Friday, January 10, 2014

Heart Disease Homocysteine and the cholesterol myth


Move over cholesterol, there’s a new molecule in town. It’s homocysteine, a by–product created in the digestion of protein, and it’s making health headlines. High levels of homocysteine have been linked to cardiovascular disease. As a result, the American Heart Association (AHA) has recently named homocysteine as a risk factor for heart attack and stroke. Now, new research is suggesting that homocysteine plays a part in such diverse health concerns as osteoporosis, depression, Alzheimer’s disease and pregnancy. To understand how one molecule can do so much, we need to take a closer look at this compound. Homocysteine is an amino acid, although not one of the twenty "standard" amino acids that serve as the building blocks of protein in our bodies.

Homocysteine is not found in our diet, and thus the answer to why it represents such a problem lies in examining how it is produced in our bodies. The story of homocysteine involves several more familiar nutritional players, the vitamins B6, B12, and B8 (more commonly known as folic acid).

Homocysteine's place in metabolism

When proteins are metabolized, they are broken down into individual amino acids, including the sulfur-containing amino acid methionine. Methionine is in turn broken down further in several steps to produce homocysteine, which, once formed, can be removed from the body in only two ways. One, it can be remade into methionine through a process called remethylation. This requires both folic acid and vitamin B12, where B12 functions as an essential "cofactor" in the reaction. Secondly, homocysteine can be made into the amino acid cysteine through a process called transulfuration, a process that requires two enzymes to work in concert with vitamin B6. Thus, if a person ingests lots of protein, and there is not enough folic acid, B6 and B12 available to help digest it, homocysteine levels can build up in the blood stream. As might be expected, the opposite is also true. Increased levels of these vitamins in the blood stream result in a reduction of homocysteine levels. Indeed, studies have shown that oral folic acid supplements are effective in bringing homocysteine levels down. In a seesaw effect, as folic acid levels rise in the blood stream, levels of homocysteine drop.

The inverse relationship between homcysteine and folic acid

The importance of homocysteine to human health first came to light in the 1960s when a doctor named Kilmer McCully became interested in homocystinuria, a rare disease that results in high homocysteine levels in the blood. It turned out that people with this condition often suffered from heart disease and strokes, even at a very young age. He wrote a paper describing several children with homocystinuria who had died of heart attacks. Despite their youth and lack of fat deposits, Dr. McCully noticed that they had blood vessels damaged by atheroschlerotic plaques. He suggested that maybe the homocysteine had something to do with how these cholesterol deposits were formed inside the arteries. Although these findings were published in a good journal, they didn’t capture the imagination of medical researchers, and Dr. McCully’s results were ignored for many years.

Homocysteine joins cholesterol in the ranks of risks of heart disease

In the meantime, cholesterol was getting all the press as the cause of cardiovascular disease. Warnings went out to avoid it in our diets to lower our risk of heart attacks and strokes. "Good" and "bad" cholesterol became household words and it became widely believed by the general public that if you could just lower that cholesterol, you wouldn’t need to worry about a heart attack. However, while high cholesterol clearly increases the risk of having a heart attack, it has always been the case that many heart attack victims actually have normal cholesterol levels. And thus there must be more to the story, and the search for answers has led back to those early observations by Dr. McCully. Recent research has confirmed his hunch that homocysteine was playing a part in heart disease, and lately much has been made in the popular press about homocysteine as the "new cholesterol," or the "cholesterol of the 90s."

Homocysteine, perhaps working in tandem with cholesterol, may indeed be behind the development of arterial plaques, which deposit where the wall of an artery has been damaged. But although cholesterol is part of the sticky plaque material, it is has never been clear whether cholesterol itself is the culprit that breaks down the arterial wall in the first place. Now studies have shown that homocysteine damages the smooth vascular wall tissue, creating a scratch in the inside of the vessel where plaque can build up. Although more research needs to be done, it looks like homocysteine causes toxic superoxide radicals to form in the blood, which in turn kill cells in the blood vessel walls. Once damaged, the affected area swells and forms a "rough spot" where sticky cholesterol, (along with platelets and white blood cells that arrive to fix the damage) start to collect into a plaque. The problem is further exacerbated because homocysteine travels around the blood stream linked to low density lipoproteins (also known as LDLs, or "bad cholesterol"), the kind of cholesterol that builds up into plaques. And as if that were not enough, homocysteine can also thiolate (add sulfur groups) to LDLs, which causes them to be even more sticky and also attracts more white blood cells. All these reasons add up to point the finger at homocysteine as a potent new "bad guy" in the world of heart disease. This evidence, and studies linking high homocysteine to both heart attack and clogging of the arteries (atheroschlerosis), finally prompted the AHA to add homocysteine to the more well known risk factors for heart disease (such as smoking, high blood pressure, high cholesterol levels, obesity and lack of exercise).

But the bad work of homocysteine does not stop with damaging the circulatory system. Besides being suspected as a causative agent of atheroschlerosis, there are some early clues that homocysteine plays a role in proper brain function. When researchers looked at how nutrition could affect depression, they found that low levels of folic acid increased the symptoms of depression and prevented anti-depressant medications from working well. Of course because of the see-saw effect, patients with low folic acid levels have high levels of homocysteine, and these high homocysteine levels may themselves contribute to the problem. Homocysteine appears to inappropriately stimulate some nerve cell receptors, which can hinder normal brain function. High homocysteine levels also lead to high levels of S-adenosylmethionine (SAM, which is needed to make neurotransmitter molecules) and S-adenosyl homocysteine (which inhibits the proper methylation of some brain chemicals). Thus, elevated homocysteine levels may adversely affect a whole range of brain processes, and cause or worsen psychological abnormalities. Of course because high homocysteine and low folic acid levels go hand in hand, it is hard to know which of these molecules is more important in combating depression. It will likely turn out to be a combination of both.

