Telomere Shortening and Its Association with Cell Dysfunction in Lung Diseases

Abstract

Telomeres are localized at the end of chromosomes to provide genome stability; however, the telomere length tends to be shortened with each cell division inducing a progressive telomere shortening (TS). In addition to age, other factors, such as exposure to pollutants, diet, stress, and disruptions in the shelterin protein complex or genes associated with telomerase induce TS. This phenomenon favors cellular senescence and genotoxic stress, which increases the risk of the development and progression of lung diseases such as idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, SARS-CoV-2 infection, and lung cancer. In an infectious environment, immune cells that exhibit TS are associated with severe lymphopenia and death, whereas in a noninfectious context, naïve T cells that exhibit TS are related to cancer progression and enhanced inflammatory processes. In this review, we discuss how TS modifies the function of the immune system cells, making them inefficient in maintaining homeostasis in the lung. Finally, we discuss the advances in drug and gene therapy for lung diseases where TS could be used as a target for future treatments.

Keywords: immune system; lung diseases; telomere shortening; treatments.

Figure 1

Telomere dysfunction regulates cellular senescence. All somatic cells have a molecular clock that leads them to develop a senescence phenotype (dotted line). This process leads to a gradual and controlled loss of telomeres so that under stimulation, cells can respond appropriately (cell fitness). However, this process can be accelerated (solid line) under environmental clock conditions given by drug therapy, genotoxic stress, irradiation, inflammatory stress, mitochondrial dysfunction, oxidative stress, or replicative stress. The environmental clock is associated with an accelerated rate of telomere decay, leading cells to acquire senescence-associated secretory phenotype (SASP). Some cellular markers of the cellular senescence process are mitochondrial dysfunction-associated senescence (MiDAS), cytoplasmic chromatin fragments (CCFs), B-galactosidase production, and regulatory factors such as p53, p21, and p16. During the last years, the SASP profile given by the uncontrolled secretion of cytokines such as IL-6, IL-8, TNF, IFN has been studied to classify and identify cells in senescence induced by telomere attrition.

Figure 2

Schematic of accelerated telomere shortening—causes and its biological consequences. Insults by environmental or genetic factors induce disruptions in one of two essential complexes that regulate the telomere length: (1) telomere/shelterin, integrated with TRF1 (telomeric repeat factor 1), TRF2 (telomeric repeat factor (2), RAP1 (repressor/activator protein (1), TIN2 (TRF1-interacting nuclear factor (2), TPP1 (tripeptidyl peptidase (1), and POT1 (protection of telomeres 1) and (2) telomerase complex, composed by TERC (telomerase RNA component), TERT (telomerase reverse transcriptase), RTEL1 (regulator of telomere elongation), and PARN (gene encoding poly(A)-specific ribonuclease) proteins. These disruptions induce rapid telomere shortening (TS) (upper panel). Consequently, TS promotes the loss of chromosomal integrity and DNA damage, enabling an inflammatory microenvironment disbalance characterized by high levels of IL-1b, ROS, and TGF-b1 (lower panel). This figure was done with CorelDRAW Graphics software.