2-Oxoglutarate, also known as alpha-ketoglutarate (AKG), is a small organic molecule naturally produced within the body. This C5 dicarboxylic acid functions as a central intermediate in various biochemical processes, playing a role in energy and cellular function.
The Central Role of 2-Oxoglutarate in Metabolism
2-Oxoglutarate occupies a central position within the tricarboxylic acid (TCA) cycle, also known as the Krebs cycle, a key pathway for cellular energy production. In this cycle, 2-oxoglutarate is formed from isocitrate and then converted into succinyl-CoA by the enzyme 2-oxoglutarate dehydrogenase. This conversion generates energy-rich molecules like NADH and carbon dioxide, contributing to the cell’s ATP production.
Beyond its involvement in energy generation, 2-oxoglutarate serves as a precursor for the synthesis of several amino acids, particularly glutamate and glutamine. It acts as a major carbon skeleton for nitrogen assimilation reactions, linking carbon and nitrogen metabolic pathways. Cells can convert 2-oxoglutarate to glutamate, which then forms glutamine, providing nitrogen for various transaminases.
Glutamate, derived from 2-oxoglutarate, can be produced through two main pathways: reductive amination with ammonium via glutamate dehydrogenase or through glutamate synthase using glutamine as a nitrogen donor. The interconversion between 2-oxoglutarate and glutamate is balanced, allowing the carbon from glutamate to re-enter the citric acid cycle. This connection highlights 2-oxoglutarate’s role as a bridge between carbohydrate and protein metabolism.
Function as a Cellular Signaling Molecule
2-Oxoglutarate also acts as a signaling molecule. It serves as an obligatory co-substrate for a large family of enzymes called 2-oxoglutarate-dependent dioxygenases (2-OGDDs). These enzymes require 2-oxoglutarate, molecular oxygen, and ferrous iron (Fe2+) to catalyze hydroxylation and demethylation reactions.
An example of this signaling role is in collagen synthesis, where 2-OGDDs, specifically prolyl and lysyl hydroxylases, modify procollagen polypeptides. Prolyl 4-hydroxylation, for instance, stabilizes the triple helical structure of collagen, a protein important to connective tissues. These hydroxylation reactions are necessary for the proper folding and function of collagen.
2-Oxoglutarate also plays a role in epigenetic regulation by influencing DNA and histone demethylation. Enzymes like the ten-eleven translocation (TET) family of DNA demethylases and Jumonji C (JmjC) domain-containing histone lysine demethylases (KDMs) require 2-oxoglutarate as a cofactor. These enzymes remove methyl groups from DNA and histones, affecting gene expression.
Connection to Longevity and the Aging Process
Research indicates a connection between 2-oxoglutarate and the aging process, particularly in animal models. Studies in organisms such as Caenorhabditis elegans (roundworms), Drosophila melanogaster (fruit flies), and mice show that supplementing or maintaining 2-oxoglutarate levels can extend lifespan and improve healthspan. These findings suggest that AKG may influence the rate of age-related decline.
The proposed mechanisms for 2-oxoglutarate’s influence on aging involve its interaction with cellular pathways. It inhibits the mechanistic target of rapamycin (mTOR) pathway, a nutrient-sensing pathway that, when suppressed, is associated with extended longevity in various organisms. Additionally, 2-oxoglutarate activates AMPK, another pathway involved in energy metabolism and cellular health.
2-Oxoglutarate plays a role in maintaining stem cell function, which declines with age. By supporting stem cell health and regenerative capacity, AKG may contribute to tissue maintenance and repair throughout an organism’s life. This influence on cellular and molecular processes suggests its potential as a modulator of biological aging.
Alpha-Ketoglutarate as a Dietary Supplement
Alpha-ketoglutarate (AKG) is available as a dietary supplement. Individuals might use AKG supplements for potential anti-aging benefits, based on promising animal studies, or to enhance athletic performance. It supports muscle protein synthesis, reduces muscle breakdown, and assists in recovery from physical stress or surgery.
Different forms of AKG supplements are available, with two common types being Arginine Alpha-Ketoglutarate (AAKG) and Calcium Alpha-Ketoglutarate (Ca-AKG). AAKG combines AKG with the amino acid L-arginine and is frequently used by athletes due to its benefits in improving blood flow and muscle growth. Ca-AKG binds AKG to calcium and is noted for its higher bioavailability and potential longevity benefits.
While animal studies show results regarding lifespan extension and healthspan improvement, human research on AKG supplements is still developing. Some human trials indicate potential benefits, such as a reduction in estimated biological age measured by epigenetic markers, and improvements in certain blood markers. However, more robust, placebo-controlled studies are needed to confirm these effects in humans.
AKG supplements are considered safe for most adults when used appropriately, with some studies reporting use for up to three years. Typical dosages in research range from 300 mg to 6 grams per day, though a universally recommended daily dose has not been established. As with any supplement, consulting a healthcare professional before starting AKG is advisable, especially for individuals who are pregnant, nursing, or managing existing health conditions.