SIRT6/RXRα/Retinoic Acid-Related Signaling Contributes to Intestinal Stem Cell Homeostasis During Aging and Is Modulated by Atractylenolide II.

Yaqian Cao, Chunhui Song, Xiaoqing Sun, Zhenyu Niu, Xueni Zhang, Kerong Qi, Jiazhong Cai, Wenfeng Guo, Gang Chen, Ning Li, Yanwu Li

Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China. · pubmed

Paper

Abstract

Intestinal aging is characterized by impaired intestinal stem cell (ISC) function, reduced mucosal regenerative capacity, and progressive epithelial barrier deterioration. However, the upstream metabolic and epigenetic mechanisms that regulate ISC homeostasis during aging remain poorly understood. This study aimed to determine how SIRT6 regulates ISC homeostasis during intestinal aging and to investigate whether Atractylenolide II (AT-II) can alleviate age-related ISC dysfunction. Jejunal tissues from young and aged mice, intestinal epithelial-specific Sirt6-deficient mice, and 3D intestinal organoids were used to evaluate crypt-villus morphology, ISC activity, and lineage differentiation. Mechanistic analyses included western blotting, immunofluorescence, and retinoic acid (RA) quantification, complemented by pharmacological and rescue experiments targeting RXRα activity and RA metabolic balance. The results showed that SIRT6 protein expression was markedly reduced in the aged jejunum, correlating with a decreased villus-to-crypt (V/C) ratio, impaired ISC proliferation, and altered epithelial differentiation. Intestinal epithelial deletion of Sirt6 recapitulated aging-related intestinal defects, including crypt atrophy and ISC-associated dysfunction. Consistently, aged organoids displayed reduced SIRT6 protein expression, while Sirt6

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Research summary

SIRT6 maintains intestinal stem cell homeostasis during aging by regulating RXRα/retinoic acid signaling, and Atractylenolide II can restore this function. This paper is relevant because it identifies a specific epigenetic and metabolic mechanism (SIRT6/RA axis) underlying age-related tissue degeneration and demonstrates that pharmacological modulation can reverse these aging-associated defects, contributing to the understanding of how to maintain tissue regenerative capacity in the aged.

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