Gene expression changes for antioxidants pathways in the mouse cochlea: relations to age-related hearing deficits.

Sherif F Tadros,Sherif F Tadros,Mary D'Souza,Mary D'Souza,Xiaoxia Zhu,Robert D Frisina,Robert D Frisina,Robert D Frisina,Luis Eduardo Soares Netto

doi:10.1371/journal.pone.0090279

Sherif F Tadros, Sherif F Tadros + Show 7 more

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https://doi.org/10.1371/journal.pone.0090279

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Abstract

Age-related hearing loss – presbycusis – is the number one neurodegenerative disorder and top communication deficit of our aged population. Like many aging disorders of the nervous system, damage from free radicals linked to production of reactive oxygen and/or nitrogen species (ROS and RNS, respectively) may play key roles in disease progression. The efficacy of the antioxidant systems, e.g., glutathione and thioredoxin, is an important factor in pathophysiology of the aging nervous system. In this investigation, relations between the expression of antioxidant-related genes in the auditory portion of the inner ear – cochlea, and age-related hearing loss was explored for CBA/CaJ mice. Forty mice were classified into four groups according to age and degree of hearing loss. Cochlear mRNA samples were collected and cDNA generated. Using Affymetrix® GeneChip, the expressions of 56 antioxidant-related gene probes were analyzed to estimate the differences in gene expression between the four subject groups. The expression of Glutathione peroxidase 6, Gpx6; Thioredoxin reductase 1, Txnrd1; Isocitrate dehydrogenase 1, Idh1; and Heat shock protein 1, Hspb1; were significantly different, or showed large fold-change differences between subject groups. The Gpx6, Txnrd1 and Hspb1 gene expression changes were validated using qPCR. The Gpx6 gene was upregulated while the Txnrd1 gene was downregulated with age/hearing loss. The Hspb1 gene was found to be downregulated in middle-aged animals as well as those with mild presbycusis, whereas it was upregulated in those with severe presbycusis. These results facilitate development of future interventions to predict, prevent or slow down the progression of presbycusis.

Highlights

Oxidative stress has a definite role in cell aging
Subject Groups: Age and Hearing Functionality The sample set segregated into 4 groups based upon age, Distortion Product Otoacoustic Emissions (DPOAEs) levels and Auditory Brainstem Responses (ABRs) thresholds: young adult control with good hearing (N = 8, 4 males, 4 females, age = 3.5+/20.4 mon), middle-aged with good hearing (N = 17, 8 males, 9 females, age = 12.3+/21.3 mon), old with mild presbycusis (N = 9, 4 males, 5 females, age = 27.7+/23.4 mon) and old with severe presbycusis (N = 6, 2 males, 4 females, age = 30.6+/21.9 mon)
In our selection of the genes to validate with real-time PCR, we relied on either a significant statistical difference of gene expression between groups or a large numerical difference in the microarray average fold change of the young adult group compared to the middle and old groups

Summary

Introduction

The multifactorial approach of explaining the processes of aging in the ear and brain results in different theories. Some of these theories explain aging as an evolutionary effect (e.g. mutation accumulation theory, for the mitochondrial genome), others explain it as a molecular effect (e.g., gene regulation theory), a cellular effect (e.g., telomere length theory), or a systemic effect (e.g., neuroendocrine and immunological theories). The main source of ROS in the cell is the mitochondrial leakage of electrons, followed by production of superoxides, and hydrogen peroxide (H2O2) [6,7]. The lack of ability to scavenge all of these oxidants from the cell leads to DNA, lipids and protein damage [8,9,10,11].

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