Long-term Senolytic Treatment Prevents Endothelial Dysfunction in Arterial Aging

Area of Science:

• Cardiovascular Biology
• Gerontology
• Cellular Senescence

Background:

• Endothelial senescence is a key factor in arterial dysfunction and age-related cardiovascular diseases.
• Senescent cells accumulate with age, contributing to tissue dysfunction and chronic diseases.

Purpose of the Study:

• To investigate the long-term effects of senolytic treatment (dasatinib plus quercetin, D+Q) on vascular endothelial senescence and function in aged mice.
• To elucidate the molecular mechanisms by which D+Q impacts endothelial cells, mitochondrial function, and vascular reactivity.

Main Methods:

• Long-term administration of D+Q (5 mg/kg + 50 mg/kg biweekly for 8 months) to aged mice.
• Assessment of senescence markers (p21, SA-β-gal) in mesenteric arteries and human umbilical vein endothelial cells (HUVECs).
• Transcriptomic analysis, assessment of eNOS (endothelial nitric oxide synthase) coupling and dimerization, mitochondrial function (ultrastructure, mass, ROS production), and vasodilation assays.

Main Results:

• D+Q treatment significantly reduced endothelial senescence markers in aged arteries and HUVECs.
• The therapy restored endothelial integrity, reversed age-related eNOS uncoupling, increased nitric oxide bioavailability, and improved mitochondrial homeostasis (reduced ROS, restored ultrastructure).
• D+Q enhanced endothelium-dependent vasodilation and blood flow in aged mesenteric arteries.

Conclusions:

• Clearance of senescent endothelial cells using D+Q senolytic therapy effectively mitigates arterial aging.
• The therapeutic benefits are linked to restored mitochondrial function and enhanced eNOS activity.
• Senolytic therapy holds significant potential for treating age-related vascular dysfunction.