Project Summary Patients with chronic kidney disease (CKD) are at increased risk of death from cardiovascular disease (CVD). Inflammation, oxidative stress, and vascular dysfunction (impaired endothelial function and increased large elastic artery stiffness) are highly prevalent in CKD and contribute to the high incidence of CVD in this patient population. In addition, patients with CKD suffer from high rates of cognitive decline for which we lack effective therapies. Thus, therapeutic interventions targeting inflammation, oxidative stress, vascular dysfunction, and cognitive impairment in CKD are a biomedical priority. Curcumin is a natural polyphenol with anti-inflammatory and antioxidant characteristics. It is safe and widely-available. Our preliminary data in old mice and healthy middle-aged (MA)/older adult humans indicate that curcumin administration improves endothelial dysfunction and large artery stiffness by reducing oxidative stress and inflammation. We also found that 12 weeks of curcumin supplementation improves episodic memory in MA/older adults. The primary goal of this R01 application is to extend our findings in healthy MA/older adults to patients with CKD, a growing clinical population with extensive baseline vascular dysfunction and cognitive impairment who presently have few treatment options. We propose that curcumin improves vascular endothelial function and large elastic artery stiffness in MA/older adults with stage IIIb and IV CKD (estimated GFR 15- 45 mL/min/1.73m2). We will also assess the possible mechanisms by which curcumin improves vascular function and determine if curcumin improves cognitive function in these patients. Specific aim 1a will determine if 12 months of curcumin supplementation will improve brachial artery-flow mediated dilation (BA-FMD) (endothelial function) and aortic pulse wave velocity (aPWV) (arterial stiffness) compared to placebo (randomized placebo-controlled double-blind study). Specific aim 1b will evaluate whether the curcumin-induced improvements in BA-FMD and aPWV are mediated by reduced oxidative stress, and will evaluate the effects of curcumin on systemic and endothelial cell markers of inflammation and oxidative stress. Importantly, specific aim 2 will evaluate the effects of curcumin supplementation on cognitive function, an important complication of CKD, using the NIH Cognitive Toolbox Battery. The study will be conducted by a highly experienced team of investigators at the Clinical and Translational Research Center at the University of Colorado-Denver Anschutz Medical Campus with support from Dr. Seals at the University of Colorado Boulder Campus and in collaboration with Dr. Tamura from Stanford University. Overall, the study has the potential to influence clinical practice guidelines in patients with CKD by establishing a novel, safe, and low-cost dietary supplement to reduce the burden of CVD in patients with CKD.