ABSTRACT Background Lung cancer is the leading cause of cancer death in the world. While cigarette smoking is the major preventable factor for cancers in general and lung cancer in particular, old age is also a major risk factor. Aging‐related chronic, low‐level inflammation, termed inflammaging, has been widely documented; however, it remains unclear how inflammaging contributes to increased lung cancer incidence. Aim The aim of this study was to establish connections between aging‐associated changes in the lungs and cancer risk. Methods We analyzed public databases of gene expression for normal and cancerous human lungs and used mouse models to understand which changes were dependent on inflammation, as well as to assess the impact on oncogenesis. Results Analyses of GTEx and TCGA databases comparing gene expression profiles from normal lungs, lung adenocarcinoma, and lung squamous cell carcinoma of subjects across age groups revealed upregulated pathways such as inflammatory response, TNFA signaling via NFκB, and interferon‐gamma response. Similar pathways were identified comparing the gene expression profiles of young and old mouse lungs. Transgenic expression of alpha 1 antitrypsin (AAT) partially reverses increases in markers of aging‐associated inflammation and immune deregulation. Using an orthotopic model of lung cancer using cells derived from EML4‐ALK fusion‐induced adenomas, we demonstrated an increased tumor outgrowth in lungs of old mice while NLRP3 knockout in old mice decreased tumor volumes, suggesting that inflammation contributes to increased lung cancer development in aging organisms. Conclusions These studies reveal how expression of an anti‐inflammatory mediator (AAT) can reduce some but not all aging‐associated changes in mRNA and protein expression in the lungs. We further show that aging is associated with increased tumor outgrowth in the lungs, which may relate to an increased inflammatory microenvironment.

Catherine Pham‐Danis

Shi B. Chia

Hannah A. Scarborough

Etienne Danis

Travis Nemkov

Vadym Zaberezhnyy

Jessica L. Christenson

Emily K. Kleczko

Andre Navarro

Andrew Goodspeed

Elizabeth A. Bonney

Charles A. Dinarello

Carlo Marchetti

Raphael A. Nemenoff

Kirk C. Hansen

James DeGregori

Aging and Cancer

Inflammation Promotes Aging‐Associated Oncogenesis in the Lung

炎症促进肺部衰老相关性肿瘤发生

Inflammation Promotes Aging‐Associated Oncogenesis in the Lung

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