The application of epigenetic clocks in degenerative musculoskeletal diseases: A systematic review

OBJECTIVE: Epigenetic clocks have emerged as powerful tools for quantifying biological aging. Degenerative musculoskeletal disorders (e.g., osteoarthritis [OA], osteoporosis) represent a group of age-related conditions characterized by progressive tissue deterioration. While their epidemiological association with aging is well-established, the precise relationship with epigenetic aging markers remains to be systematically elucidated. This review synthesizes current evidence on the application of epigenetic clocks as biomarkers and their clinical potential in managing these conditions. METHODS: We systematically searched four major biomedical databases (PubMed, PMC, Web of Science, ScienceDirect) from inception through December 2024 for observational studies examining the association between the epigenetic clock and degenerative musculoskeletal diseases using controlled vocabulary (e.g., DNA methylation age) combined with disease-specific terms. The protocol was registered with PROSPERO (CRD42024623554). RESULTS: After screening, 14 studies (case-control, cross-sectional, cohort) were included. We identified eight epigenetic clocks (based on cartilage, bone, and blood biomarkers) for assessing degenerative musculoskeletal diseases. DunedinPACE showed significant associations with chronic low back pain severity (r = 0.39-0.45) and functional impairment, while Horvath's clock revealed tissue-specific epigenetic aging in OA cartilage (ΔAge = 3.7 years). GrimAge exhibited the strongest correlations with chronic pain (ρ = 0.47) and mediated socioeconomic influences (β = 0.81). CONCLUSIONS: This systematic review of 14 clinical studies establishes epigenetic clocks as promising biomarkers for degenerative musculoskeletal diseases. The differential associations observed across epigenetic metrics highlight the need for disease-specific algorithm development. Future research should prioritize longitudinal validation and mechanistic investigations into socioeconomic influences on epigenetic aging.