From an Age-Stratified Perspective: Divergent Adaptive Mechanisms of the Traumatic Brain Injury Repair Network...

Traumatic brain injury (TBI) remains a leading cause of chronic neurological impairment across the lifespan, with significant disparities in clinical recovery trajectories between pediatric and adult patients. Previous research has often been confined to a binary debate over the relative repair capacity of different age groups; however, this paradigm is insufficient for exploring the age-dependent molecular mechanisms of adaptation in depth. This review proposes a "divergent adaptation" theoretical framework to systematically analyze age-dependent differences in the brain-derived neurotrophic factor (BDNF)-miRNA network and its microenvironmental regulation-including cerebrospinal fluid dynamics and the gut-brain axis-during TBI repair. In the pediatric brain, repair strategies primarily leverage developmental plasticity, characterized by elevated BDNF/insulin-like growth factor-1 (IGF-1) expression and the active involvement of neurogenesis-promoting miRNAs such as miR-124, which facilitate neural circuit reorganization. However, this reparative process also entails risks, including aberrant circuit formation and vascular fragility. In contrast, the adult brain employs repair strategies focused on maintaining network stability: BDNF/TrkB signaling shifts toward localized repair, while miR-129-mediated inhibition of IGF-1 and epigenetic silencing mechanisms (e.g., BDNF promoter hypermethylation) constrain regenerative capacity and favor gliotic scar formation. Furthermore, cross-system mechanisms-such as the unique cerebrospinal fluid dynamics in children and the "developmental window effect" of the gut-brain axis-may contribute to distinct injury response patterns across ages. From a clinical translational perspective, we emphasize that intervention strategies must be precisely tailored according to age-specific mechanisms. For pediatric patients, potential approaches include exosome-mediated delivery of neurogenic miRNAs (e.g., miR-133b) and IGF-1 potentiation therapies. For adults, more suitable strategies may involve electroacupuncture-mediated modulation of the BDNF-miRNA axis or CRISPR/dCas9-based reversal of epigenetic silencing. Additionally, natural compounds such as curcumin, which confer synergistic anti-inflammatory effects via the BDNF/miRNA network, could represent a universal therapeutic strategy applicable across age groups. This field faces several limitations, however, including a scarcity of high-quality pediatric TBI data, a translational gap between animal models and clinical reality, and an incomplete understanding of cross-system mechanisms. Future studies should establish developmentally staged research systems and integrate multi-omics technologies to advance precision neuroregenerative strategies.