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

描述(由申请人提供)：减少卡路里摄入量延长了各种实验动物的寿命，并延缓了年龄相关疾病的进展，如年龄相关性听力损失(AHL)(1-9)，这是美国65岁以上人口中40%以上受到影响的常见老龄化特征(13)。有证据表明，卡路里限制(CR)会导致多种组织中活性氧(ROS)的产生减少，而寿命长的组织会产生更高水平的抗氧化酶(1-4)。与这些报告一致的是，过表达定位于线粒体的抗氧化酶过氧化氢酶可延长寿命(16)，减少耳蜗组织的氧化损伤，并推迟小鼠急性淋巴细胞性白血病的发生(10)。因此，CR被认为通过增强线粒体的抗氧化防御来减少氧化应激。我们研究提案的总体目标是为CR的疗效提供新的基础知识，CR是延长哺乳动物寿命的最具重复性的干预措施，以延缓AHL的发展。越来越多的证据表明，活性氧(ROS)在AHL中起着核心作用。线粒体中有两个主要的抗氧化防御系统保护细胞免受ROS的伤害：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抗氧化防御系统在保护内耳细胞在老化或CR条件下免受氧化应激中的作用尚不清楚。我们建议的中心假设是，在衰老过程中，耳蜗线粒体TXN抗氧化防御系统下降，导致AHL，而在卡路里限制的条件下，TXN系统上调，进而保护内耳细胞免受氧化应激，从而减缓哺乳动物AHL的发展。为了验证这一假设，我们将在标准和卡路里限制的饮食条件下，探索两个主要成分Txn2(硫氧还蛋白2)和Txnrd2(硫氧还蛋白还原酶2)在AHL线粒体TXN抗氧化防御系统中的作用。目前还没有治疗急性淋巴细胞性白血病的方法。我们的建议的结果将提供机会，以确定将延缓人类老年性耳聋的干预措施。

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.