NRH attenuates age-related hearing loss by suppressing cochlear ferroptosis and cellular senescence via Sirt3 activation.

BACKGROUND

Age-related hearing loss (ARHL) is a prevalent sensory disorder with significant clinical and social burdens, yet no FDA-approved pharmacological treatments are currently available. Emerging evidence implicates declined cellular NAD+ levels in the pathogenesis of age-related diseases, suggesting NAD+ metabolism as a potential therapeutic target.

PURPOSE: In this study, we investigate the efficacy of Dihydronicotinamide riboside (NRH), a highly bioavailable NAD+ precursor, in mitigating ARHL.

METHODS

C57BL/6 mice were used as animal model of ARHL and received oral administration of NRH (125 mg/kg) every other day. Then hearing thresholds were assessed and cochlear structure was evaluated. D-galactose (D-gal)-induced aging models were generated using organ explants and HEI-OC1 cells to investigate the protective effects of NRH treatment. Transcriptomic profiling and molecular docking characterized NRH's mechanism of action, while H&E staining confirmed its safety profile. Temporal NRH metabolism in organ explants was tracked using fluorophore-conjugated NRH.

RESULTS

NRH administration ameliorated ARHL in C57BL/6 mice, as evidenced by improved auditory thresholds and elevated cochlear NAD+ levels. Treatment preserved cochlear hair cells, synapses, and auditory neurons. Mechanistically, NRH activated Sirt3, thereby inhibiting oxidative stress and lipid peroxidation via modulation of ferroptosis-related pathways, ultimately mitigating cochlear cellular senescence. NRH demonstrated a favorable safety profile and exhibited temporal distribution across distinct cochlear cell types.

CONCLUSION

Our findings demonstrate that NRH mitigates ARHL in C57BL/6 mice, holding significant translational potential for ARHL treatment.