sirolimus and Presbycusis

Our previous studies revealed that miR-34a suppresses autophagy in the ageing cochlea, which correlates with cochlear hair cell loss and age-related hearing loss (AHL). However, the mechanisms underlying miR-34a regulation of autophagy in the cochlea remain unclear. Here, we show that nuclear translocation of transcription factor EB (TFEB), a master regulator of autophagy, was regulated by miR-34a in HEI-OC1 cells. Moreover, ATG9A, one of the main targets of miR-34a, was shown to interact with TFEB and thus promote its nuclear translocation in HEI-OC1 cells. Rapamycin rescued the inhibition of TFEB nuclear translocation induced by miR-34a/ATG9A activation, restored autophagic flux and consequently prevented HEI-OC1 cell death. Long-term supplementation with rapamycin attenuated outer hair cells (OHCs) and inner hair cell synaptic ribbons, and delayed AHL in C57BL/6 mice. Most importantly, rapamycin partially restored TFEB's nuclear localization and autophagic flux in OHCs of the ageing cochlea. These findings open new avenues for protection against AHL through miR-34a/ATG9a/TFEB modulation of autophagy.

Topics: Animals; Autophagy; Autophagy-Related Proteins; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Hair Cells, Auditory; Membrane Proteins; Mice; Mice, Inbred C57BL; MicroRNAs; Presbycusis; Sirolimus; Vesicular Transport Proteins

Adding rapamycin or acarbose to diet at 9-10 months of age has been shown to significantly increase life span in both male and female UM-HET3 mice. The current study examined cochleae of male and female UM-HET3 mice at 22 months of age to determine if either treatment also influenced age-related loss of cochlear hair cells. A large loss of cochlear outer hair cells was observed at 22 months of age in untreated mice in both apical and basal halves of the cochlear spiral. Addition of acarbose to diet had no significant effect on the amount of outer hair cell loss at 22 months of age or in its pattern, with large loss in both apical and basal halves. The addition of rapamycin to diet, however, significantly reduced outer hair cell loss in the basal half of the cochlea at 22 months of age when compared to untreated mice. There was no significant difference between male and female mice in any of the conditions. Age-related outer hair cell loss in the apical cochlea precedes outer hair cell loss in the base in many mouse strains. The results of the present study suggest that rapamycin but not acarbose treatment can delay age-related loss of outer hair cells at doses at which each drug increases life span.

Topics: Acarbose; Age Factors; Animals; Cell Death; Cytoprotection; Disease Models, Animal; Female; Genetic Predisposition to Disease; Hair Cells, Auditory, Outer; Hearing; Male; Mice, Transgenic; Phenotype; Presbycusis; Sirolimus