Underlying data for Figs 6, S5, and S6.

Human Werner syndrome (adult progeria, a well-established model of human aging) is caused by mutations in the Werner syndrome (WRN) gene. However, the expression patterns and functions of WRN in natural aging remain poorly understood. Despite the link between WRN deficiencies and progeria, our analyses of human colon tissues, mouse crypts, and Drosophila midguts revealed that WRN expression does not decrease but rather increases in intestinal stem cells (ISCs) with aging. Mechanistically, we found that the Drosophila WRN homologue (WRNexo) binds to Heat shock 70-kDa protein cognate 3 (Hsc70-3/Bip) to regulate the unfolded protein response of the endoplasmic reticulum (UPRER). Activation of the WRNexo-mediated UPRER in ISCs is required for ISC proliferation during injury repair. However, persistent DNA damage during aging leads to chronic upregulation of WRNexo in ISCs, where excessive WRNexo-induced ER stress drives age-associated gut hyperplasia in Drosophila. This study reveals how elevated WRNexo contributes to stem cell aging, providing new insights into organ aging and the pathogenesis of age-related diseases, such as colon cancer.人类沃纳综合征（Werner syndrome，又称成人早老症，是公认的人类衰老研究模型）由WRN基因（WRN gene）突变引发。然而，WRN在自然衰老过程中的表达模式与功能仍未得到充分阐明。尽管WRN功能缺陷与早老症存在明确关联，但我们对人类结肠组织、小鼠隐窝及果蝇（Drosophila）中肠的分析显示，肠干细胞（intestinal stem cells, ISCs）中WRN的表达并未随衰老下调，反而呈上升趋势。机制层面，我们发现果蝇WRN同源蛋白WRNexo可与热休克70 kDa蛋白同源物3（Heat shock 70-kDa protein cognate 3, Hsc70-3/Bip）结合，进而调控内质网未折叠蛋白反应（unfolded protein response of the endoplasmic reticulum, UPRER）。在肠干细胞中激活WRNexo介导的内质网未折叠蛋白反应，是损伤修复过程中肠干细胞增殖所必需的。然而，衰老过程中持续的DNA损伤会导致肠干细胞内WRNexo的慢性上调，过量WRNexo诱导的内质网应激进而驱动果蝇出现衰老相关的肠道增生。本研究揭示了WRNexo表达升高如何促成干细胞衰老，为器官衰老及结肠癌等年龄相关性疾病的发病机制提供了全新的研究视角。