Alpha (α)-ketoglutarate (AKG) is a component involved in energy metabolism that is continuously synthesized and broken down. It is involved in many physiological functions and processes in our body: the synthesis of amino acids/proteins, epigenetic regulation, stem cell maintenance and differentiation, fertility and reproductive health, and the behavior of cancer cells. AKG levels decrease with age and have recently been identified as a potential anti-aging metabolite that can regulate several functions in organisms. This opens up new research opportunities for extending longevity and improving overall health. A lot of research is focused on the use of AKG to prevent age-related diseases such as diabetes, obesity, and cardiovascular diseases.

What is Alpha-ketoglutarate?
Alpha-ketoglutarate is a small organic molecule. It represents one of the key metabolites, an intermediate in the citric acid cycle, also known as the Krebs cycle, which takes place in the energy organelles – the mitochondria. As a precursor of glutamate and glutamine, alpha-ketoglutarate also plays a key role in the energy metabolism of the digestive tract. In this process, it serves as a glutamine precursor for the energy production of our intestinal cells. It also participates in the utilization of protein in the diet, the formation of bone mass and skeletal muscles. As an antioxidant, AKG interferes in nitrogen and ammonia balance, and affects epigenetic and immune regulation. An important characteristic is the non-toxicity of this compound, its ability to dissolve in water, and its high stability in aqueous solutions. Other names for this molecule include: 2-ketoglutaric acid, 2-oxoglutarate, 2-oxoglutaric acid, oxoglutaric acid, and 2-oxopentanedioic acid.
Structure of alpha-ketoglutarate
AKG Like Antioxidant
AKG can act as an antioxidant both in vitro and in vivo. AKG supplementation could directly or indirectly stimulate endogenous antioxidant defense. AKG possesses the ability to directly scavenge free radicals and reduce oxidized compounds. It reacts directly with hydrogen peroxide to produce succinate and water. An interesting fact about AKG as an antioxidant is that it is a stronger radical scavenger than ascorbic acid – vitamin C. It has been found that it can prevent mitochondrial DNA damage caused by free radicals in mouse neural cells. It has also been discovered that the application of this molecule positively modulates antioxidant levels in rats during induced liver cancer. Its impact restores antioxidants and the activity of antioxidant enzymes to levels close to normal.
AKG as an Immunomodulatory Agent
AKG is also known as an immune nutrient factor and plays an important role in overall immune metabolism. Research has shown that during inflammatory conditions such as sepsis and injury, the consumption of glutamine increases in circulating and immune cells. As AKG is a precursor of glutamine, it has a direct impact on strengthening cellular immunity. AKG, as a homolog of glutamine, can also maintain the intestinal barrier, increase immune cells and the activity of neutrophils and phagocytosis, and reduce bacterial translocation in vivo. AKG targets multiple components of the immune system, such as T cells and macrophages, to combat dysregulated responses and minimize the production of proinflammatory signaling molecules.
The Influence of AKG on Bone Tissue
As we age, bones become more fragile and weaker. The large network of bony components becomes thinner, leading to an increased risk of fracture. Osteoporosis is responsible for 80-90% of all fractures in old age and this can have a huge impact on quality of life. For this reason, healthy, strong bones are especially important in old age. Many in vivo studies have shown that supplementation of AKG or its derivatives during animal growth has positive effects on skeletal development by improving the mechanical properties of skeletal bone. In a study of menopausal women, it was observed that the administration of AKG inhibited bone resorption and reduced the effects of osteopenia. AKG, in addition to the ability to inhibit bone resorption, can also cause the reconstruction of bone tissue in conditions of osteopenia and osteoporosis. It also has a positive effect on bone mineral density and strength. It can stimulate the production of anabolic hormones that regulate bone modeling and remodeling.
Loss of Muscle Mass
Skeletal muscle mass is determined by the dynamic balance between protein synthesis and breakdown. AKG is extremely important for skeletal muscle protein synthesis and the promotion of muscle hypertrophy. An imbalance of protein breakdown and synthesis leads to atrophy or sarcopenia. Sarcopenia, the loss of muscle mass, strength, and function, is highly prevalent in older adults and is associated with adverse outcomes such as falls, fractures, and mortality. AKG should be tested in older people with sarcopenia and in younger people mainly with atrophy to preserve muscle mass and strength. Oral administration of AKG has been shown to significantly increase the weight of certain muscle fibers in mice.
Aging
Numerous studies show that alpha-ketoglutarate can extend lifespan in various organisms. Alpha-ketoglutarate affects the aging process in multiple ways. Epigenetic dysregulation is one of the reasons why we age, and alpha-ketoglutarate has epigenetic effects. As cells age, they become less flexible, protein metabolism slows down, and energy is produced more slowly. However, alpha-ketoglutarate can help cells maintain metabolic flexibility for longer. Mitochondrial ATP synthase is a significant ubiquitous enzyme in the energy metabolism of virtually all living cells. AKG reduces ATP levels and decreases oxygen consumption. It also increases autophagy, which collectively contributes to extending cell lifespan. Additionally, it is involved in the regulation of energy metabolism through proteins that are crucial for cellular energy and longevity. AKG has pleiotropic functions, which has implications for its use as a longevity-enhancing mimetic.
