Natural flavonoid glycosides Chrysosplenosides I & A rejuvenate intestinal stem cell aging via activation of PPARγ signaling

Author:

Ye Jinbao1,Yan La1,Yuan Yu1,Fu Fang1,Yuan Lu2,Fan Xinxin1,Zhou Juanyu1,Zhu Yuedan1,Liu Xingzhu1,Ren Gang2,Chen Haiyang1ORCID

Affiliation:

1. Laboratory of Stem cell and anti-Aging Research, 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 610041 , China

2. Research Center of Natural Resources of Chinese Medicinal Materials and Ethnic Medicine, Jiangxi University of Chinese Medicine , Nanchang 330004 , China

Abstract

Abstract The decline in intestinal stem cell (ISC) function is a hallmark of aging, contributing to compromised intestinal regeneration and increased incidence of age-associated diseases. Novel therapeutic agents that can rejuvenate aged ISCs are of paramount importance for extending healthspan. Here, we report on the discovery of Chrysosplenosides I and A (CAs 1 & 2), flavonol glycosides from the Xizang medicinal plant Chrysosplenium axillare Maxim., which exhibit potent anti-aging effects on ISCs. Our research, using Drosophila models, reveals that CAs 1 & 2 treatments not only restrain excessive ISC proliferation, thereby preserving intestinal homeostasis, but also extend the lifespan of aging Drosophila. In aged mouse intestinal organoids, CAs 1 & 2 enhance the growth and budding of intestinal organoids, indicating improved regenerative capacity. Mechanistic investigations show that CAs 1 & 2 exert their effects by activating the peroxisome proliferator-activated receptor-gamma (PPARγ) and concurrently inhibiting the epidermal growth factor receptor (EGFR) signaling pathways. Our findings position CAs 1 & 2 as promising candidates for ameliorating ISC aging and suggest that targeting PPARγ, in particular, may offer a therapeutic strategy to counteract age-related intestinal dysfunction.

Funder

National Natural Science Foundation of China

National Key Research and Development Program of China

National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University

West China Hospital, Sichuan University

Publisher

Oxford University Press (OUP)

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