Reducing caloric intake extends the lifespan of a variety of laboratory animals and delays the progression of age-associated diseases such as age-related hearing loss (AHL) (1-9), a common feature of aging that affects more than 40% of people over 65 years of age in the US (13). Evidence indicates that caloric restriction (CR) leads to a reduction in the production of reactive oxygen species (ROS) in multiple tissues, while long-lived species produce higher levels of antioxidant enzymes (1-4). Consistent with these reports, overexpressing the antioxidant enzyme catalase localized to mitochondria increases lifespan (16), reduces oxidative damage in the cochlea, and delays the onset of AHL in mice (10). Thus, CR is thought to reduce oxidative stress through enhanced mitochondrial antioxidant defenses. The overall goal of our research proposal is to provide new basic knowledge of the mechanism underlying the efficacy of CR - the most reproducible intervention for increasing lifespan in mammals - to delay the development of AHL. A growing body of evidence indicates that reactive oxygen species (ROS) play a central role in AHL. There are two major antioxidant defense systems in mitochondria protecting cells from ROS: the glutathione (GSH) and thioredoxin (TXN) systems (11). Thioredoxin is an oxidoreductase enzyme and an essential component of the mitochondrial antioxidant defense system (11-12). Currently, the role of the TXN antioxidant defense system in protecting the inner ear cells from oxidative stress during aging or under CR conditions is not known. The central hypothesis of our proposal is that during aging, the mitochondrial TXN antioxidant defense system declines in the cochlea, leading to AHL, while under calorie restricted conditions, there is an up-regulation of the TXN system which in turn protects the inner ear cells from oxidative stress, thereby slowing the development of AHL in mammals. To test this hypothesis, we will explore the roles of two major components, Txn2 (thioredoxin 2) and Txnrd2 (thioredoxin reductase 2), in the mitochondrial TXN antioxidant defense system in AHL under standard and calorie restricted diet conditions. Currently there is no treatment for AHL. The results of our proposal will provide the opportunity to identify interventions that will delay presbycusis in humans.

Public Health Relevance

Reducing caloric intake extends the lifespan of a variety of species and delays the progression of age- associated diseases such as age-related hearing loss (AHL) (1-9), a common feature of aging that affects more than 40% of people over 65 years of age in the US (13). The overall goal of our research proposal is to provide new basic knowledge of the mechanism underlying the efficacy of CR - the most reproducible intervention for increasing lifespan in mammals - to delay the development of AHL in mammals. The results of our proposal will provide an enhanced understanding of the fundamental mechanisms underlying AHL, and the opportunity to identify interventions that will delay presbycusis in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
1R01DC012552-01A1
Application #
8575581
Study Section
Special Emphasis Panel (ZRG1-IFCN-B (02))
Program Officer
Cyr, Janet
Project Start
2013-07-01
Project End
2018-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$371,172
Indirect Cost
$121,172
Name
University of Florida
Department
Other Health Professions
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
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
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
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
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
Xu, Yuqun; Liu, Lingwen; Nakamura, Akira et al. (2017) Studies on the regulatory mechanism of isocitrate dehydrogenase 2 using acetylation mimics. Sci Rep 7:9785
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
Han, Chul; Ding, Dalian; Lopez, Maria-Cecilia et al. (2016) Effects of Long-Term Exercise on Age-Related Hearing Loss in Mice. J Neurosci 36:11308-11319
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
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
Anton, Stephen D; Woods, Adam J; Ashizawa, Tetso et al. (2015) Successful aging: Advancing the science of physical independence in older adults. Ageing Res Rev 24:304-27

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