High levels of homocysteine have now also been linked to diseases that cause dementia such as Alzheimer’s Disease. Deficiencies in vitamin B12 and folic acid have already been linked to neuropsychiatric disorders, although the biochemical reasons for these relationships remain to be worked out. Now, although the research is still in its early stages, it seems that certain thinking skills, such as making sense of visual input and understanding spatial relationships, are decreased by high homocysteine levels. Such links of folic acid, vitamins B6, B12 and homocysteine to cognitive function suggest that good nutrition may help prevent, or at least delay, the onset of diseases such as Alzheimer’s, good news in an age where more and more people are living longer, healthier lives.

Homocysteine is critically important during pregnancy

But keeping homocysteine levels in check is not just important as we age. Homocysteine has been identified as playing an important part in healthy fetal development. High maternal homocysteine levels in the bloodstream increase the chance of miscarriage, and of serious pregnancy complications such as pre-eclampsia and placental abruption. Such conditions can result in premature birth of the baby, low birth weight and, sadly, even the death of the baby or mother. Clearly, preventing high homocysteine levels during pregnancy is important for the health of both mother and child. Luckily, because folic acid has gotten so much attention as a vital nutrient for preventing serious neural tube birth defects such as Spina Bifida, pregnant women and women planning to get pregnant are already routinely advised to take folic acid supplements, which has the added benefit of keeping homocysteine levels down as well. The results from these studies that link high homocysteine levels with poor pregnancy outcomes now make taking those folic acid supplements during pregnancy doubly important.

As if all these studies pointing to the importance of homocysteine in human health are not enough, high homocysteine levels have even been proposed as causative agents for osteoporosis, a condition where bones become progressively weaker in postmenopausal women, and presbyopia, far sightedness due to aging. Connections to yet other health disorders are sure to follow. Yet despite the mounting evidence that high homocysteine levels correlate to increased risk of heart attack, stroke, birth defects, mental health problems, and perhaps other ailments, studies still need to be done to determine if lowering homocysteine levels in the general population, perhaps by supplementing the food supply, could increase our health as a nation.

The importance of homocysteine in health and well-being

Because folic acid supplements do significantly lower homocysteine levels in the blood stream, such proposals to add folic acid to foods have been made. Proponents note that the addition of vitamin B6 to the food supply has resulted in a gradual drop in death from cardiovascular causes since the 1960s. However, such plans are controversial, for one because folic acid supplements can mask the symptoms of pernicious anemia, a vitamin B12 deficiency that hampers the bone marrow’s ability to make blood, which can cause irreversible nerve damage. Thankfully, in the absence of metabolic defects that keep homocysteine levels abnormally high, all the risks associated with high homocysteine levels seem to be avoidable with good nutrition. Leafy green vegetables, orange juice and beans are good sources of folic acid. Vitamin B6is found in starchy foods such as whole grains, potatoes, bananas, as well as turkey and tuna, and vitamin B12 is found in meat, seafood and dairy products. A well balanced diet can provide ample amounts of these important nutrients.

Much work on this simple yet powerful molecule still needs to be done. While high homocysteine levels are found in tandem with many ailments, proving a real biochemical connection between homocysteine and disease is important before serious recommendations can be made about diet and vitamin supplementation. Scientists will need to unearth more clues as to the harmful effects of homocysteine, and then hopefully come up with practical ideas to apply this knowledge for the health of everyone.
Homocysteine Reduction

Homocysteine is an amino acid that inflicts damage to the inner arterial lining (endothelium) and other cells of the body.

In 1968, a Harvard researcher observed that children with a genetic defect that caused them to have sharply elevated homocysteine levels suffered severe atherosclerotic occlusion and vascular disorders similar to what is seen in middle-aged patients with arterial disease. This was the first indication that excess homocysteine might be an independent risk factor for heart disease.

Life Extension has identified elevated homocysteine as one of 17 independent risk factors for cardiovascular disease. This has been graphically illustrated as “daggers aimed at the heart” (See Figure 1 Cardiovascular Risk Factors: The 17 Daggers Aimed At The Heart). Any one of these “daggers” can initiate and propagate vascular disease. Among such risk factors, homocysteine’s role in cardiovascular and cerebrovascular disease continues to be misunderstood by mainstream medicine.

Much of this confusion stems from highly publicized results of clinical trials that used B vitamins to reduce blood levels of homocysteine yet failed to prevent cardiovascular events in people with advanced atherosclerosis (Albert 2008; Méndez-Gonzales 2010). The Life Extension Foundation believes these studies were seriously flawed, most notably because they used doses of B vitamins that were too low to reduce homocysteine to Life Extension’s recommended optimal range of <7-8 11-15="" 1995="" 2009="" a="" achieve="" and="" as="" at="" between="" br="" clinical="" consequently="" consider="" contrary="" data="" despite="" doctors="" doses="" for="" homocysteine-lowering="" homocysteine="" laboratories="" limit="" many="" medical="" misinformed="" mol="" normal="" number="" nutrients="" nygard="" of="" optimal="" present="" range.="" range="" remain="" required="" robust="" target="" testing="" the="" this="" to="" uo="" upper="">Homocysteine Basics

All homocysteine in the body is biosynthesized from methionine, an essential amino acid found abundantly in meats, seafood, dairy products, and eggs. Vegetables, with few exceptions (eg, sesame seeds and Brazil nuts), are low in methionine; even such protein-rich legumes as beans, peas, and lentils contain relatively small amounts of methionine compared to animal-derived foods.

Homocysteine exists in several forms (Jacobsen 1998); the sum of all homocysteine forms is termed ‘total homocysteine.’ Protein-rich diets contain ample amounts of methionine and consequently produce significant levels of homocysteine in the body (Verhoef 2005).

Homocysteine is metabolized through two pathways: remethylation and transsulfuration (See Figure 2 Homocysteine Metabolic Pathways). Remethylation requires folate and B12 coenzymes; transsulfuration requires pyridoxal-5’-phosphate, the B6 coenzyme (Selhub 1999a).

Active folate, known as 5-MTHF or 5-methyltetrahydrofolate, works in concert with vitamin B12 as a methyl-group donor in the conversion of homocysteine back to methionine.

