Epigenetic Aging Mediates the Association between Pain Impact and Brain Aging 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 biological markers of aging are associated with each other in those 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 y) 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 predicted epigenetic and brain age from chronological age (DNAmGrimAge-Difference and Brain-PAD, respectively). There was a significant main effect for pain impact group (F (2,167) = 3.847, P = 0.023, rotational energy = 1/2Iω2= 0.038, ANCOVA) on Brain-PAD and DNAmGrimAge-difference (F (2,167) = 6.800, P = 0.001, I = mk2 = 0.075, ANCOVA) after controlling for covariates.DNAmGrimAge-Difference and Brain-PAD were modestly correlated (r =0.198; P =0.010).Exploratory analysis revealed that DNAmGrimAge-difference mediated GCPS pain impact, GCPS pain severity, and pain-related 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.

Pain interference mediates the association between epigenetic aging and grip strength in middle to older aged males and females with chronic pain

“…Of the 245 individuals who participated in the parent study, 148 individuals had some degree of pain as reported on the GCPS, complete epigenetic, handgrip, and all covariate data (97 of the original sample did not have complete data). Participant demographics have been previously reported ( Peterson et al, 2022a , b ; Strath et al, 2022b ). Participants in the sample were mostly female (62.2%), evenly distributed non-Hispanic black (46%) and non-Hispanic White (54%) and had a mean age of 57.84 ± 7.72 years.…”

“…For example, changes in DNA methylation that occur with a healthy diet and exercise may be mechanistically involved in slowing down the aging process ( Horvath, 2013 ; Moore et al, 2013 ; Brown, 2015 ; Lu et al, 2019 ). We have previously suggested that chronic pain could be a symptom of the aging body due to its associations with biological aging ( Peterson et al, 2022b ). Pain is a complex phenomenon that involves many physiological systems and is a major contributor to disability that could affect lifestyle and therefore indirectly hasten biological aging.…”

“…We have previously reported various components of this large-scale project in recent papers ( Cruz-Almeida et al, 2022 ; Peterson et al, 2022a , b ). In short, potential participants underwent an initial phone screening to determine study eligibility for sociodemographic (e.g., age, sex, and race) and health information (e.g., knee pain symptoms).…”

“…The blood sampling and processing method that we perform has been previously reported ( Cruz-Almeida et al, 2022 ; Peterson et al, 2022a , b ). In summary, blood samples were collected in a 10 ml K2 EDTA tube that was subsequently used for DNA extraction and methylation analysis.…”

“…Similar to our prior work ( Cruz-Almeida et al, 2022 ; Peterson et al, 2022a , b ), the raw data generated by Infinium Methylation EPIC array (.idat files) were processed using R package minfi ( Aryee et al, 2014 ). Methylation beta values (percentage of methylation for each CpG site) were obtained and uploaded to the DNA Methylation Age online calculator 1 ( Horvath, 2013 ) where we followed tutorial recommendations.…”