Disordered Proteostasis as a Driver of Disease in the Aging Lung

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 condition.

Although pneumonia is more common and more severe in older patients, with access to modern health care most of these patients 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, dementia, and cognitive impairment. Hence, 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 to older patients during recovery from pneumonia or other environmental stressors 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 PPG award, led by SQLIFTS Director Scott Budinger, MD, the investigators have generated substantial published and preliminary data supporting our central hypothesis 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 focus on tissue recovery after infection with 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.

Scott Budinger, MD, leads a project to investigate alveolar macrophages as age-related drivers of disordered tissue repair. SQLIFTS Discovery Program Director Navdeep Chandel, PhD, leads a project to test the hypothesis that modulating mitochondrial function can alter lung repair to promote proteostasis in the aging lung. SQLIFTS Technology Program Director Alexander Misharin, MD, PhD, leads a project to investigate how activating proteostasis in aging resident macrophages can prevent muscle and cognitive dysfunction after pneumonia, and a project to monitor the aging lung using genomics, proteomics, and informatics.