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.
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).
For More Information
To learn more about the conditions associated with hyperhomocysteinemia, see the following chapters: