**2. Betaine**

Trimethylglycine (betaine) is a derivative of the amino acid glycine. Betaine can be endogenously synthesized through the metabolism of choline, or exogenously consumed through dietary intake [12]. Although betaine concentrations in foods vary depending on cooking and preparation methods, grain products and vegetables such as wheat bran (1340 mg·100 g<sup>−</sup>1), wheat germ (1240 mg·100 g<sup>−</sup>1), spinach (600–645 mg·100 g<sup>−</sup>1), and beets (114–297 mg·100 g<sup>−</sup>1) are the best sources of dietary betaine [13]. Average dietary intake for Western culture typically ranges from 100 to 400 mg·day−1, with a mean of 208 ± 90 mg·day−<sup>1</sup> and results in an average resting plasma betaine concentration of 0.02–0.07 mmol·L−<sup>1</sup> [14,15]. As betaine is a short-chain, neutral, amino acid derivative, absorption across the enterocyte is thought to primarily use the sodium-dependent Amino Acid Transport System A, however sodium-independent absorption is also known to occur [12,16]. A single dose of betaine (50 mg·kg−1) in healthy young men (mean age: 28 years old) free of any known diseases resulted in a peak concentration of ~1 mmol·L−1, in ~1 h [15]. The elimination half-life of a single dose of betaine is ~14 ± 7 h, with <5% of the original dose present in 72 h [15]. However, a loading strategy of 50 mg·kg−<sup>1</sup> per 12 h for 5 days in the same population resulted in a peak concentration of ~1.5 mmol·L−1, ~1 h after ingestion [15]. Likewise, the elimination half-life of the five-day loading of betaine is ~41 ± 14 h, with <5% of the original dose present in 8.6 days. Thus, a five-day loading protocol of betaine increases blood concentrations 50% more than a single dose and may function nearly three times as long.
