Abstract Advancing age is the single greatest risk factor for many diseases including TMJ degenerative disorders. TMJ degeneration significantly impair the quality of life by causing acute and chronic pain, thus making this disease a global health issue and a financial burden of epidemic proportion. As the United States and the world population ages over the next several decades, the incidence of the TMJ degenerative disorders are expected to rise substantially. As there is no effective treatment for the TMJ degeneration in an aged individual, there is an unmet clinical need for an effective approach to treat TMJ degenration associated with old age. The current proposal seeks to address this unmet clinical challenge using a highly innovative approach (senolytics) that has never been tested before for the treatment of TMJ degenration. Our overarching hypothesis is that cellular senescence plays a central role in age-related TMJ degeneration and targeted elimination of the senescent cells may prevent or reverse the TMJ degeneration. To test this hypotheses, we will examine: (1) Does eliminating the senescent cells by senolytics can inhibit or delay the development of age related degeneration of the osteochondral tissues of TMJ? Using a triple transgenic reporter mouse (Col1a1 X Col2a1 X Col10a1), we will examine the effects and mechanism of senolytics on the homeostasis of the osteochondral tissues of the TMJ. (2) Does transfer of senescent cells into the young mice make the osteochondral tissue of TMJ more prone to degeneration? We will transplant the senescent or non-senescent control cells into 12-week-old male and female triple transgenic reporter mice and then assess the the degeneration after the animals are euthanized. A combination of mechanical, immunohistochemical, molecular biology and imaging techniques coupled with novel genetic mice models will be used to study the proposed specific aims. The proposed project has the immense potential to reveal new regulatory pathways that controls homeostasis of the osteochondral tissues of the TMJ in an aged individual and to open new insight on understanding the disease mechanism and developing therapeutic interventions.