Both primary (age-derived) SNCs and secondary (atherosclerosis-derived) SNCs may promote atherosclerosis. In young arteries (top left), senescence burden is low. Vessel homeostasis is achieved by endothelium-derived NO acting on VSMCs, promoting vasodilation, quiescence, contractile phenotype, and endothelial health. During normal aging (top right), endothelial cells and VSMCs undergo primary senescence (red cells). Loss of NO tone may arise due to failure of endothelial cell homeostasis, leading to endothelial dysfunction and senescence. Excessive VSMC proliferation in aging vessels may also drive VSMC senescence, further exacerbating VSMC hyperplasia via SASP-mediated growth factor release. Whatever the causal chain, loss of NO tone converts VSMC to the synthetic phenotype, prompting VSMC hyperplasia, medial thickening, collagen overproduction, and synthesis of elastin-degrading metalloproteases (MMPs), collectively producing vessel stiffening, widened pulse pressure, hypertension, and increased cardiac afterload. Vessel stiffening interrupts normal shear stress signals that suppress VCAM expression, with proatherogenic effects. Absence of risk factors in late life may produce late-onset cardiovascular disease (CVD; bottom right). Alternatively, early-life CVD risk factors (e.g., diabetes, hypertension, metabolic syndrome, and dyslipidemia) promote aberrant oxi-LDL accumulation in the subendothelial space, initially producing secondary senescent foam cell macrophages. At later stages of disease, secondary senescent foamy endothelium and VSMCs also arise (green cells). This faster trajectory results from intense, proatherogenic stress and results in early CVD (bottom left). The relative contribution of primary and secondary SNCs to atheroprogression probably varies with life history and personal risk factors, but both types likely contribute to key features of clinical disease, including thinning of the fibrous cap as a result of VSMC growth arrest and SASP-derived collagenases and elastases; enhanced lesion growth due to expression of VCAM and ICAM; and lesion-associated aneurysm resulting from medial elastin degradation.