Betaine as an Exercise Mimetic
Exercise has been shown to induce the synthesis of the metabolite betaine (trimethylglycine) in the kidneys. Separately, delivery of betaine was developed as a therapy for the rare disease homocystinuria due to its ability to blunt the harmful buildup of homocysteine in that condition. Here, researchers briefly review recent developments in the understanding of the ability of additional betaine delivered as a therapy to act as an exercise mimetic, triggering some of the beneficial metabolic responses to exercise.
Recently, researchers identified the renal metabolite betaine as a potent exercise mimetic through comprehensive multi-omics analysis of exercise responses, offering a promising solution for individuals unable to sustain long-term exercise. The researchers systematically characterized the differential responses to Acute exercise (AE) and Long-term exercise (LE). AE primarily induced acute metabolic and immune stress, marked by significant increases in non-esterified fatty acids, decreased total bile acids, and upregulation of inflammatory factors including IL-6 and EN-RAGE, alongside activation of the glucocorticoid receptor pathway and enhanced anaerobic glycolysis. In contrast, LE triggered sustained adaptations involving metabolic reorganization, immune remodeling, and gut microbiota restructuring. Metabolic reorganization is achieved through the coupling of fatty acid oxidation with tricarboxylic acid cycle activity, accompanied by optimized amino acid metabolism and activated antioxidant defenses. Immune remodeling is reflected by increased naive lymphocytes, reduced neutrophils, and attenuated lymphocyte aging via ETS1 downregulation. Gut microbiota restructuring is characterized by a decrease in opportunistic pathogens and suppressed lipopolysaccharide biosynthesis. Critically, LE also specifically activated methionine metabolism pathways, inducing significant enrichment of the renal metabolite betaine.
Integrated multi-omics analysis confirmed the kidney as the central organ for exercise-induced betaine metabolism, mediated by upregulation of renal choline dehydrogenase (CHDH). Mechanistic studies demonstrated betaine directly binds and inhibits the innate immune kinase TBK1, reducing lipopolysaccharide-induced release of pro-inflammatory cytokines TNF-α and IL-6 while inhibiting immune cell adhesion. Murine models further established betaine's capacity to alleviate cellular senescence, consistently reducing established aging markers including SA-β-Gal and p21. These data reveal the kidney-betaine-TBK1 axis as the core pathway coordinating exercise-mediated anti-inflammatory and anti-senescence effects.
To validate the therapeutic efficacy of betaine, researchers conducted comprehensive supplementation studies in aged murine models. They supplemented aged mice with 1% betaine daily for 8 weeks and found that betaine concentrations in the kidneys of aged mice increased to levels comparable to those induced by LE. Functional evaluation showed that aged mice had significantly improved motor coordination, muscle strength, and spatial memory ability, and significantly reduced depression-like behaviors. Histopathological analysis revealed attenuated markers of aging, reduced lipid deposition, and reduced fibrosis in the kidney, liver, lung, and skin, along with restoration of skeletal muscle morphology and epidermal architecture. Molecular analysis confirmed that betaine could inhibit the phosphorylation of TBK1/IRF3/p65 signaling pathway, down-regulate the proinflammatory cytokines TNF-α and IL-1β, and activate AMPK/SIRT1/PGC-1α signaling pathway. These collective findings support betaine as a viable exercise-mimetic intervention for counteracting age-related physiological and functional decline.
Well this looks really promising. However, according to Wikipedia on trimethylglycine: "The most common side effect is elevated levels of methionine in the blood." This sounds somewhat dangerous as cancer cannot exist without methionine. And methionine is one of the protiens found to have a role in the reduction of the positive effects of calorie restriction. (If these protiens are restricted the effects of calorie restriction are partially simulated from what I have read.)
Also, there are side effects from taking the drug version of betaine (Cystadane):
Trimethylglycine supplementation may cause diarrhea, bloating, cramps, dyspepsia, nausea or vomiting.[24] Although rare, it can also causes excessive increases in serum methionine concentrations in the brain, which may lead to cerebral edema, a life-threatening condition.[24]
Trimethylglycine supplementation lowers homocysteine but also raises (given in high doses of 6g/day) LDL-cholesterol in obese individuals and renal patients.[25]