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AKG: jack-of-all-trades among the metabolites

News
July 13, 2022
By
Olena Mokshyna, PhD.

AKG has gained major attention thanks to its potential geroprotective applications. A pioneering study demonstrated a 50% increase in the lifespan of nematodes fed with AKG.

Compound description

Alpha-ketoglutarate (AKG, also known as 2-ketoglutaric acid or 2-oxoglutarate) is an endogenous (produced and decomposed inside the body) compound that is a part of several pathways in mammals' metabolism. From the structural point of view, it is a weak organic acid with five carbon atoms, two acid groups, and a ketone moiety. 

 

In addition to being produced endogenously, AKG can be consumed as a supplement. Calcium (Ca-AKG) and sodium (Na-AKG) salts of alpha-ketoglutarate are most often used to study its biological effects. This supplement is widely used in animals to support body growth. In clinical practice, intravenous AKG injections are used to reduce vascular insufficiency during cardiovascular surgery (1). In model organisms, AKG levels are deemed sufficient in most adults, but they tend to drop during aging, leading to multiple detrimental effects. 

Properties

AKG is best known for its crucial role in the Krebs cycle (or the tricarboxylic acid cycle) – a pivotal metabolic source of energy for cells. In this cycle, a sequence of reactions occurs that generates adenosine triphosphate (ATP), which works as a universal fuel for the whole body. AKG is one of the key players in the Krebs cycle (2), being both generated and oxidized at the different steps. However, the generated AKG may also leave the Krebs cycle and participate in a multitude of other metabolic processes

Other known functions of AKG include amino acid synthesis in the liver, modulation of signaling systems, immune regulation, and epigenetic alterations (1). Moreover, AKG regulates cellular utilization of carbon and nitrogen compounds and serves as an antioxidative agent (3). 

Studies demonstrated that in murine animal models it inhibits tumor growth by inducing hypoxia (4). And finally, AKG is involved in the regulation of gene expression and growth- and aging-related cellular pathways, including mTOR (mammalian target of rapamycin) and AMPK (AMP-activated protein kinase) pathways (5). Both these pathways were shown to be crucial for healthy aging and longevity.

Use as a supplement

Such a variety of functions led to the multiple studies of AKG supplementation in animal models with the establishment of several beneficial effects. The best-established health benefits in animals include the stimulation of amino acid absorption, maintenance of the bone structure, and improvement in protein biosynthesis (6,7). Due to AKG being one of the proline amino acid precursors and participating in collagen production (8), its supplementation also demonstrated protective effects on bones and cartilage (9). In addition, studies demonstrated links between AKG supplementation and modulation of the mTOR-signaling pathway (10), improvement of mitochondrial function (11), decreasing levels of blood glucose and cholesterol (in animals fed a high caloric diet) (12), obesity prevention (13), and modulation of gut microbiota (14). Additionally, AKG was shown to alleviate the toxic effects of many exogenous chemicals and endogenous metabolites. 

But the major attention was attracted to potential geroprotective applications of AKG. A pioneering study by Chin et al. (15) demonstrated a 50% increase in the lifespan of nematodes fed with AKG. The effect was attributed mainly to the downregulation of mTOR. The anti-aging effect was further confirmed in mice (16), showing that 2% Ca-AKG significantly extends their life- and healthspan by 9-12%, decreases systemic inflammation, and reduces frailty and hair loss. However, the effects of AKG on the mTOR pathway are far from straightforward. While in the abovementioned research anti-aging effect was mainly attributed to mTOR deactivation, multiple other studies of AKG effect on protein biosynthesis demonstrate precisely the opposite – mTOR pathway activation. This suggests that the exact mechanism and molecular links behind AKG's multiple biological activities remain to be elaborated.

The studies in humans are scarce but show protective effects of AKG supplements against osteoporosis (17), as well as a reduction in low-density lipoprotein and cholesterol levels (18). As for anti-aging properties, as of the moment, there exists a single retrospective study in 42 healthy individuals, which demonstrated that AKG supplementation for seven months reduced biological age by eight years as measured by the TruAge DNA Methylation test (19).

