Targeting the heterogeneity of cellular aging in chronic lung diseases - A road to lung regeneration

• Applicant: Professorin Dr. Mareike Lehmann
• Subject Area: Pneumology, Thoracic Surgery
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 512453064

Chronic lung diseases (CLDs) are the third leading cause of death worldwide and have no cure, leaving lung transplantation as the only option. Aging has emerged as the single biggest risk factor for the development of CLDs, such as such idiopathic pulmonary fibrosis (IPF) or chronic obstructive pulmonary disease (COPD). Aging causes chronic, sterile inflammation (inflammaging) that impairs the regenerative capacity of the lung. On a cellular level, several hallmarks of aging, especially cellular senescence have been identified as key mechanisms for the loss of regenerative capacity. Notably, it remains completely unknown how inflammaging affects epithelial cell senescence and thus might contribute to a vicious tissue destruction process in the lung. Cellular senescence describes a cell cycle arrest along with a distinct secretion of various factors called the “senescence associated secretory phenotype” (SASP). While senescence has been initially described as a tumor suppressive mechanism, more recent research revealed that the outcome of senescence programs depend highly on the affected organ, cell type, and microenvironment and thus can be pathological or result in regeneration of the tissue. In CLDs, pathological senescence of structural cells such as epithelial cells has been demonstrated to contribute to disease pathology. However, more recently, regenerative senescent cells have been described in the adult mouse lung as well. The use of drugs leading to the removal of senescent cells (senolytics) has shown promising results in mouse models of age-associated CLDs, as well as first in human trials in IPF patients. However, there are serious drawbacks to the current senolytic therapies. No senolytic compound developed to date targets specific pathological senescence programs or discriminate between regenerative and pathological senescence. For the development of a specific senolytic therapy in CLDs, the lack of a deeper knowledge on distinct senescence programs is the main hurdle that needs to be overcome. Here, I propose an innovative approach to uncover novel cellular senescence programs and aim to understand regenerative versus pathological senescence in COPD and IPF. My proposal is based on the novel concept that inflammaging drives pathological cellular senescence in structural cells of the aged and diseased lung. Thus, the proposal addresses a highly underappreciated crosstalk of immune and epithelial cells in the lung. I will employ unbiased single cell and proteomic SASP analysis from human tissue and utilize state-of-the-art functional 2D and 3D assays as well as cell transplantation assays to determine human regenerative and pathological senescence of specific senescent cell subtypes from patients with CLDs. This will ultimately enable the development cell- and disease specific senolytics and SASP biomarkers targeting pathological versus regenerative senescence in CLDs, thereby facilitating lung regeneration.

• DFG Programme: Independent Junior Research Groups