Normally, about 50% of homocysteine is remethylated; the remaining homocysteine is transsulfurated to cysteine, which requires vitamin B6 as a co-factor. This pathway yields cysteine, which is then used by the body to make glutathione, a powerful antioxidant (See Figure 2 Homocysteine Metabolic Pathways) that protects cellular components against oxidative damage.

Vitamin B2 (riboflavin) and magnesium are also involved in homocysteine metabolism. Thus a person needs several different B-vitamins to help keep homocysteine levels low and allow for it to be properly transformed into helpful antioxidants like glutathione. Without B6, B12, B2, folate, and magnesium, dangerous levels of homocysteine may build up in the body.

Blood levels of total homocysteine increase throughout life in men and women (Selhub 1999b). Prior to puberty, both sexes enjoy optimally healthy levels (about 6 µmol/L). During puberty, levels rise, more in males than females (Must 2003, Jacques 1999), reaching, on average, almost 10 µmol/L in men and more than 8 µmol/L in women (Ganji 2006). As we age, mean values of homocysteine continue to rise and the concentrations usually remain lower in women than in men (Ganji 2006).

The higher total homocysteine concentrations seen in the elderly may be caused by many factors including malabsorption of B12 or a suboptimal intake of B-vitamins (especially vitamin B12), reduced kidney function, medications that reduce the absorption of vitamins (as in the case of H2 receptor antagonists or proton-pump inhibitors reducing B12 absorption) (Ruscin 2002) or increase the catabolism of the vitamins (as in the case of metformin reducing blood levels of B12 and folic acid) (Wulffele 2003). Certain diseases are associated with higher homocysteine levels, as can such lifestyle factors as smoking (Targer 2000), coffee consumption (Temple 2000), and excessive alcohol intake (Sakuta 2005). Lack of exercise, obesity, and stress are also associated with hyperhomocysteinemia (See Figure 3: Determinants of Total Plasma Homocysteine Levels).
How Elevated Homocysteine Leads to Vascular Damage

If unhealthy levels of homocysteine accumulate in the blood, the delicate lining of an artery (endothelium) can be damaged.

Homocysteine can both initiate and potentiate atherosclerosis. For example, homocysteine-induced injury to the arterial wall is one of the factors that can initiate the process of atherosclerosis, leading to endothelial dysfunction and eventually to heart attacks and strokes (Gallai 2001, Papatheodorou 2007). Several studies have shown that homocysteine can inflict damage to the arterial wall via multiple destructive molecular mechanisms (Zeng 2003, Hofmann 2001, Osanai 2010).
Homocysteine Is Linked to Congestive Heart Failure

Small clinical studies have shown that patients with congestive heart failure (CHF) suffer from elevated plasma homocysteine levels (Cooke 2000). Based on preclinical evidence that the myocardium may be especially susceptible to homocysteine-induced injury (Chen 1999) and based on observations linking homocysteine to oxidative stress (Loscalzo 1996) and to left ventricular remodeling (Miller 2002, Blacher 1999), it has been hypothesized that elevated plasma homocysteine levels would increase the risk of CHF. Accordingly, researchers investigated the relationship of plasma homocysteine concentration to the risk of CHF in a community-based sample of adults (2491 adults, mean age 72 years, 1547 women) who participated in the well-known Framingham Heart Study during the 1979-1982 and 1986-1990 examination periods and who were free of CHF or prior myocardial infarction at baseline. In one study that examined patients without any manifestation of coronary heart disease at baseline, investigators found that the association of plasma homocysteine levels with risk of CHF was maintained in men and women and concluded “an increased plasma homocysteine level independently predicts risk of the development of CHF in adults without prior myocardial infarction” (Vasan 2003)
Reducing Homocysteine for Migraine Relief

Migraine is a debilitating disease that can be associated with elevated blood levels of homocysteine (Kurth 2008, Moschiano 2008, Hamed 2009).

A recent study showed that treatment with B-complex vitamins, including 5-MTHF, could provide relief for migraine sufferers including those with the MTHFR C677T genotype, (Lea 2009) which typically limits the clinical effectiveness of supplemental folic acid since individuals with this genotype don’t effectively convert folic acid to its active form. People with the C677T genotype consistently have higher levels of homocysteine than those with the normal C677C genotype. Headache frequency and pain severity were also reduced. The treatment proved successful in reducing homocysteine levels and migraine disability in study participants with the MTHFR C677T genotype. Researchers have long suspected that migraine headaches have a genetic component because migraine sufferers often have family members who also have the condition. Studies suggest that up to 12 percent of those living in the U.S. and Western Europe have this genetic link to migraine (Oterino 2010).
Homocysteine’s Role in Macular Degeneration

Studies of homocysteine’s role in age-related macular degeneration (AMD: both wet and dry types) reveal a strong link between the compound and the disease.

In a group of 2,335 study participants who had evidence of AMD as detected from retinal photographs, researchers found that homocysteine blood levels >15 µmol/L were associated with an increased likelihood of AMD in participants aged <75 2007="" a="" all="" also="" amd="" among="" associated="" association="" b12="" blood="" br="" for="" found="" fourfold="" higher="" homocysteine="" in="" levels="" low="" mol="" nearly="" ochtchina="" odds="" of="" participants.="" participants="" pmol="" serum="" similar="" study="" they="" vitamin="" was="" with="" years.="">
In a larger and more recent study, Harvard researchers enrolled 5,442 women who were at high risk for cardiovascular disease. The women were given a placebo or 2.5 milligrams folic acid, 50 milligrams vitamin B6, and 1 mg vitamin B12 per day. After an average of more than seven years of treatment and follow-up, researchers recorded 55 cases of AMD in the B-vitamin treatment group and 82 in the placebo group. Investigators concluded that in women at high risk of cardiovascular disease, daily long-term supplementation with folic acid, B6, and B12 may reduce the risk of AMD (Christen 2009).
Homocysteine Linked to Hearing Loss

A number of published studies suggest that hearing loss may be linked to plasma homocysteine levels, which could be reduced by folic acid supplementation.

