ABSTRACT Aging is a risk factor for many chronic conditions including Alzheimer’s disease (AD) and Alzheimer’s disease related dementias (ADRD) and impacts patient outcomes after traumatic brain injury (TBI). Aging can be chronologic aging (time since birth) or biological aging that may differ substantially from chronological age for some individuals, putting them at increased risk (accelerated biological aging) or decreased risk (decelerated biological aging) for age related conditions including AD and ADRD and poorer recovery from TBI. Epigenetic age measured using DNA methylation and epigenetic clock computations is one way to quantify biological age. Another risk factor besides age for ADRD is TBI particularly severe TBI. In our preliminary work we have developed epigenetic clock based biological age and calculated epigenetic age acceleration from DNA extracted from serial cerebrospinal fluid (CSF) samples during the acute phase following severe TBI. Our preliminary work has implicated epigenetic clock based biological age and epigenetic age acceleration during the acute phase post injury in patient outcomes at 6, 12, and 24 months after severe TBI. We also have evidence that social deprivation may impact epigenetic age acceleration in patients who have suffered a severe TBI. Additionally, DNA methylation of the BDNF gene from serial CSF samples could be a biomarker for patient outcomes after severe TBI, but the role of this biomarker appears to differ depending on the age of the patient. This project will expand these investigations in a larger cohort of well-characterized severely injured individuals with severe TBI. Expected results include finding a link between accelerated epigenetic aging and variation in patient outcomes up to 2 years after severe TBI and that social determinants of health impact accelerated epigenetic aging in this patient population. Accelerated epigenetic aging could be a useful biomarker for prognosticating about a patient’s acute and chronic outcomes as well as guiding and monitoring treatment during the acute and chronic phases after TBI. Knowledge that accelerated epigenetic aging impacts patient outcomes after severe TBI, and identifying what influences accelerated epigenetic aging in this population, could also inform treatment developments. Harnessing this knowledge could be beneficial to patients who have sustained a severe TBI. Knowing that TBI is a risk factor for AD/ADRD, caring for the severely injured brain with evidence-based interventions could also help mitigate long term sequela after TBI that includes mitigating risk for AD/ADRD.

Public Health Relevance Aging is a risk factor for many chronic conditions including Alzheimer’s disease related dementias (ADRD) and impacts patient outcomes after traumatic brain injury (TBI). Aging can be chronologic aging (time since birth) or biological aging that may differ substantially from chronological age for some individuals. Another risk factor in addition to aging for ADRD is TBI particularly severe TBI. This project brings together epigenetic aging and TBI by investigating the effect of epigenetic age acceleration present acutely after TBI on patient outcomes after severe TBI. This knowledge could assist in improving long term outcomes for individuals who have suffered a severe TBI including mitigating risk of ADRD.