Late-life aerobic exercise reverses DNA damage and telomere dysfunction in non-atheroprone aortic regions with advanced age

Abstract

Cellular senescence, a state of cell cycle arrest, contributes to arterial aging. The dominant factor driving cellular senescence is DNA damage. Moreover, telomeres, a repeated DNA sequence at the end of chromosomes, are especially vulnerable to DNA damage induced by DNA-damaging stimuli such as atheroprone shear stress. Although the adoption of aerobic exercise in later life is an effective strategy to mitigate arterial aging, its direct relationship with DNA damage and telomere dysfunction has yet to be elucidated. Additionally, the impact of late-life aerobic exercise, particularly in regions exposed to atheroprone and non-atheroprone shear stress, may not yield uniform benefits, requiring further exploration. We sought to investigate the effects of late-life aerobic exercise on DNA damage and telomere dysfunction in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) in aortic regions exposed to distinct shear stress patterns such as the major aortic arch, minor aortic arch, and thoracic aorta. Fifteen male C57BL6 (22-23 mo) were given access to voluntary running wheel (VWR) for 4 weeks. They were classified as high-running (HR), moderate-running (MR), and low-running (LR) groups based on their habitual VWR distances (n=5 per group). Habitual VWR distance was greater in HR and MR compared to LR (75.9±11.2 and 21.3±1.6 vs. 5.8±2 m/day; P≤0.0003). Maximal treadmill running distance improved in HR, did not change in MR, and diminished in the LR (HR, MR vs. LR; P≤0.035) and was correlated to habitual VWR distance at 1-month post-intervention (R2=0.252, P=0.056). Immunofluorescence-fluorescent in situ hybridization was performed to detect the abundance of 53BP1 foci, a marker of DNA damage, and colocalization to telomeres, a measure of telomere-specific DNA damage known as telomere dysfunction-induced foci (TIF). The percentage of ECs containing 53BP1 foci and TIF was lower in the non-atheroprone aortic regions, i.e. major aortic arch and thoracic aorta, of HR compared to LR (P≤0.002), but there was no difference in the atheroprone, i.e. minor aortic arch (P≥0.899). A strong to moderate correlation was observed between 53BP1 foci and habitual VWR distance in major aortic arch and thoracic aorta (R2=0.584 and R2=0.54, P≤0.002) but only between VWR and TIF in the thoracic aorta (R2=0.356, P=0.019). The 53BP1 foci and TIF in VSMCs were comparable across groups in all aortic regions (P≥0.102). Likewise, Telomere length in ECs and VSMCs were similar across groups regardless of aortic region (P≥0.296). In conclusion, our findings suggest that increased level of habitual aerobic exercise in later life has a beneficial impact on DNA damage and telomere dysfunction in ECs, particularly in aortic regions exposed to extended periods of non-atheroprone shear stress. Notably, the volume of aerobic exercise was inversely associated with DNA damage and telomere dysfunction. These effects were independent of telomere length. The improvement in DNA damage and telomere dysfunction associated with habitual aerobic exercise were specific to ECs, as VSMCs remained unaffected in all aortic regions and results were independent of telomere length. Funded in part by awards from National Institutes of Health Awards R01 AG060395, R01 AG077751, R01 AG076748, T32 HL007576, T32 HL139451, Veteran's Affairs Merit Review Award I01 BX004492 and Nora Eccles Treadwell Foundation. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.