One study conducted from September 2000 to December 2004 in 728 older men and women in the Netherlands (which does not have mandatory folic acid fortification) found that at initiation, the median threshold for hearing in the low frequency range (0.5 to 2 kHz) was 11.7 decibels (dB), and 34.2 dB in the high frequency range (4 to 8 kHz). By the end of the study, the thresholds had increased for both folic acid and placebo groups. In other words, a louder noise was required to get study participants to hear it. However, the increase was lower in the supplemented group in the low frequency range (1.0 versus 1.7 dB increase for folic acid and placebo groups, respectively). There was no significant difference in threshold decline in the higher frequency region. Thus, folic acid supplementation slowed the decline in hearing of the speech frequencies typically associated with aging (Durga 2007).

Researchers studied the levels of homocysteine in 28 male patients (mean age 37) with noise-induced hearing loss. Homocysteine levels of subjects with noise-induced hearing loss were significantly higher compared to healthy controls, suggesting a causal link between increased homocysteine levels and noise-induced hearing loss (Gok 2004).
What Is a Healthy Homocysteine Number?

Clinical testing laboratories consider a homocysteine value between 5 to 15 µmol/L as healthy. The Life Extension Foundation believes that an upper limit of 15 µmol/L is too high for optimal health. Studies indicate that adults with homocysteine values ≥6.3 µmol/L are at increased risk of atherosclerosis (Homocysteine Studies Collaboration), heart attack and stroke (Broxmeyer 2004). Homocysteine levels in the blood can increase due to age (Elias 2005), prescription drug use (see the “Drugs that Raise Homocysteine Levels” section, below), declining ability to absorb vitamin B12 (Zeng 2003), deteriorating kidney function (Mann 2008), smoking (Targer 2000), alcohol (Sakuta 2005), coffee consumption (Carlsen 2005), obesity (Guzelmeric 2007), declining levels of physical activity (Nygård 1995), and inheriting a genetic polymorphism known as the MTHFR C677T variant in methylenetetrahydrofolate reductase (MTHFR) (McNulty 2008). After age 50, a more practical target value for homocysteine is <7-8 1995="" 2004="" 30="" a="" achieve="" amounts="" and="" are="" as="" associated="" at="" b12="" b6="" b="" because="" blood="" br="" clean="" considered="" data="" depending="" epidemiological="" even="" experience="" extension="" factors="" folate="" for="" foundation="" from="" goal="" have="" healthy="" higher="" homocysteine-lowering="" homocysteine.="" homocysteine="" in="" indicate="" intakes="" is="" larger-than-usual="" level="" levels="" life="" may="" members="" mol="" more="" no="" normal="" nutrients="" obinson="" of="" optimal="" other="" over="" published="" range="" realistic="" recommends="" require="" reveal="" risk="" s="" safe="" shown="" studies="" taking="" target="" tens="" than="" that="" the="" there="" this="" thousands="" threshold="" tmg="" to="" upon="" vitamins="" well="" when="" with="" years="" you="">
The MTHFR C677T gene polymorphism is the single most important genetic determinant of blood homocysteine values in the general population. More than 40% of Hispanics and between 30-38% of whites living in the U.S. inherit at least one copy of this gene (Botto 2000),which impairs their ability to fully activate (methylate) folic acid to 5-methyltetrahydrofolate, the bioactive form of the B vitamin. Individuals who inherit this gene variant from both parents have a significantly higher (14-21%) risk of vascular disease than those who do not.

For this affected group, taking the bioactive folate supplement, 5-MTHF, may be a better strategy. 5-MTHF is clinically tested, is highly bioavailable (Willems 2004), can cross the blood-brain-barrier (Weir 1999), and is unlikely to mask a vitamin B12 deficiency as folic acid can do (Venn 2002). Those who carry this gene variant can safely reduce their risk of homocysteine-related health problems using an inexpensive, nonprescription natural folate supplement.
Flawed Studies Lead to Confusion over B-Vitamins and Heart Disease

A 2010 review of several large randomized, double-blind, placebo-controlled trials that used various B-vitamin therapies for reducing cerebrovascular risk (VISP study [Toole 2004]) and secondary cardiovascular disease risk (HOPE 2 [Saposnik 2009], NORVIT [Bønaa 2005], WAFACS [Albert 2006], and WENBIT [Ebbing 2008] studies) concluded that B-vitamin treatments effectively decrease plasma homocysteine levels and stroke risk, although such treatments failed to reduce cardiovascular risk (Méndez-Gonzales 2010). A meta-analysis of randomized clinical trials comprising 16,958 participants with preexisting vascular disease found that folic acid supplementation had no effect on the risk of cardiovascular disease or all-cause mortality (Bazzano 2006).

Critical examinations of such studies that failed to show a reduction of cardiovascular events in patients treated with B vitamins have revealed numerous design and methodological flaws including limited statistical power, relatively short duration of follow-up, and insufficient number of cardiovascular events (Bostom 2001, Clarke 2005, Ueland 2007). In addition, three of the studies were secondary prevention trials and therefore were not designed to test the ability of B vitamins to prevent heart attacks in healthy people. The most egregious flaw in these trials, however, is that they all failed to use high enough doses of B vitamins to reduce study participants’ homocysteine levels to the optimal target range of <7-8 br="" mol="">
Additional B-vitamin studies in patients undergoing balloon angioplasty and vascular stenting reveal the critical importance of lowering homocysteine levels to Life Extension’s recommended optimal target range. Two studies that failed to use high enough doses of folic acid, B6, and/or B12 to achieve optimal homocysteine reduction saw restenosis rates rise in some patients who received vitamin therapy (Namazi 2006, Lange 2004). In contrast, a prospective, double-blind, randomized trial (the “Swiss Heart Study”) examined the effects of folic acid, vitamin B6, and vitamin B12 treatment in 553 patients who underwent angioplasty (Schnyder 2002). Investigators observed a significant reduction in the need for revascularization of the target lesion at 1 year (9.9% in the treatment group vs. 16.0% in the control group). Significantly, the Swiss Study is the only randomized controlled trial to date in which treatment reduced study participants’ average plasma homocysteine levels (7.5 µmol/L) to within the range recommended by The Life Extension Foundation (<7-8 br="" mol="">Stroke Protection from B-Vitamin Therapy