AKG as an Anticancer Agent
AKG and other Krebs cycle metabolites play an essential role in the development of cancer. In cancer cells, the reactions associated with glycolysis are disrupted. Metabolites of the Krebs cycle are diverted from the energy production pathway to produce compounds and macromolecules needed for cell proliferation, a hallmark of cancer cells. AKG may use different mechanisms in different cancers to control cell proliferation, migration and metastasis. it also regulates signaling pathways associated with oncogenesis, making it one of the potential anticancer agents. The anticancer effect of AKG is attributed to its ability to reverse the metabolic response to hypoxia and restore oxidative phosphorylation in cancer cells.
AKG and Skin
Collagen is one of the most important structural proteins in the skin and keeps it healthy, tight and young. AKG has a strong effect on increasing the amount of proline during collagen production. It has also been shown to increase the activity of prolidase, which is known to play an important role in collagen metabolism. AKG has a beneficial effect on skin hydration and barrier function. It was concluded that AKG promotes skin hydration and barrier function by activating cell proliferation and regulating mRNA expression of various proteins in keratinocytes. Also has been tested as a cosmetic product and has shown a significant reduction in skin warts. The effect on wound healing has also been investigated in humans, particularly in burn victims. Alpha-ketoglutarate could contribute to faster wound healing and scar recovery.
References
1. What is alpha-ketoglutarate (AKG)? – MoleQlar Longevity. https://www.moleqlar.de/en/was-ist-calcium-alphaketoglutarat-akg/.
2. The Benefits and Side Effects of AKG | Lifespan.io. https://www.lifespan.io/topic/alpha-ketoglutarate-benefits-side-effects/.
3. The Anti-Aging & Longevity Effects of Alpha-Ketoglutarate. NOVOS https://novoslabs.com/novos-anti-aging-longevity-supplement/alpha-ketoglutarate-anti-aging-supplement-longevity/.
4. Examine.com. Examine.com https://examine.com/.
5. Alpha-ketoglutarate: Health Benefits, Side Effects, Uses, Dose & Precautions. RxList https://www.rxlist.com/supplements/alpha-ketoglutarate.htm.
6. ALPHA-KETOGLUTARATE (AKG): Overview, Uses, Side Effects, Precautions, Interactions, Dosing and Reviews. https://www.webmd.com/vitamins/ai/ingredientmono-144/alpha-ketoglutarate-akg.
7. Alpha Ketoglutarate (AKG) – Health Information Library | PeaceHealth. https://www.peacehealth.org/medical-topics/id/hn-4451004.
8. Tello, C. AAKG Benefits + Side Effects & Dosage. SelfDecode Supplements https://supplements.selfdecode.com/blog/health-benefits-aakg/ (2019).
9. PubChem. alpha-Ketoglutarate. https://pubchem.ncbi.nlm.nih.gov/compound/164533.
10. Zdzisińska, B., Żurek, A. & Kandefer-Szerszeń, M. Alpha-Ketoglutarate as a Molecule with Pleiotropic Activity: Well-Known and Novel Possibilities of Therapeutic Use. Arch. Immunol. Ther. Exp. (Warsz.) 65, 21–36 (2017).
11. 7 Questions Need To Ask Alpha-Ketoglutarate Powder Supplier. https://www.nutriavenue.com/alpha-ketoglutarate-powder-supplier/ (2023).
12. Wu, N. et al. Alpha-Ketoglutarate: Physiological Functions and Applications. Biomol. Ther. 24, 1–8 (2016).
13. Son, E. D. et al. Alpha-ketoglutarate stimulates procollagen production in cultured human dermal fibroblasts, and decreases UVB-induced wrinkle formation following topical application on the dorsal skin of hairless mice. Biol. Pharm. Bull. 30, 1395–1399 (2007).
14. Naeini, S. H., Mavaddatiyan, L., Kalkhoran, Z. R., Taherkhani, S. & Talkhabi, M. Alpha-ketoglutarate as a potent regulator for lifespan and healthspan: Evidences and perspectives. Exp. Gerontol. 175, 112154 (2023).
15. Iniguez, A. B., Du, M. & Zhu, M.-J. α-Ketoglutarate for Preventing and Managing Intestinal Epithelial Dysfunction. Adv. Nutr. 15, (2024).
16. Gyanwali, B. et al. Alpha-Ketoglutarate dietary supplementation to improve health in humans. Trends Endocrinol. Metab. 33, 136–146 (2022).
17. Diener, Y. What is alpha-ketoglutarate (AKG)? MoleQlar Longevity https://www.moleqlar.de/en/was-ist-calcium-alphaketoglutarat-akg/ (2023).
18. Cai, X. et al. Alpha-ketoglutarate promotes skeletal muscle hypertrophy and protein synthesis through Akt/mTOR signaling pathways. Sci. Rep. 6, 26802 (2016).
19. Bayliak, M. M. & Lushchak, V. I. Pleiotropic effects of alpha-ketoglutarate as a potential anti-ageing agent. Ageing Res. Rev. 66, 101237 (2021).