Effects of Long-Term Exercise on Age-Related Hearing Loss in Mice

Abstract

Regular physical exercise reduces the risk for obesity, cardiovascular diseases, and disability and is associated with longer lifespan expectancy (Taylor et al., 2004; Pahor et al., 2014; Anton et al., 2015; Arem et al., 2015). In contrast, decreased physical function is associated with hearing loss among older adults (Li et al., 2013; Chen et al., 2015). Here, we investigated the effects of long-term voluntary wheel running (WR) on age-related hearing loss (AHL) in CBA/CaJ mice, a well established model of AHL (Zheng et al., 1999). WR activity peaked at 6 months of age (12,280 m/d) and gradually decreased over time. At 24 months of age, the average WR distance was 3987 m/d. Twenty-four-month-old runners had less cochlear hair cell and spiral ganglion neuron loss and better auditory brainstem response thresholds at the low and middle frequencies compared with age-matched, non-WR controls. Gene ontology (GO) enrichment analysis of inner ear tissues from 6-month-old controls and runners revealed that WR resulted in a marked enrichment for GO gene sets associated with immune response, inflammatory response, vascular function, and apoptosis. In agreement with these results, there was reduced stria vascularis (SV) atrophy and reduced loss of capillaries in the SV of old runners versus old controls. Given that SV holds numerous capillaries that are essential for transporting oxygen and nutrients into the cochlea, our findings suggest that long-term exercise delays the progression of AHL by reducing age-related loss of strial capillaries associated with inflammation.

Significance statement: Nearly two-thirds of adults aged 70 years or older develop significant age-related hearing loss (AHL), a condition that can lead to social isolation and major communication difficulties. AHL is also associated with decreased physical function among older adults. In the current study, we show that regular exercise slowed AHL and cochlear degeneration significantly in a well established murine model. Our data suggest that regular exercise delays the progression of AHL by reducing age-related loss of strial capillaries associated with inflammation.

Keywords: aging; exercise; hearing loss; stria vascularis.

Figure 1.

Effects of long-term voluntary WR on body weight. a, Running distances (m/d) for the WR group were recorded and averaged between 4 and 24 months of age (n = 5–10). b, Body weights of WR and NWR groups were recorded and averaged (n = 5–10) between 4 and 24 months of age. c, Body weight of WR and NWR groups at 3, 6, 12, and 24 months of age (n = 5–10). Data are shown as means ± SEM. *p < 0.001 versus NWR.

Figure 2.

Effects of long-term WR on tissue weights and blood glucose. The blood glucose level (g) and weights of liver (a), heart (b), lung (c), kidney (d), quadriceps (e), and gastrocnemius (f) were measured in NWR and WR groups at 6 or 24 months of age (n = 5–10). Data are shown as means ± SEM. *p < 0.05 versus NWR.

Figure 3.

Effects of long-term WR on ABR (auditory brainstem response) hearing thresholds. a–f, ABR hearing thresholds from the 3-month-old NWR, 24-month-old NWR, and 24-month-old WR groups were measured at 4 (a), 8 (b), 16 (c), 32 (d), 48 (e), and 64 (f) kHz (n = 5–10). Data are shown as means ± SEM. *p < 0.05 versus 3-month-old NWR group. #p < 0.05 versus 24-month-old NWR group. g, ABR hearing thresholds at all frequencies from the 3-month-old NWR, 24-month-old NWR, and 24-month-old WR groups.

Figure 4.

Effects of long-term WR on age-related hair cell loss. a, b, Cochleograms were recorded and averaged in the cochlear tissues of the young NWR (3-month-old), 24-month-old NWR, and WR groups (n = 5). The graphs show the quantification of cell loss in the IHCs (a) and OHCs (b). Data are shown as means ± SEM. *p < 0.05 versus 3-month-old NWR group; #p < 0.05 versus 24-month-old NWR.

Figure 5.

Effects of long-term WR on SGN loss. a–i, Number of SGNs in each different region (apical, middle, and basal) of cochlea tissue from young NWR (3-month-old; a–c), old NWR (24-month-old, d–f), and old WR (24-month-old, g–i) groups (n = 4–5) was counted and quantified (j–l). Data are shown as means ± SEM. *p < 0.05 vs 3-month-old NWR; #p < 0.05 versus 24-month-old NWR. Scale bar, 25 μm.

Figure 6.

GO term analysis. a, Average running distance per day of 6-month-old WR group, b, Body weight of NWR and WR groups between 3 and 6 months of age. Data are shown as means ± SEM. c, 529 BP categories displayed in a pie chart with seven subdivisions. d, 88 “Biological Regulation” categories displayed in a pie chart with seven subdivisions. e, 60 “Cellular Process” categories displayed in a pie chart with five subdivisions. f, 50 “Response to Stimulus” categories displayed in a pie chart with five subdivisions.

Figure 7.

PCR array analysis. mRNA expression levels of 15 genes involved in inflammation were measured in the inner ears from the 6-month-old NWR (black bars) and WR (red bars) groups. Data are shown as means ± SEM. *p < 0.05 versus controls (NWR), Student's t test.

Figure 8.

Effects of long-term WR on SV atrophy. a–i, Thickness of SV in each different region (apical, middle, and basal) of cochlea tissue from young NWR (3-month-old; a–c), old NWR (24-month-old; d–f), and old WR (24-month-old, g–i) groups (n = 4–5) was measured and quantified (j–l). Data are shown as means ± SEM. Scale bar, 25 μm. *p < 0.05 versus 3-month-old NWR; #p < 0.05 versus 24-month-old NWR.

Figure 9.

Effects of long-term WR on age-related loss of strial capillaries. a–i, Numbers of endomucin-positive capillaries (red circles) in the SV in each different region (apical, middle, and basal region) of cochlea tissue from young NWR (3-month-old; a–c), old NWR (24-month-old; d–f), and old WR (24-month-old; g–i) groups (n = 4–5) were counted and quantified (j–l). Arrows indicate endomucin-positive capillaries in the SV. Data are shown as means ± SEM. Scale bar, 25 μm. *p < 0.05 versus 3-month-old NWR; #p < 0.05 versus 24-month-old NWR.