357: Pain, Body Composition, and Epigenetic Aging Are Linked to Brain Aging Longitudinally

Topic: Clinical Science
Subtopic: Pain category (ICD-11), Chronic primary musculoskeletal pain, Genetics and Epigenetics, Epidemiology, Imaging (e.g. fMRI, PET, MRS)

Background and Aims: Chronic pain, excess adiposity, and epigenetic aging are highly intertwined and have each been linked to adverse neurobiological changes. Neuroimaging-derived brain age predictors provide quantitative indicators of neurobiological aging. We examined longitudinal interrelationships among chronic pain, body mass index (BMI), epigenetic aging, and brain aging in middle-aged and older adults with and without knee osteoarthritis.

Methods: Longitudinal analysis of 87 participants (45−85 years) with DNA methylation and brain neuroimaging assessed at baseline and 2-year follow-up. The Graded Chronic Pain Scale was used to assess pain grade (0-4), pain intensity (0-10), and pain interference (0-10). Epigenetic age was estimated with the DNA methylation-based GrimAge clock, and brain age with the DeepBrainNet model (BrainAgeDBN). Linear mixed-effects models with random intercepts were used to evaluate associations with BrainAgeDBN, adjusting for demographic characteristics (chronological age, sex, race/ethnicity) and study site (University of Florida; University of Alabama-Birmingham).

Results: Higher pain grade was associated with accelerated brain aging (pain grade × time: β=0.91, SE=0.33, p=0.006). In secondary models, both pain intensity (pain intensity × time: β=0.35, SE=0.12, p=0.005) and pain-related interference (pain interference × time: β=0.49, SE=0.13, p < 0.001) were similarly associated with accelerated brain aging. Across all models, GrimAge and BMI were each positively associated with BrainAgeDBN. A significant interaction indicated that the association between epigenetic and brain aging was attenuated at higher BMI (GrimAge × BMI: β range=−0.019 to −0.020, p≤0.007).

Conclusions: Chronic pain may contribute to accelerated brain aging, with pain interference showing the strongest association. Epigenetic aging and BMI are also linked to brain aging, a relationship that warrants further research. These findings underscore the complex and multifactorial nature of aging and the importance of considering pain impact, body composition, and molecular aging processes together.

References: Cruz-Almeida, Y., Fillingim, R. B., Riley, J. L., 3rd, Woods, A. J., Porges, E., Cohen, R., & Cole, J. (2019). Chronic pain is associated with a brain aging biomarker in community-dwelling older adults. Pain, 160(5), 1119–1130. https://doi.org/10.1097/j.pain.0000000000001491

Tamargo, J. A., Strath, L. J., & Cruz-Almeida, Y. (2024). High-Impact Pain Is Associated With Epigenetic Aging Among Middle-Aged and Older Adults: Findings From the Health and Retirement Study. The journals of gerontology. Series A, Biological sciences and medical sciences, 79(8), glae149. https://doi.org/10.1093/gerona/glae149

Valdes-Hernandez, P. A., Laffitte Nodarse, C., Johnson, A. J., Montesino-Goicolea, S., Bashyam, V., Davatzikos, C., Peraza, J. A., Cole, J. H., Huo, Z., Fillingim, R. B., & Cruz-Almeida, Y. (2023). Brain-predicted age difference estimated using DeepBrainNet is significantly associated with pain and function-a multi-institutional and multiscanner study. Pain, 164(12), 2822–2838. https://doi.org/10.1097/j.pain.0000000000002984

Presenting Author: Javier A. Tamargo, PhD
Submitting Author: Javier Tamargo

Senior Author: Yenisel Cruz-Almeida, MSPH, PhD

IASP 2026 Global Year theme of Neuropathic Pain: No

• Pedro Valdes-Hernandez: PhD - University of Florida
• Thomas C. Foster: PhD - University of Florida
• Ronald Staud: MD, FACP - University of Florida
• Burel R. Goodin: PhD - Washington University in Saint Louis
• Roger B. Fillingim: PhD - University of Florida
• Yenisel Cruz-Almeida: MSPH, PhD - University of Florida