Researchers have discovered how and why α-ketoglutaric acid (AKG) affects cellular senescence and how a small molecule may be useful in affecting this process. They published their findings in Cell Reports.
A crucial molecule
AKG is a major part of multiple fundamental metabolic processes, including the Krebs cycle that mitochondria use to generate energy, and it has been observed to affect both epigenetics and how the body handles nitrogen compounds such as ammonia [1]. It is also integral to the ability of embryonic stem cells to renew themselves [2]. AKG is widely known as a supplement, and previous work has found that it extends lifespan and compresses morbidity in mice [3].
Isocitrate dehydrogenase 1 (IDH1) is an enzyme responsible for the synthesis of AKG, and its levels decline with age [4]. Mutations in the relevant gene lead to cancer [5]. The researchers note that the links between IDH1, AKG, and long-term cellular health have not been thoroughly explored, and so they resolved to investigate its potential effects in the realm of cellular senescence.
Looking closely at AKG biochemistry
The researchers first examined the Krebs cycle and how it changes with aging. Younger mesenchymal stem cells (MSCs) in culture produce more of the fundamental metabolites associated with each point of the Krebs cycle. Administering these metabolites to other MSCs, the researchers found that only AKG has effects on cellular proliferation, which declines with age. Similarly, AKG levels were substantially reduced in senescent cells, whether they naturally became senescent or were driven senescent through D-galactose administration.
AKG had beneficial effects on MSCs whether administered as its normal form or as a derivative, DM-AKG, which significantly increased the amount of AKG present in the cells. Administering DM-AKG to older human MSCs greatly increased their proliferation, decreased the levels of the DNA damage marker γH2AX, and decreased overall senescence according to multiple senescence biomarkers, such as interleukins, p16, p21, and the core senescence biomarker SA-β-gal.
The researchers then took a very close look at the proteins involved. They found that many of the the molecules interacting with AKG were responsible for the function of ribosomes, which are responsible for protein synthesis in cells. One particularly crucial effect was on the ribosomal RPS23 protein, but this was actually a downstream consequence; the researchers found that another factor, OGFOD, binds tightly to AKG. AKG had no beneficial effects on senescent MSCs that were altered to not express OGFOD, suggesting that this is the key reason for its anti-senescence effects. Affecting RPS23 also nullified the effects of AKG as well.
This turned out to be due to the placement of iron. The researchers used a molecular dynamics model and found that iron atoms cannot be properly placed in the reaction between RPS23 and OGFOD unless AKG is present to mediate the reaction. Mutations in the genes responsible for the particular amino acids involved led to premature senescence.
On the other hand, overexpression of IDH1 delayed senescence instead; markers of proliferation were significantly increased, and markers of senescence were greatly diminished. These results were confirmed to be due to the increase of AKG, which increased reaction rates between RPS23 and OGFOD. IDH2 and IDH3 were found to have similar relationships.
There were benefits related to accurate protein translation. Administering AKG both increased overall protein translation, which is necessary for rapid cellular replication, and increased the accuracy of genetic reading: stop codon readthrough mistakes were significantly decreased by the administration of AKG. As expected, disrupting OGFOD led to an increase in these mistakes. Inducing senescence by directly disrupting proteostasis, however, could not be recovered by AKG.
A potential solution
The researchers then examined scutellarin, a small molecule that increases IDH1 production [6]. Similar to AKG, it was found to have beneficial effects on MSC proliferation and anti-senescence, which were themselves found to be directly linked to AKG’s effects on OGFOD and RPS23; disrupting this chain at any point nullified these effects. These effects were recapitulated in a microfluidic model of the intestine, demonstrating that it can be administered orally.
Therefore, the researchers administered scutellarin to a population of 20-month-old mice for 80 days. Compared to a control group, the treated mice had better performance on the Morris water maze test and the Y-maze test along with visible improvements in physical health, including bone and skin, in addition to decreases in p21 and p16.
This was a cellular and murine study, and these findings may or may not apply to human beings. While scutellarin is already a known plant-derived drug with a wide variety of reported positive effects, further studies will need to be undertaken to determine if it has long-term benefits against increased cellular senescence and its downstream consequences in older people.
Literature
[1] Gyanwali, B., Lim, Z. X., Soh, J., Lim, C., Guan, S. P., Goh, J., … & Kennedy, B. K. (2022). Alpha-Ketoglutarate dietary supplementation to improve health in humans. Trends in Endocrinology & Metabolism, 33(2), 136-146.
[2] Carey, B. W., Finley, L. W., Cross, J. R., Allis, C. D., & Thompson, C. B. (2015). Intracellular α-ketoglutarate maintains the pluripotency of embryonic stem cells. Nature, 518(7539), 413-416.
[3] Shahmirzadi, A. A., Edgar, D., Liao, C. Y., Hsu, Y. M., Lucanic, M., Shahmirzadi, A. A., … & Lithgow, G. J. (2020). Alpha-ketoglutarate, an endogenous metabolite, extends lifespan and compresses morbidity in aging mice. Cell metabolism, 32(3), 447-456.
[4] Wang, S., Zheng, Y., Li, J., Yu, Y., Zhang, W., Song, M., … & Liu, G. H. (2020). Single-cell transcriptomic atlas of primate ovarian aging. Cell, 180(3), 585-600.
[5] Dang, L., Yen, K., & Attar, E. C. (2016). IDH mutations in cancer and progress toward development of targeted therapeutics. Annals of Oncology, 27(4), 599-608.
[6] Cui, Z., Li, C., Liu, W., Sun, M., Deng, S., Cao, J., … & Chen, P. (2024). Scutellarin activates IDH1 to exert antitumor effects in hepatocellular carcinoma progression. Cell Death & Disease, 15(4), 267.
