Unveiling mechanisms of lung aging in COPD: A promising target for therapeutics development

Abstract

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease characterized by airflow limitation and changes in airway structures that can lead to chronic bronchitis, small airway diseases, and emphysema. COPD is the 3^rd leading cause of death worldwide and despite current research, there are no curative disease treatments for COPD. As the prevalence of COPD is higher in people over 60 years old than in younger age groups, COPD is considered a condition of accelerated lung aging. Natural lung aging is associated with molecular, cellular, and physiological changes that cause alteration in lung structure, in lung function and regeneration, and decreased immune system response that could lead to lung disease like COPD. Mechanisms of accelerated lung aging are complex and composed by increased oxidative stress induced by exposure to cigarette smoke, by chronic inflammatory processes, and increased number of senescent cells within the airways. Cellular senescence is the cessation of cell division after a finite number of proliferation cycles or in response to cell stressors, such as oxidative stress. Senescent cells show activation of the cell cycle regulators p21^CIP1 (cyclin-dependent kinase inhibitor-1), p16^INK4 (cyclin-dependent kinase inhibitor-2A), and p53 (cellular tumor antigen p53) that lead to cell cycle arrest. Senescent cells exhibit a change in their phenotype and their metabolic activity, along with the production of proinflammatory proteins collectively known as senescence-associated secretory phenotype (SASP). This review aims to describe recent developments in our understanding of aging mechanisms and how the acceleration of lung aging participates in COPD pathophysiology and comorbidities. Understanding and targeting aging mechanisms may result in the development of new therapeutics that could be effective for COPD and also for other age-related diseases.

Keywords: Aging; Cellular senescence; Chronic obstructive pulmonary disease; MicroRNAs; Senescence-associated secretory phenotype.

Fig. 1

Hallmarks of aging. Twelve hallmarks of aging have been proposed and classified into 3 categories. The primary hallmarks are the primary damages that accumulate within the genome and organelles of the cells. They compile genomic instability, telomere shortening, epigenetic alterations, loss of proteostasis, and disabled macroautophagy. The antagonistic hallmarks reflect the consequences of the damages accumulated within the cells including cellular senescence, mitochondrial dysfunction and deregulated nutrient sensing. Finally, the integrative hallmarks arise when the accumulation of the primary and antagonistic damages cannot be compensated within the organ. They include dysbiosis, chronic inflammation, altered intercellular communication, and stem cell exhaustion.

Fig. 2

Normal aging of the lungs. Normal aging of the lungs is characterized by the accumulation of DNA damages and oxidative stress that leads to the accumulation of senescent cells, particularly within the small airways. As a result, the epithelium is defective and the number of basal cells, AT1 and AT2 cells diminished. Moreover, the defective mucociliary clearance due to the decreased number of cilia and their defective beating, leads to an increased susceptibility of the elderly to infection. Airway immune response is dysfunctional with aging and is characterized by the accumulation of inflammatory cells such as macrophages, neutrophils, and cytotoxic T cells, within the lungs. These immune cells have decreased functions and may present a senescent phenotype. Aged lungs are also characterized by the production of pro-inflammatory factors, by senescent cells and immune cells, which induce a low-grade inflammation of the lungs called inflammaging. AT1: Alveolar type 1 cell; AT2: Alveolar type 2 cell.

Fig. 3

Cellular senescence pathway in COPD. Oxidative stress inhibits PTEN, leading to the activation of PI3K and consequently to the activation of mTOR. Decreased activation of AMPK also increases mTOR activity which leads to the upregulation of microRNA (miR)-34a. Activation of p38 MAPK leads to the upregulation of c-Jun and AP1, which increases miR-570. miR-34a targets SIRT1 and SIRT6 and miR-570 targets SIRT1 but not SIRT6. Decreased SIRT1 and SIRT6 play a key role in the induction of cellular senescence through SASP production via activation of NF-κB and through the increased expression of p53, p21^CIP1, and p16^INK4. SIRT1 is involved in the diminution of DDR by inhibiting FOXO3 and participates in mitochondria dysfunction by inhibiting autophagy and PGC1α. Downregulation of SIRT6 inhibits the antioxidant Nrf2 which leads to chronic oxidative stress. Senescent cells produce a large number of EVs that contain miRNAs and induce cellular senescence phenotype to healthy cells, thus participating in the propagation of aging within the lungs. AMPK: AMP-activated protein kinase; AP-1: Activating protein-1; COPD: Chronic obstructive pulmonary disease; DDR: DNA damage response; EVs: Extracellular vesicles; FOXO3: Forkhead box O3; miRNAs: MicroRNAs; MAPK: Mitogen-activated protein kinase; mTOR: Mammalian target of rapamycin; NF-κB: Nuclear factor-κB; Nrf2: Nuclear factor erythroid 2-related factor; PTEN: Phosphatase and tensin homolog from chromosome 10; PGC1α: Peroxisome proliferator-activated receptor-γ coactivator 1-α; PI3K: Phosphoinositide 3-kinase; ROS: Reactive oxygen species; SA-βgal: Senescent-associated β-galactosidase; SASP: Senescence-associated secretory phenotype; SIRT1: Sirtuin 1; SIRT6: Sirtuin 6.