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07.02.2023

Alpha-ketobyturate | Another endogenous life extender

Alpha-ketoglutarate, a metabolite found in the body and in a variety of foods, extends the lifespan of laboratory animals and perhaps also of humans. One substance that is very similar to alpha-ketoglutarate is alpha-ketobyturate. Alpha-ketobyturate, like alpha-ketoglutarate, may make longer life possible, Chinese researchers discovered.

Study
In their paper, which appeared in Nature Communications in the first weeks of 2023, Chinese biologists affiliated with Yunnan University describe experiments with the worm Caenorhabditis elegans.

The researchers exposed the worms to a concentration of 200-500 micromoles of alpha-ketobyturate.

Alpha-ketobutyrate is a substance that arises in the body through metabolism of amino acids such as threonine and methionine, plays a role in chemical processes in the mitochondria and undoubtedly occurs in countless foods. The structure of alpha-ketobutyrate is somewhat similar to that of alpha-ketoglutarate, a substance whose longevity properties have been known for some time.

Results
The worms lived longer due to exposure to alpha-ketobyturate than worms kept under normal conditions [Veh], according to the figure at the bottom left.

As Caenorhabditis elegans ages, the organism moves and eats less. Exposure to alpha-ketobyturate inhibited these aging processes. You can see this on the right in the figure below.

The concentration of NAD, another substance known in the longevity scene, increased due to supplementation with alpha-ketobyturate. You can see this at the bottom left. Click on the figure for a larger version.

When the researchers repeated their tests with worms in which they had switched off the gene Sirt2 [RNAi] - lower right - supplementation no longer had any effect. Sirt2 in humans is Sirt1. The longevity enzyme SIRT1, which is produced by this gene, appears to play a crucial role in the life-prolonging action of alpha-ketobyturate.

The concentration of the oxidant H2S increased due to supplementation with alpha-ketobyturate.

At the same time, co-supplementation with NAC, a building block for the endogenous antioxidant glutathione, led to a complete elimination of the life-prolonging effect of alpha-ketobyturate. [Figuur]

The Chinese suspect, based on their experiments, that the mechanism of action of alpha-ketobyturate looks similar to the one below. (Too) simply put, alpha-ketobyturate allows energy production in the mitochondria to proceed. Cells responds by producing longevity enzymes, which causes cellular rendering companies - the peroxisomes - to work harder. As a result, the cells function better and the organism lives longer.

Conclusion
"Our findings present new insights into the mechanism underlying endogenous metabolite-mediated longevity", write the researschers.

"Besides alpha-ketobyturate, other endogenous metabolites, such as oxaloacetate [...] and alpha-ketoglutarate, can also delay aging and extend lifespan, suggesting that the key to longevity is hidden in our body."

Source:
Nat Commun. 2023 Jan 16;14(1):240.

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