Hair Bundle Degeneration is a Key Contributor to Age-Related Vestibular Dysfunction

Abstract Age-related vestibular dysfunction (ARVD) is a prevalent, debilitating condition in the elderly. The etiology and molecular mechanisms are poorly understood. We focused on mechanosensitive hair cells (HCs) as they are vulnerable to aging. Using single-cell RNA-seq transcriptomes of young and old mouse vestibular HCs, we show that aging vestibular HCs display both universal molecular signatures, such as genomic instability, mitochondrial dysfunction, and impaired proteostasis, and cell type-specific changes associated with deterioration of hair bundles and mechanotransduction. In alignment with transcriptomic findings, imaging and electrophysiological recordings from aged vestibular sensory epithelia confirmed the degeneration of the hair bundles and a reduction in mechanotransduction. Importantly, this deterioration of hair bundles and vestibular function precedes HC loss, highlighting impaired mechanotransduction as a key contributor to ARVD. Furthermore, molecular and cellular changes associated with aging signatures are less pronounced in vestibular HCs than in cochlear HCs, underscoring tissue-specific age-related differences between the two sensory epithelia in the inner ear. Competing Interest Statement The authors have declared no competing interest. Footnotes Teaser: Hair bundle degeneration and age-related vestibular dysfunction The main text, figures, and supplementary figures have been revised to reflect updated analyses and improved clarity. Changes include corrections, additional data, and enhanced visual representations to support the findings more effectively.