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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Small Research Grants (R03)
Project #
5R03DC011840-03
Application #
8473203
Study Section
Special Emphasis Panel (ZDC1-SRB-Y (51))
Program Officer
Cyr, Janet
Project Start
2011-07-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$139,175
Indirect Cost
$44,175
Name
University of Florida
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Han, Chul; Someya, Shinichi (2013) Mouse models of age-related mitochondrial neurosensory hearing loss. Mol Cell Neurosci 55:95-100
Yamasoba, Tatsuya; Lin, Frank R; Someya, Shinichi et al. (2013) Current concepts in age-related hearing loss: epidemiology and mechanistic pathways. Hear Res 303:30-8
Han, Chul; Someya, Shinichi (2013) Maintaining good hearing: calorie restriction, Sirt3, and glutathione. Exp Gerontol 48:1091-5
Ding, Dalian; Qi, Weidong; Yu, Dongzhen et al. (2013) Addition of exogenous NAD+ prevents mefloquine-induced neuroaxonal and hair cell degeneration through reduction of caspase-3-mediated apoptosis in cochlear organotypic cultures. PLoS One 8:e79817
Lee, Wei-Hua; Kumar, Ashok; Rani, Asha et al. (2012) Influence of viral vector-mediated delivery of superoxide dismutase and catalase to the hippocampus on spatial learning and memory during aging. Antioxid Redox Signal 16:339-50