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Grant Abstract: Endothelial Progenitor Cells and Particulate Air Pollution

Grant Number: 5R01ES019217-08
PI Name: O'Toole
Project Title: Endothelial Progenitor Cells and Particulate Air Pollution

Abstract: Improvements in clinical care and the promotion of health life styles have contributed to an aging population, but one that also increasingly presents with neurological disorders such as Alzheimer’s, Parkinson’s, dementia, and cognitive decline in general. While the basis of these outcomes is complex, they likely result from an interplay of genetic and environmental factors and are biochemically associated with inflammation and oxidative stress. One environmental factor linked to neurological dysfunction across all age groups is exposure to fine air borne particulate matter (PM2.5). PM2.5 exposures have been associated with autism spectrum disorders and learning disabilities in the young and with dementia in older populations. Carnosine is a naturally-occurring, ß-alanine-L-histidine dipeptide found in abundance in skeletal muscle and the brain. It is thought to promote physiological homeostasis through its ability to sequester hydroxyl radicals and oxidized lipids, chelate metals, buffer pH, and limit glycation. Given these chemical properties and abundance in the brain, carnosine has been proposed to limit neurological dysfunction and promote cognition. In this regard, prior supplementation studies generated inconsistent results or reported limited efficacy, but most of these studies have used vulnerable populations or had an abbreviated interventional time frame. It remains unclear therefore, if carnosine supplementation can promote cognition in a generally healthy cohort devoid of comorbidities. Thus, to test the efficacy of carnosine in promoting cognition and in limiting PM2.5-induced neurological dysfunction in humans, we will measure cognitive function in participants in the Nucleophilic Defense Against PM Toxicity (NEAT) trial. In this study, we will enroll participants in the Louisville, KY area with endogenous carnosine levels that are in the lower third of the normal distribution. Once we have obtained baseline measures of biomarkers and indices of pre-clinical cardiovascular disease, these participants will be instructed to take carnosine or placebo supplements for the following 12 weeks, during the summer months when local PM2.5 levels are at their highest. At two intervals during this time, the participants will return and we will collect blood and urine samples to assess cardiovascular function, immune responses, and oxidative stress levels. As outlined in this supplement application, we will also assess cognitive function at baseline and follow up clinical visits using the validated and highly sensitive Cognition software platform. By enrolling participants with the lowest endogenous carnosine levels, we will enhance our ability to observe carnosine-mediated protective effects. Thus, by leveraging the ongoing NEAT study, we will be able to test the additional hypothesis that dietary carnosine supplementation improves cognitive function in a generally healthy cohort and mitigates the adverse influences of PM2.5 exposure.

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