Senolytic-facilitated Reversal of End-Organ Dysfunction in a Murine Model of Obstructive Sleep Apnea

Rationale: Obstructive sleep apnea (OSA) is a highly prevalent condition that is associated with accelerated biological aging and multiple end-organ morbidities. Current treatments, such as continuous positive airway pressure (CPAP), have shown limited cognitive, metabolic, and cardiovascular beneficial outcomes despite adherence. Thus, adjunct therapies aiming to reduce OSA burden, such as senolytics, could improve OSA outcomes. Objectives: To assess if targeting senescence in addition to partial normoxia mimicking “good” CPAP adherence can improve physiological outcomes in mice exposed to chronic intermittent hypoxia (IH). Methods: We compared the effects of 6 weeks therapy with either partial normoxic recovery alone or combined with the senolytic Navitoclax (NAV) after 16 weeks of IH exposures, a hallmark of OSA, on multi-phenotypic cardiometabolic and neurocognitive parameters. Results: Our findings indicate that only when combined with NAV, partial normoxic recovery significantly improved sleepiness (sleep in the dark phase: 34 ± 4% vs. 26 ± 3%, p < 0.01), cognition (Preference score: 51 ± 19% vs. 70 ± 11%, p = 0.048), coronary artery function (response to acetylcholine (vasodilation): 56 ± 13% vs. 72 ± 10%, p < 0.001), glucose, and lipid metabolism, and reduced intestinal permeability and senescence in multiple organs. Conclusions: These findings indicate that the reversibility of end-organ morbidities induced by OSA are not only contingent on restoration of normal oxygenation patterns and can be further enhanced by targeting other OSA-mediated detrimental cellular processes, such as accelerated senescence.