Single-nucleus interrogation of primate small intestinal aging reveals NCoR1 decline as a conserved feature that is reversed by metformin.

Jingyi Li, Xiaoyong Lu, Tianhong Tong, Xin Zhou, Baohu Zhang, Xiaoyan Sun, Bing Zhao, Gang Xu, Jinjiang Yang, Yanling Fan, Jianli Hu, Haoteng Yan, Zhejun Ji, Mingheng Li, Shanshan Che, Yuanhan Yang, Yingjie Ding, Qiaoran Wang, Shuhui Sun, Shuai Ma, Si Wang, Juan Carlos Izpisua Belmonte, Jing Qu, Weiqi Zhang, Guang-Hui Liu

State Key Laboratory of Organ Regeneration and Reconstruction, Human Organ Physiopathology Emulation System, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.State Key Laboratory of Organ Regeneration and Reconstruction, Human Organ Physiopathology Emulation System, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. · pubmed

Paper

Abstract

How the small intestine ages at the cellular and molecular level has been unclear. Here we profile single nuclei from young and aged primate small intestine and find that aging brings barrier dysfunction, chronic inflammation and a shift in stem cell differentiation away from absorptive cells toward secretory cells. Through integrative multimodal analysis, we identify the transcriptional corepressor NCoR1 as a key player whose decline is conserved in the aging human gut. In human intestinal epithelial cells and organoids, knocking down NCOR1 recapitulates aging phenotypes including senescence, disrupted junctions and lineage imbalance, whereas overexpressing NCoR1 alleviates them. Metformin-a geroprotective drug-restores NCoR1 levels and delays intestinal aging in nonhuman primates. Our work points to NCoR1 as a central regulator of small intestinal aging and suggests a pharmacologically actionable strategy to counter age-related intestinal decline.

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Research summary

The paper claims that the decline of NCoR1 is a central feature of small intestinal aging that can be reversed by metformin. This research is relevant as it addresses a potential root cause of aging in the small intestine and suggests a pharmacological intervention to mitigate age-related decline.

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