Methylglyoxal (MGO)

Methylglyoxal (MGO) is a highly reactive α-oxoaldehyde (dicarbonyl) formed as a spontaneous byproduct of glycolysis via non-enzymatic phosphate elimination from dihydroxyacetone phosphate and glyceraldehyde-3-phosphate. MGO is the dominant endogenous precursor of advanced glycation end-products (AGEs): it reacts with arginine residues to form hydroimidazolone adducts — most abundantly MG-H1 — and with lysine residues to produce protein crosslinks. Detoxification proceeds through the glyoxalase system: GLO1 converts MGO to S-lactoylglutathione; GLO2 then hydrolyses this intermediate to D-lactate. Failure of this pathway causes dicarbonyl stress — pathological MGO accumulation beyond cellular detoxification capacity. GLO1 expression and activity decline with age in C. elegans and rodents; low GLO1 activity correlates with elevated plasma MG-H1 in humans, though causality remains associational. Chronically elevated MGO modifies proteins, DNA, and lipids, activates NF-κB and p38 MAPK signalling, and impairs mitochondrial function, linking dicarbonyl stress to diabetes, cardiovascular disease, and neurodegeneration. Plasma or urinary MG-H1 is the standard biomarker; pharmacological strategies targeting GLO1 induction or MGO scavenging remain investigational as of 2025.