Late‐Life Aerobic Exercise Attenuates <scp>DNA</scp> Damage and Telomere Dysfunction in Non‐Atheroprone but Not in Atheroprone Aortic Regions

Cellular senescence is a state of persistent cell cycle arrest and is a critical contributor to arterial aging. The primary drivers of cellular senescence are the DNA damage response (DDR) and telomere dysfunction, which is induced by increasing exposure to DNA-damaging stimuli such as atheroprone shear stress. While late-life aerobic exercise is an effective intervention to mitigate arterial aging, its specific impact on the DDR and telomere dysfunction is unknown and may not show uniform benefits across aortic regions subjected to atheroprone and non-atheroprone shear stress. This study investigates the influence of late-life aerobic exercise on DDR and telomere dysfunction in endothelial cells (EC) and vascular smooth muscle cells (VSMC) within the aortic regions exposed to distinct shear stress patterns. Old male C57BL6 mice were randomly assigned to a negative control (NC) group and habitual voluntary wheel running (VWR) groups for 16 weeks. The habitual VWR groups were further categorized into low (LR), moderate (MR), and high running (HR) groups based on their daily running distance throughout the intervention. EC and VSMC DDR and telomere dysfunction in NC, LR, and MR groups were comparable across the aortic regions. Interestingly, EC DDR and telomere dysfunction were mitigated in the non-atheroprone aortic regions in HR, but not in VSMC. These improvements were independent of telomere length. Collectively, these data provide evidence that late-life aerobic exercise selectively mitigates DDR and telomere dysfunction in ECs within non-atheroprone aortic regions, rather than atheroprone aortic regions, in an exercise volume-dependent manner, independent of telomere length.