Alpha-Ketoglutarate (Ca-AKG) — Supplements

Overview

Alpha-ketoglutarate (AKG, also called 2-oxoglutarate) is a central intermediate in the tricarboxylic acid (TCA/Krebs) cycle and a key hub molecule linking cellular energy metabolism to epigenetics, amino acid metabolism, and redox homeostasis. Endogenous AKG levels decline dramatically with age in humans and animals — a pattern conserved across species and mechanistically linked to aging phenotypes. The foundational human relevance was established by a landmark 2020 Cell Metabolism study demonstrating that calcium α-ketoglutarate (Ca-AKG) supplementation in middle-aged (18-month) mice extended median lifespan, reduced frailty, and compressed morbidity — animals lived longer AND healthier. The first rigorous placebo-controlled human RCT — the ABLE trial (NCT05706389, Singapore National University, n=120, ages 40–60) — completed enrollment in 2025 and is measuring DNA methylation biological age, grip strength, arterial stiffness, inflammatory markers, and aerobic capacity at 6 months. An earlier observational study using Rejuvant (sustained-release Ca-AKG, n=42) reported an average 8-year reduction in DNA methylation biological age over 4–10 months (p=6.54×10⁻¹²), though the absence of a placebo arm limits interpretation. The preferred supplemental form is calcium α-ketoglutarate (Ca-AKG) — the calcium salt provides superior stability and sustained release compared to plain AKG or ornithine AKG. AKG's biological significance extends beyond longevity: it is an essential cofactor for the TET enzyme family (epigenetic DNA demethylation), prolyl hydroxylases (HIF-1α regulation, collagen synthesis), and serves as a nitrogen scavenger during amino acid catabolism.

Indications

• Biological age reduction — DNA methylation clock improvement (investigational)
• Longevity and healthspan extension (strong animal evidence; human RCT pending)
• Muscle mass and strength maintenance in aging
• Bone density support and collagen synthesis
• Post-surgical recovery and nitrogen balance optimization
• Inflammaging and chronic inflammation reduction

Mechanism of Action

AKG is an obligate cofactor for TET1/2/3 dioxygenases — the enzymes responsible for oxidative DNA demethylation (5-methylcytosine → 5-hydroxymethylcytosine → unmethylated cytosine). Age-associated AKG decline impairs TET activity, allowing progressive epigenetic drift and aberrant hypermethylation at gene regulatory regions. AKG supplementation restores TET activity, partially reversing the epigenetic aging signature measured by DNA methylation clocks

Dosing

Safety & Contraindications

• Excellent safety profile — GRAS status (Generally Recognized as Safe, grandfathered pre-1994); doses up to 6 g/day well tolerated in human studies
• Most common AEs are mild GI discomfort (nausea, diarrhea) at doses >3 g/day — start low and titrate
• AKG is rapidly converted to glutamate in the gut; theoretical concern about glutamate excitotoxicity at very high doses is not supported at supplemental doses
• Mild hypoglycemic effect documented — monitor blood glucose in diabetics or those on hypoglycemic medications
• May reduce cortisol levels — beneficial in most contexts but monitor in adrenal insufficiency
• No significant drug interactions identified at supplement doses, though CYP enzyme effects are understudied
• Avoid in ornithine transcarbamylase (OTC) deficiency and other urea cycle disorders — AKG participates in nitrogen shuttling