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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 <jats:italic>Drosophila<\/jats:italic> midguts revealed that WRN expression does not decrease but rather increases in intestinal stem cells (ISCs) with aging. Mechanistically, we found that the <jats:italic>Drosophila<\/jats:italic> 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 (UPR<jats:sup>ER<\/jats:sup>). Activation of the WRNexo-mediated UPR<jats:sup>ER<\/jats:sup> 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 <jats:italic>Drosophila<\/jats:italic>. 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.<\/jats:p>","DOI":"10.1371\/journal.pbio.3003121","type":"journal-article","created":{"date-parts":[[2025,4,22]],"date-time":"2025-04-22T17:39:19Z","timestamp":1745343559000},"page":"e3003121","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Werner syndrome exonuclease promotes gut regeneration and causes age-associated gut hyperplasia in Drosophila"],"prefix":"10.1371","volume":"23","author":[{"given":"Kun","family":"Wu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juanyu","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yiming","family":"Tang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiaoqiao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lishou","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaorong","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhangpeng","family":"Zhuo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mei","family":"Luo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xingzhu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhendong","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"XiaoXin","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zihua","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao","family":"Sheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guanzheng","family":"Luo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8305-4060","authenticated-orcid":true,"given":"Haiyang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,4,22]]},"reference":[{"issue":"5","key":"pbio.3003121.ref001","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1038\/nrm2161","article-title":"Werner and Hutchinson-Gilford progeria syndromes: mechanistic basis of human progeroid diseases","volume":"8","author":"BA Kudlow","year":"2007","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"6","key":"pbio.3003121.ref002","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1002\/humu.20337","article-title":"The spectrum of WRN mutations in Werner syndrome patients","volume":"27","author":"S Huang","year":"2006","journal-title":"Hum Mutat"},{"issue":"7","key":"pbio.3003121.ref003","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1002\/humu.9435","article-title":"Werner syndrome and mutations of the WRN and LMNA genes in France","volume":"27","author":"NA Uhrhammer","year":"2006","journal-title":"Hum Mutat"},{"key":"pbio.3003121.ref004","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.arr.2016.03.002","article-title":"Werner syndrome: clinical features, pathogenesis and potential therapeutic interventions","volume":"33","author":"J Oshima","year":"2017","journal-title":"Ageing Res Rev"},{"issue":"6","key":"pbio.3003121.ref005","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1016\/j.cell.2013.05.039","article-title":"The hallmarks of aging","volume":"153","author":"C L\u00f3pez-Ot\u00edn","year":"2013","journal-title":"Cell"},{"issue":"6239","key":"pbio.3003121.ref006","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1126\/science.aaa1356","article-title":"Aging stem cells. 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