Gene expression meta-analysis reveals aging and cellular senescence signatures in scleroderma-associated interstitial lung disease

Front Immunol. 2024 Jan 25:15:1326922. doi: 10.3389/fimmu.2024.1326922. eCollection 2024.

Abstract

Aging and cellular senescence are increasingly recognized as key contributors to pulmonary fibrosis. However, our understanding in the context of scleroderma-associated interstitial lung disease (SSc-ILD) is limited. To investigate, we leveraged previously established lung aging- and cell-specific senescence signatures to determine their presence and potential relevance to SSc-ILD. We performed a gene expression meta-analysis of lung tissues from 38 SSc-ILD and 18 healthy controls and found that markers (GDF15, COMP, and CDKN2A) and pathways (p53) of senescence were significantly increased in SSc-ILD. When probing the established aging and cellular senescence signatures, we found that epithelial and fibroblast senescence signatures had a 3.6- and 3.7-fold enrichment, respectively, in the lung tissue of SSc-ILD and that lung aging genes (CDKN2A, FRZB, PDE1A, and NAPI12) were increased in SSc-ILD. These signatures were also enriched in SSc skin and associated with degree of skin involvement (limited vs. diffuse cutaneous). To further support these findings, we examined telomere length (TL), a surrogate for aging, in the lung tissue and found that, independent of age, SSc-ILD had significantly shorter telomeres than controls in type II alveolar cells in the lung. TL in SSc-ILD was comparable to idiopathic pulmonary fibrosis, a disease of known aberrant aging. Taken together, this study provides novel insight into the possible mechanistic effects of accelerated aging and aberrant cellular senescence in SSc-ILD pathogenesis.

Keywords: aging; cellular senescence; gene expression; interstitial lung disease; systemic sclerosis.

Publication types

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

MeSH terms

  • Aging / genetics
  • Cellular Senescence / genetics
  • Gene Expression
  • Humans
  • Idiopathic Pulmonary Fibrosis* / complications
  • Idiopathic Pulmonary Fibrosis* / genetics
  • Lung Diseases, Interstitial* / complications
  • Lung Diseases, Interstitial* / genetics
  • Scleroderma, Systemic* / complications
  • Scleroderma, Systemic* / genetics