Ageing is associated with a decline in the number and fitness of adult stem cells^1,2. Ageing-associated loss of stemness is posited to suppress tumorigenesis^3,4, but this hypothesis has not been tested in vivo. Here we use physiologically aged autochthonous genetically engineered^5,6 mouse models and primary cells^5,6 to demonstrate that ageing suppresses lung cancer initiation and progression by degrading the stemness of the alveolar cell of origin. This phenotype is underpinned by the ageing-associated induction of the transcription factor NUPR1 and its downstream target lipocalin-2 in the cell of origin in mice and humans, which leads to functional iron insufficiency in the aged cells. Genetic inactivation of the NUPR1–lipocalin-2 axis or iron supplementation rescues stemness and promotes the tumorigenic potential of aged alveolar cells. Conversely, targeting the NUPR1–lipocalin-2 axis is detrimental to young alveolar cells through ferroptosis induction. Ageing-associated DNA hypomethylation at specific enhancer sites is associated with increased NUPR1 expression, which is recapitulated in young alveolar cells through DNA methylation inhibition. We uncover that ageing drives functional iron insufficiency that leads to loss of stemness and tumorigenesis but promotes resistance to ferroptosis. These findings have implications for the therapeutic modulation of cellular iron homeostasis in regenerative medicine and in cancer prevention. Furthermore, our findings are consistent with a model whereby most human cancers initiate at a young age, thereby highlighting the importance of directing cancer prevention efforts towards young individuals.

衰老与成体干细胞的数量和健康状况的下降有关^1,2。被认为与衰老相关的干性丧失会抑制肿瘤发生^3,4，但这一假设尚未在体内得到检验。在这里，我们使用生理衰老的本土基因工程小鼠模型^5,6 和原代细胞^5,6 来证明衰老通过降解起源肺泡细胞的干性来抑制肺癌的发生和进展。这种表型的基础是小鼠和人类来源细胞中转录因子 NUPR1 及其下游靶标脂质运载蛋白-2 的衰老相关诱导，这导致衰老细胞中的功能性铁不足。NUPR1-脂质运载蛋白-2 轴的基因失活或补铁可挽救干性并促进衰老肺泡细胞的致瘤潜力。相反，靶向 NUPR1-脂质运载蛋白-2 轴通过铁死亡诱导对年轻的肺泡细胞有害。特定增强子位点的衰老相关 DNA 低甲基化与 NUPR1 表达增加有关，NUPR1 表达通过 DNA 甲基化抑制在年轻的肺泡细胞中概括。我们发现衰老会导致功能性铁不足，从而导致干性丧失和肿瘤发生，但会促进对铁死亡的抵抗力。这些发现对再生医学中细胞铁稳态的治疗调节和癌症预防具有意义。此外，我们的研究结果与大多数人类癌症在年轻时发病的模型一致，从而强调了将癌症预防工作针对年轻人的重要性。