A genomic perspective of the aging human and mouse lung with a focus on immune response and cellular senescence

Abstract

Abstract Background The aging lung is a complex process and influenced by various stressors, especially airborne pathogens and xenobiotics. Additionally, a lifetime exposure to antigens results in structural and functional changes of the lung; yet, an understanding of the cell type specific responses remains elusive. To gain insight into age-related changes in lung function and inflammaging, we evaluated genes mechanistically linked to extracellular matrix (ECM), cellular senescence, immune response and pulmonary surfactant and interrogated single cell RNAseq data to fingerprint cell type specific changes. Results We identified 139 and 52 mouse and human genes linked to ECM remodeling which accounted for 54% and 20%, respectively of ECM coding genes. Furthermore, we identified 64 and 13 mouse and human genes linked to cellular senescence, and the majority code for the senescence associated secretory phenotype. These cytokines, chemokines and growth factors are primarily secreted by macrophages and fibroblasts. Single-cell RNAseq data confirmed age-related induced expression of marker genes of macrophages, neutrophil, eosinophil, dendritic, NK-, CD4+, CD8+-T and B cells in the lung of aged mice. This included the highly significant regulation of 20 genes coding for the CD3-T-cell receptor complex. Conversely, for the human lung we observed primarily macrophage marker genes that changed with age. Additionally, we observed an age-related induced expression of marker genes for mouse AT1, AT2, ciliated, club, goblet and endothelial cells while for the human lung, fibroblasts and myofibroblasts marker genes increased with age. We therefore infer a change in cellular activity of these cell types with age. Furthermore, we identified predominantly repressed expression of surfactant coding genes, especially the surfactant transporter Abca3, thus highlighting remodeling of surfactant lipids with implications for the production of inflammatory lipids and immune response. Conclusion We report the genomic landscape of the aging lung and provide a rationale for its growing stiffness and age related inflammation. By comparing the mouse and human pulmonary genome, we identified important differences between the two species and highlight the complex interplay of inflammaging, senescence and its links to ECM remodeling in healthy but aged individuals.