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 signaling. We pharmacologically inhibited duanyu1531ε in ex vivo mouse models of aging. We measured a slowing of CBF with aging that was reversed with inhibition using the novel inhibitor, Ro-31-8220, as well as the duanyu1531ε inhibitor, Inhibition of duanyu1531ε using siRNA in mouse trachea also returned CBF to normal. In addition, antioxidants decrease duanyu1531ε activity and speed cilia. We also aged wild-type and duanyu1531ε KO mice and measured CBF. The duanyu1531ε 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 duanyu1531ε with siRNA. We measured a slowing of CBF with aging that was reversed with siRNA inhibition of 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 duanyu1531ε. In summary, in human and mouse models, aging is associated with increased oxidant stress, which activates duanyu1531ε and slows CBF.

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