Alpha-Ketoglutarate

Alpha-ketoglutarate (AKG) is an intermediate in the Krebs cycle involved in various metabolic and cellular pathways, and it acts as an antioxidant, interferes in nitrogen and ammonia balance, and affects epigenetic and immune regulation. ^[1] AKG is a key molecule in the Krebs cycle determining the overall rate of the citric acid cycle of the organism, and it is a nitrogen scavenger and a source of glutamate and glutamine that stimulates protein synthesis and inhibits protein degradation in muscles. ^[2] Unlike synthetic anti-aging drugs, AKG is one of the metabolites of the tricarboxylic acid (TCA) cycle and is synthesized in the body, where it plays a role in cell energy metabolism, amino acid and protein synthesis, and epigenetic regulation. ^[3]

AKG can extend the lifespan of adult Caenorhabditis elegans by inhibiting ATP synthase and TOR, and it also delays age-related disease. ^[2] AKG exerts its effects through mechanisms such as inhibiting mTOR and ATP-synthase, modulating DNA and histone demethylation, and reducing reactive oxygen species (ROS) formation. ^[3] As a caloric restriction mimetic, AKG enhances mitochondrial function, activates autophagy, and reprograms energy metabolism. ^[4]

Recent studies in worms and mice support the concept that AKG may extend human healthspan. ^[1] A few studies published in the 1980s and 1990s in humans suggested potential benefits of AKG in muscle growth, wound healing, and in promoting faster recovery after surgery. ^[1] So far there are no recently published studies demonstrating the role of AKG in treating aging and age-related diseases, and further clinical studies are required to better understand the role of AKG in humans. ^[1] As a caloric restriction mimetic, AKG has demonstrated lifespan extension and healthspan improvement in preclinical models. ^[4] In humans, the metabolite alpha-ketoglutarate has been associated with the reduction or reversal of predicted biological age as measured by aging clocks, although rigorous clinical trials are needed to validate these initial findings. ^[5]

AKG has been introduced as a potential anti-aging metabolite that can control several functions in organisms, thereby increasing longevity and improving healthspan. ^[3] These pleiotropic functions of AKG suggest it may also extend human healthspan, and the molecule has potential therapeutic use to treat age-related diseases. ^[1]