_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.
_OVERALL Pneumonia is the most common cause of death from an infectious disease worldwide and disproportionately affects the elderly. Most elderly patients survive pneumonia, but they have an increased chance of developing ongoing lung inflammation, skeletal muscle dysfunction and cognitive decline. We show that metabolic interventions that restore proteostasis in older animals can accelerate recovery after pneumonia with implications for therapy.
|Sala, Marc A; Chen, Cong; Zhang, Qiao et al. (2018) JNK2 up-regulates hypoxia-inducible factors and contributes to hypoxia-induced erythropoiesis and pulmonary hypertension. J Biol Chem 293:271-284|
|Sala, Marc A; Balderas-Martínez, Yalbi Itzel; Buendía-Roldan, Ivette et al. (2018) Inflammatory pathways are upregulated in the nasal epithelium in patients with idiopathic pulmonary fibrosis. Respir Res 19:233|
|Dela Cruz, Charles S; Wunderink, Richard G; Christiani, David C et al. (2018) Future Research Directions in Pneumonia. NHLBI Working Group Report. Am J Respir Crit Care Med 198:256-263|
|Galluzzi, Lorenzo; Vitale, Ilio; Aaronson, Stuart A et al. (2018) Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ 25:486-541|
|Soberanes, Saul; Misharin, Alexander V; Jairaman, Amit et al. (2018) Metformin Targets Mitochondrial Electron Transport to Reduce Air-Pollution-Induced Thrombosis. Cell Metab :|
|Wang, Chao; Balch, William E (2018) Bridging Genomics to Phenomics at Atomic Resolution through Variation Spatial Profiling. Cell Rep 24:2013-2028.e6|
|Kong, Hyewon; Chandel, Navdeep S (2018) Regulation of redox balance in cancer and T cells. J Biol Chem 293:7499-7507|
|Hutt, Darren M; Mishra, Sanjay Kumar; Roth, Daniela Martino et al. (2018) Silencing of the Hsp70-specific nucleotide-exchange factor BAG3 corrects the F508del-CFTR variant by restoring autophagy. J Biol Chem 293:13682-13695|
|Hsiao, Hsi-Min; Fernandez, Ramiro; Tanaka, Satona et al. (2018) Spleen-derived classical monocytes mediate lung ischemia-reperfusion injury through IL-1?. J Clin Invest 128:2833-2847|
|McQuattie-Pimentel, Alexandra C; Budinger, G R Scott; Ballinger, Megan N (2018) Monocyte-derived Alveolar Macrophages: The Dark Side of Lung Repair? Am J Respir Cell Mol Biol 58:5-6|
Showing the most recent 10 out of 58 publications