Dual treatment of sarcopenia and osteoarthritis with a Nrf2 activator

项目概述：PAR-15-190旨在加快发展的步伐，新的疗法，为前 健康问题影响老年人。该项目建议同时处理与年龄有关的损失 肌肉功能（肌肉减少症）和骨关节炎（OA）。传统上，预防肉瘤发病的研究- NIA和OA在人类受试者中的并发症是由于以下因素的长期和不可预测的发展/进展： 这种疾病该项目提倡使用一种新的豚鼠模型， 自然发生/自发性肌肉减少症和OA，其方式与人类相似。所建议的治疗 针对肌肉减少症和OA的策略是重要和合乎逻辑的，因为：1）这两种情况都是首要的， 玛丽的贡献者年龄相关的损失，在流动性和功能的独立性，2）损失的肌肉力量， OA经常同时发生，3）这两种疾病有共同的发病机制，涉及炎症和氧化损伤。 与格重音该项目的长期目标是将以前的研究集中在基础生物学上， 将衰老转化为可行的人类治疗方法，以减缓与年龄相关的损伤。本项目的目标是使用 一种Nrf 2激活剂，用于减缓豚鼠中年龄相关的肌肉功能丧失和原发性OA的进展 加速肌肉骨骼老化的模型。核心假设是，通过靶向导致 随着时间的推移，在维持蛋白质稳态的过程中，有可能减缓肌肉减少症的发作/进展 原发性OA这一假设得到了数据的支持，表明：1）维持蛋白质稳态是一种共享的 2）用Nrf 2激活剂处理增加了蛋白质抑制作用， 3）用Nrf 2激活剂治疗已被证明是安全和可行的 美国国立老龄研究院（NIA）干预测试计划证明的长期治疗 （ITP）。为了实现这些目标，提出了以下具体目标： 用Nrf 2激活剂（PB 125）治疗以预防肌肉减少症和原发性OA的发作/进展， 以及与年龄相关的活动能力下降。该项目的主要成果是改善流动性， 由线粒体功能、组织学、形态学和蛋白质稳定性结果支持，以确定 减缓OA和肌肉减少症的进展。这一贡献是重要的，因为肌肉减少症和OA是两个 与年龄相关的残疾的主要原因，往往同时发生，和治疗，有效地减缓 他们的进步是缺乏的。所提出的研究是创新的，因为它：1）提出了一种方法， 通过靶向共同的发病机制同时治疗两种病症，2）使用治疗方法， 靶向内源性机制，3）使用在延长寿命方面具有已证实功效的治疗 和大概的healthspan，以及4）在一个模型中证明了这种治疗的有效性， 人类的状况，虽然在较短的时间内。因此，该项目实现了既定的目标， 由NIA在PAR-15-190中列出，以加快老年人新疗法的开发步伐。

Project Summary: PAR-15-190 seeks to accelerate the pace of development of novel therapeutics for pre- venting health issues affecting the elderly. This project proposes to simultaneously treat the age-related loss of muscle function (sarcopenia) and osteoarthritis (OA). Traditionally, studies to prevent the onset of sarcope- nia and OA in human subjects are complicated by prolonged and unpredictable development/progression of the disease. This project advocates the use of a novel guinea pig model that rapidly and predictably develops naturally-occurring/spontaneous sarcopenia and OA in a manner similar to humans. The suggested treatment strategy, which targets both sarcopenia and OA, is important and logical because: 1) both conditions are pri- mary contributors to age-related loss in mobility and functional independence, 2) loss of muscle strength and OA often occur concurrently, and 3) both disorders have shared pathogenesis involving inflammation and oxi- dative stress. The long-term goal of this project is to translate previous studies focused on the basic biology of aging into viable human treatments to slow age-related impairments. The goal of this current project is to use a Nrf2 activator to slow the progression of age-related loss in muscle function and primary OA in a guinea pig model of accelerated musculoskeletal aging. The central hypothesis is that, by targeting pathways that result in the maintenance of proteostasis over time, it will be possible to slow the onset/progression of sarcopenia and primary OA. The hypothesis is supported by data indicating that: 1) maintained proteostasis is a shared characteristic of multiple slowed-aging rodent models, 2) treatment with a Nrf2 activators increases proteostatic processes in skeletal muscle, and 3) treatment with a Nrf2 activator has been shown to be safe and viable long-term treatments as demonstrated by the National Institutes of Aging (NIA) Interventions Testing Program (ITP). To accomplish these goals, the following specific aim is proposed: to examine the potential of long-term treatment with a Nrf2 activator (PB125) for preventing the onset/progression of sarcopenia and primary OA, and the age-related decline in mobility. The primary outcome of the project is improved mobility, which will be supported by mitochondrial function, histological, morphological, and proteostatic outcomes to determine slowed progression of OA and sarcopenia. This contribution is significant because sarcopenia and OA are two leading causes of age-associated disability that often occur concurrently, and treatments that effectively slow their progression are lacking. The proposed research is innovative in that it: 1) proposes an approach that treats both conditions simultaneously by targeting common mechanisms of pathogenesis, 2) uses a treatment that targets endogenous mechanisms, 3) uses a treatment with demonstrated efficacy in extending lifespan and presumably healthspan, and 4) demonstrates the efficacy of this treatment in a model that closely models the human condition, albeit in a shorter period of time. Therefore, the project accomplishes the goal estab- lished by NIA in PAR-15-190 to accelerate the pace of development of novel therapeutics for older individuals.