The 2009 HOPE-2 trial for homocysteine therapy and stroke risk, which randomized 5,522 adults with known cardiovascular disease to a daily treatment regimen of B-vitamin therapy (2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12) for 5 years, achieved reduction in stroke risk of 25% (Saposnik 2009). HOPE-2 was the first large randomized, double blind, placebo-controlled trial to use clinically adequate doses of vitamin B12. It included high-risk participants with and without history of cerebrovascular disease drawn from countries with and without folic acid food fortification. Significantly, homocysteine concentration decreased by 2.2 µmol/L in the B-vitamin therapy group and increased by 0.80 µmol/L in the placebo group.

Another meta-analysis that focused on a subset of 7 of 12 randomized studies added a randomized trial from China to assess the efficacy of folic acid supplementation in stroke prevention. Study investigators found that folic acid supplementation significantly reduced the risk of stroke by 18% (Wang 2007).
Additional Studies on Homocysteine Reduction and Vascular Disease

A number of controlled studies that found positive effects of B-vitamin therapy on vascular disease yielded the following results:
Folate supplementation improved arterial function in patients with peripheral arterial disease (Khandanpour 2009). Two measures of arterial health, brachial pressure index (ABPI) and pulse wave velocity (PWV), were measured; ABPI improved significantly in all patients receiving folate compared with controls, while PWV improved significantly in individuals receiving an active form of folic acid (5-MTHF), and tended to be improved in those taking folic acid, compared with controls.
Twenty hypercholesterolemic adults taking Lovastatin® were given a daily folate supplement (5 mg) for 8 weeks while 20 patients received a placebo (Shidfar 2009); only the folate-supplemented group experienced decreased blood levels of homocysteine.
Reducing blood levels of homocysteine through B-vitamin therapy was shown to improve endothelial function in renal transplant recipients with hyperhomocysteinemia (Xu 2008). Investigators assigned 36 stable renal transplant recipients with hyperhomocysteinemia to either a B-vitamin treatment group (5 mg folic acid, 50 mg vitamin B6 and 1,000 mg vitamin B12 per day) or to a control group (placebo only) for 6 months. Investigators found that homocysteine significantly decreased in the B-vitamin treatment group compared with baseline (12.6 vs. 20.1 µmol/l); no significant changes in homocysteine levels were observed in the control group. Vasodilatation responses were significantly improved in the treatment group compared to controls.
Folic acid treatment in patients undergoing hemodialysis (10 mg 3 times weekly after dialysis treatment for 6 months) lowered plasma homocysteine levels while it significantly increased total plasma antioxidant capacity levels (Alvares Delfino 2007). Twenty patients receiving placebo treatment showed no statistically significant effect on any of the parameters studied.
A study treated liver transplant recipients with 5-methyltetrahydrofolate (5-MTHF; 1 mg) vs. folic acid (1 mg) vs placebo in an 8-week double-blind placebo-controlled trial. Investigators observed a significant decrease of total serum homocysteine in the 5-MTHF group by Week 8; they found no significant decrease of total serum homocysteine in either the folic acid group or the placebo group. The effects of 5-MTHF (active folate) were found to be significantly more potent than folic acid at lowering elevated homocysteine levels in liver transplant recipients (Akoglu 2008).
A randomized study in 103 patients at increased risk of heart attack or stroke investigated the effect of daily supplementation of folic acid (5 mg) on carotid artery intima-media thickness (IMT). Study participants were randomized to receive either a daily dose of 5 mg folic acid or placebo. After 18 months of folic acid supplementation, participants in the active treatment group saw their homocysteine levels significantly reduced, compared to a significant increase in the placebo group. Investigators noted significant regression of carotid IMT in the treatment group compared to significant IMT progression in the placebo group (Ntaios 2010).
A controlled study was carried out to assess whether folic acid supplementation could produce a reduction in homocysteine levels and improvement in endothelial function in patients with unstable angina (UA) and hyperhomocysteinemia (Guo 2009). Investigators treated patients with 5 mg of folic acid for 8 weeks, rechecking homocysteine, folic acid, and vitamin B12 levels at the end of 4 and 8 weeks. Plasma homocysteine levels were significantly higher in patients with UA than in patients without UA at baseline (19.2 vs. 10.7 µmol/L), whereas plasma levels of folic acid and vitamin B12 were significantly lower. After 8 weeks of folic acid supplementation, homocysteine levels were reduced by 55.3% in the 22 UA patients with hyperhomocysteinemia. Flow-mediated dilation, an indirect measure of endothelial function, also improved significantly after 8 weeks of treatment with folic acid.
A 2008 study examined carotid artery atherosclerosis as determined by measurements of carotid intima-media thickness (IMT) and plaque calcification in 923 patients with vascular disease or diabetes (Held 2008). Study investigators found an inverse association between plasma folate and plaque calcification score; there was a trend toward an inverse association with IMT as well.
N-Acetyl-Cysteine and Homocysteine Reduction

