Mitochondrial Thioredoxin, Caloric Restriction, and Age-related Hearing Loss

描述（由申请人提供）：减少热量摄入可以延长各种实验动物的寿命，并延缓年龄相关疾病的进展，如年龄相关性听力损失（AHL）（1-9），这是一种常见的衰老特征，影响了美国超过40%的65岁以上人群（13）。有证据表明，热量限制（CR）会导致多个组织中活性氧（ROS）的产生减少，而长寿的物种会产生更高水平的抗氧化酶（1-4）。与这些报道一致，线粒体过氧化氢酶的过表达可以延长寿命（16），减少耳蜗的氧化损伤，并延缓小鼠AHL的发病（10）。因此，CR被认为通过增强线粒体抗氧化防御来减少氧化应激。我们的研究计划的总体目标是提供新的基础知识，揭示CR -延长哺乳动物寿命的最可重复的干预措施-延迟AHL发展的机制。越来越多的证据表明活性氧（ROS）在AHL中起着核心作用。线粒体中有两种主要的抗氧化防御系统：谷胱甘肽（GSH）和硫氧还蛋白（TXN）系统（11）。硫氧还蛋白是一种氧化还原酶，是线粒体抗氧化防御系统的重要组成部分（11-12）。目前，TXN抗氧化防御系统在老化或CR条件下保护内耳细胞免受氧化应激的作用尚不清楚。本研究的核心假设是，随着年龄的增长，耳蜗线粒体TXN抗氧化防御系统下降，导致AHL，而在卡路里限制条件下，TXN系统上调，从而保护内耳细胞免受氧化应激，从而减缓AHL的发展。为了验证这一假设，我们将探讨两种主要成分Txn2（硫氧还蛋白2）和Txnrd2（硫氧还蛋白还原酶2）在标准饮食和卡路里限制饮食条件下AHL线粒体TXN抗氧化防御系统中的作用。目前还没有治疗AHL的方法。我们的建议的结果将提供机会，以确定干预措施，将延缓人类老年性痴呆。

DESCRIPTION (provided by applicant): 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.