Disordered Proteostasis as a Driver of Disease in the Aging Lung

项目汇总_总体 老年科学假说是基于这样一种观察，即健康寿命在生命接近尾声时会下降。 通常表现为单一的与年龄相关的疾病，随后与年龄相关的快速积累 并发症发生的时间相对较短。根据这个假设，治疗这些情况中的任何一种 如果不治疗衰老的基本生物学，只会导致它被另一个人取代。这一发现 针对衰老生物学以提高韧性和减少虚弱为目标的疗法解决了老年科学 假设，但完全根据年龄进行这些治疗将不可避免地导致 在过度治疗中。虽然肺炎在老年人中更常见也更严重，但大多数老年患者 在他们患病后仍能获得现代医疗服务。然而，在出院后的第二年，这些年纪较大的 肺炎幸存者罹患包括持续性肺在内的年龄相关疾病的风险增加 损伤、骨骼肌功能障碍导致行动不便、痴呆症和认知障碍。因此， 肺炎是一种复杂的发病率，限制了生命末期的健康寿命。因此，我们 原因是针对衰老生物学的干预措施改善修复和促进复原力 在肺炎康复期间或其他环境压力对老年人会产生广泛的影响。 蛋白质平衡是指细胞控制浓度、构象、结合的动态过程 相互作用，以及组成蛋白质组的单个蛋白质的稳定性。在这个奖项的第一个周期中， PPG调查人员已经生成了大量已公布的和初步的数据，支持中央 PPG的假设认为，高龄与肺炎康复受损有关，以及 针对线粒体电子传输链复合体I的代谢干预可以逆转这些 通过整合的应激反应和ATF4恢复蛋白平衡的变化。要解决这个问题 在衰老的根本问题上，项目研究人员将重点放在感染后的组织恢复上 小鼠体内的甲型流感病毒，一种临床相关的模型，可以在整个生命周期内严格应用， 它概括了可以在实验室研究的时间框架内的人类生物学。我们将对此进行测试 三个相互关联的项目/目标中的假设： 目的1.确定与年龄相关的肺泡巨噬细胞修复功能损伤是否可以 通过ISR和ATF4，通过短暂的低水平抑制复合体I抑制剂的电子传递而逆转。 目的2.确定线粒体电子传递的抑制是否延长了寿命 导致甲型流感肺炎后与年龄相关的康复障碍。 目的3.确定老年居民骨骼清道夫受体功能是否受损 肌巨噬细胞和小胶质细胞可被复合体I的抑制剂通过ISR和ATF4逆转 改善肺炎后的运动和认知功能。

PROJECT SUMMARY_OVERALL The Geroscience hypothesis is based on the observation that healthspan decline toward the end of life often presents with a single age-related illness that is followed by rapid accumulation of age-related complications over a relatively short period. According to this hypothesis, treating any one of these conditions without treating the fundamental biology of aging will only result in its substitution by another. The discovery of therapies that target aging biology to improve resilience and reduce frailty address the geroscience hypothesis, but administering these therapies based exclusively on chronological age will inevitably result in overtreatment. While pneumonia is more common and more severe in the elderly, most older patients with access to modern health care survive their illness. However, in the year after hospital discharge these older pneumonia survivors have an increased risk of developing age-related disorders including persistent lung injury, skeletal muscle dysfunction leading to immobility, dementia, and cognitive impairment. As such, pneumonia is a gateway for the compounding morbidity that limits healthspan at the end of life. We therefore reason that interventions that target aging biology to improve repair and promote resilience administered during recovery from pneumonia or other environmental stressors in the elderly will have broad impact. Proteostasis refers to the dynamic process by which cells control the concentration, conformation, binding interactions, and stability of individual proteins making up the proteome. In the first cycle of this award, the PPG investigators have generated substantial published and preliminary data supporting the central hypothesis of this PPG that advanced age is associated with impaired recovery from pneumonia, and metabolic interventions targeting complex I of the mitochondrial electron transport chain can reverse these changes by restoring proteostasis through the integrated stress response and ATF4. To address this fundamental question in aging, the project investigators will focus on tissue recovery after infection with the influenza A virus in mice, a clinically relevant model that can be rigorously applied across the entire lifespan and which recapitulates human biology on a time frame that can be studied in the laboratory. We will test this hypothesis in three interrelated projects/aims: Aim 1. To determine whether age-related impairments in the reparative function of alveolar macrophages can be reversed by transient low level inhibition of electron transport with complex I inhibitors via the ISR and ATF4. Aim 2. To determine whether inhibition of mitochondrial electron transport at complex I over the lifespan drives the age related impairment in recovery after influenza A pneumonia. Aim 3. To determine whether the impaired scavenger receptor function of aged resident skeletal muscle macrophages and microglia can be reversed by inhibitors of complex I via the ISR and ATF4 to improve motor and cognitive function after pneumonia.