Aging is one of the key contributing factors for
chronic obstructive pulmonary diseases (
COPD) and other chronic inflammatory
lung diseases. Cigarette
smoke is a major etiological risk factor that has been shown to alter cellular processes involving mitochondrial function, cellular senescence and telomeric length. Here we determined how aging contribute to the alteration in the gene expression of above mentioned cellular processes that play an important role in the progression of
COPD and IPF. We hypothesized that aging may differentially alter the expression of mitochondrial, cellular senescence and telomere genes in smokers and patients with
COPD and IPF compared to non-smokers. Total
RNA from human lung tissues from non-smokers, smokers, and patients with
COPD and IPF were processed and analyzed based on their ages (younger: <55 yrs and older: >55 yrs). NanoString nCounter panel was used to analyze the gene expression profiles using a custom designed codeset containing 112 genes including 6 housekeeping controls (mitochondrial biogenesis and function, cellular senescence, telomere replication and maintenance).
mRNA counts were normalized, log2 transformed for differential expression analysis using linear models in the limma package (R/Bioconductor). Data from non-smokers, smokers and patients with
COPD and IPF were analyzed based on the age groups (pairwise comparisons between younger vs. older groups). Several genes were differentially expressed in younger and older smokers, and patients with
COPD and IPF compared to non-smokers which were part of the mitochondrial biogenesis/function (HSPD1, FEN1, COX18, COX10, UCP2 & 3), cellular senescence (
PCNA, PTEN, KLOTHO, CDKN1C, TNKS2, NFATC1 & 2, GADD45A) and telomere replication/maintenance (PARP1, SIRT6, NBN, TERT, RAD17, SLX4, HAT1) target genes. Interestingly, NOX4 and TNKS2 were increased in the young IPF as compared to the young
COPD patients. Genes in the mitochondrial dynamics and other quality control mechanisms like FIS1 and RHOT2 were decreased in young IPF compared to their age matched
COPD subjects. ERCC1 (Excision Repair Cross-Complementation Group 1) and GADD45B were higher in young
COPD as compared to IPF. Aging plays an important role in various
infectious diseases. Elderly patients with chronic
lung disease and smokers were found to have high incidence and mortality rates in the current pandemic of
SARS-CoV-2 infection. Immunoblot analysis in the lung homogenates of smokers,
COPD and IPF subjects revealed increased
protein abundance of important
proteases and spike
proteins like TMPRSS2,
furin and DPP4 in association with a slight increase in SARS-CoV-2 receptor ACE2 levels. This may further strengthen the observation that smokers,
COPD and IPF subjects are more prone to
COVID-19 infection. Overall, these findings suggest that altered transcription of target genes that regulate mitochondrial function, cellular senescence, and telomere attrition add to the pathobiology of lung aging in
COPD and IPF and other smoking-related chronic
lung disease in associated with alterations in SARS-CoV-2 ACE2-TMPRSS2-Furin-DPP4 axis for
COVID-19 infection.