Smoking accelerated aging of the small airway epithelium

Aging involves multiple biologically complex processes characterized by a decline in cellular homeostasis over time leading to a loss and impairment of physiological integrity and function. Specific cellular hallmarks of aging include abnormal gene expression patterns, shortened telomeres and associated biological dysfunction. Like all organs, the lung demonstrates both physiological and structural changes with age that result in a progressive decrease in lung function in healthy individuals. Cigarette smoking accelerates lung function decline over time, suggesting smoking accelerates aging of the lung. Based on this data, we hypothesized that cigarette smoking accelerates the aging of the small airway epithelium, the cells that take the initial brunt of inhaled toxins from the cigarette smoke and one of the primary sites of pathology associated with cigarette smoking. Using the sensitive molecular parameters of aging-related gene expression and telomere length, the aging process of the small airway epithelium was assessed in age matched healthy nonsmokers and healthy smokers with no physical manifestation of lung disease or abnormalities in lung function. Analysis of a 73 gene aging signature demonstrated that smoking significantly dysregulates 18 aging-related genes in the small airway epithelium. In an independent cohort of male subjects, smoking significantly reduced telomere length in the small airway epithelium of smokers by 14% compared to nonsmokers. These data provide biologic evidence that prior to the clinical manifestation of lung disease; smoking accelerates aging of the small airway epithelium. This study provides biologic evidence that before the clinical manifestation of lung function decline, smoking accelerates aging of the small airway epithelium by dysregulation of age-related gene expression and enhanced telomere erosion.

衰老涉及多种生物学层面的复杂进程，其特征为细胞稳态随时间推移逐渐衰退，进而导致生理完整性与功能的丧失及损伤。衰老的特异性细胞标志包括异常基因表达模式、端粒（telomere）缩短及相关生物学功能异常。与所有器官一样，肺部随衰老会同时出现生理与结构层面的改变，进而导致健康个体的肺功能进行性下降。香烟烟雾暴露会随时间加快肺功能衰退的进程，提示吸烟会加速肺部衰老。基于上述发现，我们提出假说：香烟烟雾暴露会加速小气道上皮（small airway epithelium）的衰老进程——这类细胞是吸入香烟烟雾毒素时首当其冲的靶细胞，同时也是与吸烟相关病理损伤的主要发生部位之一。本研究采用衰老相关基因表达与端粒长度这两类灵敏的分子指标，对年龄匹配的健康非吸烟者与无肺部疾病临床表现、肺功能无异常的健康吸烟者的小气道上皮衰老进程进行了评估。对包含73个基因的衰老特征基因集进行分析后发现，吸烟会显著失调小气道上皮内的18个衰老相关基因。在一项独立的男性受试者队列中，与非吸烟者相比，吸烟者的小气道上皮端粒长度显著缩短了14%。上述数据提供了生物学证据，证明在肺部疾病出现临床表现之前，吸烟就已加速了小气道上皮的衰老进程。本研究提供的生物学证据表明，在肺功能衰退出现临床表现之前，吸烟会通过失调衰老相关基因表达、加剧端粒侵蚀，进而加速小气道上皮的衰老进程。