Grant Abstract: Nicotinamide riboside supplementation for treating elevated systolic blood pressure and arterial stiffness in middle-aged and older adults
Grant Number: 5R01AG061514-02
PI Name: Seals
Project Title: Nicotinamide riboside supplementation for treating elevated systolic blood pressure and arterial stiffness in middle-aged and older adults
Abstract: More than 90% of cardiovascular diseases (CVD) occur in men and women =50 years of age. Changes in age demographics in the U.S. predict progressive increases in these disorders without effective, evidence based interventions. The age-related increase in systolic blood pressure (SBP) is a major factor driving the increased risk of CVD in late middle-aged and older (MA/O) adults. This increase in SBP is due primarily to stiffening of the aorta, as indicated by increased carotid-femoral pulse wave velocity (CFPWV). We recently performed a pilot study showing that six weeks of treatment with nicotinamide riboside, a caloric-restriction mimicking dietary supplement that boosts NAD+ bioavailability to stimulate activity of the metabolic energy sensing and CV-protective enzyme SIRT-1, reduced SBP (-8 mmHg) and CFPWV in MA/O adults with above-normal baseline SBP (120-139 mmHg). We have since translated these findings into an appropriately powered, NIH-funded (R01 AG061514) clinical trial assessing the efficacy of three months of dietary supplementation with nicotinamide riboside for decreasing SBP and CFPWV in MA/O adults with baseline SBP in the elevated to stage 1 hypertension range (120-139 mmHg). Chronic low-grade systemic inflammation is thought to be a primary mechanism underlying the age-related increases in SBP and aortic stiffness. Preclinical data suggest nicotinamide riboside improves physiological function, in part, by reducing systemic inflammation. Additionally, our preliminary data on human subjects suggest nicotinamide riboside tends to decrease pro-inflammatory cytokine production from peripheral blood mononuclear cells (PBMCs). Given current interest in this novel compound, understanding the cellular and molecular mechanisms through which nicotinamide riboside improves cardiovascular function is an important research goal and necessary to fully interrogate the efficacy of nicotinamide riboside for disease prevention. However, the efficacy of nicotinamide riboside supplementation for decreasing chronic inflammation has never been rigorously evaluated within the context of a well-controlled clinical trial. Therefore, the purpose of this administrative supplement is to assess the efficacy of three months of dietary supplementation with nicotinamide riboside for reducing chronic low-grade inflammation compared to placebo. This will be accomplished by 1) measuring changes in PBMC inflammatory cytokine production, a sensitive and novel marker of inflammation; 2) evaluating changes to molecular (metabolic) pathways associated with inflammation through metabolomics analysis; and 3) testing the direct effect of nicotinamide riboside-related metabolites for reducing pro-inflammatory cytokine production from PBMCs. Further, we will investigate how changes in markers of inflammation with nicotinamide riboside supplementation relate to changes in SBP and aortic stiffness across the intervention. The expected results will establish nicotinamide riboside as a novel anti-inflammatory compound for improving physiological function with aging in humans.
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