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

Area of Science:

• Gerontology
• Cardiovascular Biology
• Cellular Biology

Background:

• Aging causes cellular senescence, particularly in endothelial cells, contributing to cardiovascular diseases.
• Senolytics show promise in reducing cellular senescence in cell cultures.
• Translational studies are needed to confirm senolytic efficacy and impact on cellular aging in vivo.

Purpose of the Study:

• To investigate the in vivo effects of the senolytic cocktail dasatinib and quercetin (D+Q) on senescent endothelial cells in aged mice.
• To determine if D+Q treatment reduces hallmarks of cellular aging in endothelial cells.
• To assess the impact of D+Q on DNA damage and telomere dysfunction in aged endothelial cells.

Main Methods:

• Aged mice (24 months old) were treated with D+Q or a vehicle control.
• p21 gene expression was measured in carotid artery endothelial cells to assess senescence.
• DNA damage, telomere dysfunction, and telomere length were analyzed in lung endothelial cells.

Main Results:

• D+Q treatment significantly reduced p21 gene expression in carotid artery endothelial cells, indicating decreased senescence.
• Fewer lung endothelial cells exhibited DNA damage and telomere dysfunction after D+Q treatment.
• D+Q treatment shortened telomere length in endothelial cells, but not to critically dysfunctional levels.

Conclusions:

• Senolytic cocktail D+Q effectively clears senescent endothelial cells in vivo in aged mice.
• D+Q treatment reduces key hallmarks of cellular aging, including DNA damage and telomere dysfunction, in endothelial cells.
• Clearing senescent cells leaves a healthier endothelial cell population with fewer signs of vascular aging.