Research studies have documented the homocysteine-lowering effect of the nutraceutical, N-acetyl-cysteine (NAC), which can lead to a highly significant reduction in cardiovascular events, owing to the ability of NAC to lower plasma homocysteine levels and improve endothelial function. Researchers believe that NAC displaces homocysteine from its protein carrier in the blood. This promotes the formation of cysteine and NAC disulfide molecules with high renal clearance, thereby removing homocysteine from plasma (Zoccali 2007, Nolin 2010).
A 2007 study randomized 60 patients with hyperhomocysteinemia and confirmed coronary artery disease to folic acid 5 mg, NAC 600 mg, or placebo daily for eight weeks. Folic acid and NAC supplementation both lowered homocysteine levels and improved endothelial function. Folic acid decreased homocysteine from 21.7 µmol/L to 12.5 µmol/L and NAC decreased homocysteine from 20.9 µmol/L to 15.6 µmol/L. Both treatments improved endothelium-dependent dilation compared to placebo (Yilmaz 2007).
In a double-blind crossover design study, Swedish investigators gave NAC supplements to 11 patients with high plasma lipoprotein(a), which is an independent risk factor for cardiovascular disease (Wiklund 1996). While investigators observed no significant effect on plasma lipoprotein(a) levels, they did find that plasma levels of homocysteine were significantly reduced during treatment with NAC by an astounding 45%.
One study examined the effect of oral NAC supplementation in nine young healthy females and found that the supplement induced a rapid and significant decrease in plasma homocysteine levels and an increase in whole blood concentration of the antioxidant glutathione. Study investigators concluded that NAC might therefore be a highly efficient nutraceutical for reducing blood levels of homocysteine (Roes 2002).
Omega-3 PUFAs Lower Homocysteine

A growing body of research on marine lipids, rich in omega-3 polyunsaturated fatty acids (PUFAs), reveals that omega-3 rich fish oil supplementation can reduce elevated homocysteine levels:
A 2010 animal model study examined the effect of fish oil rich in omega-3 PUFAs on homocysteine metabolism. Three groups of randomly divided rats were fed olive oil, tuna oil, or salmon oil for 8 weeks. The level of plasma homocysteine was significantly decreased only in the group fed tuna oil, rich in omega-3 PUFAs. It is not clear why the salmon oil did not reduce homocysteine as it too is rich in omega-3 PUFAs (Huang 2010).
A 2009 randomized double-blind placebo-controlled clinical trial conducted on 81 patients with type 2 diabetes assigned each patient either three capsules of omega-3 fatty acids (3g) or a placebo every day for a period of 2 months. Homocysteine levels in the treatment group declined as much as 3.10 µmol/L; glycolsylated hemoglobin (HbA1C, a measure of long-term sugar levels in the blood) decreased in the treatment group and increased in the control group (Pooya 2010).
Taurine and Homocysteine Reduction

Supplementing with the amino acid taurine can protect against coronary artery disease by favorably modulating blood levels of homocysteine. Research suggests that taurine can block methionine absorption from the diet, thereby reducing available substrate for homocysteine synthesis (Zulli A 2009). One animal study found that taurine normalized hyperhomocysteinemia and reduced atherosclerosis by 64% over control animals and reduced endothelial cell apoptosis by 30% (Zulli 2009). Study investigators also observed that taurine supplementation reduced left main coronary artery wall pathology due to a favorable effect on plasma total homocysteine and apoptosis.

A study of 22 healthy middle-aged women (33 to 54 years) found that after taurine supplementation (3g per day for 4 weeks), plasma homocysteine levels exhibited a significant decline, from 8.5 µmol/L to 7.6 µmol/L. The investigators concluded that sufficient taurine supplementation might effectively prevent cardiovascular disease (Ahn 2009).
Trimethylglycine (TMG), Choline and Homocysteine Reduction

TMG was originally called betaine after its discovery in sugar beets in the 19th century. TMG serves as a methyl donor in a reaction converting homocysteine to methionine. It is commonly used for reducing high homocysteine levels though it has yet to be effectively studied to determine its full cardiovascular benefits through its ability to lower homocysteine (Lv 2009).

A 2009 study examined the effect of betaine (TMG) supplementation on atherosclerotic lesion progression in apolipoprotein E-deficient mice (Lv 2009). After a 14-week treatment with TMG, analyses revealed that the higher dose of TMG was related to smaller atherosclerotic lesion area. Compared with mice not treated with TMG after 14 weeks, mice receiving 1%, 2%, or 4% TMG had 10.8%, 41%, and 37% smaller lesion areas, respectively. TMG supplementation also reduced aortic expression of the inflammatory cytokine, TNF-alpha, in a dose-dependent way. These data suggest that in addition to its homocysteine-lowering action, TMG may also exert its anti-plaque effect by inhibiting aortic inflammatory responses mediated by TNF-alpha.

Data from the Framingham Offspring Study found that intakes of TMG and choline (choline is metabolized to TMG in the body) were inversely related to circulating homocysteine concentrations, particularly among participants with low folate intake or among those who consumed alcoholic beverages (Cho 2006). Other studies have shown that choline deficiency in mice and humans is associated with increased plasma homocysteine levels after consuming methionine (da Costa 2005). A Finnish study of TMG supplementation showed that a daily supplement of 6 g TMG for 12 weeks reduced blood homocysteine values in healthy subjects by approximately 9 percent (Schwab 2002).
SAMe and homocysteine reduction

SAMe (S-adenosyl-L-methionine), biosynthesized from methionine and ATP, functions as a primary methyl group donor in a variety of reactions in the body and is directly involved in homocysteine synthesis and metabolism. Taking supplemental SAMe promotes the conversion of homocysteine to cysteine and glutathione, thus lowering homocysteine levels (Devlin TM 2001). One study found that taking SAMe supplements increased the activity of 5-MTHF, a major co-factor involved in the metabolism of homocysteine (Loehrer 1997).

In effect, SAMe acts as a ‘switch’ to control enzymes involved in the remethylation and transulfuration pathways of homocysteine metabolism (Brosnan 2006). Since some of the SAMe’s methyl groups are used in the body’s production of creatine (an energy substrate used primarily by skeletal muscle), it has been suggested that supplementing one’s diet with creatine would free up SAMe’s methyl groups to favorably modulate homocysteine levels (Stead 2006). One study found that lab animals maintained on creatine-supplemented diets exhibited significantly lower (~25%) plasma homocysteine levels than controls (Brosnan 2004). Those who use SAMe should make sure they are taking supplemental folate, B6 and B12 to ensure that SAMe promotes the conversion of homocysteine to beneficial compounds in the body.
Riboflavin and Homocysteine Reduction

Vitamin B2 (riboflavin) has long been known to be a determinant of plasma homocysteine levels in healthy individuals with the 5-MTHFR C677T gene variant that causes hyperhomocysteinemia (Hustad 2000). Homocysteine is highly responsive to riboflavin (riboflavin is required as a co-factor by MTHFR), specifically in individuals with the MTHFR 677 TT genotype (McNulty 2006).

