Homocysteine is an amino acid that inflicts damage to the inner arterial lining (endothelium) and other cells of the body.
Many people carry a genetic variation that is linked with elevated homocysteine levels. People carrying this gene variant suffer from an impaired ability to metabolise folic acid to its active form but may achieve a significant reduction in plasma homocysteine by taking an active folate (5-MTHF) supplement.
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.
The Life Extension foundation 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”.
Any one of these “dangers” 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.
At Health Renewal, our recommended optimal range of Homocysteine is <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. 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.
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 ensure 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. 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.
Many people who take ordinary B-vitamin supplements are unable to sufficiently lower their homocysteine levels enough to prevent disease Fortunately, there’s hope for those with seemingly intractable homocysteine levels. One study found that giving L-methyl folate (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.
5- MTHF is the predominant biologically active form of folate in cells, the blood and the cerebrospinal fluid. 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 metabolised 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-methyl folate 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.
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.
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, 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.
Homocysteine is metabolised through two pathways: 1) remethylation and 2) transsulfuration.
- 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 transsulfuration to cysteine, which requires vitamin B6 as a cofactor. This pathway yields cysteine, which is then used by the body to make glutathione, a powerful antioxidant 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, active 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. Prior to puberty, both sexes enjoy optimally healthy levels (about 6 µmol/L). During puberty, levels rise, more in males than females reaching, on average, almost 10 µmol/L in men and more than 8 µmol/L in women. As we age, mean values of homocysteine continue to rise and the concentrations usually remain lower in women than in men.
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)
- Medications that increase the catabolism of the vitamins (as in the case of metformin reducing blood levels of B12 and folic acid).
Lifestyle factors:
- Certain diseases are associated with higher homocysteine levels, as can such lifestyle factors as:
- Smoking
- Coffee consumption
- Excessive alcohol intake
- Lack of exercise
- Obesity
- Stress is also associated with hyperhomocysteinemia.
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.
Several studies have shown that homocysteine can inflict damage to the arterial wall via multiple destructive molecular mechanisms.
Small clinical studies have shown that patients with congestive heart failure (CHF) suffer from elevated plasma homocysteine levels. Based on preclinical evidence that the myocardium may be especially susceptible to homocysteine-induced injury and based on observations linking homocysteine to oxidative stress and to left ventricular remodelling.
It has been hypothesised that elevated plasma homocysteine levels would increase the risk of CHF. Accordingly, researchers investigated the relationship off the 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 concludes “an increased plasma homocysteine level independently predicts the risks of the development of CHF in adults without prior myocardial infarction”.
Migraines is a debilitating disease that can be associated with elevated blood levels of homocysteine.
MTHFR C677T genotype: can't convert folic acid to active form.
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 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 migraines.
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 with 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.
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 of folic acid, 50 milligrams of vitamin B6, and 1 mg vitamin B12 per day. 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.
A number of published studies suggest that hearing loss may be linked to plasma homocysteine levels, which could be reduced by folic acid supplementation.
Folic acid supplementation slowed the decline in hearing of the speech frequencies typically associated with ageing.
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.
Normal Clinical testing laboratories consider a homocysteine value between 5 to 15 µmol/L as healthy. At Health Renewal, we believe 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
- Heart attack
- Stroke
Homocysteine levels in the blood can increase due to age , prescription drug use such as Metformin, declining ability to absorb vitamin B12, deteriorating kidney function, smoking, alcohol, coffee consumption, obesity, declining levels of physical activity, and inheriting a genetic polymorphism known as the MTHFR C677T variant in methylenetetrahydrofolate reductase (MTHFR).
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".
This 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 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, can cross the blood-brain-barrier and is unlikely to mask a vitamin B12 deficiency as folic acid can do. Those who carry this gene variant can safely reduce their risk of homocysteine-related health problems using an inexpensive, nonprescription natural folate supplement.
N-Acetyl-Cysteine reduces homocysteine:
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 . 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. 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.
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.
Taurine and Homocysteine Reduction:
Supplementing with the amino acid taurine can protect against coronary artery disease by favourably modulating blood levels of homocysteine. Research suggests that taurine can block methionine absorption from the diet, thereby reducing available substrate for homocysteine synthesis.
Trimethylglycine (TMG), Choline and Homocysteine Reduction:
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).
Homocysteine and cognitive function: Alzheimer’s Disease
An increased plasma homocysteine level is a strong, independent risk factor for the development of dementia and Alzheimer’s disease.
B Vitamins Prevent Brain Atrophy by Lowering Homocysteine
A two-year randomised 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.
What Dietary and Lifestyle Considerations reduce Homocysteine?
- 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.
- Decrease or eliminates: Alcohol, coffee (filtered and unfiltered), and smoking.
- Weight loss: obesity is associated with higher homocysteine.
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®
- Folate/folic acid, with several options:
- 5-MTHF/L-methyl folate
- (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:
1 ) Chemistry Panel & Complete Blood Count (CBC)
2) Vitamin B12 & Folate
3) Omega Score
