Aging is characterized by the functional and regenerative decline of tissues and organs. This regenerative decline is a consequence of the numerical and functional loss of adult stem cells, which are the corner stone of tissue homeostasis and repair. A palpable example of this decline is provided by skeletal muscle, a specialized tissue composed of postmitotic myofibers that contract to generate force. Skeletal muscle stem cells (satellite cells) are long-lived and support muscle regeneration throughout life, but at advanced age they fail for largely undefined reasons. Here, we discuss recent advances in the understanding of how satellite cells integrate diverse intrinsic and extrinsic processes to ensure optimal homeostatic function and how this integration is perturbed during aging, causing regenerative failure. With this increased understanding, it is now feasible to design and test interventions that delay satellite cell aging. We discuss the exciting new therapeutic potential of integrating and combining distinct anti-aging strategies for regenerative medicine.