Lipoic acid functions in Paneth cells to prevent human intestinal stem cell aging
Abstract Intestinal stem cell (ISC) aging diminishes the regenerative capacity of the intestinal epithelia, but effective therapeutic strategies to counteract human ISC aging remain elusive. Here, we find that the synthesis of α-lipoic acid (ALA) is reduced in old human small intestine. Notably, ALA...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-61070-z |
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| author | Zehong Zhang Qianyi Wan Yuedan Zhu Jinbao Ye Fang Fu Xinxin Fan Haiou Chen Gang Ren Wei Jiang Xiaoxin Guo Juanyu Zhou La Yan Jinhua Yan Xingzhu Liu Yu Yuan Yi Chen Haiyang Chen |
| author_facet | Zehong Zhang Qianyi Wan Yuedan Zhu Jinbao Ye Fang Fu Xinxin Fan Haiou Chen Gang Ren Wei Jiang Xiaoxin Guo Juanyu Zhou La Yan Jinhua Yan Xingzhu Liu Yu Yuan Yi Chen Haiyang Chen |
| author_sort | Zehong Zhang |
| collection | DOAJ |
| description | Abstract Intestinal stem cell (ISC) aging diminishes the regenerative capacity of the intestinal epithelia, but effective therapeutic strategies to counteract human ISC aging remain elusive. Here, we find that the synthesis of α-lipoic acid (ALA) is reduced in old human small intestine. Notably, ALA supplementation inhibits ISC aging and decreases the number of atypical Paneth cells in old human intestinal organoids and in old mouse small intestines. Importantly, we discern that the effect of ALA on mitigating ISC aging is contingent upon the presence of Paneth cells. Inhibiting the mTOR pathway in Paneth cells with ALA or rapamycin significantly increases cyclic ADP ribose (cADPR) secretion and decreases Notum secretion, which, in turn, enhances ISC functions. In this work, our findings substantiate the role of ALA in inhibiting human ISC aging and present a potential therapeutic approach for managing age-related human intestinal diseases. |
| format | Article |
| id | doaj-art-e29c44996b6442aaaa0d03af2f3d64f2 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-e29c44996b6442aaaa0d03af2f3d64f22025-08-20T04:01:34ZengNature PortfolioNature Communications2041-17232025-07-0116112010.1038/s41467-025-61070-zLipoic acid functions in Paneth cells to prevent human intestinal stem cell agingZehong Zhang0Qianyi Wan1Yuedan Zhu2Jinbao Ye3Fang Fu4Xinxin Fan5Haiou Chen6Gang Ren7Wei Jiang8Xiaoxin Guo9Juanyu Zhou10La Yan11Jinhua Yan12Xingzhu Liu13Yu Yuan14Yi Chen15Haiyang Chen16West China Centre of Excellence for Pancreatitis and Laboratory of Metabolism and Aging, Frontiers Science Center for Disease-related Molecular Network and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan UniversityWest China Centre of Excellence for Pancreatitis and Laboratory of Metabolism and Aging, Frontiers Science Center for Disease-related Molecular Network and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan UniversityWest China Centre of Excellence for Pancreatitis and Laboratory of Metabolism and Aging, Frontiers Science Center for Disease-related Molecular Network and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan UniversityWest China Centre of Excellence for Pancreatitis and Laboratory of Metabolism and Aging, Frontiers Science Center for Disease-related Molecular Network and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan UniversityWest China Centre of Excellence for Pancreatitis and Laboratory of Metabolism and Aging, Frontiers Science Center for Disease-related Molecular Network and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan UniversityWest China Centre of Excellence for Pancreatitis and Laboratory of Metabolism and Aging, Frontiers Science Center for Disease-related Molecular Network and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan UniversityWest China Centre of Excellence for Pancreatitis and Laboratory of Metabolism and Aging, Frontiers Science Center for Disease-related Molecular Network and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan UniversityResearch Center of Natural Resources of Chinese Medicinal Materials and Ethnic Medicine, Jiangxi University of Chinese MedicineResearch Center of Natural Resources of Chinese Medicinal Materials and Ethnic Medicine, Jiangxi University of Chinese MedicineWest China Centre of Excellence for Pancreatitis and Laboratory of Metabolism and Aging, Frontiers Science Center for Disease-related Molecular Network and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan UniversityWest China Centre of Excellence for Pancreatitis and Laboratory of Metabolism and Aging, Frontiers Science Center for Disease-related Molecular Network and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan UniversityWest China Centre of Excellence for Pancreatitis and Laboratory of Metabolism and Aging, Frontiers Science Center for Disease-related Molecular Network and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan UniversityWest China Centre of Excellence for Pancreatitis and Laboratory of Metabolism and Aging, Frontiers Science Center for Disease-related Molecular Network and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan UniversityWest China Centre of Excellence for Pancreatitis and Laboratory of Metabolism and Aging, Frontiers Science Center for Disease-related Molecular Network and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan UniversityWest China Centre of Excellence for Pancreatitis and Laboratory of Metabolism and Aging, Frontiers Science Center for Disease-related Molecular Network and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan UniversityDivision of Gastrointestinal Surgery, Department of General Surgery, West China Hospital, Sichuan UniversityWest China Centre of Excellence for Pancreatitis and Laboratory of Metabolism and Aging, Frontiers Science Center for Disease-related Molecular Network and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan UniversityAbstract Intestinal stem cell (ISC) aging diminishes the regenerative capacity of the intestinal epithelia, but effective therapeutic strategies to counteract human ISC aging remain elusive. Here, we find that the synthesis of α-lipoic acid (ALA) is reduced in old human small intestine. Notably, ALA supplementation inhibits ISC aging and decreases the number of atypical Paneth cells in old human intestinal organoids and in old mouse small intestines. Importantly, we discern that the effect of ALA on mitigating ISC aging is contingent upon the presence of Paneth cells. Inhibiting the mTOR pathway in Paneth cells with ALA or rapamycin significantly increases cyclic ADP ribose (cADPR) secretion and decreases Notum secretion, which, in turn, enhances ISC functions. In this work, our findings substantiate the role of ALA in inhibiting human ISC aging and present a potential therapeutic approach for managing age-related human intestinal diseases.https://doi.org/10.1038/s41467-025-61070-z |
| spellingShingle | Zehong Zhang Qianyi Wan Yuedan Zhu Jinbao Ye Fang Fu Xinxin Fan Haiou Chen Gang Ren Wei Jiang Xiaoxin Guo Juanyu Zhou La Yan Jinhua Yan Xingzhu Liu Yu Yuan Yi Chen Haiyang Chen Lipoic acid functions in Paneth cells to prevent human intestinal stem cell aging Nature Communications |
| title | Lipoic acid functions in Paneth cells to prevent human intestinal stem cell aging |
| title_full | Lipoic acid functions in Paneth cells to prevent human intestinal stem cell aging |
| title_fullStr | Lipoic acid functions in Paneth cells to prevent human intestinal stem cell aging |
| title_full_unstemmed | Lipoic acid functions in Paneth cells to prevent human intestinal stem cell aging |
| title_short | Lipoic acid functions in Paneth cells to prevent human intestinal stem cell aging |
| title_sort | lipoic acid functions in paneth cells to prevent human intestinal stem cell aging |
| url | https://doi.org/10.1038/s41467-025-61070-z |
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