BME PhD Dissertation Defense: Emma Stowe

Title: "Aging and Senescence Dysregulate Tendon Adaptation to Mechanical Load"

Advisory Committee: Brianne Connizzo, PhD – BME, ME (Research Advisor) Michael Smith, PhD – BME, MSE (Chair) Elise Morgan, PhD – ME, BME, MSE Béla Suki, PhD – BME, MSE Daniel Roh, MD, PhD-BUSM

Abstract: Tendon injuries are a leading cause of impaired mobility and chronic pain in aging populations, yet the biological mechanisms underlying age-related declines in tendon function remain poorly understood. Dynamic extracellular matrix (ECM) remodeling is essential for tendon adaptation to mechanical loading, and its dysregulation is a central feature of chronic tendon degeneration and injury susceptibility. We hypothesize that aging impairs cellular mechanosensing and downstream remodeling responses, leading to compromised load-driven ECM adaptation. Among age-associated cellular changes, cellular senescence is a key candidate mechanism, as senescent cells secrete pro-inflammatory factors that promote matrix degradation. The overall goal of this thesis was to define the molecular mechanisms governing tendon responses to mechanical loading, identify age-related deficits in these adaptations, and determine the contribution of cellular senescence to impaired ECM remodeling. To accomplish this, young, aged, and senescent-induced murine tendon explants were subjected to controlled mechanical loading using ex vivo tensile bioreactors. Graded cyclic strains were applied to establish age-specific response profiles and physiological strain setpoints. We then developed a novel adaptive loading protocol incorporating step changes in strain to isolate mechanical perturbations and identify regulators of load-dependent ECM remodeling. This framework was integrated with genome-wide transcriptomics to identify age-specific impairments in the regulatory programs by which tendons sense and respond to changes in their mechanical environment. Finally, we developed a novel senescent tendon explant model and identified significant dysregulation of ECM remodeling associated with the presence of senescent cell populations. Together, our findings define the mechanistic basis of age-related impairments in tendon mechanobiology and identify cellular senescence as a targetable driver of dysfunction. This work advances understanding of tendon aging and establishes a foundation for targeted therapeutic and rehabilitation strategies to reduce injury risk and improve functional recovery in aging populations.