Single-cell Transcriptomics Unravel Stereocilia Degeneration as a Key Contributor to Age-related Vestibular Dysfunction in Mice and Humans

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 particularly vulnerable to aging. Using single-cell RNA-seq transcriptomes of young and old mouse vestibular HCs, we show that aging HCs display both universal molecular blueprints, such as genomic instability, mitochondrial dysfunction, and impaired proteostasis, and cell type-specific aging signatures associated with deterioration of hair bundles and mechanotransduction. These signatures are also observed in aged human vestibular HCs, suggesting shared mechanisms. Importantly, morphological and functional analysis revealed that bundle degeneration and vestibular functional decline precede HC loss, highlighting the deterioration of 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 the different pace of aging between the two mammalian inner ear sensory epithelia.