Vascular Aging and Multi-Omic Regulation in Ischemic Stroke: Toward Precision Neurorepair

Ischemic stroke (IS) remains a leading cause of disability and mortality in aging populations. Recovery trajectories are shaped not only by the acute vascular insult but also by pre-existing comorbidities, genetic predisposition, and age-dependent molecular remodeling. Common vascular risk factors, such as diabetes mellitus, atrial fibrillation, hypertension, and dyslipidemia, sustain systemic and cerebral inflammation, promote endothelial dysfunction, disrupt blood-brain barrier integrity, and impair neuroplasticity, collectively limiting neurovascular repair and recovery potential. Recent advances in genomic, epigenomic, and transcriptomic profiling have identified dynamic molecular networks that regulate neuronal survival, angiogenesis, and synaptic plasticity after stroke. However, most discoveries remain correlative. Establishing causality will require perturbation-based approaches, including genome and epigenome editing, patient-derived stem cell and organoid models, and longitudinal multi-omics analyses across diverse ancestries and comorbidity profiles. Such integration will clarify how metabolic and inflammatory states imprint the epigenetic and transcriptional landscape of the aging brain. Emerging evidence implicates DNA methylation, histone modifications, and noncoding RNAs, including circular RNAs, as pivotal regulators of ischemic resilience and neurovascular recovery. Translational studies combining genomic insights with epigenetic pharmacology have demonstrated proof-of-concept efficacy for genotype-guided therapies, RNA-based interventions, and histone deacetylase inhibition. Collectively, these strategies support a systems-level framework that unites vascular biology, multi-omics, and neurorestoration. Within this paradigm, aging is reframed not as a static risk factor but as a modifiable molecular trait, guiding the timing and intensity of interventions to enhance neurorepair, restore vascular integrity, and preserve cognitive resilience.