Alpha-Ketoglutarate (TCA cycle)
The Krebs-cycle metabolite that regulates aging from the cell's core
Definition
Alpha-ketoglutarate (AKG, α-ketoglutarate or 2-oxoglutarate) is a central endogenous metabolite of the Krebs cycle (citric acid or TCA cycle), where it links mitochondrial energy metabolism to amino-acid production. Beyond generating energy, AKG serves as an obligatory cofactor for α-ketoglutarate–dependent dioxygenases —including the TET enzymes that demethylate DNA and the collagen hydroxylases— so it regulates epigenetics, collagen synthesis and mTOR signaling. Its levels fall up to 10-fold with age, and restoring it has extended healthy lifespan in animal models, making it a leading target in aging research.
Detailed explanation
Interest in AKG for longevity surged after Asadi Shahmirzadi et al. published in Cell Metabolism (2020): giving alpha-ketoglutarate as a calcium salt (CaAKG) to mice starting at 18 months of age extended lifespan and, more strikingly, compressed morbidity —the animals spent a larger fraction of life free of frailty— alongside a marked drop in circulating inflammatory cytokines. This effect on "inflammaging" is one of its proposed mechanisms.
Mechanistically, AKG is the substrate for 2-oxoglutarate–dependent dioxygenases: the TET enzymes (which hydroxylate 5-methylcytosine to initiate DNA demethylation, tuning the epigenetic clock), the JmjC-family histone demethylases, and the prolyl hydroxylases required for collagen folding. It also modulates the mTOR pathway and ATP synthase activity. In humans, a retrospective analysis published in Aging (2021) of an AKG-based formulation (Rejuvant) reported an average ~8-year reduction in DNA-methylation biological age after ~7 months of use —though these are observational data with no control group and require confirmation in randomized trials.
Scientific sources
- PubMed — Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Aging Mice (Asadi Shahmirzadi, Cell Metabolism 2020)
- PubMed — Rejuvant, an alpha-ketoglutarate based formulation, conferred an average 8-year reduction in biological aging in the TruAge DNA methylation test (Demidenko, Aging 2021)
- Cell — Alpha-Ketoglutarate, the Metabolite that Regulates Aging in Mice (Cell Metabolism preview)
Related terms
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