PTSD-Related Accelerated Aging in DNA Methylation and Risk for Metabolic Syndrome

Va Boston Health Care System, Boston MA

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Abstract

? DESCRIPTION (provided by applicant): Posttraumatic Stress Disorder (PTSD) is a debilitating condition that is prevalent in nearly 10% of the overall VA population and in approximately 25% of Veterans returning from the conflicts in Iraq and Afghanistan (Institute of Medicine, 2014; Fulton et al. 2015). It is associated with substantial individual and societal burden, including increased prevalence of pre-mature medical morbidity (e.g., Schnurr et al., 2000) and mortality (Ahmadi et al., 2011). Metabolic syndrome is an age-dependent condition defined by obesity, high blood pressure, insulin resistance, and dyslipidemia, and is also highly prevalent among Veterans (Keane et al., 2009), and among individuals with PTSD (Rosenbaum et al., 2015). We hypothesize that PTSD-associated pre- mature medical morbidities are clinical manifestations of an underlying accelerated cellular aging process that is potentiated by PTSD (Miller & Sadeh, 2014). DNA methylation, which is a biochemical process that regulates gene transcription and can effectively enhance or silence a gene, has been identified as a potential biomarker of aging (Christensen et al., 2009). Variation at methylation sites across the genome have been shown to serve, collectively, as an astonishingly good index of cellular age (DNA methylation age, e.g., Horvath, 2013; Hannum et al., 2013). This discovery paves the way for research on the pathogenic environmental factors that may alter the rate of biological aging. The primary aim of this study is to test the hypothesis that PTSD longitudinally predicts accelerated cellular aging in DNA methylation and that accelerated aging in DNA methylation is associated with metabolic syndrome. We further plan to identify the broader pathways implicated in PTSD-related accelerated aging by testing if the DNA methylation age loci that are most strongly influenced by PTSD are enriched for their involvement in autonomic reactivity, oxidative stress, inflammation, and stress-response processes, and if these same methylation loci are associated with metabolic syndrome. We propose to evaluate if other forms of psychiatric comorbidity are also associated with accelerated aging and if accelerated DNA methylation age is predictive of additional age-related medical morbidities, such as inflammation and cardiovascular diseases. To do so, we will draw from, and add to, a cohort of trauma-exposed, white non-Hispanic male and female U.S. military Veterans who will, or have already, taken part in two research assessments over the course of 2-10 years (anticipated Time 1 n = 561; anticipated Time 2 n = 400). Data at each time point will include methylation profiles (Infinium HumanMethylation450 BeadChip arrays), physical health diagnoses, metabolic lab values, and psychiatric symptoms and diagnoses assessed via structured diagnostic interviews. Replication analyses will be conducted using data from 1,723 individuals with longitudinal DNA methylation and PTSD data from the Psychiatric Genomics Consortium PTSD Epigenetics Workgroup. Ultimately, this work would help to pre-morbidly identify those at greatest risk for accelerated aging and pre-mature health decline, and identify the pathways implicated in PTSD-related age acceleration and metabolic syndrome. This will inform the development of interventions to prevent or mitigate these problems, using a precision medicine approach. This is critical because both PTSD and metabolic syndrome are hugely costly to VA (Sullivan et al., 2007; Tanielian et al., 2008) and carry a heavy personal and societal burden. The ability to measure cellular aging in DNAm is a major scientific advance and it is time to leverage this cutting-edge discovery to improve Veterans' health.