NIA Interlab: Prevention of hearing loss in Cockayne Syndrome through NAD supplementation

National Institute On Aging

Investigators

Abstract

Age-related hearing loss occurs due to symmetric sensorineural hearing loss which arises from loss of cochlear hair or auditory nerve cells in inner ear; or loss of synaptic connections in between them. These cells contain mitochondria and are highly metabolically active, particularly cochlear hair cells which are high energy demanding cells. These cells use energy for their mechanosensory functions in response to sound stimulation, making them extremely vulnerable to mitochondrial dysfunction. Indeed, hearing impairment are often seen and are a common feature in patients with mitochondrial diseases and those patients suffer from sensorineural hearing loss in age-related hearing loss. Interestingly, our lab has demonstrated that CS resembles mitochondrial diseases and is associated with reduced levels of the essential cellular metabolite NAD. Further we showed that CS mitochondrial abnormalities could be partially reversed by NAD+ supplementation. Given that sensorial hair cells are high energy requiring cells due to their active metabolism and that CS shows mitochondrial dysfunction, we hypothesized that various forms of NAD+ supplementation may ameliorate the hearing loss seen in Cockayne Syndrome through enhancement of mitochondrial homeostasis. Our preliminary experiments show that the levels of NAD, an essential metabolite with numerous critical functions, are decreased in the cochlea of CSBm/m mice. Remarkably, short-term NAD supplementation treatment prevents progressive hearing loss, restores outer hair cell loss, and improves cochlear health in CSBm/m mice. We observed similar but more modest effects in CSA-/- mice. Interestingly, we identified a defect in synaptic transmission in the inner hair cells of the cochlear base in CS mice due to reduced synaptic ribbon formation. The mechanism whereby NAD supplementation augments this pathway is under investigation. Since hearing loss in CS resembles age-related hearing loss, our findings have potential therapeutic implications for both individuals with CS- or age-related hearing loss.