Accelerated epigenetic aging and prospective morbidity and mortality among U.S. veterans

Abstract Epigenetic measures of aging derived from DNA methylation are promising biomarkers associated with prospective morbidity and mortality, but require validation in real-world medical settings. Using data from 2,216 post-9/11 veterans, we examined whether accelerated DunedinPACE aging scores were associated with chronic disease morbidity, predicted healthcare costs, and mortality assessed over an average of 13.1 years of follow up in VA electronic health records. Veterans with faster DunedinPACE aging scores developed more chronic disease and showed larger increases in predicted healthcare costs over the subsequent 5, 10, and 15 years. Faster aging was associated with incident myocardial infarction, stroke, diabetes, cancer, liver disease, and renal disease, as well greater risk of mortality due to all-causes and chronic disease. These findings provide evidence that accelerated epigenetic aging is associated with worsening prospective health across multiple chronic diseases and organ systems assessed using electronic health records from an integrated healthcare system. Competing Interest Statement Drs. Terrie Moffitt, Avshalom Caspi, and Karen Sugden are named as an inventor on a license issued by Duke University for the DunedinPACE. The algorithm to calculate DunedinPACE is publicly available on Github, https://github.com/danbelsky/DunedinPACE. No other authors have conflicts of interest to report. Funding Statement This work was supported by Award #IK2CX002694 to Dr. Bourassa from the Clinical Science Research and Development (CSR&D) Service, Award #I01RX003120 to Dr. Hall from the Rehabilitation Research and Development (RR&D) Service, Award #IK2CX000525 from the CSR&D Service to Dr. Kimbrel, Award #I01BX002577 from the Biomedical Laboratory Research and Development (BLRD) Service and a Senior Research Career Scientist Award (#lK6BX003777) to Dr. Beckham from CSR&D of VA ORD, and Award #R01AG073207 to Drs. Moffitt and Caspi from the National Institute on Aging. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Durham, Richmond, and Salisbury VA Medical Centers Institutional Review Boards approved the PDMH study protocol and all participants provided informed consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability Data from the Post Deployment Mental Health (PDMH) Study are part of a Veterans Affairs data repository and are available to researchers who request access through the VISN 6 MIRECC and follow the appropriate data access protocols. Medical record data from the Veteran Affairs Corporate Data Warehouse are available to researchers who request and are approved for access through the Office of Research and Development (ORD) Data Access Request Tracker (DART). Mortality Data Repository (MDR) data is available to researchers who request MDR data through an MDR Data Request.