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.
