Senolytics Reduce Endothelial Cell DNA Damage and Telomere Dysfunction Despite Reductions in Telomere Length.

Abstract

Aging results in cellular damage that can induce cell cycle arrest known as cellular senescence. Endothelial cells are one of the first cell types to become senescent in advancing age and contribute to age-related cardiovascular diseases. Drugs known as senolytics reduce endothelial cell senescence in cell culture. From a translational perspective, a key question is whether this occurs in vivo and if remaining cells appear healthier and display fewer hallmarks of cellular aging. In this study, we treated old mice with the senolytic cocktail dasatinib and quercetin (D+Q) or a vehicle control. In 24-month-old mice, D+Q treatment reduced p21 gene expression in carotid artery endothelial cells, indicative of reductions in senescence. In lung endothelial cells, we examined DNA damage, telomere dysfunction (DNA damage signaling at telomeres), and telomere length, which are hallmarks of aging associated with senescence and other deleterious effects on cellular function. D+Q treatment resulted in fewer endothelial cells with DNA damage and dysfunctional telomeres. Surprisingly, D+Q reduced endothelial cell telomere length, yet this did not result in critically short telomeres and thus telomere dysfunction. Mice have longer telomeres than humans; therefore, future studies on the effect of senolytics on telomere length are warranted. Collectively, this study provides important evidence on the effect of senolytics, including that they clear senescent endothelial cells in vivo, which reduces DNA damage and telomere dysfunction. These data indicate that the clearing of senescent endothelial cells in old age leaves behind a population of cells that exhibit fewer hallmarks of vascular aging.