SUMMARY/ABSTRACT
Cardiovascular diseases (CVDs) are the leading cause of death in elderly individuals. During advancing age,
large arteries become stiffer and endothelium-dependent dilation (EDD) is impaired, both of which predict
future CVD. Chronic inflammation and oxidative stress are elevated with aging and drive arterial stiffening and
suppress EDD. Senescent cells accumulate in advanced age and promote inflammation and oxidative stress,
however, the mechanisms that lead to cellular senescence in vivo remain elusive. The working hypothesis of
this proposal is that aging results in endothelial cell telomere uncapping that induces senescence and
suppresses arterial function in advancing age. To explore this, I will determine if aging results in telomere
uncapping that is associated with senescence in endothelial cells. To determine the extent to which telomere
uncapping contributes to senescence, I will induce cell death in senescent, but not non-senescent cells using
senolytics and evaluate telomere uncapping and senescence. Furthermore, I will induce telomere uncapping in
mice by deleting the key telomere capping protein TRF2 specifically from endothelial cells. In these mice, I will
examine arterial stiffness, EDD, and hallmarks of physiological and cellular aging. The proposed studies
represent a novel application of telomere biology that will enhance our understanding of how cells become
senescent, as well as the physiological consequences of endothelial cell senescence. The findings of these
studies are clinically relevant as senolytics are currently being evaluated in clinical trials in humans.