Unravelling the pathogenic role of Advanced Glycation End Products in chronic inflammation and related diseases: molecular insights and strategic interventions

Advanced glycation End Products (AGEs) are a class of compounds which are formed through a non-enzymatic reaction between reducing sugars and proteins, lipids, or nucleic acids, playing a critical role in promoting inflammation, oxidative stress, and tissue damage. This is particularly relevant in metabolic disorders like obesity and insulin resistance, where AGE accumulation contributes to the exacerbation of systemic inflammation, a condition termed metabolic inflammation or “metaflammation”. This thesis explores the pathogenic role of Advanced Glycation End Products (AGEs) in chronic inflammation and associated diseases, with a focus on both molecular mechanisms and potential therapeutic interventions. The first part of the thesis investigates how different types of hypercaloric diets and simple sugars contribute to AGE accumulation in metabolically active organs. Using preclinical models, the thesis evaluates the impact of these diets on mitochondrial dysfunction, metabolic derangements, and the activation of inflammatory pathways in organs such as the liver and skeletal muscle. Furthermore, it explores the anti-glycation properties of natural compounds, including dietary fibres (FOS) and zinc-enriched Spirulina platensis, which show promise in preventing AGE-induced metabolic dysfunctions. Additionally, the thesis examines the role of Spleen Tyrosine Kinase (SYK) in metabolic inflammation. When activated, the receptor for AGEs (RAGE) triggers several pro-inflammatory pathways through a cascade of phosphorylation events, which present potential targets for pharmacological intervention. The repurposing of the SYK inhibitor fostamatinib, originally used for autoimmune disorders, is explored as a therapeutic option for diet-induced metabolic diseases. The research demonstrates fostamatinib's ability to reduce inflammation and improve insulin sensitivity by inhibiting key signalling pathways involved in AGEs-induced damage. The second part of the thesis focuses on the role of AGEs in childhood cancer survivors (CCS), who are at increased risk of long-term complications, including cardiovascular diseases and secondary malignancies, due to prior cancer treatments. These survivors often exhibit systemic inflammation and premature aging, conditions in which AGEs are hypothesized to play a critical role. Observational studies in CCS reveal elevated plasma levels of AGEs, suggesting that they may be involved in driving the chronic inflammatory state observed in these individuals. The research also identifies potential biomarkers of premature aging, providing insight into the molecular pathways underlying the late effects of cancer therapy. Overall, this thesis offers new insights into the pathophysiological role of AGEs in both metabolic diseases and cancer survivorship, highlighting the potential of dietary interventions, natural compounds, and pharmacological agents to mitigate AGE-induced damage. Moreover, it proposes novel research directions, including the exploration of AGE reduction strategies through diet modification and the use of nutraceutical or pharmacological approaches to improve long-term health outcomes.