Premature biological aging among WTC responders

Project Summary: The cohort of rescue and recovery workers (responders) involved in the emergency response and cleanup following the 2001 World Trade Center (WTC) disaster is aging (current median age is 60 years). Chronological aging is itself a major driver of disease. Aging, though, is a complex and nuanced biological process, and WTC responders may be experiencing “premature” or “accelerated” aging, whereby the body is aging faster than expected. Given the excess age-related morbidity and mortality associated with WTC exposure, including increased cancer risk, studies investigating WTC-associated premature aging on the biological level are warranted. Epigenetic clocks use DNA methylation levels at CpG sites throughout the genome to estimate biological age. An estimated biological age greater than actual chronological age reflects accelerated aging. In prior projects, our group has shown that DNA methylation was dysregulated because of WTC exposure, and that WTC exposure accelerated biological aging among women who are WTC survivors. Because sex is an effect measure modifier of both DNA methylation profiles and the normal aging process, studies are needed that explore this relationship in WTC-exposed males, including WTC rescue and recovery workers, who likely had higher levels of acute WTC exposure. Moreover, while DNA methylation markers derived from blood have been shown to mirror methylation signatures in tumor tissues, no studies have yet to validate tumor-tissue deregulated aging in responders. We propose here a study of WTC general responders (“exposed”) and males from the general population (“unexposed”). For each group we will calculate the mean biological age using validated epigenetic clock estimation techniques, including Horvath, Hannum, PhenoAge and GrimAge, and DunedinPACE. We will then compare rates of accelerated aging of WTC exposed vs unexposed participants, adjusting for important confounders. We intend to do this using both blood (Aim 1) and prostate tumor tissue (Aim 2). We hypothesize WTC exposure promotes accelerated aging among responders. We additionally expect to see similar aging-associated DNA methylation changes in both the blood of WTC cancer-free responders, as well as WTC tumor tissues. Improved understanding of how WTC exposure modifies the biological aging processes could improve both preventive and therapeutic care for responders, informing aging appropriate interventions such as exercise, nutritional supplementation, vitamin D, cognitive training, behavioral therapy, as a few examples. Biomarkers of dysregulated aging can also be used to screen for age-related vulnerability and conditions.