Long-term prospective associations of PFAS with musculoskeletal and cardiovascular health among older adults

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PROJECT ABSTRACT Per- and polyfluoroalkyl substances (PFAS) are persistent “forever chemicals” that contaminate water and food and are detectable in almost every individual in the US. Despite a manufacturer’s voluntary phase-out, efforts to limit production have been incomplete, and there is no US federal legislation to regulate PFAS, in part due to a lack of longitudinal data on policy-relevant health outcomes. In particular, high-quality data are limited from studies among older adults, a population rapidly expanding, and in which altered metabolism, decreased clearance, and hormonal changes may heighten PFAS vulnerability. In our highly productive first funding cycle, we reported associations of higher plasma PFAS with greater insulin resistance, cholesterol, abdominal adiposity, and diabetes risk in midlife. These intermediates presage poorer health in older age, including low muscle mass and strength, low bone mass, and cardiovascular disease (CVD). In this competing renewal R01, we propose to expand our prior work to test our hypothesis that higher and more prolonged exposure to PFAS increases risk for poor musculoskeletal and cardiovascular health in older adults. In addition, we will test a secondary hypothesis that builds on our first funding cycle finding that randomization to an exercise and dietary lifestyle intervention mitigated the effect of PFAS on cardiometabolic risk. We hypothesize that we can identify specific lifestyle factors (e.g., healthier, anti-inflammatory diet higher in omega-3 fatty acids and lower in fat) that will attenuate health effects of PFAS, information important for the growing number of communities identified with high PFAS levels due to contamination and industrial use. We will again leverage the unparalleled resources of the Diabetes Prevention Program (DPP)/Diabetes Prevention Program Outcomes Study (DPPOS), a long-term cohort study nested within a randomized trial. We will leverage the PFAS results from our first funding cycle, perform additional assays to address new hypotheses and increase sample size (n=~1400), and benefit from the study’s wealth of high quality, longitudinal data on covariates, CVD, and aging- relevant outcomes carefully collected over 20 years during critical windows of aging. In Aim 1, we will examine prospective associations of PFAS with muscle strength (e.g., hand grip) and DXA measures of muscle and bone mass. In Aim 2, we will examine prospective associations of PFAS with incident adjudicated CVD events. In Aim 3, a secondary aim, we will examine effect modification of PFAS-outcome associations by study arm and specific lifestyle factors. By examining longitudinal PFAS exposure across midlife and older age and by employing sophisticated statistical methods to examine individual PFAS and PFAS mixtures, we will overcome limitations of the few existing studies of PFAS, musculoskeletal health, and CVD. Our findings will inform PFAS legislation and health guidance for exposed individuals, with implications for musculoskeletal health and cardiovascular risk reduction.