Evidence for Sleep Apnea to Accelerate Vascular Aging via Increased Cellular Senescence
Sleep apnea is correlated with cardiovascular disease, among other conditions. It induces a state of hypoxia in tissues when regular breathing is interrupted. Here, researchers induce a similar degree, duration, and intermittency of hypoxia in mice to examine the effects it has on vascular tissue. They find that this sort of hypoxia exposure increases the burden of senescent cells in the vasculature, alongside worsened measures of cardiovascular dysfunction. The researchers further show that clearing senescent cells from the vasculature improves cardiovascular function in the mice exposed to intermittent hypoxia, suggesting that this strategy should be tried in human patients.
Obstructive Sleep Apnea (OSA) is a pervasive cardiovascular risk factor linked to accelerated aging and systemic inflammation. Intermittent hypoxia (IH), a hallmark of OSA, induces cardiovascular decline, yet the underlying tissue-specific and systemic epigenetic mechanisms and the role of cellular senescence in the pathophysiology of OSA and associated cardiovascular disease (CVD) remain poorly understood. Here, C57BL/6J male mice were exposed to IH or room air (RA) for durations ranging from 7 to 210 days. Genome-wide DNA methylation profiling was conducted on left cardiac ventricle and peripheral blood mononuclear cells (PBMCs) samples. Epigenetic age acceleration (EAA) was calculated using a multi-tissue epigenetic clock. Furthermore, p16-reporter and targeted ablation mouse models were utilized to assess the role of p16Ink4a-mediated senescence in IH-induced vascular dysfunction.
Chronic IH exposures significantly increased systolic and diastolic blood pressure and altered endothelial function. Both left cardiac ventricle and PBMCs exhibited an early peak in EAA at 7 days of exposure, differing in the trajectory in longer exposures. Pathway analysis linked these epigenetic changes to cardiac dysfunction and cellular senescence, specifically highlighting Cdkn2a gene, which encodes the p16 protein, a marker of cellular senescence. Immunofluorescence confirmed increased p16 expression in aortic endothelial cells following IH. Remarkably, systemic ablation of p16-expressing cells reversed IH-induced hypertension and restored coronary flow reserve to control levels.
Our findings provide initial evidence that p16Ink4a-mediated cellular senescence is a primary driver of OSA-induced cardiovascular morbidity and that targeting the senescent endothelium can revert vascular dysfunction, thereby establishing a novel mechanistic framework for cellular senescence as a therapeutic target in OSA.