Chronic obstructive pulmonary disease (COPD) is characterized by unrelenting airway inflammation, loss of alveolar-capillary units, and a progressive decline in lung function. Although smoking is considered to be a major risk factor for COPD, environmental exposure to air pollutants, including those resulting from indoor burning of biomass fuels, has contributed to the rising worldwide incidence and prevalence of COPD (1, 2). Thus, both intrinsic factors such as genetic susceptibility and aging, and extrinsic factors such as environmental exposures contribute to the complex phenotype of COPD (3). There is growing recognition that COPD may represent a form of accelerated aging and that cellular senescence may participate in this process (4, 5). The accumulation of senescent cells in various tissues/organs occurs in many agerelated diseases, including those of the lung (6). Recent studies have implicated senescence-linked biomarkers, specifically telomere shortening, in chronic inflammation in COPD (7–9). Cellular senescence is a state of durable growth arrest, but with a metabolic and secretory program that is referred to as the senescence-associated secretory phenotype (SASP)(10). Senescence may be triggered by both cell-intrinsic factors (eg, telomere shortening) and extrinsic stressors (eg, oxidative damage) that may lead to accelerated or premature senescence. Key features of senescence include activation of cell-cycle regulatory pathways such as p16, p53, and p21, and expression of senescence-associated b-galactosidase activity. Although cellular senescence itself is a cellautonomous process, it has profound effects on neighboring cells/tissues via the action of SASP mediators, which may include cytokines, growth factors, lipids, and reactive gaseous molecules. The SASP profile may be unique and may ultimately determine whether senescence serves useful purposes or contributes to disease pathology. For example, although some studies have shown that senescence mediates beneficial, antifibrotic effects in woundhealing responses of the liver and skin (11–13), studies from our group have shown that accumulation of senescent cells in the injured lung can contribute to persistent, nonresolving fibrosis (14). More recently, the latter concept of cellular senescence as a driver of fibrotic lung disease was proposed by another group (15). Thus, the biological effects of cellular senescence can be contextual, and its chronicity and/or SASP profile may ultimately determine its role in disease pathogenesis (16).

Cellular markers of senescence, including p16 expression, have been shown in both the airway epithelium and endothelium of subjects with COPD (7, 17). In this issue of the Journal, Sundar and colleagues (pp. 189–199) explore the role of p16 and airway epithelial senescence in the pathogenesis of COPD (18). Using genetic tools in murine models of COPD, they examined whether ablating the expression of p16, globally and in an epithelial (CC10 promoter)-specific manner, protected against cellular senescence, lung inflammation, and the development of airspace enlargement. Mice with global p16 deficiency exposed to chronic cigarette smoke (CS) and those with lung epithelial cell–specific p16 deletion