Age-related hearing loss (presbycusis) is a major health concern for the elderly. Loss of spiral ganglion neurons (SGNs), the primary sensory relay of the auditory system, is associated consistently with presbycusis. The causative molecular events responsible for age-related loss of SGNs are unknown. Recent reports directly link age-related neuronal loss in cerebral cortex with the loss of high-affinity nicotine acetylcholine receptors (nAChRs). In cochlea, cholinergic synapses are made by olivocochlear efferent fibers on the outer hair cells that express alpha9 nAChR subunits and on the peripheral projections of SGNs that express alpha2, alpha4-7, and beta2-3 nAChR subunits. A significantly decreased expression of the beta2 nAChR subunit in SGNs was found specifically in mice susceptible to presbycusis. Furthermore, mice lacking the beta2 nAChR subunit (beta2-/-), but not mice lacking the alpha5 nAChR subunit (alpha5-/-), have dramatic hearing loss and significant reduction in the number of SGNs. Our findings clearly established a requirement for beta2 nAChR subunit in the maintenance of SGNs during aging.