June 5, 2024

Lowering Homocysteine in the Elderly Despite Normal Vitamin B12 and Folate Levels

Results from a double-blind, placebo-controlled trial
Micronutrient supplementation can decrease homocysteine levels, potentially lowering the risk of cardiovascular disease and cognitive impairment.


Savic-Hartwig M, Kerlikowsky F, van de Flierdt E, Hahn A, Schuchardt JP. A micronutrient supplement modulates homocysteine levels regardless of vitamin B biostatus in elderly subjects. Int J Vitam Nutr Res. 2024;94(2):120-132. 

Study Objective

To investigate whether a micronutrient supplement could lower homocysteine (Hcy) levels in healthy elderly subjects, regardless of their initial cobalamin and folate status

Key Takeaway

The study found that micronutrient supplementation significantly reduced elevated plasma Hcy levels in elderly subjects, even those with adequate initial levels of cobalamin and folate.


Randomized, double-blind, placebo-controlled trial


Investigators enrolled 133 participants in the trial, and 128 participants completed the trial. Mean age of participants was 75.4±4.5 years, with 72.9% female and 27.1% male. Exclusion criteria included the use of dietary supplements within 3 months before the examination, a body mass index (BMI) greater than 35 kg/m², severe gastrointestinal or cardiovascular diseases, and the use of immunosuppressants or chronic corticosteroids.


Participants took 2 micronutrient capsules daily for 12 weeks. One capsule contained various vitamins and minerals, including 400 μg folic acid and 100 μg cobalamin. The other capsule contained 1.0 gram long-chain omega-3 fatty acids. The placebo group received 1 capsule with 500 mg maltodextrin and 1 capsule with 1.0 gram evening primrose oil.

Study Parameters Assessed

Subjective data included questionnaires on medical history, drug intake, health status, diet, and physical activities, while objective data included measurements of serum cobalamin, holotranscobalamin (Holo-TC), red blood cell (RBC) folate, methylmalonic acid (MMA), and plasma Hcy levels.

Primary Outcome

Change in plasma Hcy levels from baseline to the end of the 12-week intervention

Key Findings

Over 12 weeks, plasma Hcy levels decreased significantly more in the intervention group (–3.6±5.7 μmol/L) compared to the placebo group (P<0.001). In the intervention group, serum cobalamin increased (63±48 pmol/L, P=0.005), Holo-TC increased (17±19 pmol/L, P=0.021), RBC folate increased (326±253 nmol/L, P=0.014), and MMA levels decreased significantly (mean –7.4%, P=0.003).


No funding or disclosures were provided that would suggest bias in design, methods, or results.

Practice Implications & Limitations

This study suggests that micronutrient supplementation can effectively lower Hcy levels in elderly individuals, potentially reducing the risk of cardiovascular disease and cognitive decline.1,2 Practitioners should consider the benefits of such supplementation in elderly patients, especially those with elevated Hcy levels. 

Elevated Hcy, an amino acid produced as an intermediate of methionine metabolism, may contribute to endothelial dysfunction through several different mechanisms.3-10 It is also used as a functional marker of 1-carbon metabolism or methylation. Hyperhomocysteinemia lacks universally accepted cutoff values, though recent studies commonly use a threshold of 15 μmol/L. Clinically, a lower upper limit is suggested via laboratories (for males, Hcy <11.4 μmol/L, and for females, Hcy < 0.4 μmol/L) and an often even lower in integrative medicine practice.

In this study, investigators measured holotranscobalamin (Holo-TC), which has been suggested as a potentially more reliable marker than serum cobalamin, the traditionally ordered vitamin B12 test.11-13 However, this test is not as commonly available as serum cobalamin or methylmalonic acid.

The study did not evaluate genetic mutations in Hcy-metabolizing enzymes, which could affect the results. The vitamin-and-mineral combination included vitamin A (400 μg retinol equivalent [RE]), cholecalciferol (50 μg), tocopherol (18 mg, as alpha-tocopherol), vitamin K (30 μg), ascorbic acid (200 mg), thiamine (1.65 mg), riboflavin (2.1 mg), niacin (16 mg niacin equivalent [NE]), pyridoxine (2.1 mg), folic acid (400 μg), cobalamin (100 μg), biotin (50 μg), pantothenic acid (6.0 mg), (zinc 10 mg), selenium (100 μg), chromium (40 μg), molybdenum (50 μg), and iodine (100 μg). The study also did not assess the baseline biostatus of pyridoxine and riboflavin, which are involved in Hcy metabolism. 

What practitioners can take away from this study is that a deficiency of vitamin B12 and/or folate is not necessary to intervene with B-complex or multimineral supplementation when homocysteine is elevated.

It is not clear what the exact constituents of the 1 gram of omega-3 fatty acid supplement were, in terms of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) content. Several studies have been undertaken to understand if omega-3 fatty acids can reduce serum homocysteine, and most of these studies show no effect.14-16 However, at least 1 study in hemodialysis patients suggested that a 3-gram-per-day dose of omega-3 fatty acids did have a homocysteine-lowering effect.17 While not illustrated in the typical biochemical pathways of metabolism of homocysteine, omega-3 fatty acids may regulate the gene expression of enzymes or the activity of enzymes involved in plasma Hcy metabolism.18 It cannot be ruled out that the omega-3 supplementation had a contributor effect of lowering homocysteine in this study. 

An additional confounder is that common antioxidants may influence homocysteine, though the results are mixed.19-21

While this study was limited to older participants, it is plausible to consider whether similar effects could occur in at least slightly younger populations. The intervention was a modest-dose multivitamin-and-multimineral combination, along with what appears to be a low dose of omega-3 fatty acids, both of which may have additional benefits beyond the reduction of homocysteine. What practitioners can take away from this study is that a deficiency of vitamin B12 and/or folate is not necessary to intervene with B-complex or multimineral supplementation when homocysteine is elevated. 

Since initial levels of homocysteine in this study were 17.6±7.1 μmol/L, it is impossible to determine if patients without hyperhomocysteinemia would benefit similarly from such a supplement intervention. Taking into consideration the exclusion criteria of this study, we also cannot extrapolate the results to people who are currently using or have recently used supplements, those with class 2 or class 3 obesity, those with severe gastrointestinal or cardiovascular diseases, or those using immunosuppressants or chronic corticosteroids.

Conflict of Interest Disclosure

The author is an employee of a company that sells dietary supplements that contain B vitamins and omega-3 fatty acids.

Categorized Under


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