from The Johns Hopkins University School of Medicine, showed that elevated homocysteine levels were "consistently and strongly" linked to a widespread decline in neurobehavioral test scores.1
A Serious, but Modifiable Risk Factor
Unlike most other cardiovascular risk factors, homocysteine levels are remarkably easy to control. By simply increasing your ingestion of folate and a couple of other common B vitamins along with the essential nutrient choline — through diet and/or supplements — most people can virtually eliminate this particular cardiovascular danger, all without spartan diets, exhausting exercise programs, and most importantly, expensive and dangerous drugs.
Homocysteine is an amino acid normally produced in the body in small amounts from the metabolism of another amino acid, methionine, which is found commonly in meat, fish, eggs, and other foods. But, while eating lots of foods high in methionine might contribute to your homocysteine level to some degree, dietary methionine is not the major cause of hyperhomocysteinemia. For most people, homocysteine levels rise because of a chronic deficiency in their diet of folate and possibly also vitamin B6, vitamin B12, and choline. The body uses these nutrients to control homocysteine by converting it back into harmless methionine.
Exactly how homocysteine disrupts cardiovascular and cognitive health is still under study. However, it is known that homocysteine is toxic to the vascular endothelium, the layer of thin, smooth cells that line the interior of all arteries. Such injuries can become the focus of plaque formation, the primary sign of atherosclerosis. If these plaques rupture, the resulting breakaway blood clots can float downstream until they become wedged into a small coronary or cerebral artery, causing a heart attack or stroke. Homocysteine's cardiotoxicity appears to be related to a number of actions, including inhibiting nitric oxide (NO) synthesis, increasing oxidative stress and cell death, and activating pro-inflammatory factors.2-6 Its toxicity to brain cells may help explain it's deleterious effects on cognition.2, 5, 7, 8
A "Strong and Consistent" Association
The new Johns Hopkins data are but the latest reminder that homocysteine's neurotoxicity can seriously disrupt the brain's cognitive functioning.1 The study, part of the NIH (National Institutes of Health)-sponsored Baltimore Memory Study, included 1047 healthy men and women, aged 50 to 71 years (mean age, 59), from a variety of racial, ethnic, and educational backgrounds, and living in specific, targeted Baltimore neighborhoods. An unusual aspect of the study population was the large number of people with higher education; 42% had at least a 4-year college degree. In a test of cognitive function, presumably these people would have the farthest to fall.
After having a small amount of blood drawn to measure homocysteine, each of the participants took a 90-minute series of neurobehavioral tests designed to assess a wide range of cognitive abilities, including language skills, conceptual reasoning, simple motor and psychomotor speed, eye-hand coordination/manual dexterity, verbal and visual memory and learning, and others.
It was immediately apparent, upon examination of the results, that higher levels of homocysteine were associated with worse scores on every one of the 20 neurobehavioral measures used. Most seriously affected were eye-hand coordination/manual dexterity and verbal memory and learning. Since homocysteine levels typically rise with age, an increase of 4 µmol/L was found to be equivalent to an increase in age of 4.2 years. In other words, just a small excess in homocysteine could shorten your lifespan by more than 4 years.
A Two-Pronged Defense
As the dangers of high homocysteine have become more evident, most of the therapeutic attention has focused on folate, and with good reason, because it can be remarkably effective. Many studies have shown that high homocysteine levels are linked to an increased risk of cardiovascular and other diseases. Many other studies have demonstrated that folate reduces homocysteine levels via a process known as methylation, which simply converts it back to benign methionine, from whence it came. However, no large, well-controlled clinical study has yet put the two together to show that taking folate and a source of choline can reduce the risk of heart attacks or strokes. Stay tuned over the next few years for that shoe to drop, as it inevitably will. In the mean time, don't look to the FDA, AMA, and AHA, or other conservative, pharmaceutical industry-connected alphabet agenciesto encourage you to take any extra B vitamins
Choline: Of Mice and Men
Often forgotten amidst all the justifiable attention given to B vitamins is the essential nutrient choline, a nitrogenous alcohol. The human body neutralizes homocysteine (methylation) via two different metabolic pathways. Folate is central to one pathway and choline is central to the other. Dietary choline works because it gets converted to betaine (trimethylglycine), a primary player in the methylation reactions that serve to lower plasma homocysteine concentrations. The critical role of choline was illustrated by the results of an unusual recent study from the University of North Carolina that combined data from both mice and men.9
Choline Prevents Homocysteine Elevations after Methionine Ingestion
In the mouse portion of the study, the animals were placed on one of three special diets for 3 weeks: 1) choline supplemented (high choline content), 2) control (normal choline content), and 3) choline deficient (no choline). On the last day of the study, half the animals were given an oral dose of L-methionine, and 2 hours later, blood was taken to measure homocysteine levels.
Methionine ingestion was followed by an increase in plasma homocysteine levels in both groups, but the increase was significantly higher in the choline-deficient group. These results confirm that choline, a nutrient with many vital functions in the body, is also essential for lowering plasma homocysteine concentrations — even when dietary consumption of folate and the other B vitamins is considered adequate.
