The aim of this work was to investigate the role of CREB in lung aging. This study demonstrated, using a mouse model, that the protein content of total and phosphor-activated CREB in lungs reduces with age. As exemplified by human cell models (immortal lung epithelial cells A549, primary fetal and adult lung fibroblasts) cellular senescence and chronic oxidative stress have been identified as possible causes of age-mediated CREB reduction. The decrease of CREB was not transcriptionally regulated, but post-transcriptionally/-translational regulated. An increase of microRNA-34b, which can repress CREB translation, as well as a strong increase in ubiquitination of CREB was also identified. It has also been shown on mouse model that aging leads to post-translational alterations of the extracellular collagens by sugars, the so-called advanced glycation end-products (AGEs). Although they had a negative effect on the protein expression of CREB, the molecular background could not be fully clarified.Comparative gene expression analysis of human lung cells with and without knock down of CREB, senescent and pre-senescent lung cells and lung tissues of young and old mice identified RAB27A and IGFBP3 as target genes of CREB, which could play a role in lung aging.