TMG (betaine) — The Essential Methyl Donor
Trimethylglycine (TMG), also known as betaine, is a naturally occurring compound that serves as a crucial methyl donor in cellular metabolism. In the context of longevity, it is primarily used to support methylation pathways, lower homocysteine levels, and mitigate the potential methyl-depleting effects of NAD+ precursors like NMN and NR.
Mechanism of Action
TMG donates a methyl group to homocysteine, converting it back into methionine via the enzyme betaine-homocysteine S-methyltransferase (BHMT). This process supports the methionine cycle and the production of S-adenosylmethionine (SAMe), the universal methyl donor for DNA methylation and epigenetic regulation. By maintaining the methyl pool, TMG prevents the accumulation of homocysteine, a known risk factor for cardiovascular disease and neurodegeneration. Additionally, it acts as an osmolyte, protecting cells from osmotic stress and supporting protein folding.
Human Trial Evidence
TMG is well-established in human clinical trials for its ability to significantly lower plasma homocysteine levels. Meta-analyses of randomized controlled trials confirm that daily supplementation of betaine reduces homocysteine in healthy adults. While direct human longevity trials are lacking, its role in cardiovascular risk reduction and its use as an adjunct to NAD+ precursors are widely recognized in clinical practice.
Dosing Protocol
Typical longevity dosing ranges from 500 mg to 1,000 mg daily, often taken alongside NAD+ precursors (NMN or NR) in a 1:1 ratio. For clinical reduction of elevated homocysteine, higher doses of 3 to 6 grams per day are used, typically divided into two doses. It is best taken with food to minimize gastrointestinal discomfort.
Safety & Contraindications
TMG is generally recognized as safe and well-tolerated at standard doses. Mild adverse effects can include gastrointestinal upset, nausea, or diarrhea, particularly at higher doses. In rare cases, high-dose betaine supplementation has been associated with elevated serum lipid levels (cholesterol and triglycerides), so lipid monitoring is advised for those taking multi-gram doses.