Dosage, recommendations, and side effects

The optimal daily intake varies among studies, ranging from 3.6 to 6 grams/daily. In our marketplace, you can find Ca-AKG from the DoNotAge vendor, with each capsule containing 400 mg of the compound and a recommended dosage of two capsules daily.

Studies demonstrated that Ca-AKG is generally safe with no major adverse effects and a few possible gastrointestinal side effects (including bloating, nausea, and diarrhea). However, it is essential to note that long-term safety and efficacy in humans have not been studied. In case of any concerns, please, contact your healthcare provider before starting the supplementation.

References

 

1.         Gyanwali B, Lim ZX, Soh J, Lim C, Guan SP, Goh J, et al. Alpha-Ketoglutarate dietary supplementation to improve health in humans. Trends Endocrinol Metab. 2022 Feb;33(2):136–46.

2.         Legendre F, MacLean A, Appanna VP, Appanna VD. Biochemical pathways to α-ketoglutarate, a multi-faceted metabolite. World J Microbiol Biotechnol. 2020 Aug;36(8):123.

3.         Flashman E, Schofield CJ. The most versatile of all reactive intermediates? Nat Chem Biol. 2007 Feb;3(2):86–7.

4.         Matsumoto K, Obara N, Ema M, Horie M, Naka A, Takahashi S, et al. Antitumor effects of 2-oxoglutarate through inhibition of angiogenesis in a murine tumor model. Cancer Sci. 2009 Sep;100(9):1639–47.

5.         He L, Xu Z, Yao K, Wu G, Yin Y, Nyachoti C, et al. The Physiological Basis and Nutritional Function of Alpha-ketoglutarate. Curr Protein Pept Sci. 2015 Aug 10;16(7):576–81.

6.         Chen J, Su W, Kang B, Jiang Q, Zhao Y, Fu C, et al. Supplementation with α-ketoglutarate to a low-protein diet enhances amino acid synthesis in tissues and improves protein metabolism in the skeletal muscle of growing pigs. Amino Acids. 2018 Nov;50(11):1525–37.

7.         Dobrowolski P, Tomaszewska E, Bienko M, Radzki RP, Pierzynowski SG. The effect of dietary administration of 2-oxoglutaric acid on the cartilage and bone of growing rats. Br J Nutr. 2013 Aug 28;110(4):651–8.

8.         Myllyharju J. Prolyl 4-hydroxylases, key enzymes in the synthesis of collagens and regulation of the response to hypoxia, and their roles as treatment targets. Ann Med. 2008 Jan;40(6):402–17.

9.       Dobrowolski P, Tomaszewska E, Kurlak P, Pierzynowski SG. Dietary 2-oxoglutarate mitigates gastrectomy-evoked structural changes in cartilage of female rats. Exp Biol Med. 2016 Jan;241(1):14–24.

10.       Wang L, Yi D, Hou Y, Ding B, Li K, Li B, et al. Dietary Supplementation with α-Ketoglutarate Activates mTOR Signaling and Enhances Energy Status in Skeletal Muscle of Lipopolysaccharide-Challenged Piglets. J Nutr. 2016 Aug 1;146(8):1514–20.

11.       Jiang Q, Liu G, Wang X, Hou Y, Duan Y, Wu G, et al. Mitochondrial pathway is involved in the protective effects of alpha-ketoglutarate on hydrogen peroxide induced damage to intestinal cells. Oncotarget. 2017 Sep 26;8(43):74820–35.

12.       Radzki RP, Bieńko M, Pierzynowski SG. Effect of dietary alpha‐ketoglutarate on blood lipid profile during hypercholesterolaemia in rats. Scand J Clin Lab Invest. 2009 Jan;69(2):175–80.