A four-week randomized placebo-controlled double-blind trial found that 10 mg/day oral riboflavin supplementation for 28 days lowered plasma homocysteine concentrations in 42 subjects (60 to 94 years) with low riboflavin status (Tavares 2009).
Homocysteine, Alzheimer’s Disease

In a 2002 study published in the New England Journal of Medicine, dementia developed in 111 study participants of which 83 were diagnosed with Alzheimer’s disease over an eight-year follow up. In those with a plasma homocysteine level greater than 14 µmol/L, the risk of Alzheimer’s disease nearly doubled. Investigators concluded, “An increased plasma homocysteine level is a strong, independent risk factor for the development of dementia and Alzheimer’s disease.” (Seshadri 2002)
B Vitamins Prevent Brain Atrophy by Lowering Homocysteine

A two-year randomized clinical trial (known as VITACOG) completed in 2010 found that the accelerated rate of brain atrophy in elderly patients suffering from mild cognitive impairment could be significantly slowed by treatment with homocysteine-lowering B vitamins (Smith 2010).

Researchers at Oxford University, UK randomized study participants to receive either placebo or a combination of folic acid (0.8 mg/d), vitamin B12 (0.5 mg/d) and vitamin B6 (20 mg/d) for 24 months. A subset of participants agreed to have cranial MRI scans at the start and finish of the study for the purpose of measuring the change in rate of atrophy of the entire brain.

A total of 168 participants (85 in active treatment group; 83 receiving placebo) completed the MRI section of the trial. Results showed that the B-vitamin treatment response was related to baseline homocysteine levels: Participants in the B-vitamin treatment group with the highest levels of homocysteine (≥ 13.0 µmol/L) at the start of the trial experienced half the brain shrinkage over two years compared to those participants with the highest homocysteine blood levels at the start of the trial and who received the placebo.

This important study demonstrated that the accelerated rate of brain atrophy seen in approximately 16% of elderly patients suffering from mild cognitive impairment (Plassman 2008) could be significantly slowed by simple treatment with folic acid and vitamins B6 and B12.
Dietary and Lifestyle Considerations
Avoid methionine-rich foods, Particularly red meats and dairy products. Although methionine is an essential amino acid, it is also suspected to indirectly promote atherosclerotic plaque growth by increasing homocysteine levels.
Exercise: In a cardiac rehabilitation program following bypass surgery, angioplasty, or heart attack, 76 participants experienced a modest 12% reduction in homocysteine just by engaging in a program of regular exercise (Ali 1998).
Decrease or eliminate: Alcohol, coffee (filtered and unfiltered), and smoking.
Weight loss: obesity is associated with higher homocysteine.

What You Need To Know
Elevated blood levels of homocysteine have been linked with a wide range of health disorders including heart disease, stroke, macular degeneration, hearing loss, migraine, brain atrophy, dementia and cancer.
A high-protein diet, especially one that includes red meats and dairy products, is also high in methionine, the parent compound of homocysteine. Following such a diet can increase blood levels of homocysteine.
Numerous factors, including prescription drug use, smoking, coffee and alcohol consumption, advancing age, genetics, and obesity contribute to elevated homocysteine levels.
Many people carry a genetic variation that is linked with elevated homocysteine levels. People carrying this gene variant suffer from an impaired ability to metabolize folic acid to its active form, but may achieve a significant reduction in plasma homocysteine by taking an active folate (5-MTHF) supplement.
Vitamin B2, B6, and B12 supplements as well as those containing choline and TMG work together with active folate to maintain homocysteine levels within a healthy range.
As humans grow older, homocysteine levels increase substantially. However, although these increased levels are “normal,” they are still associated with higher risk of various health problems.
Although some clinical testing laboratories consider homocysteine levels of up to 15.0 µmol/L as normal, Life Extension believes this is too high for optimal health and therefore recommends keeping homocysteine levels < 7-8 µmol/L.
People taking active folate can achieve plasma folate levels 700% higher than by taking an ordinary folic acid (Willems 2004) supplement and may therefore more effectively lower elevated homocysteine levels.

A program of regular exercise may help people recovering from a heart attack, bypass surgery, or angioplasty to modestly reduce homocysteine levels.

Ordinary B-Vitamin Supplements and Folate-Rich Foods May Not Be Enough to Lower Homocysteine

Even though folic acid-fortified foods are ubiquitous, and despite peoples’ best efforts to insure adequate intake of the vitamin through supplementation, many individuals run the risk of not obtaining sufficient amounts of folate necessary to achieve healthy blood levels of homocysteine unless they supplement with bioactive folate. Cooking and food processing destroy natural folates (McKillop 2002). Although red blood cells can retain folate for 40-50 days following discontinuation of supplementation, synthetic folic acid is poorly transported to the brain and is rapidly cleared from the central nervous system (Levitt 1971).

Many people who take ordinary B-vitamin supplements are unable to sufficiently lower their homocysteine levels enough to prevent disease (Schwammenthal 2004). Fortunately, there’s hope for those with seemingly intractable homocysteine levels. One study found that giving L-methylfolate (5-MTHF; also called active folate) to patients with coronary artery disease resulted in a 700-percent higher plasma concentration of folate-related compounds compared to folic acid. This difference was irrespective of the patient's genotype (Willems 2004).

