Replicative and Air Pollution-Induced Senescence: Telomere Dysfunction, Mitochondrial Stress, and Modulatory Effects...

Telomere dysfunction and mitochondrial impairment are central drivers of vascular cell senescence and atherosclerosis, but their molecular interplay-especially under environmental stress-remains poorly defined. Fine particulate matter (PM) is an important contributor to vascular aging, but effective strategies to mitigate its detrimental effects are still lacking. This study investigated telomeric and mitochondrial alterations in human umbilical vein endothelial cells (HUVECs) and human coronary artery  smooth muscle cells (hVSMCs) during replicative senescence (RS) and stress-induced premature senescence (SIPS), and evaluated the potential protective effects of Astragaloside IV (AS-IV), a natural compound with telomere and mitochondria-protective properties, against PM-induced vascular senescence. RS was induced by serial passaging and categorized as young (passages 6-7), intermediate (10-11), and old (17-20). SIPS was induced in early-passage cells by 48-h exposure to fine dust (FD), a PM₁₀-like certified reference material representative of urban traffic emissions, at concentrations of 50 and 100 μg/mL. For the intervention experiments, cells were exposed to FD at 100 μg/mL for 48 h, followed by AS-IV (50 μM) for 24 h. Both HUVECs and hVSMCs showed hallmark features of RS, including SA-β-gal positivity, telomere shortening, activation of p16^INK4a/p21^Cip1, and mitochondrial dysfunction. FD-induced SIPS predominantly affected HUVECs, leading to premature senescence, telomere shortening, TERRA upregulation, and acute mitochondrial impairment, whereas hVSMCs showed relative resistance despite telomere shortening. AS-IV partially attenuated FD-induced telomeric and mitochondrial damage in HUVECs but had only limited effects in hVSMCs, underscoring the endothelial susceptibility to FD. These findings demonstrate that vascular senescence is governed by cell type-specific telomere-mitochondria interactions that are differentially modulated by FD. The selective protective effects of AS-IV in endothelial cells support the development of telomere-targeted therapeutic strategies to mitigate pollution-induced vascular aging.