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Homocysteine Science Update

Friday, September 08, 2017

Homocysteine is an amino acid intermediate in the production of two other amino acids, methionine and cysteine. Although homocysteine is naturally present in our bodies, too much homocysteine in the blood has been thought to affect cardiovascular health, which is where the research focused for years.

Clinical research has indicated that a plasma homocysteine level less than 10 micromoles/L is associated with a lower risk of declining health.

Nutrients thought to be involved in the metabolism of homocysteine have includeed folic acid, vitamin B12, vitamin B6, riboflavin, and choline. Although supplementation with these nutrients at or around RDA levels is suggested to lower homocysteine concentration in the blood for some people, no significant effect on cardiovascular health risk has been demonstrated.

Could we have been guilty of looking for positive outcomes in the wrong place, or not seeing the forest for the trees?

Let’s look at the function of each of these homocysteine-linked nutrients and the role of B vitamins in biological methylation, the chemical reaction that occurs in every cell and tissue in the body. 

Chemically speaking, methylation is the process of adding methyl groups to a molecule. A methyl group is a chemical structure made of one carbon and three hydrogen atoms. Since methyl groups are chemically inert, adding them to a protein (the process of methylation) changes how that protein reacts to other substances in the body, thus affecting how that protein behaves in the body and brain. Enzymes, hormones, genes, and sticky plaques are all proteins, and the process of methylation affects them all. 

Folate is the natural B-vitamin also referred to as B9, required for the formation of new cells. It acts as the donor of the one-carbon unit in a variety of methylation reactions critical to the metabolism of nucleic and amino acids essential for normal heart and brain function. It plays a vital role in DNA metabolism from its precursors, thymidine and purines, and is required for the synthesis of methionine, which is required for the synthesis of S-adenosylmethionine (SAM-e), the methyl donor used in many biological methylation reactions, including both DNA and RNA.

MTHFR is an enzyme that our bodies must have to convert synthetic folic acid into a usable form that our bodies need for the important detoxification reaction in the body, one that converts toxic homocysteine to benign methionine to cysteine, which is eliminated from the body as waste material. If this enzyme is impaired, this detoxification reaction is impaired, frequently leading to elevated homocysteine blood levels that can become abrasive to blood vessels, essentially scratching them, leaving damage linked to declining cardiovascular and brain health. 

There is also MTHFR gene mutation that affects how this enzyme works. A simple blood test can identify a variant copy of this gene, which we recommend that everyone have tested at their next physical.

If the MTHFR enzyme if inefficient, it's suggested that the body's ability to methylate folic acid efficiently may be compromised, resulting in unnatural levels of unmetabolized folic acid entering the systemic circulation, which can mask B12 deficiency and lead to a deterioration of the central nervous system function in the elderly.  

On the other hand, 5-methyltetrahydrofolate (the natural folate found in food and in well-designed multiple supplements) readily converts homocysteine to methionine by the enzyme methionine synthase, when it's partnered with vitamin B6, B12 (as methylcobalamin) B2 and Choline.

The bottom line: Increased intake of natural folate from food or natural folate supplements far more efficiently decreases homocysteine concentration in the blood, particularly in those with a defective MTHFR gene.

Vitamin B12 helps convert food into usable energy, makes red blood cells, and is required for proper nerve function.

B12, as methylcobalamin, is also clinically suggested to help protect against brain volume loss in older people.

B12 deficiency is common in individuals over 60 years of age and contributes to elevated blood levels of homocysteine.

Vitamin B6 helps convert food into usable energy and assists in the formation of neurotransmitters, red blood cells and DNA.

B6 partners with folate and B12 to maintain normal concentrations of homocysteine.

Riboflavin (vitamin B2) assists several metabolic and antioxidant enzymes and helps convert food into usable adenosine triphosphate (ATP) energy.


B2 also assists the enzyme MTHFR conversion of folate to the transformation of homocysteine to methionine to cysteine. 

Choline is also considered a B vitamin by many and sometimes considered a neurotropic. It functions as vital structural components of cell and mitochondria membrane fluidity in the body and brain.

It helps nutrients cross cellular membranes and allows the detoxification reaction to remove toxic homocysteine from the cells via the methionine process. In the case of choline, it is also a potent anti-inflammatory that also facilitates proper nerve and other cellular signaling and function.

Choline is also a water-soluble essential nutrient precursor for the neurotransmitter acetylcholine, which is required for memory function. It must be consumed in the diet or through supplementation, particularly for vegans and vegetarians. Betaine is an active metabolite of choline. 

Enter Elevated Homocysteine and Brain Structure / Function Research

Elevated homocysteine levels have been linked to accumulation of amyloid-B peptide, intensified tau protein hyper-phosphorylation and neurofibrillary tangles, all identified markers in declining brain function.


Amyloid plaque formation is also thought to be an important event in the etiology of declining brain function, and there is evidence that elevated levels of homocysteine can impact the plaque formation by reducing the clearing rate of amyloid-B in the brain.

It has been suggested that elevated homocysteine's effect on brain capillaries is a further mechanism linked to declining brain structure / function.

Elevated homocysteine is thought to affect vascular endothelial integrity by promoting the generation of peroxides and also by reducing the availability of nitric oxide through a reduction of intracellular glutathione peroxide levels. It has also been speculated that there might be a more direct effect on brain cells in those with the ApoE-4 genotype.

A growing body of evidence suggests that persons with specific genotypes are more susceptible to imbalances in homocysteine levels, insufficient DNA repair, methylation and / or synthesis, as well as reduced availability of neurotransmitters, phospholipids, and myelin. 

Reduced enzymatic activity might be compensated for by biologically active folate and B vitamins, but by the time the decline in brain health is recognized, it might be too late to help reverse the decline in many people. 



 It has been suggested in a number of studies that the health care costs of declining brain health in the aging process could exceed one trillion dollars by the year 2050. Many questions remain concerning declining brain health, since neuropathological changes are suggested to start developing decades before even mild symptoms of declining brain health manifest. 

Three obvious questions: (1) Has the role that natural folate supplementation plays in biological methylation been hiding in plain sight.  (2) Has natural folate supplementation been appropriately considered in homocysteine study design affecting cardiovascular and brain health or have all of the published studies included folic acid? (3) Could the considered healthy plasma homocysteine level less than 10 micromoles/L possibly still be a bit too high?


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