Advanced glycation end products and PTSD: molecular insights and dietary approaches for neuropsychiatric health

Post-Traumatic Stress Disorder is a complex psychiatric condition characterized by persistent fear, emotional dysregulation, cognitive impairment, hyperarousal, and chronic stress. Although PTSD is typically triggered by exposure to traumatic events, the underlying biological mechanisms contributing to its development and progression remain incompletely understood. Glycation, a non-enzymatic biochemical process leading to the formation of Advanced Glycation End Products (AGEs), has emerged as a potential mechanistic link between chronic stress, neuroinflammation, and stress-related neuropsychiatric disorders, including PTSD. This review explores the role of glycation and deglycation in the pathophysiology of PTSD. It examines how chronic psychological stress contributes to AGE accumulation, neuroinflammation, oxidative damage, and neuronal dysfunction. Additionally, the review discusses diagnostic biomarkers, potential therapeutic targets, dietary and nutritional interventions, and hormonal therapies that may help restore glycation-deglycation balance and improve clinical outcomes in individuals with PTSD. A comprehensive review of the literature was conducted to evaluate the molecular and physiological mechanisms underlying PTSD, with particular emphasis on glycation-related pathways. Studies investigating the roles of AGEs, their receptors, endogenous deglycation systems, dietary factors, and pharmacological interventions were analysed. The review also assessed emerging precision medicine approaches and nutritional strategies aimed at reducing AGE formation and mitigating stress-induced neurobiological alterations. Chronic psychological stress may disrupt the physiological balance between glycation and deglycation, leading to carbonyl stress, excessive AGE formation, mitochondrial dysfunction, oxidative stress, and persistent neuroinflammation. AGEs activate the receptor for advanced glycation end products (RAGE), triggering inflammatory signalling pathways such as NF-κB and promoting neuronal injury. Key molecular targets linking PTSD and glycation include RAGE, hypoxia-inducible factor-1 alpha (HIF-1α), KEAP1/Nrf2 signalling, FKBP5-glucocorticoid receptor pathways, the glyoxalase system (GLO1 and GLO2), and DJ-1/PARK7. Biomarker studies reveal alterations across neuroendocrine, inflammatory, genetic, epigenetic, psychophysiological, and neuroanatomical pathways in PTSD. Nutritional interventions rich in polyphenols, antioxidants, omega-3 fatty acids, probiotics, vitamins, and anti-inflammatory compounds may reduce AGE formation, enhance endogenous deglycation mechanisms, and improve neurobiological resilience. Emerging hormonal therapies, including glucocorticoids, DHEA, allopregnanolone, estrogen, testosterone, oxytocin, vasopressin antagonists, and IGF-1 modulation, may further complement conventional PTSD treatment strategies. Dysregulation of glycation and deglycation pathways represents a promising mechanistic framework for understanding the development and progression of PTSD. Excessive AGE accumulation may contribute to neuroinflammation, oxidative stress, impaired neuroplasticity, and accelerated biological aging observed in affected individuals. Targeting AGE formation and enhancing endogenous deglycation mechanisms through pharmacological, nutritional, and hormonal interventions may offer novel therapeutic opportunities for PTSD and related stress-associated disorders. These findings support the development of personalized treatment approaches aimed at improving long-term outcomes and resilience in individuals with PTSD.