Betaine (trimethylglycine) is the osmolyte that is found in high concentrations in the beets, the spinach, the quinoa, and the wheat bran — and it is the primary methyl donor in the homocysteine metabolism, where it donates a methyl group to the homocysteine to form the methionine through the betaine-homocysteine methyltransferase (BHMT) pathway. The homocysteine metabolism is the critical pathway for the maintenance of the normal homocysteine levels and for the synthesis of the methionine (the essential amino acid that is the precursor of the S-adenosylmethionine, SAMe, which is the universal methyl donor for more than 100 methyltransferase reactions in the human body). The homocysteine is a sulfur-containing amino acid that is formed from the methionine metabolism, and it is either recycled back to the methionine (through the methionine synthase pathway, which requires the vitamin B12 and the folate, or through the betaine-homocysteine methyltransferase pathway, which requires the betaine) or converted to the cysteine (through the transsulfuration pathway, which requires the vitamin B6). The elevated homocysteine (hyperhomocysteinemia) is a major risk factor for the cardiovascular disease, the stroke, the thrombosis, and the cognitive impairment — and it is one of the most common and most treatable nutritional deficiencies in the developed world. The betaine is unique among the methyl donors because it is not a vitamin — it is a naturally occurring compound that is found in the food, and it can be synthesised in small amounts from the choline in the human cells. Without adequate betaine and methyl donation, the homocysteine accumulates, the methionine synthesis is impaired, the DNA methylation is disrupted, and the cardiovascular disease risk increases — the hallmark of the betaine deficiency. The typical dietary betaine intake from the beets and the other betaine-rich foods is 100-500mg daily, and the therapeutic doses for the homocysteine reduction are 1.5-6g of the betaine supplement daily — making the betaine one of the most effective interventions for the hyperhomocysteinemia and for the cardiovascular risk reduction.
Betaine and the Homocysteine Metabolism
Betaine lowers the homocysteine primarily through the betaine-homocysteine methyltransferase (BHMT) pathway — this is an alternative pathway to the methionine synthase pathway (which requires the folate and the vitamin B12) for the conversion of the homocysteine to the methionine. The BHMT is expressed primarily in the liver and the kidneys, and it uses the betaine as the methyl donor to convert the homocysteine to the methionine — this pathway is particularly important when the folate levels are low or when the methionine synthase pathway is impaired (as it often is in the older adults and in people with the B12 deficiency). The betaine supplementation has been shown in multiple studies to significantly reduce the homocysteine levels — a meta-analysis of 12 RCTs found that the betaine supplementation at 1.5-6g daily reduced the fasting homocysteine by 1.5-3 µmol/L (approximately 10-20% reduction) and reduced the post-methionine-load homocysteine by 5-10 µmol/L — making it one of the most effective non-vitamin interventions for the hyperhomocysteinemia. The betaine also improves the methionine synthesis (which is essential for the SAMe production and for the DNA methylation), and it supports the liver function (by acting as an osmolyte and by protecting the liver cells from the osmotic stress and from the fatty liver infiltration).
The clinical importance of the betaine for the cardiovascular health is underscored by the observation that the elevated homocysteine is a major independent risk factor for the cardiovascular disease, the stroke, and the venous thrombosis. A meta-analysis of 30 prospective cohort studies found that the elevated homocysteine (greater than 15 µmol/L) was associated with a 60-70% increased risk of the coronary heart disease, a 40-50% increased risk of the stroke, and a 30-40% increased risk of the venous thrombosis — making the homocysteine one of the most important modifiable risk factors for the cardiovascular disease. The betaine supplementation reduces the homocysteine and thereby reduces the cardiovascular risk — though the direct effect of the betaine on the cardiovascular outcomes (heart attacks, strokes) has not been established in the large RCTs.
Practical Application
For general betaine supplementation for the homocysteine reduction and for the cardiovascular support, the evidence-based approach is to supplement with 1.5-6g of betaine daily (as the betaine anhydrous or as the betaine hydrochloride, which is the form that is commonly used in the sports supplements). The betaine should be taken with the meals (to enhance the absorption and to reduce the gastrointestinal side effects). The betaine is generally well-tolerated with no significant adverse effects at doses up to 6g daily, though it may cause the nausea, the diarrhoea, and the fishy body odour (due to the trimethylamine formation in people with the trimethylaminuria) at the high doses. For comprehensive homocysteine management and cardiovascular support, betaine pairs well with the folate (which works through the methionine synthase pathway to convert the homocysteine to the methionine), with the vitamin B12 (which is the other cofactor for the methionine synthase), with the vitamin B6 (which supports the transsulfuration pathway and the conversion of the homocysteine to the cysteine), and with the omega-3 fatty acids (which have complementary effects on the cardiovascular health and on the inflammation).
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