Mechanistic Modulation of Food Bioactives and Metabolites on Reactive Carbonyl Species and Advanced Glycation End Products

Abstract Reactive carbonyl species (RCS) and advanced glycation end products (AGEs) are strongly linked to numerous chronic diseases, including diabetes complications, nephropathy, hepatopathy, neurodegenerative diseases, cardiovascular diseases, and certain cancers. While extensive drug development efforts have targeted RCS and AGE inhibition, several candidates, even those reaching Phase III trials, were ultimately terminated due to safety concerns and economic reasons. In contrast, food-derived bioactive compounds and their metabolites are generally recognized as safe and well accepted by consumers, presenting promising alternatives for modulating RCS and AGEs and preventing related diseases. This review provides a comprehensive overview of such bioactives with potent RCS and/or AGE modulation capabilities, detailing their action mechanisms. Covered compounds include flavonoids (e.g., tea catechins, citrus flavanones like hesperetin and didymin, apple dihydrochalcones such as phloretin and phloridzin, and myricetin), non-flavonoids (e.g., oxyresveratrol, emodin, and physcion from Polygonum multiflorum; 6 shogaol and 6 gingerol from ginger; curcumin from turmeric), and macromolecules (e.g., the dipeptide carnosine and various polysaccharides). Mechanistically, these compounds act through primarily direct trapping of RCS and Amadori intermediates, inhibition of AGE formation (via carbonyl stress alleviation, glycoxidation suppression, crosslink cleavage), and upregulation of detoxifying enzymes such as glyoxalase I. Many food bioactives demonstrate better RCS/AGE inhibition capabilities than pharmaceutical positive controls such as aminoguanidine. However, their poor oral bioavailability remains a major hurdle and requires further research in economic improvement strategies. Exploring new bioactive compounds and metabolites is also a key area for future research.