Traumatic Brain Injury: Multi-Omics Insights into Brain Aging, Neurodegeneration, and Precision Therapeutics.

Traumatic brain injury (TBI) is a major cause of mortality and persistent neurological disability and is increasingly recognized as a potential contributor to accelerated brain aging and long-term neurodegenerative processes. Beyond the immediate mechanical insult, TBI initiates dynamic secondary injury cascades involving chronic neuroinflammation, oxidative stress, mitochondrial dysfunction, synaptic and axonal degeneration, metabolic disturbances, and blood-brain barrier disruption. The persistence and temporal evolution of these molecular alterations may interact with intrinsic aging mechanisms, contributing to progressive neuronal dysfunction and increased vulnerability to age-associated neurodegenerative disorders. The marked biological and temporal heterogeneity of TBI therefore presents major challenges for conventional diagnostic, prognostic, and therapeutic approaches. Recent advances in multi-omics technologies, including genomics, epigenomics, transcriptomics, proteomics, metabolomics, lipidomics, and single-cell and spatial approaches offer unprecedented opportunities to characterize the molecular trajectories linking TBI, brain aging, and neurodegeneration. Integrative multi-omics frameworks, coupled with network biology, artificial intelligence, machine learning, and causal inference, enable the identification of molecular signatures, age-related regulatory networks, clinically relevant biomarkers, and therapeutically actionable targets. This review synthesizes emerging multi-omics insights into the molecular mechanisms through which TBI may influence brain aging and neurodegenerative progression, with particular emphasis on phase-specific molecular signatures, biomarker discovery, patient stratification, therapeutic target prioritization, and precision neurotherapeutics. We further discuss longitudinal profiling, single-cell and spatial approaches, and AI-assisted modeling for patient stratification and therapeutic optimization. Integrating multi-omics with systems biology may provide a framework for studying TBI-associated brain aging and developing personalized interventions, although prospective clinical validation remains essential.