5- MTHF is the predominant biologically active form of folate in cells (Zettner 1981), the blood (Schuster 1993), and the cerebrospinal fluid (Levitt 1971). Until recently, 5- MTHF was available only in prescription medicines and medicinal food products. Now, this active form of folate, which provides increased protection against homocysteine-related health problems, is available as a dietary supplement. This form of the vitamin is unlikely to mask a vitamin B12 deficiency, a well-known shortcoming of folic acid. Since 5-MTHF is the only form of folate used directly by the body, it doesn’t have to be converted and metabolized to be clinically useful, as does synthetic folic acid.

Synthetic folic acid, as used in ordinary dietary supplements and vitamin-fortified foods, must first be converted in cells to active L-methylfolate in order to be effective. These steps require several enzymes, adequate liver and gastrointestinal function, and sufficient supplies of niacin (vitamin B3), pyridoxine (B6), riboflavin (B2), vitamin C, and zinc (Wright 2007).

The low dose requirements for 5-MTHF make it a relatively inexpensive supplement with superior clinical benefits over folic acid. People who would benefit from taking active folate include:
Those who desire to take advantage of 5-MTHF as a part of their anti-aging strategy due to its potency, low-cost, and bioavailability.
Those with elevated risk factors for cardiovascular disease.
Those taking drugs known to interfere with the absorption or metabolism of folate.
People with the gene variant 5-MTHFR C677T.

Individuals with the 5-MTHFR C677T polymorphism are at higher risk of cardiovascular disease, stroke, preeclampsia (high blood pressure in pregnancy), and birth defects that occur during the development of the brain and spinal cord (neural tube defects). The mutation replaces the DNA nucleotide cytosine with thymine at position 677 in the MTHFR gene (nucleotides are the building blocks of DNA.) This change in the MTHFR gene produces a form of the enzyme, methylenetetrahydrofolate reductase, which is thermolabile, meaning its activity is reduced at higher temperatures.

A daily dose of 0.8 mg 5-MTHF is typically used in research studies to achieve a clinically beneficial reduction in elevated plasma homocysteine concentrations. In some cases, doses as low as 0.2 mg to 0.4 mg have been shown to achieve this effect (Wierzbicki 2007).

Drugs That Raise Homocysteine Levels

A number of prescription drugs and natural compounds can elevate blood levels of homocysteine by interfering with folate absorption or metabolism of homocysteine. These include:
Caffeine (Verhoef 2002): Cafcit®, Cafergot®, Esgic®, Excedrin Migraine®, Fioricet®, Fiorinal®, Norgesic®, Synalgos-DC®
Cholestyramine (Tonstad 1998): Questran®, Questran Light®, Cholybar®
Colestipol: Cholestid® (Seshadri 1999)
Fenofibrate (Foucher 2010): Antara®, Fenoglide®, Lipfen®, Lofibra®, Tricor®, Trilpix®
Levadopa (Lee 2010): Parcopa®, Sinemet®, Stalevo®
Metformin (Desouza 2002): ActoPlus Met®, Avandamet®, Fortamet®, Glucophage® Glucovance®, Glumetza®, Janumet® Metaglip® Prandimet® Riomet®
Methotrexate (Desouza 2002): Rheumatrex®
Niacin (Desouza 2002): Advicor®, Ocuvite®, Cardio Basics®CitraNatal®,Heplive®, Niaspan®, Simcor®
Nitrous oxide (Myles 2008)
Pemetrexed (Li 2007) Alimta®
Phenytoin(Mintzer 2009): Dilantin®, Phenytek®
Pyrimethamine (Das 1976): Daraprim®, Fansidar®
Sulfasalazine (Haagsma 1999): Asulfidine®

For More Information

To learn more about the conditions associated with hyperhomocysteinemia, see the following chapters:
Congestive Heart Failure
Managing High Blood Pressure
Thyroid Disorders

Life Extension Suggestions
Folate/folic acid, with several options:
5-MTHF/L-methylfolate (active folate): 800 – 1000 mcg daily; certain individuals may require up to 5 mg daily (under medical supervision). This is the best choice for those with higher homocysteine levels, those with the MTHFR 677TT genotype, and those who are not getting their homocysteine levels low enough with regular folic acid.
Natural folate: 800 – 1600 mcg. This is the form that is found naturally in food.
Folic acid: 1 – 2 mg. This is another option. However, if a 2 mg dose does not provide benefit then consider using the active folate (5-MTHF) form instead.

N-acetylcysteine (NAC): 600 – 1800 mg daily
SAMe (S-adenosylmethionine): 400 mg two to four times daily
Taurine: 1000 – 3000 mg daily
TMG (trimethylglycine): 2000 – 6000 mg daily
Vitamin B12 (cobalamin): 1 – 2 mg daily
Vitamin B2 (riboflavin): 10 – 100 mg daily
Vitamin B6 (as pyridoxal-5’-phosphate): 100 – 200 mg daily
Zinc (as OptiZinc®): 30 – 60 mg daily
Micronized creatine: 500 mg (in capsule form) four to eight times daily
CDP Choline: 250 – 500 mg daily.

In addition, the following blood testing resources may be helpful:
Chemistry Panel & Complete Blood Count (CBC)
Vitamin B12 & Folate
Omega Score®

Disclaimer and Safety Information

This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the treatments discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information container herein.

The protocols raise many issues that are subject to change as new data emerge. None of our suggested protocol regimens can guarantee health benefits. The publisher has not performed independent verification of the data contained herein, and expressly disclaim responsibility for any error in literature.

Natural Ways to Lower Homocysteine Levels Healthy Foods (try to obtain organic)





Raw Nuts


Black-Eyed Peas



Organic Brown Rice


Chick Peas


Healthy fats and oils

Vitamins and Supplements Vitamin B12

Methyycobolamin Folate

Vitmain B2

Vitamin B6 Z



Lifestyle Changes

Healthy Diet

Lose Extra Weight

Control Diabetes

Control High Blood Pressure

Decrease Stress

Daily Exercise

Eliminate coffee

No Smoking Limited Alcohol

Read more at WPBeginner: Lowering Homocysteine Levels Naturally

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