Accelerated Epigenetic Aging Mediates the Association between Pain Impact and Predicted Brain Age Difference in Middle to Older Age Individuals with Knee Pain

Abstract

Chronic musculoskeletal pain is a health burden that may accelerate the aging process. Accelerated brain aging and epigenetic aging have separately been observed in those with chronic pain. However, it is unknown whether these markers of aging are associated with chronic pain. We aimed to explore the association of epigenetic aging and brain aging in middle-to-older age individuals with varying degrees of knee pain. Participants (57.91 ± 8.04 years) with low impact knee pain (n=95), high impact knee pain (n=53) and pain-free controls (n=26) completed self-reported pain, a blood draw and an MRI scan. We used an epigenetic clock previously associated with knee pain (DNAmGrimAge), the subsequent difference of epigenetic age from chronological age (AgeAccelGrim) and used machine learning to predict brain age difference (brain-PAD). There was a significant main effect for pain group (F (2,167) = 3.847, p = 0.023, η_p^2 = 0.038, ANCOVA) on Brain-PAD and AgeAccelGrim (F (2,167) = 6.800, p = 0.001, η_p^2 = 0.075, ANCOVA) after controlling for covariates. Hierarchical regression analysis revealed that pain score in those who reported pain (not controls) was a significant predictor of Brain-PAD (F (1,146) = 3.689, p=0.038). AgeAccelGrim also mediated the indirect effect of various pain severity and disability scores on Brain-PAD. Based upon the current study findings, we suggest that pain could be a driver for accelerated brain aging via epigenome interactions. Grant support from NIH/NIA Grants R01AG059809, R01AG067757 (PI: Yenisel Cruiz-Almeida) and R37AG033906 (PI: Roger Fillingim).