In the human arm of the study, eight healthy male volunteers (aged 20-46 years) were placed on a diet containing an "adequate" amount of choline (550 mg/70 kg body weight). After 10 days, their plasma homocysteine levels were assessed before and again 4 hours after an oral dose of methionine (think, eating a big, juicy steak). At this point, they were switched to a diet containing almost no choline, and they remained on this diet for up to 42 days. About half the men developed a fatty liver (hepatic steatosis), which is a strong indication of choline depletion. These men were also found to have significantly higher levels of plasma homocysteine, compared to those judged not to be choline depleted.
The difference was even more striking after the men were challenged with a dose of methionine. As shown in the figure, before methionine, choline depletion had virtually no effect on homocysteine levels. However, after the men were choline depleted, the methionine dose triggered an 800% increase in homocysteine production. By comparison, when dietary choline was "adequate," homocysteine levels actually declined slightly.
The researchers hypothesized that folate (+ vitamin B6 and vitamin B12) is responsible for controlling homocysteine on an everyday/baseline basis. But once homocysteine production starts to rise, choline (or betaine) is required to keep homocysteine levels down.
It is evident today that high homocysteine levels are a major risk for cardiovascular disease and general cognitive decline. Homocysteine may also be a factor in Parkinson's disease and Alzheimer's disease, but these dangers haven't always been so well accepted by the conventional medical community. Back in the late 1960s and 70s, when a young Harvard Medical School researcher, Kilmer S. McCully, MD, published his first studies linking homocysteine to the progression of atherosclerosis and the risk of heart attacks and strokes, he was actively ignored, even ridiculed. After all, everyone knew that cardiovascular disease was a result of too much cholesterol (at least too much of the wrong kind of cholesterol).
How could homocysteine, a common amino acid present in every human body, be more important than cholesterol? And how could everyday, inexpensive, unpatentable, vitamins and other nutrients be so successful in controlling it? It's as though someone had found that you could control cholesterol by taking vitamin C and E, rather than expensive, dangerous patented drugs. It's tantamount to admitting that cardiovascular disease, Alzheimer's disease, Parkinson's disease, high blood pressure, cancer (especially colorectal), depression, alcoholism, age-related cognitive impairment, and other serious chronic diseases, are due, at least in part, to an easily prevented nutritional deficiency. This is the kind of finding that gives pharmaceutically dominated medicine chills.
Given the forces allied against him, it's unfortunately not surprising that McCully was eventually rewarded for his important insights and creative iconoclasm with forced exile from Harvard. Yet, he persevered, and eventually the weight of the evidence from his lab and others' became too much for even conventional medicine to resist, and McCully was vindicated, well, sort of.... In the absence of any large, prospective, double-blind, placebo-controlled trials showing that lowering homocysteine prevents heart attacks, etc, the presiding orthodoxy remains resolutely resistant to actually recommending folate and choline as a prophylactic measures for heart attacks and strokes. Forget about cognitive decline, Alzheimer's, or Parkinson's. If you want to take advantage of this remarkably simple, inexpensive, nonpharmaceutical measure, you're going to have to go without the blessings of the government and the conventional medical establishment.
Because high homocysteine is considered such a readily modifiable risk factor, we must now ask a tough question: How many people are dying of heart disease and strokes every day, or having their minds gradually, imperceptibly fade away, who could easily prevent these disastrous events by taking a few vitamin pills every day? Are you one of them?
- Schafer JH, Glass TA, Bolla KI, Mintz M, Jedlicka AE, Schwartz BS. Homocysteine and cognitive function in a population-based study of older adults. J Am Geriatr Soc. 2005;53:381-388.
- Austin RC, Lentz SR, Werstuck GH. Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease. Cell Death Differ. 2004;11 Suppl 1:S56-64.
- Mattson MP, Haberman F. Folate and homocysteine metabolism: Therapeutic targets in cardiovascular and neurodegenerative disorders. Curr Med Chem. 2003;10:1923-1929.
- Mattson MP, Shea TB. Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders. Trends Neurosci. 2003;26:137-146.
- Suhara T, Fukuo K, Yasuda O, et al. Homocysteine enhances endothelial apoptosis via upregulation of fas-mediated pathways. Hypertension. 2004;43:1208-1213.
- Rodrigo R, Passalacqua W, Araya J, Orellana M, Rivera G. Implications of oxidative stress and homocysteine in the pathophysiology of essential hypertension. J Cardiovasc Pharmacol. 2003;42:453-461.
- Robert K, Santiard-Baron D, Chasse JF, et al. The neuronal sapk/jnk pathway is altered in a murine model of hyperhomocysteinemia. J Neurochem. 2004;89:33-43.
- Kruman, II, Culmsee C, Chan SL, et al. Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity. J Neurosci. 2000;20:6920-6926.
- da Costa KA, Gaffney CE, Fischer LM, Zeisel SH. Choline deficiency in mice and humans is associated with increased plasma homocysteine concentration after a methionine load. Am J Clin Nutr. 2005;81:440-444.