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  3. Identifying the target, mechanism, and agonist of α-ketoglutaric acid in delaying mesenchymal stem cell senescence

Identifying the target, mechanism, and agonist of α-ketoglutaric acid in delaying mesenchymal stem cell senescence

  • Cell Rep. 2025 Jul 22;44(7):115917. doi: 10.1016/j.celrep.2025.115917.
Zhao Cui 1,  Jiameng Li 2,  Caifeng Li 3,  Shiwen Deng 3,  Wei Liu 3,  Tong Lei 4,  Junxian Cao 3,  Ziyi Wang 3,  Xiaoxu Wang 5,  Shuhua Ma 3,  Yinhua Zhu 6,  Hongjun Yang 7,  Peng Chen 8
Affiliations

Affiliations

  • 1 Experimental 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, China.
  • 2 The 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, China.
  • 3 Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China.
  • 4 Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China.
  • 5 AstraZeneca Pharmaceuticals LP, Gaithersburg, MD 20878, USA.
  • 6 Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China.
  • 7 Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China. Electronic address: hjyang@icmm.ac.cn.
  • 8 Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China. Electronic address: sdzpchenpeng@qq.com.
PMID: 40570373 DOI: 10.1016/j.celrep.2025.115917
Abstract

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.

Keywords

CP: Metabolism; CP: Stem cell research; OGFOD1; RPS23; Scutellarin; isocitrate dehydrogenase; mesenchymal stem cells; protein homeostasis; senescence; α-ketoglutaric acid.

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