α-ketoglutarate (Ca-AKG) — The Krebs Cycle Intermediate
α-ketoglutarate (Ca-AKG) is a fundamental endogenous metabolite involved in energy production, amino acid metabolism, and epigenetic regulation. Its levels decline significantly with age, and supplementation has been shown to extend lifespan, compress morbidity, and reduce frailty in animal models, making it a promising candidate for human longevity interventions.
Mechanism of Action
α-ketoglutarate (AKG) is a key intermediate in the Krebs cycle, serving as a critical node for cellular energy metabolism and amino acid synthesis. It acts as an obligate co-substrate for a family of dioxygenases, including TET enzymes and Jumonji C-domain-containing histone demethylases, thereby regulating DNA and histone demethylation and influencing the epigenetic landscape. Additionally, AKG has been shown to extend lifespan in model organisms by inhibiting the mechanistic target of rapamycin (mTOR) pathway and activating AMP-activated protein kinase (AMPK), mimicking the effects of caloric restriction. It also plays a role in reducing systemic inflammation and oxidative stress.
Human Trial Evidence
A retrospective analysis of 42 individuals taking a sustained-release Ca-AKG formulation (Rejuvant) for an average of 7 months showed an average 8-year reduction in biological age as measured by the TruAge DNA methylation clock. However, this was not a placebo-controlled trial. Several other randomized, placebo-controlled trials are currently underway to evaluate its effects on aging biomarkers in humans.
Dosing Protocol
1–3 g/day is the most common range used in human studies and clinical practice, typically taken as a sustained-release formulation. It is often taken with or without food. Dose-finding for optimal longevity benefits in humans remains unestablished.
Safety & Contraindications
Generally considered safe and well-tolerated at standard doses. High doses may cause mild gastrointestinal distress, such as nausea or diarrhea. Calcium-bound forms (Ca-AKG) may increase the risk of kidney stones in susceptible individuals due to the added calcium load. Long-term safety data in healthy humans for longevity purposes is still limited.
Key Papers
Rejuvant®, a potential life-extending compound formulation with alpha-ketoglutarate and vitamins, conferred an average 8 year reduction in biological aging, after an average of 7 months of use, in the TruAge DNA methylation test
Aging · 2021
Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Aging Mice
Cell Metabolism · 2020