Single-cell profiling identifies hair cell SLC35F1 deficiency as a signature of primate cochlear aging

Abstract

Cochlear aging causes substantial hearing impairment in older adults, yet primate-specific mechanisms remain poorly characterized. Our comprehensive analysis combining single-cell and histopathological profiling in aging Macaca fascicularis demonstrates progressive cochlear degeneration featuring accelerated sensory hair cell loss, senescent spiral ganglion neurons with elevated neuroinflammation, and marked stria vascularis atrophy. We discovered that downregulation of transmembrane transport proteins, particularly SLC35F1, serves as a critical biomarker of hair cell aging. Functional validation through Slc35f1 knockdown in adult mice successfully recapitulated key aspects of age-related hearing loss, including hair cell degeneration and auditory function decline. Notably, we showed that long-term metformin administration at clinically relevant doses effectively delays cochlear aging in primates. These findings provide fundamental insights into the cellular and molecular basis of primate cochlear aging while establishing a foundation for developing targeted interventions against age-related hearing loss.