Stem cells must preserve their function in order to sustain organ and tissue formation, homeostasis and repair. Adult stem cells, particularly those resident in tissues with little turnover, remain quiescent for most of their life, activating only in response to regenerative demands. Among the best studied long-lived quiescent stem cells are skeletal muscle stem cells, which are fully equipped to sustain repair in response to tissue trauma. Recent evidence indicates that the preservation of muscle stem-cell quiescence and regenerative capacity depends on intracellular networks linking metabolism and protein homeostasis. Here, we review recent research into how these networks control stem cell function and how their dysregulation contributes to aging, with a particular focus on senescence entry in extreme old age. We also discuss the implications of these new findings for anti-aging research in muscle stem-cell-based regenerative medicine.