Chronic obstructive pulmonary disease (COPD) has become a global epidemic and is the third leading cause of death worldwide. COPD is characterized by chronic airway inflammation, loss of alveolar-capillary units, and progressive decline in lung function. Major risk factors for COPD are cigarette smoking and aging. COPD-associated pathomechanisms include multiple aging pathways such as telomere attrition, epigenetic alterations, altered nutrient sensing, mitochondrial dysfunction, cell senescence, stem cell exhaustion and chronic inflammation. In this review, we will highlight the current literature that focuses on the role of age and aging-associated signaling pathways as well as their impact on current treatment strategies in the pathogenesis of COPD. Furthermore, we will discuss established and experimental COPD treatments including senolytic and anti-aging therapies and their potential use as novel treatment strategies in COPD.

The number of adults living with cystic fibrosis (CF) has already increased significantly because of drastic improvements in life expectancy attributable to advances in treatment, including the development of highly effective modulator therapy. Chronic airway inflammation in CF contributes to morbidity and mortality, and aging processes like inflammaging and cell senescence influence CF pathology. Our results show that single-cell RNA sequencing data, human primary bronchial epithelial cells from non-CF and CF donors, a CF bronchial epithelial cell line, and Cftr -knockout ( Cftr ^–/– ) rats all demonstrated increased cell senescence markers in the CF bronchial epithelium. This was associated with upregulation of fibroblast growth factor receptors (FGFRs) and mitogen-activated protein kinase (MAPK) p38. Inhibition of FGFRs, specifically FGFR4 and to some extent FGFR1, attenuated cell senescence and improved mucociliary clearance, which was associated with MAPK p38 signaling. Mucociliary dysfunction could also be improved using a combination of senolytics in a CF ex vivo model. In summary, FGFR/MAPK p38 signaling contributes to cell senescence in CF airways, which is associated with impaired mucociliary clearance. Therefore, attenuation of cell senescence in the CF airways might be a future therapeutic strategy improving mucociliary dysfunction and lung disease in an aging population with CF.

Background and Objectives: Chronic inflammation due to Pseudomonas aeruginosa (PA) infection in people with cystic fibrosis (CF) remains a concerning issue in the wake of modulator therapy initiation. Given the perpetuating cycle of colonization, infection, chronic inflammation, and recurrent injury to the lung, there are increases in the risk for mortality in the CF population. We have previously shown that fibroblast growth factor (FGF) 23 can exaggerate transforming growth factor (TGF) beta-mediated bronchial inflammation in CF. Our study aims to shed light on whether FGF23 signaling also plays a role in PA infection of the CF bronchial epithelium. Materials and Methods: CF bronchial epithelial cells were pretreated with FGF23 or inhibitors for FGF receptors (FGFR) and then infected with different PA isolates. After infection, immunoblot analyses were performed on these samples to assess the levels of phosphorylated phospholipase C gamma (PLCγ), total PLCγ, phosphorylated extracellular signal-regulated kinase (ERK), and total ERK. Additionally, the expression of FGFRs and interleukins at the transcript level (RT-qPCR), as well as production of interleukin (IL)-6 and IL-8 at the protein level (ELISA) were determined. Results: Although there were decreases in isoform-specific FGFRs with increases in interleukins at the mRNA level as well as phosphorylated PLCγ and the production of IL-8 protein with PA infection, treatment with FGF23 or FGFR blockade did not alter downstream targets such as IL-6 and IL-8. Conclusions: FGF23 signaling does not seem to modulate the PA-mediated inflammatory response of the CF bronchial epithelium.