Pulmonary aging increases MUC5AC in the airway epithelium, increasing the risk of carcinogenesis

The lung is known to undergo changes with aging, including alterations in the airway epithelium. Older people have higher rates of lung cancer, with over 70% of lung cancers diagnosed in those over age 65. This suggests that the aged lung cell is particularly sensitive to carcinogenic insults. Very little is known about how cellular changes with aging in the lung may lead to carcinogenesis. We have compelling pilot data showing that MUC5AC is increased in the airways of healthy older people, as well as in a murine model of aging. We have also recently found that we can increase the expression of MUC5AC in the airway epithelium of cells from young donors by inducing oxidative stress or producing DNA damage. These findings suggest that not only is MUC5AC increased in the aging lung, but also that specific aging-related cell stresses drive the upregulation of MUC5AC/muc5ac in aging. The upregulation of MUC5AC in older cells serves as a link between aging and the increasing risk of developing lung cancer. In particular, the increased expression of MUC5AC makes the airway epithelium more susceptible to DNA damage and then potentially creates an environment that is favorable to carcinogenesis. Our preliminary data suggest that lung aging leads to decreases in Sirtuin 1 (SIRT1). SIRT 1 is known to play a prominent role in aging and DNA damage. SIRT1 is also known to deacetylate Mitogen-activated protein kinase phosphatase 1 (MKP1). Decreased SIRT1 activity leads to increased acetylation of MKP1, which increases MKP1 activity. Inhibition of MKP1 in lung cells from aged donors restores MUC5AC to low, youthful levels. This suggests it plays a key role in the upregulation of MUC5AC in aging. These data led us to hypothesize that: Aging leads to cellular changes that increase MUC5AC expression, promoting lung cancer development. In this proposal we will 1) Determine the aging mechanisms that promote the upregulation of MUC5AC. 2) Elucidate the mechanisms linking aging processes to increased expression of MUC5AC, and determine how to rejuvenate aged cells. 3) Identify the consequences of aging and upregulated Muc5ac in a murine model of lung cancer.