It is well established that reducing food consumption by 25-60% without malnutrition consistently extends both the mean and maximum lifespan of a variety of species. Caloric restriction (CR) also delays the progression of a variety of age-associated diseases such as age-related hearing loss (AHL), a common feature of aging, in mammals. A previous study has shown that CR slows the progression of AHL in CBA/J mice, while we have shown previously that CR delays the onset of AHL in C57BL/6J mice and reduces cochlear cell loss. Understanding the mechanism of action of CR is a central area of aging research, since it is likely to yield novel therapeutic approaches for aging and age-related related diseases. Yet, the molecular mechanisms underlying AHL prevention by CR remain largely unknown. My central hypothesis is that the antioxidant enzyme glutathione reductase (Gsr) plays an essential role in protecting the inner ear from oxidative stress and slowing the development of AHL during aging and under CR conditions. Therefore, this proposed study will determine the role and the molecular mechanisms of Gsr in AHL in mammals.
In Specific Aim 1, I propose to determine whether during aging, Gsr plays an essential role in: 1) protection of the inner ear from oxidative stress and slowing the development of AHL in mice and 2) maintenance of the appropriate glutathione antioxidant defense under basal diet conditions.
In Specific Aim 2, I propose to determine whether under CR conditions, Gsr plays an essential role in: 1) reduction of oxidative stress in the inner ear and prevention of AHL and 2) enhancement of the glutathione system in the inner ear. This proposed study will advance understanding of the fundamental molecular mechanisms underlying the anti-aging action of CR in the auditory system in mammals.

Public Health Relevance

Age-related hearing loss (AHL) is a common feature of mammalian aging and is the most frequently occurring sensory disorder in the elderly population. The main goal of this proposed project is to determine the role and the molecular mechanisms of the antioxidant enzyme glutathione reductase in AHL. Knowledge of these molecular mechanisms has enormous potential for improving health outcomes through the discovery/development of novel therapeutics for human AHL and other age-related sensory disorders.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Small Research Grants (R03)
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Special Emphasis Panel (ZDC1-SRB-Y (51))
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Cyr, Janet
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University of Florida
Internal Medicine/Medicine
Schools of Medicine
United States
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White, Karessa; Kim, Mi-Jung; Han, Chul et al. (2018) Loss of IDH2 Accelerates Age-related Hearing Loss in Male Mice. Sci Rep 8:5039
Han, Chul; Kim, Mi-Jung; Ding, Dalian et al. (2017) GSR is not essential for the maintenance of antioxidant defenses in mouse cochlea: Possible role of the thioredoxin system as a functional backup for GSR. PLoS One 12:e0180817
Zhang, Celia; Sun, Wei; Li, Ji et al. (2017) Loss of sestrin 2 potentiates the early onset of age-related sensory cell degeneration in the cochlea. Neuroscience 361:179-191
White, Karessa; Kim, Mi-Jung; Ding, Dalian et al. (2017) G6pd Deficiency Does Not Affect the Cytosolic Glutathione or Thioredoxin Antioxidant Defense in Mouse Cochlea. J Neurosci 37:5770-5781
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Cho, Joonseok; Zhang, Yujian; Park, Shi-Young et al. (2017) Mitochondrial ATP transporter depletion protects mice against liver steatosis and insulin resistance. Nat Commun 8:14477
Someya, Shinichi; Kujoth, Gregory C; Kim, Mi-Jung et al. (2017) Effects of calorie restriction on the lifespan and healthspan of POLG mitochondrial mutator mice. PLoS One 12:e0171159
Yu, Hong; Vikhe Patil, Kim; Han, Chul et al. (2016) GLAST Deficiency in Mice Exacerbates Gap Detection Deficits in a Model of Salicylate-Induced Tinnitus. Front Behav Neurosci 10:158
Han, Chul; Linser, Paul; Park, Hyo-Jin et al. (2016) Sirt1 deficiency protects cochlear cells and delays the early onset of age-related hearing loss in C57BL/6 mice. Neurobiol Aging 43:58-71
Mankowski, Robert T; Ahmed, Shakeel; Beaver, Thomas et al. (2016) Intraoperative hemidiaphragm electrical stimulation reduces oxidative stress and upregulates autophagy in surgery patients undergoing mechanical ventilation: exploratory study. J Transl Med 14:305

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