Werner syndrome exonuclease promotes gut regeneration and causes age-associated gut hyperplasia in Drosophila.

Kun Wu, Juanyu Zhou, Yiming Tang, Qiaoqiao Zhang, Lishou Xiong, Xiaorong Li, Zhangpeng Zhuo, Mei Luo, Yu Yuan, Xingzhu Liu, Zhendong Zhong, XiaoXin Guo, Zihua Yu, Xiao Sheng, Guanzheng Luo, Haiyang Chen

West China Centre of Excellence for Pancreatitis and Laboratory of Metabolism and Aging, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Respiratory Health and Multimorbidity and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China. · pubmed

Paper

Abstract

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.

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Research summary

The study claims that elevated WRNexo contributes to stem cell aging and drives age-associated gut hyperplasia in Drosophila. This research provides insights into the mechanisms of aging at the cellular level, particularly in relation to stem cell function and the impact of DNA damage, which are critical for understanding the root causes of aging and age-related diseases.

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