Investigation of the molecular mechanisms of premature lung aging and enhanced susceptibility for chronic lung diseases in a postnatal stress model

• Applicants: Professor Miguel Angel Alejandre Alcázar, Ph.D.; Professor Dr. Björn Schumacher
• Subject Area: Biogerontology and Geriatric Medicine ; Pediatric and Adolescent Medicine ; Pneumology, Thoracic Surgery
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 496914708

The aging population and associated diseases are a growing public health burden in Europe and Germany. The increase in prevalence of chronic lung diseases at older ages suggests an age-associated loss of lung-intrinsic defense and regenerative mechanisms. The balance between DNA damage and repair mechanisms is central for the maintenance of cell integrity and premature aging. Accumulation of DNA damage-mediated by chronic oxidative stress during life is a major determinant of aging and is accompanied by a subacute chronic inflammation (inflammaging), senescence, and stem cell exhaustion. Early activation of these processes in life could promote premature lung aging and increase susceptibility to chronic lung disease. Our clinical and experimental studies confirm that adverse influences during development are associated with impaired lung function in adulthood. Using a well-established early postnatal stress model, we have associated inflammation, DNA damage, senescence, and loss of progenitor cells with long-term structural changes, yielding characteristics of lungs from aging patients with COPD. Based on these findings, we now aim to investigate whether acute damage to the lung during early development induces premature aging of the lung resulting in reduced alveolar regenerative capacity and increased susceptibility to chronic lung disease later in life. To address this hypothesis, we pursue the following objectives: (1) To decipher global and alveolar epithelial cell type II (ATII)-specific premature aging processes and signatures in a murine model of neonatal lung injury induced by oxidative stress; (2) To analyze cell composition by single cell-RNASeq of normally aged mouse lungs and neonatal mouse lungs after exposure to oxidative stress; (3) Investigation of DNA damage accumulation in alveolar epithelial cells during late lung development as a trigger of premature lung aging using an innovative model of alveolar epithelial cell-specific Ercc1 knockout mice; (4) To identify aging processes and to determine binarized transcriptomic aging (BiTage) clock in lungs of children with neonatal lung injury. This project proposal is a collaborative approach between aging research and lung biology. Identification of early mechanisms that promote premature lung aging and increase the susceptibility to chronic lung disease will provide predictive markers and novel therapeutic approaches for aging-associated chronic lung diseases.

• DFG Programme: Research Grants