Abstract
Our previous study demonstrated rapamycin added to diet at 4 months of age had significantly less age-related outer hair cell loss in the basal half of the cochlea at 22 months of age compared to mice without rapamycin. The present study tested adding rapamycin to diet later in life, at 14 months of age, and added a longitudinal assessment of auditory brain stem response (ABR). The present study used UMHET4 mice, a 4 way cross in which all grandparental strains lack the Cdh23753A allele that predisposes to early onset, progressive hearing loss. UMHET4 mice typically have normal hearing until 16–17 months, then exhibit threshold shifts at low frequencies/apical cochlea and later in more basal high frequency regions. ABR thresholds at 4, 12, 24, and 48 kHz were assessed at 12, 18, and 24 months of age and compared to baseline ABR thresholds acquired at 5 months of age to determine threshold shifts (TS). There was no TS at 12 months of age at any frequency tested. At 18 months of age mice with rapamycin added to diet at 14 months had a significantly lower mean TS at 4 and 12 kHz compared to mice on control diet with no significant difference at 24 and 48 kHz. At 24 months of age, the mean 4 kHz TS in rapamycin diet group was no longer significantly lower than the control diet group, while the 12 kHz mean remained significantly lower. Mean TS at 24 and 48 kHz in the rapamycin diet group became significantly lower than in the control diet group at 24 months. Hair cell counts at 24 months showed large loss in the apical half of most rapamycin and control diet mice cochleae with no significant difference between groups. There was only mild outer hair cell loss in the basal half of rapamycin and control diet mice cochleae with no significant difference between groups. The results show that a later life addition of rapamycin can decrease age-related hearing loss in the mouse model, however, it also suggests that this decrease is a delay/deceleration rather than a complete prevention.
Highlights
Age-related hearing loss (ARHL) occurs in approximately one-third of people in the United States over the age of 65 increasing to approximately half of those over the age of 75 (e.g., Gates, 2006; Gates et al, 2010)
There was no significant difference in the mean auditory brain stem response (ABR) thresholds or threshold shifts (TS) between male and females in either control diet or rapamycin diet groups at any age for any of the frequencies assessed and males and females were combined for comparisons
The progression of ABR TS in the control diet group was consistent with the pattern we have previously reported in UMHET4 mice with significant TS first appearing at low frequencies and later at higher frequencies (Schacht et al, 2012; Altschuler et al, 2015) (Figures 1A–D)
Summary
Age-related hearing loss (ARHL) occurs in approximately one-third of people in the United States over the age of 65 increasing to approximately half of those over the age of 75 (e.g., Gates, 2006; Gates et al, 2010). Among several effective treatments identified through NIA-ITP, addition of rapamycin to diet at 9 months of age was found to increase life span by 26% in male mice and 23% in female mice (Miller et al, 2014). We hypothesized that ARHL might share underlying mechanisms, such that treatments that enhance life span could reduce and/or delay ARHL This is consistent with studies that demonstrate the positive effects of rapamycin on age-related disorders in animal models, including decreases in cardiac pathology (Dai et al, 2014); muscle weakness (Bitto et al, 2016), cancer incidence (Anisimov et al, 2011), and cognitive decline (Halloran Hussong et al, 2012; Majumder et al, 2012)
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