cAMP-MFN2 Signaling Suppresses Cochlear Cell Senescence and Age-Related Hearing Loss

Yu Liu¹Jinyuan Cao¹Jie Cui¹Haitong Chen¹Shujing Qin¹Qi Li^2*Zhongwu Su^2*

• ¹The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
• ²Department of Otolaryngology, Nanfang Hospital, Southern Medical University, Guangzhou, China

Age-related hearing loss (presbycusis) is the most common sensory deficit in the elderly, yet it lacks effective pharmacological treatments. The decline of the cyclic AMP (cAMP) signaling pathway is implicated in aging, but its functional role in the auditory system remains largely unknown. Here, we investigated whether enhancing cAMP signaling could counteract presbycusis and elucidated the underlying molecular mechanism. Using a D-galactose-induced cellular senescence model and an in vivo aged mouse model, we found that the cAMP analog, dibutyryl-cAMP (dbcAMP), potently suppressed cellular senescence and the associated inflammatory phenotype. In addition, cAMP treatment alleviated mitochondrial dysfunction, as indicated by improved mitochondrial bioenergetics and morphology. Mechanistically, we identified Mitofusin 2 (MFN2) as an essential downstream mediator. The anti-senescence effects of cAMP were significantly blunted upon siRNA-mediated knockdown of Mfn2, establishing MFN2 as a key, though perhaps not the sole, component of this protective pathway. Importantly, systemic administration of dbcAMP to aged mice significantly preserved hearing function and protected cochlear hair cells. This in vivo protection was accompanied by an upregulation of cochlear MFN2 and a coordinated suppression of senescence and inflammation markers. In conclusion, our study reveals a critical protective role for the cAMP-MFN2 axis in auditory aging by suppressing cellular senescence. These findings identify this axis as a novel and promising therapeutic target for the treatment of age-related hearing loss.