13.       Tian Q, Zhao J, Yang Q, Wang B, Deavila JM, Zhu MJ, et al. Dietary alpha‐ketoglutarate promotes beige adipogenesis and prevents obesity in middle‐aged mice. Aging Cell [Internet]. 2020 Jan [cited 2022 May 25];19(1). Available from: https://onlinelibrary.wiley.com/doi/10.1111/acel.13059

14.       Chen S, Bin P, Ren W, Gao W, Liu G, Yin J, et al. Alpha-ketoglutarate (AKG) lowers body weight and affects intestinal innate immunity through influencing intestinal microbiota. Oncotarget. 2017 Jun 13;8(24):38184–92.

15.       Chin RM, Fu X, Pai MY, Vergnes L, Hwang H, Deng G, et al. The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature. 2014 Jun;510(7505):397–401.

16.       Asadi Shahmirzadi A, Edgar D, Liao CY, Hsu YM, Lucanic M, Asadi Shahmirzadi A, et al. Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Aging Mice. Cell Metab. 2020 Sep;32(3):447-456.e6.

17.       Filip, Pierzynowski, Lindegard, Wernerman, Haratym-Maj, Podgurniak. Alpha-Ketoglutarate Decreases Serum Levels of C-terminal Cross-Linking Telopeptide of Type I Collagen (CTX) in Postmenopausal Women with Osteopenia: Six-Month Study. Int J Vitam Nutr Res. 2007 Mar 1;77(2):89–97.

18.       Harrison AP, Pierzynowski SG. Biological effects of 2-oxoglutarate with particular emphasis on the regulation of protein, mineral and lipid absorption/metabolism, muscle performance, kidney function, bone formation and cancerogenesis, all viewed from a healthy ageing perspective state of the art--review article. J Physiol Pharmacol Off J Pol Physiol Soc. 2008 Aug;59 Suppl 1:91–106.

19.       Demidenko O, Barardo D, Budovskii V, Finnemore R, Palmer FR, Kennedy BK, et al. 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 Nov 30;13(22):24485–99.

Compound description

Alpha-ketoglutarate (AKG, also known as 2-ketoglutaric acid or 2-oxoglutarate) is an endogenous (produced and decomposed inside the body) compound that is a part of several pathways in mammals' metabolism. From the structural point of view, it is a weak organic acid with five carbon atoms, two acid groups, and a ketone moiety. 

 

In addition to being produced endogenously, AKG can be consumed as a supplement. Calcium (Ca-AKG) and sodium (Na-AKG) salts of alpha-ketoglutarate are most often used to study its biological effects. This supplement is widely used in animals to support body growth. In clinical practice, intravenous AKG injections are used to reduce vascular insufficiency during cardiovascular surgery (1). In model organisms, AKG levels are deemed sufficient in most adults, but they tend to drop during aging, leading to multiple detrimental effects. 

Properties

AKG is best known for its crucial role in the Krebs cycle (or the tricarboxylic acid cycle) – a pivotal metabolic source of energy for cells. In this cycle, a sequence of reactions occurs that generates adenosine triphosphate (ATP), which works as a universal fuel for the whole body. AKG is one of the key players in the Krebs cycle (2), being both generated and oxidized at the different steps. However, the generated AKG may also leave the Krebs cycle and participate in a multitude of other metabolic processes

Other known functions of AKG include amino acid synthesis in the liver, modulation of signaling systems, immune regulation, and epigenetic alterations (1). Moreover, AKG regulates cellular utilization of carbon and nitrogen compounds and serves as an antioxidative agent (3). 

Studies demonstrated that in murine animal models it inhibits tumor growth by inducing hypoxia (4). And finally, AKG is involved in the regulation of gene expression and growth- and aging-related cellular pathways, including mTOR (mammalian target of rapamycin) and AMPK (AMP-activated protein kinase) pathways (5). Both these pathways were shown to be crucial for healthy aging and longevity.

Use as a supplement

Such a variety of functions led to the multiple studies of AKG supplementation in animal models with the establishment of several beneficial effects. The best-established health benefits in animals include the stimulation of amino acid absorption, maintenance of the bone structure, and improvement in protein biosynthesis (6,7). Due to AKG being one of the proline amino acid precursors and participating in collagen production (8), its supplementation also demonstrated protective effects on bones and cartilage (9). In addition, studies demonstrated links between AKG supplementation and modulation of the mTOR-signaling pathway (10), improvement of mitochondrial function (11), decreasing levels of blood glucose and cholesterol (in animals fed a high caloric diet) (12), obesity prevention (13), and modulation of gut microbiota (14). Additionally, AKG was shown to alleviate the toxic effects of many exogenous chemicals and endogenous metabolites. 

