Age-related hearing loss (ARHL) is one of the most common disorders affecting elderly individuals. There is an urgent need for effective preventive measures for ARHL because none are currently available. Cockayne syndrome (CS) is a premature aging disease that presents with progressive hearing loss at a young age, but is otherwise similar to ARHL. There are two human genetic complementation groups of CS, A and B. While the clinical phenotypes in patients are similar, the proteins have very diverse functions, and insight into their convergence is of great interest. Here, we use mouse models for CS (CSA−/− and CSBm/m) that recapitulate the hearing loss in human CS patients. We previously showed that NAD+, a key metabolite with various essential functions, is reduced in CS and associated with multiple CS phenotypes. In this study, we report that NAD+ levels are reduced in the cochlea of CSBm/m mice and that short-term treatment (10 days) with the NAD+ precursor nicotinamide riboside (NR), prevents hearing loss, restores outer hair cell loss, and improves cochlear health in CSBm/m mice. Similar, but more modest effects were observed in CSA−/− mice. Remarkably, we observed a reduction in synaptic ribbon counts in the presynaptic zones of inner hair cells in both CSA−/− and CSBm/m mice, pointing to a converging mechanism for cochlear defects in CS. Ribbon synapses facilitate rapid and sustained synaptic transmission over long periods of time. Ribeye, a core protein of synaptic ribbons, possesses an NAD(H) binding pocket which regulates its activity. Intriguingly, NAD+ supplementation rescues reduced synaptic ribbon formation in both CSA−/− and CSBm/m mutant cochleae. These findings provide valuable insight into the mechanism of CS- and ARHL-associated hearing loss, and suggest a possible intervention.
Hearing loss is one of the most prominent age-associated conditions. Its prevalence almost doubles every decade starting from adult life and affects up to 80% of individuals over the age of 85.There are two major types of hearing loss: conductive and sensorineural. Any damage or obstruction that prevents sound from being conducted into the inner ear is considered conductive hearing loss. Sensorineural hearing loss derives from deficits in sensory cells or auditory nerves of the inner ear. A common type of sensorineural hearing loss is age-related hearing loss (ARHL), which occurs progressively in individuals as they age.Despite its high prevalence and cost, there are no interventions that prevent ARHL.
Cockayne syndrome (CS) is a premature aging disorder with prominent sensorineural hearing loss, similar to ARHL.CS is primarily caused by mutations in CSA and CSB proteins that participate in various biological processes including DNA repair, transcription, and mitochondrial functions.Hearing loss is a cardinal clinical symptom of CS, affecting up to 80% of CS patients by age 10.Hearing loss in CS resembles ARHL as both are bilateral, sensorineural, and progressive. Mouse models of CS (CSA−/− and CSBm/m) recapitulate the progressive hearing loss and manifest sensory hair cell degeneration seen in the patients.Notably, hearing loss progression is slower in CSA−/− than in CSBm/m mice, reflecting the situation in CS patients.
We find that NAD+ levels were reduced in the cochlea of CSBm/m mice and that a brief intervention with NR (only 10 days) rescues progressive high-frequency hearing loss, improves outer hair cell survival, and normalizes DPAOEs in CSBm/m mice. We observed similar but more modest effects on hearing loss in CSA−/− mice following NAD+ intervention. Remarkably, we detected reduced numbers of synaptic ribbons in inner hair cells in both CSA−/− and CSBm/m mice, which were normalized after NAD+ supplementation. The assembly and function of synaptic ribbons in inner hair cells, which facilitate high vesicle turnover,are modulated by NAD+ and NADH. Therefore, these results provide insight into a converging mechanism underlying hearing loss in CSA−/− and CSBm/m mice, which may be similar to the mechanism underlying hearing loss in humans.
We previously reported that NAD+ supplementation can activate Sirt1 and rescue CS-related phenotypes. Sirt1 is a NAD+-dependent protein deacetylase and is known to have protective effects against aging-associated degeneration.Notably, Sirt1 expression also declines in the mouse cochlea during aging and its overexpression protects cochlear hair cells and delays early-onset ARHL. Given that Sirt1 activation is attenuated in CSBm/m patient fibroblasts, the benefits of NAD+ supplementation on hearing in CS might also be mediated by Sirt1 activation. Indeed, Sirt1 activation by resveratrol treatment prevents outer hair cell loss and rescues the reduced synaptic ribbon counts in inner hair cells upon aging.Future studies exploring the CSB-Sirt1-NAD axis in the context of hearing loss are warranted as the role of Sirt1 on cochlear function is still a subject of debate.