TY - JOUR TI - FoxO maintains a genuine muscle stem-cell quiescent state until geriatric age AU - García-Prat, Laura AU - Perdiguero, Eusebio AU - Alonso-Martín, Sonia AU - Dell’Orso, Stefania AU - Ravichandran, Srikanth AU - Brooks, Stephen R. AU - Juan, Aster H. AU - Campanario, Silvia AU - Jiang, Kan AU - Hong, Xiaotong AU - Ortet, Laura AU - Ruiz-Bonilla, Vanessa AU - Flández, Marta AU - Moiseeva, Victoria AU - Rebollo, Elena AU - Jardí, Mercè AU - Sun, Hong-Wei AU - Musarò, Antonio AU - Sandri, Marco AU - Sol, Antonio del AU - Sartorelli, Vittorio AU - Muñoz-Cánoves, Pura T2 - Nature Cell Biology AB - Tissue regeneration declines with ageing but little is known about whether this arises from changes in stem-cell heterogeneity. Here, in homeostatic skeletal muscle, we identify two quiescent stem-cell states distinguished by relative CD34 expression: CD34High, with stemness properties (genuine state), and CD34Low, committed to myogenic differentiation (primed state). The genuine-quiescent state is unexpectedly preserved into later life, succumbing only in extreme old age due to the acquisition of primed-state traits. Niche-derived IGF1-dependent Akt activation debilitates the genuine stem-cell state by imposing primed-state features via FoxO inhibition. Interventions to neutralize Akt and promote FoxO activity drive a primed-to-genuine state conversion, whereas FoxO inactivation deteriorates the genuine state at a young age, causing regenerative failure of muscle, as occurs in geriatric mice. These findings reveal transcriptional determinants of stem-cell heterogeneity that resist ageing more than previously anticipated and are only lost in extreme old age, with implications for the repair of geriatric muscle. DA - 2020/10/26/ PY - 2020 DO - 10.1038/s41556-020-00593-7 DP - www.nature.com SP - 1 EP - 12 LA - en SN - 1476-4679 UR - https://www.nature.com/articles/s41556-020-00593-7 Y2 - 2020/10/26/17:32:22 ER -