Alpha-ketoglutarate, commonly abbreviated to AKG, isn’t a brand-new synthetic compound born in an obscure pharmacology lab. It is a fairly simple substance that is literally present in every cell of your body. AKG has been known since the 1930s, but only recently it is becoming clear that this simple bio-identical substance may be the key to not only an extended life span. AKG may also be the key to a longer life in which you remain healthy into old age.

 

By Willem Koert

 

In 1936, the English physician and biochemist Hans Adolf Krebs (1900-1981) discovered AKG during his research on metabolism.[1] Krebs discovered AKG while elucidating the citric acid cycle, a complex reaction in the mitochondria by which cells convert fats, carbohydrates and amino acids into carbon dioxide, water and molecular energy – in the form of molecules such as ATP, NADH and FADH2. Krebs was awarded the Nobel Prize for elucidating the citric acid cycle in 1953.

In the late 1980s, doctors discovered that adding AKG to parental nutrition reduced muscle loss in patients who had undergone major surgery or recovered from severe injuries.[2] AKG shared this property with glutamine, a non-essential amino acid with a molecular structure similar to AKG.[3] Under conditions of severe stress, during which the body is forced to convert muscle tissue into energy, AKG apparently inhibits muscle breakdown.

 

 

Sports supplement

Although it was initially unclear how exactly AKG could block catabolic processes, in the 1990s biomedical scientists published studies in which AKG, for example in the form of ornithine alpha-ketoglutarate, helped malnourished patients recover faster and accelerated wound healing.[4]

This development did not go unnoticed by the supplement industry, which launched several products containing arginine alpha-ketoglutarate. A claimed effect of these products was that they could improve sports performance. They should, among other things, make strength training more intensive and improve body composition. However, human studies in the 21st century have shown that these claims may have been a bit exaggerated.

According to an American human study, published in the Journal of the International Society of Sports Nutrition in 2012, supplementation with arginine alpha-ketoglutarate has no effect on the weights with which strength athletes can train.[5] In another American human study, researchers found that supplementation with large doses of arginine alpha-ketoglutarate increased the aerobic capacity of healthy men, but had no effect on body composition.[6]

Some supplement experts have felt so disillusioned with these and other studies that they have written off arginine alpha-ketoglutarate as a sports supplement. At least as a sports supplement. As a longevity supplement, various forms of alpha-ketoglutarate are currently gaining popularity.[7]

 

Life extension

The idea that supplementation with AKG may not only help to increase lifespan, but also stay healthy into old age is not out of the blue. In 2016, Ukrainian biochemists reported that yeast cells become healthier and more robust when grown in an environment where AKG is present.[8] The authors of this study found that AKG stimulated yeast cells to produce more endogenous antioxidants, making them more resistant to environmental toxins or other adverse conditions.

Molecular researchers at the University of California Los Angeles did similar experiments with the nematode Caenorhabditis elegans and found that AKG extended the life span of the organisms by as much as 50 percent.[9] AKG reduced the production of the energy molecule ATP in the nematode’s cells’ mitochondria. By the grace of this, AKG more or less mimicked the longevity effects of caloric restriction.

The outcome of experiments with fruit flies confirmed this theory.[10] [11] When fruit flies – biologists prefer the name Drosophila melanogaster – are supplemented with AKG, their cells take up less glucose. At the same time, the cellular growth molecule mTOR is a few notches lower in these cells. At the same time, AKG supplementation makes the AMPK molecule more active. Under normal conditions, an increased activity of AMPK is a result of caloric restriction. As this enzyme becomes more active, the activity of protective enzymes increases and cells and tissues invest more in repair mechanisms.

Mice are significantly more complex organisms than fruit flies, but AKG also extends the lifespan in mice.[12] This is apparent from an animal study that researchers from the American Buck Institute for Research on Aging published in Cell Metabolism in 2020. The lab animals that received AKG in their feed lived on average 12 percent longer than mice fed regular chow. Such a life span extension is interesting in itself, but even more striking was the effect of AKG on the health of the aging mice. The health span – the part of the lifespan in which the mice were in good health – increased by 40 percent as a result of the supplement.

 

Mechanism

In yeast cells, nematodes, insects and mammals, AKG probably works by the same mechanism. AKG shifts the molecular equilibrium in the cells’ citric acid cycle [see figure below]. As a result, the conversion of nutrients into energy becomes more difficult. This not only leads to less ATP biosynthesis and a decrease in mTOR activity, but also causes an increase in the release of aggressive molecules.[13] The cells respond by making more protective proteins that curb the activity of aggressive molecules[14] and inhibit inflammation – and investing more energy in all kinds of cellular repair processes.

 

Human data

The human equivalent of the doses used by researchers in animal studies is usually on the high side. Fortunately, according to human research, such extreme doses are not necessary to achieve a longevity effect. At least that is the conclusion of an open trial in which 42 subjects took a daily supplement containing 1 gram of calcium-bound alpha-ketoglutarate [Ca-AKG] for 4-10 months.[15]

Before and after the supplementation period, the researchers determined the aging at the molecular level using the TruAge test. This test measures in saliva how many methyl groups are attached to the DNA. The more methyl groups there are attached to the DNA, the further the aging process has progressed. Based on these measurements, the researchers concluded that Ca-AKG had reduced molecular age by 8 years.

