Intervention
Alpha-Ketoglutarate (AKG)
Last updated Sat May 30 2026 00:00:00 GMT+0000 (Coordinated Universal Time)
Pre-clinical— One mouse lifespan study + small human pilot
What it is
Alpha-ketoglutarate (also called 2-oxoglutarate) is a central intermediate of the Krebs (citric acid) cycle. It is also a co-substrate for the dioxygenase family (including the TET methylcytosine dioxygenases that regulate DNA methylation, and the prolyl hydroxylases that regulate HIF stability). Tissue AKG levels decline with age.
Evidence
- Mouse lifespan: Asadi Shahmirzadi et al. (2020) reported ~12% median lifespan extension and ~40% reduction in frailty in aged C57BL/6 mice fed Ca-AKG.
- Human pilot (TruDiagnostic + Ponce de Leon Health, 2021): reported ~8-year reduction in DNAm GrimAge after 7 months in 42 adults — unblinded, no placebo, retrospective biological-age testing.
Mechanism
- Restoration of TCA cycle flux.
- Co-substrate for TET enzymes (potentially explaining epigenetic-age effects).
- HIF stabilisation modulation via prolyl hydroxylases.
- Possibly extends lifespan partly via mTOR suppression.
Practical
- Ca-AKG (Rejuvant) is the most-studied longevity formulation.
- Arginine-AKG is widely sold as a workout supplement (purported NO booster); no longevity evidence.
Related entries
Mitochondrial dysfunction, Epigenetic alterations, Brian Kennedy.
References
- Asadi Shahmirzadi, A. et al. Alpha-ketoglutarate, an endogenous metabolite, extends lifespan and compresses morbidity in aging mice. Cell Metab. 32, 447–456 (2020).