Abstract
Age-related vestibular dysfunction (ARVD) is a prevalent and debilitating condition among the elderly, yet its etiology and underlying molecular mechanisms remain poorly understood. We focused on vestibular sensory epithelia, which comprise mechanosensitive hair cells (HCs) and non-sensory supporting cells (SCs), which are widely recognized as susceptible to aging. Using single-cell RNA-seq transcriptomic analysis of young and old mice, we show that old vestibular HCs exhibit conserved transcriptomic hallmarks of cellular aging, including cellular senescence, mitochondrial dysfunction, and impaired proteostasis, along with prominent cell type-specific changes linked to hair bundle architecture and the mechanotransduction machinery. In non-sensory supporting cells, we observed downregulation of genes and processes associated with several key SC-specific functions, including otoconia and otolithic membrane maintenance, ion and metal homeostasis, various metabolic processes, cell-cell adhesion, and HC-SC interactions. These alterations may directly influence HC function, as HCs depend on SCs for structural, metabolic, and homeostatic support required for mechanotransduction, the first key step in vestibular signal processing. Consistent with these transcriptomic findings, imaging and electrophysiological recordings from old vestibular sensory epithelia reveal hair bundle degeneration and reduced mechanotransduction activity. Importantly, this structural and functional deterioration precedes HC loss, underscoring impaired hair bundle function as a key driver of ARVD. Furthermore, our comparative analysis identifies both shared and distinct aging signatures in vestibular and cochlear HCs, providing broader insight into the mechanisms that may underlie their different rates of age-related degeneration.