Disordered Proteostasis as a Driver of Disease in the Aging Lung

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DESCRIPTION (provided by applicant): The aging lung contributes to the loss of resiliency and frailty in the aging population that impairs the healthspan--reducing the duration of freedom from disability, pain and independence. Interventional strategies to improve healthspan and reduce the social and economic burdens of aging require novel approaches targeting malleable systems that improve resiliency and reduce frailty of the aging lung in response to pathogens and other environmental agents. Proteostasis refers to the dynamic process by which cells control the concentration, conformation, binding interactions, and location of individual proteins making up the proteome through a system of regulated networks. Dysfunction in the proteostasis networks in the cell is a common final pathway in aging phenotypes and declines during aging in model organisms; however, biologically relevant techniques to measure these changes in the mammalian lung and/or examine their consequences for organ physiology have been lacking. The investigators in this PPG have developed novel luminescence- and mass-spectroscopy-based techniques, to measure proteostasis in the lung, which they use to examine the function of the proteostasis networks in the lung during aging and during infection with the influenza A virus, a clinically important model of lung injury. Seasonal and pandemic influenza A infection cause disproportionate morbidity and mortality in older individuals. Severe infection results in the bilateral pulmonary infiltrates and hypoxemia that define the Acute Respiratory Distress Syndrome (ARDS), which is the primary cause of the 20,000-50,000 deaths in patients with influenza A infection each year. The Project Leaders use this system to probe the frailty of the proteostasis networks during aging in three highly integrated Projects and Cores. Project 1 will test the hypothesis that replacement of the tissue-resident alveolar macrophage pool with bone marrow derived alveolar macrophages over the lifespan impairs proteostasis to increase the susceptibility to influenza A infection in aged mice. Project 2 will tst the hypothesis that reducing mitochondrial respiratory chain capacity promotes epithelial proteostasis to attenuate influenza A virus-induced lung injury during aging. Project 3 will test the hypothesis that the enhanced susceptibility of aged, influenza A infected mice to skeletal muscle dysfunction results from an altered balance between signaling from the lung that disrupts proteostasis and signaling from the lung that induces a protective heat shock response. The Project Leaders combine genetic and pharmacologic interventions predicted to enhance or impair proteostatic function in aging mice before and after infection with the influenza A virus with sophisticated assessments of the function of the proteostasis networks (Core B) and lung and skeletal muscle physiology (Core C) to establish causal links between aging, proteostasis, and lung and skeletal muscle dysfunction in a mammalian system, providing important mechanistic and therapeutic insights into human aging.