Disordered Proteostasis as a Driver of Disease in the Aging Lung

项目概要_总体 老年科学假说是基于这样一种观察，即健康寿命在生命结束时会下降 通常表现为单一的与年龄有关的疾病，随后是与年龄有关的疾病的快速积累。 在相对较短的时间内出现并发症。根据这一假设，治疗这些疾病中的任何一种 如果不治疗衰老的基本生物学，只会导致它被另一个取代。发现 针对衰老生物学的治疗方法，以提高弹性和减少脆弱性， 假设，但管理这些治疗完全基于实际年龄将不可避免地导致 过度治疗虽然肺炎在老年人中更常见，也更严重，但大多数老年患者 获得现代医疗保健的机会，使他们在疾病中幸存下来。然而，在这些老年人出院后的一年里， 肺炎幸存者患上与年龄有关的疾病的风险增加， 损伤、导致不动的骨骼肌功能障碍、痴呆和认知障碍。因此，在本发明中， 肺炎是一个网关的复合发病率，限制健康寿命在生命的尽头。因此我们 针对衰老生物学的干预措施，以改善修复和促进恢复能力， 在从肺炎或其他环境压力中恢复的老年人将产生广泛的影响。 蛋白质稳态是指细胞控制蛋白质的浓度、构象、结合 相互作用和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， PPG研究人员已经产生了大量的已发表的和初步的数据， 该PPG假设高龄与肺炎恢复受损相关，以及 针对线粒体电子传递链复合物I的代谢干预可以逆转这些 通过整合应激反应和ATF 4恢复蛋白质稳态来改变。为了解决这个 衰老的基本问题，该项目的研究人员将重点关注感染后的组织恢复。 小鼠中的甲型流感病毒，这是一种临床相关模型，可在整个生命周期中严格应用， 它在一个可以在实验室中研究的时间框架上概括了人类生物学。我们将测试这个 三个相互关联的项目/目标的假设： 目标1.为了确定肺泡巨噬细胞修复功能中与年龄相关的损伤是否可以 通过ISR和ATF 4用复合物I抑制剂对电子传递的短暂低水平抑制而逆转。 目标二。为了确定在整个生命周期内复合物I处的线粒体电子传递抑制是否 导致甲型流感肺炎后与年龄相关的恢复障碍。 目标3：目的：探讨老年人骨骼肌清道夫受体功能受损是否与骨骼肌的功能有关。 肌肉巨噬细胞和小胶质细胞可以通过ISR和ATF 4被复合物I的抑制剂逆转， 改善肺炎后运动和认知功能。

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.