Rapamycin but not acarbose decreases age-related loss of outer hair cells in the mouse Cochlea

Abstract

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.

Keywords: Acarbose; Age-related hearing loss; Aging; Auditory; Cochlea; Rapamycin.

Figure 1:

Photomicrographs showing images of basal cochlea representative of four conditions: (A) At four months of age (no treatment) there are three rows (ohc 1, 2, 3) of phalloidin labeled (red chromophore) outer hair cells (OHC) without any OHC loss and one row of labeled inner hair cells (ihc) with no loss; (B) At twenty two months of age without any treatments, there is large loss of inner and out hair cells; (C) At twenty two months of age with rapamycin added to diet at 4 months of age there is small loss of outer hair cells (asterisks show loss of one OHC in row 3 and loss of two OHCs in row 2); (1D) At twenty two months of age with acarbose added to diet at 4 months of age there is large loss of inner and out hair cells. Scale bar = 10 microns

Figure 2:

Cytochleograms comparing age-related outer hair cell loss in representative 22 month old mice that were either (2A) untreated; (2B) treated with rapamycin added to diet at 4 months of age; or (2C) treated with rapamycin added to diet at 4 months of age. Apical cochlea is to the left and base to the right, the transition from apical turn to basal turn is approximately 1.75 mm from the apex and the transition from basal turn to the hook is at approximately 3.9 mm from apex. There is large loss of outer hair cells in the basal half of the cochlea (including hook) in the untreated and acarbose treated rats at twenty two months of age. In the rat with rapamycin added to diet at four months of age there is only minor outer hair cell loss in the basal half of the cochlea. There is large outer hair cell loss at twenty two months of age in the apical cochlea in all three conditions

Figure 3:

A comparison of the mean percent loss of outer hair cells (OHC) and inner hair cells (IHC) in all turns (apex, base and hook) of the cochlear spiral in the group of mice at twenty two months of age without any treatments (CONT22); in the group of mice at twenty two months of age with rapamycin added to diet at 4 months of age (RAPA22) and in the group of mice at twenty two months of age with acarbose added to diet at 4 months of age (ACA22). There is a significant difference in mean OHC loss between the control (untreated) and rapamycin treated groups (p <0.01).

Figure 4:

Scatter plot showing the mean percent loss of outer hair cells in the basal half of the cochlear spiral in the group of mice at twenty two months of age without any treatments (Control-22); in the group of mice at twenty two months of age with rapamycin added to diet at 4 months of age (Rapa-22); in the group of mice at twenty two months of age with acarbose added to diet at 4 months of age (Aca-22) and in the group of mice at 4 months of age (Young). Mice at 22 months of age are divided into males (blue triangles) and females (red circles). Young (4 month old) mice are not divided and shown as unfilled triangles. Error bars show standard error of the mean. There is a significant difference between control (untreated) and rapamycin treated groups (p <0.01).