Abstract
Aging impairs tissue function and tolerance to cellular stress by reprogramming the behavior of resident cells. With global increases in lifespan, the prevalence of chronic and degenerative musculoskeletal disorders, including tendon degeneration, continues to rise; however, effective interventions to counteract age-related decline remain limited. Here, we investigate how a central age-associated stressor, inflammation, differentially modulates tendon cell behavior derived from young and mature-aged donors. Using super-resolution microscopy to resolve nanoscale chromatin organization in conjunction with epigenomic and transcriptomic profiling, we identify age-dependent regulatory mechanisms that govern inflammatory responsiveness. Mature-aged tendon cells exhibit exaggerated pro-inflammatory and catabolic responses across chromatin, gene expression, and protein signaling levels, characterized by enhanced TNFα receptor organization, elevated accessibility at pro-inflammatory regulatory elements, and robust induction of matrix-degrading enzymes. Notably, the AP-1 transcription factor family emerges as a central age-dependent regulator, displaying distinct motif accessibility patterns that bias mature tenocytes toward inflammatory and degenerative transcriptional programs. Taken together, our findings demonstrate that age-dependent epigenetic priming amplifies inflammatory sensitivity and constrains reparative gene regulation in mature tendon cells. This work provides a mechanistic framework linking chromatin remodeling to tendon degeneration and holds potential to identify epigenetic and transcriptional pathways as potential targets for rejuvenation strategies in aging musculoskeletal tissues.