Translation of the Aging and Immunity Multiome (TAIM): a Pilot Lifestyle Investigation in WTC Exposed FDNY Responders

New York University School Of Medicine, New York NY

Investigators

Abstract

SUMMARY The World Trade Center (WTC) attacks on September 11, 2001, exposed first-responders to toxic particulate matter (PM) resulting in morbidity and disability. Accelerated aging due to environmental and nutritional exposure is an area of investigation of global significance and pertinent to our WTC-exposed cohorts. We have identified that metabolic syndrome was a risk factor of worsening lung disease, and implemented a successful multidisciplinary dietary randomized clinical trial; Food Intake REstriction for Health OUtcome Support and Education (FIREHOUSE). Subjects that lost weight had improved lung function and respiratory quality of life symptoms. We have assayed their gut microbiome, metabolomics, and inflammatory profile, and collected genetic samples. However, the mechanisms that link WTC-PM exposure, metabolism, aging, hyper-inflammation and WTC-PM related lung disease are yet to be identified. We will focus on innovative concepts linking aging and increased autoantibodies under the hypothesis that both processes can cause persistent hyper-inflammatory states contributing to worsening lung function. We further hypothesize that: i. A nutritional lifestyle intervention can modify aging and autoantibody biosignatures in a WTC-PM exposed cohort. ii. WTC-PM exposure induced chronic inflammation and metabolic markers will be exacerbated by metabolic syndrome, age and transient depletion of a key anti-inflammatory mediator in mice, increasing autoantibodies and decreasing lung function. AIM 1. Lifestyle, Aging and Autoimmunity. Defining the MultiOme of Aging and Autoimmunity in the context of a nutritional intervention is designed to identify a subgroup of firefighters who have a chronic hyperinflammatory state, accelerated aging, and increased circulating autoantibodies that will be associated with health and lung function metrics. We will then integrate the MultiOME using systems biology to optimize disease specific models and identify mechanistic processes of WTC-Lung Injury. AIM 2. Mechanistic pathways will be examined utilizing a mouse model to determine a cause-effect relationship of WTC-PM exposure and high fat diet on aging and the exacerbation of hyperinflammatory responses (including autoantibodies). We will use mice from a well-established, commercial model of aging with features of metabolic syndrome, and expose them to WTC-PM. We will further study the effects of blocking a key anti-inflammatory cytokine to determine adverse effects (lung function, structural lung and heart remodeing) of WTC-PM exposure. The overall goal of this 2-year pilot is to begin to understand the mechanisms by which our nutritional intervention improves health outcomes, focusing on the interactions between a diet high in fat, aging, diminished control of inflammation and autoimmune antibodies. Our study outcomes will improve the overall understanding of how WTC lung disease persists, enhance our ability to better manage adverse health effects, benefit the health/well- being of WTC-exposed first-responders and falls squarely within the purview of the James Zadroga 9/11 Health & Compensation Act. This pilot will help lay the ground work for targeted immune/lifestyle driven therapies.