FOXG1 promotes aging inner ear hair cell survival through activation of the autophagy pathway.

Presbycusis is the cumulative effect of aging on hearing. Recent studies have shown that common mitochondrial gene deletions are closely related to deafness caused by degenerative changes in the auditory system, and some of these nuclear factors are proposed to participate in the regulation of mitochondrial function. However, the detailed mechanisms involved in age-related degeneration of the auditory systems have not yet been fully elucidated. In this study, we found that FOXG1 plays an important role in the auditory degeneration process through regulation of macroautophagy/autophagy. Inhibition of FOXG1 decreased the autophagy activity and led to the accumulation of reactive oxygen species and subsequent apoptosis of cochlear hair cells. Recent clinical studies have found that aspirin plays important roles in the prevention and treatment of various diseases by regulating autophagy and mitochondria function. In this study, we found that aspirin increased the expression of FOXG1, which further activated autophagy and reduced the production of reactive oxygen species and inhibited apoptosis, and thus promoted the survival of mimetic aging HCs and HC-like OC-1 cells. This study demonstrates the regulatory function of the FOXG1 transcription factor through the autophagy pathway during hair cell degeneration in presbycusis, and it provides a new molecular approach for the treatment of age-related hearing loss.Abbreviations: AHL: age-related hearing loss; baf: bafilomycin A1; CD: common deletion; D-gal: D-galactose; GO: glucose oxidase; HC: hair cells; mtDNA: mitochondrial DNA; RAP: rapamycin; ROS: reactive oxygen species; TMRE: tetramethylrhodamine, ethyl ester.

The nuclear transcription factor FoxG1 affects the sensitivity of mimetic aging hair cells to inflammation by regulating autophagy pathways.

Inflammation is a self-defense response to protect individuals from infection and tissue damage, but excessive or persistent inflammation can have adverse effects on cell survival. Many individuals become especially susceptible to chronic-inflammation-induced sensorineural hearing loss as they age, but the intrinsic molecular mechanism behind aging individuals' increased risk of hearing loss remains unclear. FoxG1 (forkhead box transcription factor G1) is a key transcription factor that plays important roles in hair cell survival through the regulation of mitochondrial function, but how the function of FoxG1 changes during aging and under inflammatory conditions is unknown. In this study, we first found that FoxG1 expression and autophagy both increased gradually in the low concentration lipopolysaccharide (LPS)-induced inflammation model, while after high concentration of LPS treatment both FoxG1 expression and autophagy levels decreased as the concentration of LPS increased. We then used siRNA to downregulate Foxg1 expression in hair cell-like OC-1 cells and found that cell death and apoptosis were significantly increased after LPS injury. Furthermore, we used d-galactose (D-gal) to create an aging model with hair cell-like OC-1 cells and cochlear explant cultures in vitro and found that the expression of Foxg1 and the level of autophagy were both decreased after D-gal and LPS co-treatment. Lastly, we knocked down the expression of Foxg1 under aged inflammation conditions and found increased numbers of dead and apoptotic cells. Together these results suggest that FoxG1 affects the sensitivity of mimetic aging hair cells to inflammation by regulating autophagy pathways.

Protection and Prevention of Age-Related Hearing Loss.

Presbycusis is a sensorineural hearing loss caused by hearing system aging and degeneration. The clinical manifestations are progressive bilateral symmetrical hearing loss, and the hearing curve is mostly slope-shaped with high-frequency reduction, sometimes flat. The results of the second national sample survey of disabled persons (2006) showed that the total number of hearing and speech disability in China was 27.8 million, accounting for 34% of the total number of disabled people in China. Among them are people over 60 years old. There are 20.4541 million people with hearing disabilities. There are 9.49 million senile deaf patients, accounting for 34.1% of the total number of hearing disabilities. As society gradually becomes aging, the incidence of presbycusis is getting higher and higher. The study of its pathogenesis is of great significance for the diagnosis, treatment, and prevention of presbycusis. The rapid progress of molecular biology experimental technology has provided us with a new opportunity to fully understand and reveal the presbycusis. In the near future, early diagnosis of presbycusis-related genes and early prevention or delay of the occurrence and development of presbycusis will become a reality.