The elderly are four times more likely to develop pneumonia than younger age groups and nearly 90% of deaths due to pneumonia occur in those 65 or older. We know that mucociliary clearance is impaired in normal aging in humans, however the mechanisms of this slowing are unknown. We have recently established a mouse model of aging that will allow us to determine the mechanisms of ciliary slowing. Our supporting data suggest that increases in protein kinase C epsilon (PKC?) activity and expression of PKC? protein play a role in the slowing of ciliary beat frequency (CBF) with age. Aging is a pleotropic, complex process that can vary greatly from individual to individual. We wanted to focus on how one hallmark of aging, DNA damage, affects CBF. In addition, DNA strand breaks also play a role. We hypothesize that normal aging leads to DNA strand breaks, and elevated PKC? signaling, resulting in dysfunctional mucociliary clearance. We will test this hypothesis through the following specific aims: 1) Establish that elevated PKC? signaling slows CBF in aging, and then restore normal CBF by inhibiting this pathway. 2) Determine how double-stranded DNA breaks, a hallmark of aging, affect CBF. 3) Demonstrate that CBF is slowed in aging humans and determine the role of both double- stranded DNA breaks and PKC? in slowing CBF.
Our long-term goal is to understand how normal aging leads to dysfunctional mucociliary clearance. With this understanding, we can develop new methods to prevent pneumonia and more effectively treat pneumonia in elderly patients.
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