Sestrins are a family of stress-inducible proteins that can function as antioxidants and as inhibitors of target of rapamycin complex 1. In this research perspective, we discuss the possible roles of Sestrins in diverse stress-induced patho-physiological contexts that can result in premature aging and age-related diseases. We suggest that Sestrins provide critical feedback regulation that adjust metabolic and stress responses to different environmental cues and evolutionary constraints.