Cellular Senescence Contributes to Large Elastic Artery Stiffening and Endothelial Dysfunction With Aging: Amelioration With Senolytic Treatment
Zachary S. Clayton, Matthew J. Rossman, Sophia A. Mahoney, Ravinandan Venkatasubramanian, Grace S. Maurer, David A. Hutton, Nicholas S. VanDongen, Nathan T. Greenberg, Abigail G. Longtine, Katelyn R. Ludwig, Vienna E. Brunt, Thomas J. LaRocca, Judith Campisi, Simon Melov, Douglas R. Seals- Internal Medicine
BACKGROUND AND METHODS:
To determine the role of cellular senescence and the senescence-associated secretory phenotype (SASP) in age-related aortic stiffening and endothelial dysfunction, we studied young (6–8 months) and old (27–29 months) p16-3MR mice, which allows for genetic-based clearance of senescent cells with ganciclovir (GCV). We also treated old C57BL/6 N mice with the senolytic ABT-263.
RESULTS:
In old mice, GCV reduced aortic stiffness assessed by aortic pulse wave velocity (pulse wave velocity, 477±10 versus 382±7 cm/s; P <0.05) to young levels (old GCV versus young vehicle; P =0.35); ABT-263 also reduced aortic pulse wave velocity in old mice (446±9 to 356±11 cm/s; P <0.05). Aortic adventitial collagen was reduced by GCV ( P <0.05) and ABT-263 ( P =0.12) in old mice. To show an effect of the circulating SASP, we demonstrated that plasma exposure from old-vehicle p16-3MR mice, but not from old- GCV mice, induced aortic stiffening assessed ex vivo (elastic modulus; P <0.05). Plasma proteomics implicated glycolysis in circulating SASP-mediated aortic stiffening. In old p16-3MR mice, GCV increased endothelial function assessed via peak carotid artery endothelium-dependent dilation (old ganciclovir, 94±1% versus old vehicle, 84±2%, P <0.05) to young levels (old GCV versus young vehicle, P =0.98), and endothelium-dependent dilation was higher in old C57BL/6 N mice treated with ABT-263 versus vehicle (96±1% versus 82±3%; P <0.05). Improvements in endothelial function were mediated by increased nitric oxide bioavailability ( P <0.05) and reduced oxidative stress ( P <0.05). Circulating SASP factors related to nitric oxide signaling were associated with higher nitric oxide–mediated endothelium-dependent dilation following senescent cell clearance.
CONCLUSIONS:
Cellular senescence and the SASP contribute to vascular aging, and senolytics hold promise for improving age-related vascular function.