Aging increases vulnerability to cognitive decline after repetitive mild traumatic brain injury (rm-TBI), yet mechanisms linking age-related factors to neurodegeneration remain poorly understood. This study investigated how brain-derived exosomes from aged mice (A-Exo) worsen rm-TBI outcomes. In a murine rm-TBI model, intranasal A-Exo administration significantly exacerbated spatial memory deficits and hippocampal neuronal apoptosis compared to brain-derived exosomes from young mice (Y-Exo) or controls. Proteomic analysis revealed the enrichment of Tnfrsf21 in brain-derived exosomes from aged mice, and these exosomes were closely associated with the neuronal death pathway. Our further investigations demonstrated that A-Exo could upregulate the expression of tumor necrosis factor receptor superfamily member 25 (Tnfrsf25) in neurons. Knockdown of Tnfrsf25 reversed A-Exo-induced apoptosis, confirming its mechanistic role. Molecular docking identified desoxycortone and propantheline as potent Tnfrsf25 inhibitors, which rescued neuronal viability in A-Exo treated cells. These findings establish aged exosomes as active contributors to post-TBI neurodegeneration and implicate Tnfrsf25 as a key mediator of neuronal damage. The discovery of repurposed drugs targeting Tnfrsf25 provides a novel therapeutic strategy for age-exacerbated neurotrauma. This study bridges critical gaps in understanding rm-TBI-related cognitive decline by elucidating age-dependent exosomal mechanisms and identifying actionable molecular targets.Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.