Microbiota and Methylglyoxal-Derived AGEs: Implications in Ageing and Age-Related Disease

Ageing is characterized by progressive metabolic and inflammatory dysregulation, in which methylglyoxal (MGO), a highly reactive dicarbonyl by-product of glycolysis, is involved in the formation of advanced glycation end products (AGEs). This review provides an integrated overview of the bidirectional relationship between MGO-derived carbonyl stress and the gut microbiota, focusing on its implications for ageing and age-related diseases. We summarize current evidence on MGO production, clearance, tissue distribution, and reactivity, with particular attention to the intestinal lumen as a site where dietary compounds, host metabolism, and microbial activity converge. Age-related dysbiosis may impair intestinal barrier integrity, alter microbial metabolite production, and promote chronic low-grade inflammation, thereby reinforcing metabolic dysfunction and favoring free MGO accumulation. Conversely, MGO and AGEs can reshape microbial communities, compromise epithelial tight junctions, and amplify inflammatory signalling through receptor-dependent and independent mechanisms. Evidence from in vitro, animal, and clinical studies supports a role for the MGO-microbiota axis in metabolic, cardiovascular, gastrointestinal, neurodegenerative, and frailty-related conditions. Targeting microbiota composition, intestinal barrier function, and MGO scavenging pathways may therefore represent a promising strategy to mitigate carbonyl stress and preserve health during ageing.