But the major attention was attracted to potential geroprotective applications of AKG. A pioneering study by Chin et al. (15) demonstrated a 50% increase in the lifespan of nematodes fed with AKG. The effect was attributed mainly to the downregulation of mTOR. The anti-aging effect was further confirmed in mice (16), showing that 2% Ca-AKG significantly extends their life- and healthspan by 9-12%, decreases systemic inflammation, and reduces frailty and hair loss. However, the effects of AKG on the mTOR pathway are far from straightforward. While in the abovementioned research anti-aging effect was mainly attributed to mTOR deactivation, multiple other studies of AKG effect on protein biosynthesis demonstrate precisely the opposite – mTOR pathway activation. This suggests that the exact mechanism and molecular links behind AKG's multiple biological activities remain to be elaborated.

The studies in humans are scarce but show protective effects of AKG supplements against osteoporosis (17), as well as a reduction in low-density lipoprotein and cholesterol levels (18). As for anti-aging properties, as of the moment, there exists a single retrospective study in 42 healthy individuals, which demonstrated that AKG supplementation for seven months reduced biological age by eight years as measured by the TruAge DNA Methylation test (19).

Dosage, recommendations, and side effects

The optimal daily intake varies among studies, ranging from 3.6 to 6 grams/daily. In our marketplace, you can find Ca-AKG from the DoNotAge vendor, with each capsule containing 400 mg of the compound and a recommended dosage of two capsules daily.

Studies demonstrated that Ca-AKG is generally safe with no major adverse effects and a few possible gastrointestinal side effects (including bloating, nausea, and diarrhea). However, it is essential to note that long-term safety and efficacy in humans have not been studied. In case of any concerns, please, contact your healthcare provider before starting the supplementation.

References

 

1.         Gyanwali B, Lim ZX, Soh J, Lim C, Guan SP, Goh J, et al. Alpha-Ketoglutarate dietary supplementation to improve health in humans. Trends Endocrinol Metab. 2022 Feb;33(2):136–46.

2.         Legendre F, MacLean A, Appanna VP, Appanna VD. Biochemical pathways to α-ketoglutarate, a multi-faceted metabolite. World J Microbiol Biotechnol. 2020 Aug;36(8):123.

3.         Flashman E, Schofield CJ. The most versatile of all reactive intermediates? Nat Chem Biol. 2007 Feb;3(2):86–7.

4.         Matsumoto K, Obara N, Ema M, Horie M, Naka A, Takahashi S, et al. Antitumor effects of 2-oxoglutarate through inhibition of angiogenesis in a murine tumor model. Cancer Sci. 2009 Sep;100(9):1639–47.

5.         He L, Xu Z, Yao K, Wu G, Yin Y, Nyachoti C, et al. The Physiological Basis and Nutritional Function of Alpha-ketoglutarate. Curr Protein Pept Sci. 2015 Aug 10;16(7):576–81.

6.         Chen J, Su W, Kang B, Jiang Q, Zhao Y, Fu C, et al. Supplementation with α-ketoglutarate to a low-protein diet enhances amino acid synthesis in tissues and improves protein metabolism in the skeletal muscle of growing pigs. Amino Acids. 2018 Nov;50(11):1525–37.

7.         Dobrowolski P, Tomaszewska E, Bienko M, Radzki RP, Pierzynowski SG. The effect of dietary administration of 2-oxoglutaric acid on the cartilage and bone of growing rats. Br J Nutr. 2013 Aug 28;110(4):651–8.

8.         Myllyharju J. Prolyl 4-hydroxylases, key enzymes in the synthesis of collagens and regulation of the response to hypoxia, and their roles as treatment targets. Ann Med. 2008 Jan;40(6):402–17.

