Oxidative stress associated with aging activates protein kinase Cε, leading to cilia slowing

Older people are four times more likely to develop pneumonia than younger people. As we age, many components of pulmonary innate immunity are impaired, including slowing of mucociliary clearance. Ciliary beat frequency (CBF) is a major determinant of mucociliary clearance, and it slows as we age. We hypothesized that CBF is slowed in aging because of increased oxidative stress, which activates PKC epsilon signaling. We pharmacologically inhibited PKC epsilon in ex vivo mouse models of aging. We measured a slowing of CBF with aging that was reversed with inhibition using the novel PKC inhibitor, Ro-31-8220, as well as the PKC epsilon inhibitor, PKCe141. Inhibition of PKC epsilon using siRNA in mouse trachea also returned CBF to normal. In addition, antioxidants decrease PKC epsilon activity and speed cilia. We also aged wild-type and PKC epsilon KO mice and measured CBF. The PKC epsilon KO mice were spared from the CBF slowing of aging. Using human airway epithelial cells from younger and older donors at air-liquid interface (ALI), we inhibited PKC epsilon with siRNA. We measured a slowing of CBF with aging that was reversed with siRNA inhibition of PKC epsilon. In addition, we measured bead clearance speeds in human ALI, which demonstrated a decrease in bead velocity with aging and a return to baseline after inhibition of PKC epsilon . In summary, in human and mouse models, aging is associated with increased oxidant stress, which activates PKC epsilon and slows CBF.