Identifying the target, mechanism, and agonist of α-ketoglutaric acid in delaying mesenchymal stem cell senescence
Summary: α-ketoglutaric acid (AKG), a tricarboxylic acid cycle metabolite central to aerobic metabolism and longevity, retains unresolved anti-aging protein targets. Here, we demonstrate that reduced isocitrate dehydrogenase 1 (IDH1) expression during senescence lowers AKG production, accelerating t...
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Elsevier
2025-07-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725006886 |
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| author | Zhao Cui Jiameng Li Caifeng Li Shiwen Deng Wei Liu Tong Lei Junxian Cao Ziyi Wang Xiaoxu Wang Shuhua Ma Yinhua Zhu Hongjun Yang Peng Chen |
| author_facet | Zhao Cui Jiameng Li Caifeng Li Shiwen Deng Wei Liu Tong Lei Junxian Cao Ziyi Wang Xiaoxu Wang Shuhua Ma Yinhua Zhu Hongjun Yang Peng Chen |
| author_sort | Zhao Cui |
| collection | DOAJ |
| description | Summary: α-ketoglutaric acid (AKG), a tricarboxylic acid cycle metabolite central to aerobic metabolism and longevity, retains unresolved anti-aging protein targets. Here, we demonstrate that reduced isocitrate dehydrogenase 1 (IDH1) expression during senescence lowers AKG production, accelerating the aging of mesenchymal stem cells (MSCs). Exogenous AKG or IDH1 overexpression restores AKG levels, enabling 2-oxoglutarate and Fe(II)-dependent oxygenase domain-containing protein 1 (OGFOD1)-catalyzed hydroxylation of ribosomal protein S23 (RPS23) at proline 62. Mechanistically, AKG stabilizes the OGFOD1-RPS23 complex, enhancing translation accuracy to limit misfolded protein accumulation while sustaining synthesis rates, thereby balancing proteostasis. The natural flavonoid scutellarin (Scu), identified as an IDH1 agonist, elevates AKG to delay MSC senescence. In aged mice, Scu improves cognitive function, reduces osteoporosis and skin aging, and suppresses senescence-associated secretory phenotype. Our findings identify the AKG-IDH1-RPS23 axis as a regulator of stem cell senescence and we propose metabolic reprogramming strategies for anti-aging therapies. |
| format | Article |
| id | doaj-art-59765c41a9b64fcea020d87cac96c1dd |
| institution | OA Journals |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-59765c41a9b64fcea020d87cac96c1dd2025-08-20T02:35:36ZengElsevierCell Reports2211-12472025-07-0144711591710.1016/j.celrep.2025.115917Identifying the target, mechanism, and agonist of α-ketoglutaric acid in delaying mesenchymal stem cell senescenceZhao Cui0Jiameng Li1Caifeng Li2Shiwen Deng3Wei Liu4Tong Lei5Junxian Cao6Ziyi Wang7Xiaoxu Wang8Shuhua Ma9Yinhua Zhu10Hongjun Yang11Peng Chen12Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China; Laboratory of Cardiovascular Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing 100091, ChinaThe First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China; CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Chinese Academy of Sciences and National Center for Nanoscience and Technology of China, Beijing 100190, ChinaExperimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, ChinaExperimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, ChinaExperimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, ChinaInstitute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, ChinaExperimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, ChinaExperimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, ChinaAstraZeneca Pharmaceuticals LP, Gaithersburg, MD 20878, USAExperimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, ChinaBeijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Nutrition and Health, China Agricultural University, Beijing 100193, ChinaExperimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China; Corresponding authorExperimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China; Corresponding authorSummary: α-ketoglutaric acid (AKG), a tricarboxylic acid cycle metabolite central to aerobic metabolism and longevity, retains unresolved anti-aging protein targets. Here, we demonstrate that reduced isocitrate dehydrogenase 1 (IDH1) expression during senescence lowers AKG production, accelerating the aging of mesenchymal stem cells (MSCs). Exogenous AKG or IDH1 overexpression restores AKG levels, enabling 2-oxoglutarate and Fe(II)-dependent oxygenase domain-containing protein 1 (OGFOD1)-catalyzed hydroxylation of ribosomal protein S23 (RPS23) at proline 62. Mechanistically, AKG stabilizes the OGFOD1-RPS23 complex, enhancing translation accuracy to limit misfolded protein accumulation while sustaining synthesis rates, thereby balancing proteostasis. The natural flavonoid scutellarin (Scu), identified as an IDH1 agonist, elevates AKG to delay MSC senescence. In aged mice, Scu improves cognitive function, reduces osteoporosis and skin aging, and suppresses senescence-associated secretory phenotype. Our findings identify the AKG-IDH1-RPS23 axis as a regulator of stem cell senescence and we propose metabolic reprogramming strategies for anti-aging therapies.http://www.sciencedirect.com/science/article/pii/S2211124725006886CP: MetabolismCP: Stem cell research |
| spellingShingle | Zhao Cui Jiameng Li Caifeng Li Shiwen Deng Wei Liu Tong Lei Junxian Cao Ziyi Wang Xiaoxu Wang Shuhua Ma Yinhua Zhu Hongjun Yang Peng Chen Identifying the target, mechanism, and agonist of α-ketoglutaric acid in delaying mesenchymal stem cell senescence Cell Reports CP: Metabolism CP: Stem cell research |
| title | Identifying the target, mechanism, and agonist of α-ketoglutaric acid in delaying mesenchymal stem cell senescence |
| title_full | Identifying the target, mechanism, and agonist of α-ketoglutaric acid in delaying mesenchymal stem cell senescence |
| title_fullStr | Identifying the target, mechanism, and agonist of α-ketoglutaric acid in delaying mesenchymal stem cell senescence |
| title_full_unstemmed | Identifying the target, mechanism, and agonist of α-ketoglutaric acid in delaying mesenchymal stem cell senescence |
| title_short | Identifying the target, mechanism, and agonist of α-ketoglutaric acid in delaying mesenchymal stem cell senescence |
| title_sort | identifying the target mechanism and agonist of α ketoglutaric acid in delaying mesenchymal stem cell senescence |
| topic | CP: Metabolism CP: Stem cell research |
| url | http://www.sciencedirect.com/science/article/pii/S2211124725006886 |
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