Telomere-mediated lung disease

Abstract

Parenchymal lung disease is the fourth leading cause of death in the United States; among the top causes, it continues on the rise. Telomeres and telomerase have historically been linked to cellular processes related to aging and cancer, but surprisingly in the recent decade, genetic discoveries have linked the most apparent manifestations of telomere and telomerase dysfunction in humans to the etiology of lung disease: both idiopathic pulmonary fibrosis and emphysema. The short telomere defect is pervasive in a subset of idiopathic pulmonary fibrosis (IPF) patients, and human IPF is the phenotype most intimately tied to germline defects in telomere maintenance. One-third of families with pulmonary fibrosis carries germline mutations in telomerase or other telomere maintenance genes, and one half of patients with apparently sporadic IPF have short telomere length. Beyond explaining genetic susceptibility, short telomere length uncovers clinically relevant syndromic extrapulmonary disease including a T cell immunodeficiency and a propensity to myeloid malignancies. Recognizing this subset of patients who shares a unifying molecular defect has provided a precision medicine paradigm wherein the telomere-mediated lung disease diagnosis provides more prognostic value than histopathology or multi-disciplinary evaluation. Here, we critically evaluate this progress emphasizing how the genetic findings puts forth a new pathogenesis paradigm of age-related lung disease that links telomere abnormalities to alveolar stem senescence, remodeling and defective gas exchange.

Loss of ANT1 Increases Fibrosis and Epithelial Cell Senescence in Idiopathic Pulmonary Fibrosis

“…Senescent cells also secrete a milieu of signaling molecules, including proinflammatory chemokines and growth factors, collectively known as the senescence-associated secretory phenotype (SASP) (15) that may propagate inflammation and tissue remodeling. Upregulation of these senescence markers and SASP have been identified in epithelial cells and fibroblasts in lung fibrosis (5,16). The clearance of these senescent cells and SASP inhibition have both been found to enhance pulmonary function in mouse models (17,18).…”

A clinical short‐cut to identifying short telomeres in idiopathic pulmonary fibrosis?

“…Genes, primarily through their effect on the telomere complex (a length of repeating DNA found at the end of chromosomes, which interacts with a series of proteins that function to ensure integrity of DNA replication during cell division) determine the pre-ordained capacity of stem cells for replication. 4 Broadly speaking, the longer an individual's telomeres, the greater the capacity of their stem cells to divide over a lifetime before reaching senescence. Genes and environment interact; an individual born with short telomeres at birth might develop IPF despite a healthy life, lacking any relevant exposures or injury to the lung.…”

“…[5][6][7] Furthermore, in genetic studies of patients with sporadic IPF, approximately 7%-10% of those studied have single-nucleotide polymorphisms affecting genes coding for telomere complex proteins. 4,8 IPF patients with telomererelated polymorphisms tend to have an earlier age of diagnosis and more rapidly progressive disease. 8 Dyskeratosis congenita (DC), a genetic disorder characterized by mucocutaneous abnormalities, bone marrow failure and a predisposition to cancer, is now known to be caused by abnormalities affecting any of at least 18 genes related to telomere biology.…”

“…Injury to the alveolus requires stem cells to undergo cell division to restore the damaged epithelial barrier, thus accelerating the onset of replicative senescence. Genes, primarily through their effect on the telomere complex (a length of repeating DNA found at the end of chromosomes, which interacts with a series of proteins that function to ensure integrity of DNA replication during cell division) determine the pre‐ordained capacity of stem cells for replication 4 . Broadly speaking, the longer an individual's telomeres, the greater the capacity of their stem cells to divide over a lifetime before reaching senescence.…”

“…Individuals with IPF have shorter telomeres in both lung epithelial cells and circulating leucocytes compared with unaffected individuals and frequently have telomeres that tend to lie in the lowest decile of length when assessed by age 5–7 . Furthermore, in genetic studies of patients with sporadic IPF, approximately 7%–10% of those studied have single‐nucleotide polymorphisms affecting genes coding for telomere complex proteins 4,8 . IPF patients with telomere‐related polymorphisms tend to have an earlier age of diagnosis and more rapidly progressive disease 8 .…”