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Health Protocols

Homocysteine Reduction

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 < 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:

    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 contained 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.