Molecular programs of fibrotic change in aging human lung

Nat Commun. 2021 Nov 2;12(1):6309. doi: 10.1038/s41467-021-26603-2.


Lung fibrosis is increasingly detected with aging and has been associated with poor outcomes in acute lung injury or infection. However, the molecular programs driving this pro-fibrotic evolution are unclear. Here we profile distal lung samples from healthy human donors across the lifespan. Gene expression profiling by bulk RNAseq reveals both increasing cellular senescence and pro-fibrotic pathway activation with age. Quantitation of telomere length shows progressive shortening with age, which is associated with DNA damage foci and cellular senescence. Cell type deconvolution analysis of the RNAseq data indicates a progressive loss of lung epithelial cells and an increasing proportion of fibroblasts with age. Consistent with this pro-fibrotic profile, second harmonic imaging of aged lungs demonstrates increased density of interstitial collagen as well as decreased alveolar expansion and surfactant secretion. In this work, we reveal the transcriptional and structural features of fibrosis and associated functional impairment in normal lung aging.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age Factors
  • Aged
  • Cellular Senescence / physiology
  • Cohort Studies
  • Collagen / metabolism*
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Female
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Gene Expression Regulation*
  • Humans
  • Idiopathic Pulmonary Fibrosis / metabolism
  • Idiopathic Pulmonary Fibrosis / pathology*
  • Lung / metabolism
  • Lung / pathology*
  • Male
  • Middle Aged
  • Sequence Analysis, RNA
  • Telomere Shortening*
  • Tumor Suppressor Protein p53 / metabolism
  • Young Adult


  • CDKN2A protein, human
  • Cyclin-Dependent Kinase Inhibitor p16
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Collagen