Sestrins are a family of stress-responsive antioxidant proteins responsible for regulation of cell viability and metabolism. The best known Sestrin targets are mTORC1 and mTORC2 kinases that control different cellular processes including growth, viability, autophagy, and mitochondrial metabolism. Inactivation of the single Sestrin gene in invertebrates has an adverse impact on their healthspan and longevity, whereas each of the three Sestrin genes in mammals and other vertebrate organisms has a different impact on maintenance of a particular tissue, affecting its stress tolerance, function and regenerative capability. As a result, Sestrins attenuate ageing and suppress development of many age-related diseases including myocardial infarction, muscle atrophy, diabetes and immune dysfunction, but exacerbate the development of chronic obstructive pulmonary disease. Moreover, Sestrins play opposite roles in carcinogenesis in different tissues. Stem cells support tissue remodelling that influence ageing, and Sestrins might suppress ageing and age-related pathologies through the control of stem cell biology. In this review, we will discuss the potential link between Sestrins, stem cells, and ageing.Copyright © 2020. Published by Elsevier B.V.