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: CD34^High, with stemness properties (genuine state), and CD34^Low, 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.

组织再生会随着衰老而下降，但人们对这是否源于干细胞异质性的变化知之甚少。在这里，在稳态骨骼肌中，我们确定了两种以相对 CD34 表达为特征的静止干细胞状态：CD34^高，具有干性特性（真正状态）和 CD34^低，致力于成肌分化（启动状态）。真正的静止状态出乎意料地保留到了晚年，由于获得了启动状态的特征，只有在极度年老时才会屈服。利基衍生的 IGF1 依赖性 Akt 激活通过 FoxO 抑制施加启动状态特征来削弱真正的干细胞状态。中和 Akt 和促进 FoxO 活性的干预措施驱动了从准备状态到真正状态的转换，而 FoxO 失活会在年轻时恶化真正的状态，导致肌肉再生衰竭，就像老年小鼠发生的那样。这些发现揭示了干细胞异质性的转录决定因素，这些因素比以前预期的更能抵抗衰老，并且仅在极老时丢失，对老年肌肉的修复有影响。