Abstract
Aging of the auditory system is associated with the incremental production of reactive oxygen species (ROS) and the accumulation of oxidative damage in macromolecules, which contributes to cellular malfunction, compromises cell viability, and, ultimately, leads to functional decline. Cellular detoxification relies in part on the production of NADPH, which is an important cofactor for major cellular antioxidant systems. NADPH is produced principally by the housekeeping enzyme glucose‐6‐phosphate dehydrogenase (G6PD), which catalyzes the rate‐limiting step in the pentose phosphate pathway. We show here that G6PD transgenic mice (G6PD‐Tg), which show enhanced constitutive G6PD activity and NADPH production along life, have lower auditory thresholds than wild‐type mice during aging, together with preserved inner hair cell (IHC) and outer hair cell (OHC), OHC innervation, and a conserved number of synapses per IHC. Gene expression of antioxidant enzymes was higher in 3‐month‐old G6PD‐Tg mice than in wild‐type counterparts, whereas the levels of pro‐apoptotic proteins were lower. Consequently, nitration of proteins, mitochondrial damage, and TUNEL+ apoptotic cells were all lower in 9‐month‐old G6PD‐Tg than in wild‐type counterparts. Unexpectedly, G6PD overexpression triggered low‐grade inflammation that was effectively resolved in young mice, as shown by the absence of cochlear cellular damage and macrophage infiltration. Our results lead us to propose that NADPH overproduction from an early stage is an efficient mechanism to maintain the balance between the production of ROS and cellular detoxification power along aging and thus prevents hearing loss progression.
Highlights
Age-related hearing loss (ARHL), or presbycusis, is defined as the progressive and bilateral worsening of auditory function
Loss of outer hair cell (OHC) by apoptosis measured by TdT-mediated dUTP nick-end labeling (TUNEL) staining was confirmed in whole mounts of the organ of Corti prepared from basal, middle, and apical turns of 9-month-old cochleae (Figure 5A), with a significantly lower number of TUNEL-positive cells in all the cochlear turns in glucose-6-phosphate dehydrogenase (G6PD)-Tg mice than in WT mice (Figure 5B)
We used a genetic mouse model of G6PD overexpression to show that increased NADPH production efficiently tempers the progression of early-onset ARHL
Summary
Age-related hearing loss (ARHL), or presbycusis, is defined as the progressive and bilateral worsening of auditory function. Increased reactive oxygen species (ROS) and consequent oxidative stress are a hallmark of aging that contribute to functional decline and to the onset of chronic pathologies (Ferrucci et al, 2019). Among the cellular antioxidants that play a specific role in ROS homeostasis, thioredoxins (TRXs), glutaredoxins (GRXs), glutathione (GSH), and GSH-related enzymes constitute the main antioxidant system to prevent or repair oxidative damage to macromolecules (Hanschmann et al, 2013) This system is highly dependent on the reductive power provided by NADPH that is produced by a small number of mammalian cytosolic and mitochondrial enzymes, including isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 (IDH1 and IDH2), malic enzyme 1 and malic enzyme 3 (ME1 and ME3), glucose-6-phosphate dehydrogenase (G6PD), phosphogluconate dehydrogenase (PGD), and glutamate dehydrogenase (GLUD1) (Lewis et al, 2014). We show here using G6PD-Tg mice that G6PD overexpression efficiently delays ARHL progression by protecting the cochlea from ROS-derived oxidative damage
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
