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 µmol/L. At present, medical testing laboratories consider a homocysteine number between 11-15 µmol/L as the upper limit of “normal” despite robust clinical data to the contrary (Guo 2009, Nygard 1995). Consequently, many doctors remain misinformed as to the optimal target range for homocysteine and the doses of homocysteine-lowering nutrients required to achieve this optimal range.
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 2003, 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 years. They also found a similar association for blood levels of vitamin B12 <125 pmol/L among all study participants. In participants with homocysteine levels ≤15 µmol/L, low serum B12 was associated with nearly fourfold higher odds of AMD (Rochtchina 2007).
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 µmol/L. Depending upon other factors, you may require larger-than-usual intakes of B vitamins to achieve a healthy blood level of homocysteine. Data from published studies reveal that there is no safe “normal range” for homocysteine. Epidemiological studies have shown that higher homocysteine levels are associated with higher risk, even at levels that are considered “normal” (Robinson 1995). Life Extension recommends a target of <7-8 µmol/L because published data, as well as the Foundation's experience with homocysteine in tens of thousands of members over more than 30 years, indicate that this threshold target is a realistic goal when taking optimal amounts of vitamins B6, B12, folate, TMG, and other homocysteine-lowering nutrients (McLean 2004).
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 µmol/L.
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 µmol/L).
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).