Childhood trauma, accelerated biological aging and chronic pain across two population cohorts
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Background
Adverse childhood experiences are associated with reduced healthy longevity, multimorbidity, and chronic pain, but the biological mechanisms involved remain poorly understood. Epigenetic age acceleration (EAA), a DNA methylation marker of biological aging, may represent a pathway through which early-life stress becomes embedded. We therefore examined associations between childhood trauma (CT), EAA and chronic pain, and investigated whether accelerated biological aging mediates the relationship between CT and chronic pain in women and men.
Methods
We analysed two independent population cohorts from the UK and USA: Generation Scotland (n = 901) and MIDUS (n = 1041). EAA was derived from first-generation (Hannum and Horvath) and second-generation (GrimAge and PhenoAge) DNA methylation clocks relative to chronological age. DunedinPACE, a third-generation measure, was used to estimate pace of aging. Associations between CT, EAA and chronic pain were examined using sex-stratified regression models adjusted for confounders and covariates, followed by mediation analyses.
Findings
CT was associated with chronic pain and with accelerated biological aging measured primarily using second- and third-generation clocks. Associations were consistently stronger in women, and smoking-related methylation contributed substantially to the relationship between EAA and chronic pain. Mediation analyses revealed that EAA partially accounts for the link between CT and chronic pain in women.
Interpretation
Second- and third-generation clocks appeared more sensitive to the long-term consequences of childhood trauma than clocks trained primarily on chronological age. The findings suggest that CT contributes to chronic pain vulnerability partly through accelerated biological aging pathways, particularly in women.
Funding
UK Research and Innovation, Lily, and Arthritis UK.
Research in context
Evidence before this study
Adverse childhood experiences are associated with increased risk of chronic pain, multimorbidity and premature mortality. DNA methylation-based epigenetic clocks are emerging biomarkers of biological aging and predictors of morbidity. Several studies have examined associations between childhood adversity and epigenetic age acceleration, but findings remain heterogeneous across cohorts, adversity measures and clock types. Chronic pain has also been linked to altered biological aging profiles. However, no previous study has integrated childhood trauma, biological aging and chronic pain within a unified analytical framework across multiple generations of epigenetic clocks. In addition, few studies have stratified by sex despite evidence that women exhibit greater chronic pain burden and multimorbidity across the lifespan.
Added value of this study
Using two independent population cohorts from the UK and USA, we demonstrate that childhood trauma is associated with both chronic pain and epigenetic age acceleration, with associations preferentially captured by second- and third-generation epigenetic clocks. These relationships were more consistent in women than men and were dose-dependent with trauma severity. Furthermore, epigenetic age acceleration established using GrimAge clocks, partially mediates the relationship between childhood trauma and chronic pain in women. Sequential adjustment models and sensitivity analyses additionally demonstrated that smoking-related biological aging pathways contribute substantially to these relationships, particularly in women.
Implications of all the available evidence
These findings support the hypothesis that childhood trauma contributes to chronic pain vulnerability partly through accelerated biological aging. The preferential involvement of second-generation epigenetic clocks suggests that morbidity-related aging measures capture the long-term biological consequences of early-life adversity more sensitively than chronological age predictors. The stratified analyses indicate that biological embedding of childhood trauma likely differs between women and men and may contribute to sex-specific trajectories of morbidity. Additional studies are required to determine whether accelerated biological aging following childhood trauma is modifiable through behavioural, clinical, or public health interventions.
