The aging lung: tissue telomere shortening in health and disease

Abstract

BackgroundTelomere shortening has been associated with several lung diseases. However, telomere length is generally measured in peripheral blood leucocytes rather than in lung tissue, where disease occurs. Consequently, telomere dynamics have not been established for the normal human lung nor for diseased lung tissue. We hypothesized an age- and disease-dependent shortening of lung tissue telomeres.MethodsAt time of (re-)transplantation or autopsy, 70 explant lungs were collected: from unused donors (normal, n = 13) and patients with cystic fibrosis (CF, n = 12), chronic obstructive pulmonary disease (COPD, n = 11), chronic hypersensitivity pneumonitis (cHP, n = 9), bronchiolitis obliterans syndrome (BOS) after prior transplantation (n = 11) and restrictive allograft syndrome (RAS) after prior transplantation (n = 14). Lungs were inflated, frozen and then scanned using CT. Four tissue cores from distinct lung regions were sampled for analysis. Disease severity was evaluated using CT and micro CT imaging. DNA was extracted from the samples and average relative telomere length (RTL) was determined using real-time qPCR.ResultsThe normal lungs showed a decrease in RTL with age (p < 0.0001). Of the diseased lungs, only BOS and RAS showed significant RTL decrease with increasing lung age (p = 0.0220 and p = 0.0272 respectively). Furthermore, we found that RTL showed considerable variability between samples within both normal and diseased lungs. cHP, BOS and RAS lungs had significant shorter RTL in comparison with normal lungs, after adjustment for lung age, sex and BMI (p < 0.0001, p = 0.0051 and p = 0.0301 respectively). When investigating the relation between RTL and regional disease severity in CF, cHP and RAS, no association was found.ConclusionThese results show a progressive decline in telomere length with age in normal, BOS and RAS lungs. cHP, BOS and RAS lungs demonstrated shorter RTL compared to normal lungs. Lung tissue RTL does not associate with regional disease severity within the lung. Therefore, tissue RTL does not seem to fully reflect peripheral blood telomere length.Electronic supplementary materialThe online version of this article (10.1186/s12931-018-0794-z) contains supplementary material, which is available to authorized users.

From organ to cell: Multi-level telomere length assessment in patients with idiopathic pulmonary fibrosis

“…The finding provides rationale for further investigation of the association of lung telomere length and fibrosis in IPF lung. Telomere shortening is a hallmark of aging and just recently it was shown that, similar to other organs, telomeres in control lungs shorten with age [26]. However, lung telomere length in our IPF samples was shorter than in age-matched controls and did not correlate with age.…”

“…On HRCT, IPF lungs typically show an apicobasal gradient, in which fibrosis is most abundant subpleurally in the basal lung fields [1]. In control lungs, in which such a gradient is absent, it was recently found that telomere length in the basal fields was significantly shorter than in the apical fields of the same lung [26]. It is unknown whether telomere shortening in the IPF lung associates with the apicobasal gradient.…”

Evidence that Telomere Length is Causal for Idiopathic Pulmonary Fibrosis but not Chronic Obstructive Pulmonary Disease: A Mendelian Randomisation Study

“…Increasing senescent cell burden has been attributed to both IPF and COPD, with evidence from several cellular compartments including type II alveolar epithelium and fibroblasts (see [33] for a comprehensive review). Both IPF and COPD have significantly shorter leukocyte telomere length [5,6]; shortened telomeres have also been identified directly within lung tissue from IPF patients [8,34] but not in COPD [35]. In light of our findings, these observations suggest that telomere shortening can act as an intrinsic and systemic driving force of cellular senescence in IPF, akin to the relationship between telomere-associated driver mutations in familial PF.…”

Shared mechanisms of multimorbidity in COPD, atherosclerosis and type-2 diabetes: the neutrophil as a potential inflammatory target

“…A reduction in RTL was observed in peripheral lymphocytes in patients with COPD [57] and in lung epithelial cells exposed to cigarette smoke in vitro [58]. However, no significant difference in RTL was found in lung biopsies from patients with COPD compared to healthy controls [59], suggesting that these changes might be cell-type specific. Similarly, in T2D and atherosclerosis, RTL has been shown to be reduced in circulating leukocytes but with variable penetration across disease severity [60,61].…”