It is not yet clear how exactly such an effect translates into health. Animal studies indicate that AKG protects against aging-related disorders such as osteoporosis, the development of wrinkles and baldness. In addition, animal studies suggest that AKG may facilitate muscle recovery under conditions where the body can process fewer amino acids, strengthen the immune system or help prevent heart failure.

Whether AKG has such beautiful effects in humans? We do not know yet. No scientific studies have yet been published that tell us. If you want, you can wait for these publications. But if you can’t muster the patience, no one will stop you from finding out on your own…

 

 

1  Krebs HA, Salvin E, Johnson WA. The formation of citric and alpha-ketoglutaric acids in the mammalian body. Biochem J. 1938 Jan;32(1):113-7.

2  Wernerman J, Hammarqvist F, Vinnars E. Alpha-ketoglutarate and postoperative muscle catabolism. Lancet. 1990 Mar 24;335(8691):701-3.

3  Wernerman J, Hammarkvist F, Ali MR, Vinnars E. Glutamine and ornithine-alpha-ketoglutarate but not branched-chain amino acids reduce the loss of muscle glutamine after surgical trauma. Metabolism. 1989 Aug;38(8 Suppl 1):63-6.

4  Cynober L. Ornithine alpha-ketoglutarate in nutritional support. Nutrition. 1991 Sep-Oct;7(5):313-22.

5  Wax B, Kavazis AN, Webb HE, Brown SP. Acute L-arginine alpha ketoglutarate supplementation fails to improve muscular performance in resistance trained and untrained men. J Int Soc Sports Nutr. 2012 Apr 17;9(1):17.

6  Campbell B, Roberts M, Kerksick C, Wilborn C, Marcello B, Taylor L, Nassar E, Leutholtz B, Bowden R, Rasmussen C, Greenwood M, Kreider R. Pharmacokinetics, safety, and effects on exercise performance of L-arginine alpha-ketoglutarate in trained adult men. Nutrition. 2006 Sep;22(9):872-81.

7  Gyanwali B, Lim ZX, Soh J, Lim C, Guan SP, Goh J, Maier AB, Kennedy BK. Alpha-Ketoglutarate dietary supplementation to improve health in humans. Trends Endocrinol Metab. 2022 Feb;33(2):136-46.

8  Bayliak M, Burdyliuk N, Lushchak V. Growth on Alpha-Ketoglutarate Increases Oxidative Stress Resistance in the Yeast Saccharomyces cerevisiae. Int J Microbiol. 2017;2017:5792192.

9  Chin RM, Fu X, Pai MY, Vergnes L, Hwang H, Deng G, Diep S, Lomenick B, Meli VS, Monsalve GC, Hu E, Whelan SA, Wang JX, Jung G, Solis GM, Fazlollahi F, Kaweeteerawat C, Quach A, Nili M, Krall AS, Godwin HA, Chang HR, Faull KF, Guo F, Jiang M, Trauger SA, Saghatelian A, Braas D, Christofk HR, Clarke CF, Teitell MA, Petrascheck M, Reue K, Jung ME, Frand AR, Huang J. The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature. 2014 Jun 19;510(7505):397-401.

10  Su Y, Wang T, Wu N, Li D, Fan X, Xu Z, Mishra SK, Yang M. Alpha-ketoglutarate extends Drosophila lifespan by inhibiting mTOR and activating AMPK. Aging (Albany NY). 2019 Jun 26;11(12):4183-4197.

11  Lylyk MP, Bayliak MM, Shmihel HV, Storey KB, Lushchak VI. Effects of alpha-ketoglutarate on lifespan and functional aging of Drosophila melanogaster flies. Ukr Biochem J. 2018 Nov-Dec;90(6):49-61.

12  Asadi Shahmirzadi A, Edgar D, Liao CY, Hsu YM, Lucanic M, Asadi Shahmirzadi A, Wiley CD, Gan G, Kim DE, Kasler HG, Kuehnemann C, Kaplowitz B, Bhaumik D, Riley RR, Kennedy BK, Lithgow GJ. Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Aging Mice. Cell Metab. 2020 Sep 1;32(3):447-456.e6.

13  Muller FL, Liu Y, Abdul-Ghani MA, Lustgarten MS, Bhattacharya A, Jang YC, Van Remmen H. High rates of superoxide production in skeletal-muscle mitochondria respiring on both complex I- and complex II-linked substrates. Biochem J. 2008 Jan 15;409(2):491-9.

14  Bayliak MM, Shmihel HV, Lylyk MP, Vytvytska OM, Storey JM, Storey KB, Lushchak VI. Alpha-ketoglutarate attenuates toxic effects of sodium nitroprusside and hydrogen peroxide in Drosophila melanogaster. Environ Toxicol Pharmacol. 2015 Sep;40(2):650-9.

15  Demidenko O, Barardo D, Budovskii V, Finnemore R, Palmer FR, Kennedy BK, Budovskaya YV. 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 (Albany NY). 2021 Nov 30;13(22):24485-24499.

16  Yang F, Zhou Z, Guo M, Zhou Z. The study of skin hydration, anti-wrinkles function improvement of anti-aging cream with alpha-ketoglutarate. J Cosmet Dermatol. 2022 Apr;21(4):1736-43.