9.       Dobrowolski P, Tomaszewska E, Kurlak P, Pierzynowski SG. Dietary 2-oxoglutarate mitigates gastrectomy-evoked structural changes in cartilage of female rats. Exp Biol Med. 2016 Jan;241(1):14–24.

10.       Wang L, Yi D, Hou Y, Ding B, Li K, Li B, et al. Dietary Supplementation with α-Ketoglutarate Activates mTOR Signaling and Enhances Energy Status in Skeletal Muscle of Lipopolysaccharide-Challenged Piglets. J Nutr. 2016 Aug 1;146(8):1514–20.

11.       Jiang Q, Liu G, Wang X, Hou Y, Duan Y, Wu G, et al. Mitochondrial pathway is involved in the protective effects of alpha-ketoglutarate on hydrogen peroxide induced damage to intestinal cells. Oncotarget. 2017 Sep 26;8(43):74820–35.

12.       Radzki RP, Bieńko M, Pierzynowski SG. Effect of dietary alpha‐ketoglutarate on blood lipid profile during hypercholesterolaemia in rats. Scand J Clin Lab Invest. 2009 Jan;69(2):175–80.

13.       Tian Q, Zhao J, Yang Q, Wang B, Deavila JM, Zhu MJ, et al. Dietary alpha‐ketoglutarate promotes beige adipogenesis and prevents obesity in middle‐aged mice. Aging Cell [Internet]. 2020 Jan [cited 2022 May 25];19(1). Available from: https://onlinelibrary.wiley.com/doi/10.1111/acel.13059

14.       Chen S, Bin P, Ren W, Gao W, Liu G, Yin J, et al. Alpha-ketoglutarate (AKG) lowers body weight and affects intestinal innate immunity through influencing intestinal microbiota. Oncotarget. 2017 Jun 13;8(24):38184–92.

15.       Chin RM, Fu X, Pai MY, Vergnes L, Hwang H, Deng G, et al. The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature. 2014 Jun;510(7505):397–401.

16.       Asadi Shahmirzadi A, Edgar D, Liao CY, Hsu YM, Lucanic M, Asadi Shahmirzadi A, et al. Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Aging Mice. Cell Metab. 2020 Sep;32(3):447-456.e6.

17.       Filip, Pierzynowski, Lindegard, Wernerman, Haratym-Maj, Podgurniak. Alpha-Ketoglutarate Decreases Serum Levels of C-terminal Cross-Linking Telopeptide of Type I Collagen (CTX) in Postmenopausal Women with Osteopenia: Six-Month Study. Int J Vitam Nutr Res. 2007 Mar 1;77(2):89–97.

18.       Harrison AP, Pierzynowski SG. Biological effects of 2-oxoglutarate with particular emphasis on the regulation of protein, mineral and lipid absorption/metabolism, muscle performance, kidney function, bone formation and cancerogenesis, all viewed from a healthy ageing perspective state of the art--review article. J Physiol Pharmacol Off J Pol Physiol Soc. 2008 Aug;59 Suppl 1:91–106.

19.       Demidenko O, Barardo D, Budovskii V, Finnemore R, Palmer FR, Kennedy BK, et al. 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 Nov 30;13(22):24485–99.

Article reviewed by
Dr. Ana Baroni MD. Ph.D.
SCIENTIFIC & MEDICAL ADVISOR
Quality Garant
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Dr. Ana Baroni MD. Ph.D.

Scientific & Medical Advisor
Quality Garant

Ana has over 20 years of consultancy experience in longevity, regenerative and precision medicine. She has a multifaceted understanding of genomics, molecular biology, clinical biochemistry, nutrition, aging markers, hormones and physical training. This background allows her to bridge the gap between longevity basic sciences and evidence-based real interventions, putting them into the clinic, to enhance the healthy aging of people. She is co-founder of Origen.life, and Longevityzone. Board member at Breath of Health, BioOx and American Board of Clinical Nutrition. She is Director of International Medical Education of the American College of Integrative Medicine, Professor in IL3 Master of Longevity at Barcelona University and Professor of Nutrigenomics in Nutrition Grade in UNIR University.

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