For whom the bell tolls: psychopathological and neurobiological correlates of a DNA methylation index of time-to-death.

Psychopathology is a risk factor for accelerated biological aging and early mortality. We examined associations between broad underlying dimensions of psychopathology (reflecting internalizing and externalizing psychiatric symptoms), PTSD, and age-adjusted GrimAge ("GrimAge residuals"), a DNA methylation biomarker of mortality risk relative to age. We also examined neurobiological correlates of GrimAge residuals, including neurocognitive functioning, blood-based biomarkers (of inflammation, neuropathology, metabolic disease), and cortical thickness. Data from two independent trauma-exposed military cohorts (n = 647 [62.9% male, M age  = 52], n = 434 [90% male, M age  = 32]) were evaluated using linear regression models to test associations between GrimAge residuals, psychopathology, and health correlates. Externalizing psychopathology significantly predicted GrimAge residuals in both cohorts (ps < 0.028). PTSD predicted GrimAge residuals in the younger (p = 0.001) but not the older cohort. GrimAge residuals were associated with several neurobiological variables available in the younger cohort, including cognitive disinhibition (p adj  = 0.021), poorer memory recall (p adj  = 0.023), cardiometabolic pathology (p adj  < 0.001), oxidative stress (p adj  = 0.003), astrocyte damage (p adj  = 0.021), inflammation (C-reactive protein: p adj  < 0.001; IL-6: p adj  < 0.001), and immune functioning (p adj  < 0.001). A subset of inflammatory and neuropathology analytes were available in the older cohort and showed associations with GrimAge residuals (IL-6: p adj  < 0.001; TNF-α: p adj  < 0.001). GrimAge residuals were also associated with reduced cortical thickness in right lateral orbitofrontal cortex (p adj  = 0.018) and left fusiform gyrus (p adj  = 0.030), which are related to emotion regulation and facial recognition, respectively. Psychopathology may be a common risk factor for elevated mortality risk. GrimAge could help identify those at risk for adverse health outcomes and allow for early disease identification and treatment.