Erryana Martati, Haomiao Wang, Ivonne M. C. M Rietjens, Liang Zheng
Background Advanced glycation end products (AGEs), formed through non-enzymatic reactions between sugars or reactive dicarbonyls and biomolecules, contribute to the pathogenesis of chronic diseases mainly through dicarbonyl-induced biomolecular damage, tissue accumulation of AGEs, and receptor for AGE (RAGE)-mediated inflammation and oxidative stress. Purpose This review aimed to summarize experimental models used to evaluate the protective effects of food-borne natural compounds against AGE-related adverse effects, to further uncover underlying mechanisms, highlight current limitations, inform future research, and guide methodological refinement in the study of AGEs and the protective effects of natural compounds. Methods Literature was searched, analyzed, and collected using databases, including PubMed, Web of Science, ScienceDirect, and Google Scholar. The search terms used included “advanced glycation end products”, “AGEs”, “dicarbonyl scavenging”, “polyphenols”, “natural compounds”, “cell model”, “ in vitro model ”, “ in vivo model”, etc., and several combinations of these keywords were used to identify relevant studies related to AGE formation, toxicity, and protection by natural products. Results In vitro studies primarily employed endothelial and neuronal cell models and revealed protection against AGE-induced cellular effects by especially polyphenolic natural compounds via dicarbonyl scavenging, Nrf2 activation, mitochondrial protection, and anti-inflammatory effects. However, limitations such as the reliance on cell lines with limited physiological relevance or complexity, the use of supraphysiological concentrations of AGEs and natural inhibitors tested, confounding effects from co-exposure, and lack of metabolic processing in the cell models used complicate the data interpretation and limit the translational relevance of findings to humans. In vivo models including streptozotocin (STZ)-induced diabetes, high-fat diets, and oral AGE or methylglyoxal (MGO) exposure simulate different aspects of endogenous and/or dietary AGE-mediated effects. While these models provide organ-level insights and confirm many mechanistic findings from in vitro work, their translational value is constrained by interspecies differences, exaggerated exposures, and ethical considerations. Conclusion To overcome these challenges and improve human relevance, new approach methodologies (NAMs), including human stem-cell-derived systems, organoids, organ-on-chip platforms, and in silico tools such as physiologically based kinetic (PBK) modeling, represent promising strategies. Integrated into a NAM-based framework, these tools can enable quantitative in vitro -to- in vivo extrapolation (QIVIVE) and help identify effective and safe human-relevant doses for nutritional or therapeutic interventions. © 2026 The Author(s).
Department of Food Science and Biotechnology, Faculty of Agricultural Technology, Brawijaya University, Jalan Veteran, East Java, Malang, 65145, Indonesia; Division of Toxicology, Wageningen University and Research, WE Wageningen, 6708, Netherlands
