MicroRNA-Mediated Regulation of Brain Aging Hallmarks: Implications for Neurodegeneration and Neural Recovery.

Abstract

Aging is a progressive biological process characterized by the decline of cellular and tissue homeostasis, increasing vulnerability to chronic diseases, especially neurodegeneration. This review examines the role of microRNAs (miRNAs) in brain aging by linking them to the updated hallmarks of aging and key neurobiological processes. This is an integrative literature review of studies on brain aging, neurodegeneration, and miRNA-mediated regulation. Evidence was synthesized from transcriptomic analyses, experimental studies, and research on circulating systemic factors, including extracellular vesicle-associated miRNAs and plasma proteins. The review focuses on miRNA involvement in genomic stability, nutrient sensing, proteostasis, autophagy, mitochondrial function, telomere maintenance, epigenetic regulation, and cellular senescence. miRNAs regulate multiple aging-related pathways, including DNA repair, IGF-1/AKT/mTOR signaling, proteostasis, autophagy, and mitochondrial homeostasis. In aging brains, transcriptomic data consistently show reduced expression of genes involved in synaptic plasticity, metabolism, and maintenance, alongside increased inflammatory and immune signaling. Circulating systemic factors and extracellular vesicle miRNAs also influence brain aging, affecting neuroplasticity, cognitive function, and regenerative capacity. These mechanisms contribute to neuroinflammation, synaptic dysfunction, myelin impairment, and neurovascular unit disruption. miRNAs are key regulators of brain aging and neurodegeneration and hold promise as biomarkers and therapeutic targets. However, clinical application is limited by disease heterogeneity, context-dependent effects, off-target activity, and challenges in central nervous system delivery. Further research is needed to support safe and effective miRNA-based interventions.