Alpha-Ketoglutarate (AKG)

Alpha-ketoglutarate (AKG, also known as 2-oxoglutarate) is a key metabolite in the tricarboxylic acid (TCA/Krebs) cycle — the central hub of cellular energy metabolism. Its longevity credentials extend well beyond simple energy production. AKG is a required cofactor for ten-eleven translocation (TET) enzymes and Jumonji-domain histone demethylases that regulate DNA methylation and histone modification patterns — the epigenetic machinery central to the hallmark of epigenetic alterations. As AKG levels decline with age, epigenetic drift accelerates. Additionally, AKG inhibits ATP synthase and activates AMPK (mimicking aspects of caloric restriction), inhibits mTOR signaling (overlapping with rapamycin's mechanism through a distinct pathway), and serves as a direct precursor for glutamate and glutathione (the primary intracellular antioxidant). This positions AKG at the convergence of at least five aging pathways: epigenetic regulation, nutrient sensing (mTOR/AMPK), mitochondrial function, oxidative stress, and proteostasis. The human evidence is anchored by the Rejuvant trial (PMC8660611), which tested a calcium alpha-ketoglutarate formulation in 42 participants over approximately seven months. Using the Horvath DNA methylation clock (an epigenetic measure of biological age) as the primary endpoint, the trial found a mean biological age reduction of approximately 8 years. The confidence intervals were wide given the small sample size, but the direction and magnitude of the signal attracted immediate attention from the aging research community. A follow-up RCT is currently registered on ClinicalTrials.gov (NCT07114536), with larger sample size and pre-registered endpoints that will substantially clarify the compound's efficacy. AKG is available OTC as calcium AKG (Ca-AKG) — typically dosed at 1–2 grams/day — at a cost of approximately $50–100/month for quality formulations. It is well-tolerated with minimal reported side effects at standard doses, and the mechanistic rationale for its epigenetic effects is grounded in basic biochemistry.