Project Summary Obstructive sleep apnea (OSA) is an independent risk factor for development of diabetes and cardiovascular (CV) disease and is associated with worse CV outcomes. With the increase in obese and aging populations, the prevalence of OSA is also increasing. Therefore, strategies that reduce cardiometabolic risk in OSA will have high public health impact. The need for alternate approaches to mitigate CV risk in OSA is also highlighted by the inconsistent effects of CPAP therapy in improving insulin sensitivity, lowering blood pressure (BP), and reducing CV events. In recent years, the role of cellular damage and senescence in the development of obesity- and age-related metabolic disorders has been demonstrated, and therapeutics aimed at clearing senescent cells are being developed. More specifically, the role of cellular senescence in causing adipose tissue dysfunction and thereby contributing to chronic inflammation, increased BP, and insulin resistance (IR) is now recognized. Among the factors known to trigger cellular senescence, oxidative stress, AngII, and inflammation are elevated in OSA. Therefore it is likely that OSA will be associated with increased cellular damage and senescence. Our overall hypothesis is that intermittent hypoxia (IH) in OSA triggers cellular damage via increases in AngII, inflammation, and generation of reactive oxygen species (ROS) in adipose tissue. The increase in damaged cells in adipose tissue would, in turn, further increase AngII, inflammation, and ROS. These may together alter adipose tissue function, and contribute to IR, hypertension, and CV disease. This hypothesis is supported by our compelling preliminary data showing: i) increased presence of damaged p16 and γH2AX positive cells in adipose tissue of OSA subjects; ii) IH mediated increases in inflammation, AngII, ROS and senescence in cultured primary human preadipocytes; iii) attenuation of IH-dependent increases in senescent cells by atorvastatin and iv) lower prevalence of damaged cells in adipose tissue of OSA patients taking statin+CPAP. We will test our hypothesis using comprehensive characterization of blood and adipose tissue samples from 30 non-OSA (AHI<5) and 90 OSA (AHI>15) subjects to determine the presence of cellular damage (Aim 1). We will also identify potential mechanisms through which OSA causes cellular senescence, using in-vitro and ex-vivo approaches (Aim 2). Further, using a double blind randomized clinical trial design, we will evaluate the effects of 6 months of CPAP therapy and 80 mg atorvastatin on adipose tissue cellular damage, inflammation, BP, IR, and vascular function (Aim 3). The novelty and strengths of our proposal include the identification of adipose tissue cellular damage and senescence as a mediator of OSA-related cardiometabolic pathology, the multi-disciplinary translational approach, and the longitudinal randomized controlled trial in comprehensively phenotyped subjects, complemented by mechanistic in-...