The novel target, mechanism and agonist of α-Ketoglutaric acid in delaying mesenchymal stem cell senescence

α-Ketoglutaric acid (aKG) participates in the tricarboxylic acid cycle in the process of cell aerobic metabolism and is of significant physiological importance. Although aKG is genetically associated with human longevity and decreased fertility, its anti-aging mechanism remain largely unknown. Here, we used interdisciplinary techniques such as metabolomics, chemical biology, and organoid microfluidic devices to explore the regulatory effect of aKG on senescence in a mesenchymal stem cell (MSC) model. We found that the expression of isocitrate dehydrogenase 1 (IDH1) in MSCs decreased after senescence, leading to reduced production of the active product aKG. Increasing intracellular aKG by supplementation with exogenous aKG or overexpression of IDH1 can promote MSC proliferation and delay MSC senescence, while inhibiting aKG production by knocking down IDH1 can induce premature MSC senescence. Specifically, aKG facilitates the interaction of ribosomal protein S23 (RPS23) with 2-oxoglutarate and Fe(II)-dependent oxygenase domain containing protein 1 (OGFOD1), and subsequently enhancing the hydroxylation of RPS23. This modulation of the RPS23–OGFOD1 complex contributes to the augmentation of protein translational fidelity. Finally, we attempted to activate IDH1 as a new anti-aging strategy. IDH1 is activated by the natural active molecule scutellarin (Scu), which not only increases the production of aKG but also delays the senescence of MSCs and ameliorates the aging phenotype of aged mouse. In summary, our study elucidates the effect of aKG on protein translation accuracy during MSC senescence and provides a potential therapeutic target for the treatment of aging-related diseases.