Single-cell atlas of human lung aging identifies cell type dyssynchrony and increased transcriptional entropy

Age is a major risk factor for lung disease. We characterized the changing cellular, transcriptional, and genomic landscape of human lung aging using single-cell RNA sequencing. We find that lung aging is cell-type dyssynchronous, with alveolar epithelial and endothelial cells exhibiting the greatest transcriptional changes. Among alveolar epithelial cells, aging is associated with a decreased relative proportion of surfactant-expressing SPC^high AT2 cells. Among alveolar capillary cells, we observed loss of differentiation and capillary function. Analysis of somatic mutations called from single-cell data revealed an increase with aging, with alveolar epithelial and endothelial cell types exhibiting greater mutation burdens. Transcriptional entropy was increased with aging and was an independent predictor of age. Notably, cells expressing commonly accepted senescence signatures did not increase with age. Our results reveal cell type dyssynchrony in human lung aging with age-related changes concentrated in alveolar epithelial and endothelial cells.