Aging is one of the most significant risk factors for breast cancer. With the growing interest in the alterations of the aging breast tissue microenvironment, it is identified that aging is related to tumorigenesis, invasion, and drug resistance. However, current pre-clinical disease models often neglect the impact of aging and sometimes result in worse clinical outcomes. In this study, aged animal-generated materials are utilized to create and validate a novel age-mimetic breast cancer model that generates an aging microenvironment for cells and alters cells toward a more invasive phenotype found in the aged environment. Furthermore, the age-mimetic models are utilized for 3D breast cancer invasion assessment and high-throughput screening of over 700 drugs in the FDA-approved drug library. 36 potential effective drug targets as well as 34 potential drug targets with different drug responses in different age groups are identified, demonstrating the potential of this age-mimetic breast cancer model for further in-depth breast cancer studies and drug development.