Browse > Article
http://dx.doi.org/10.4062/biomolther.2015.078

Alpha-Ketoglutarate: Physiological Functions and Applications  

Wu, Nan (Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University)
Yang, Mingyao (Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University)
Gaur, Uma (Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University)
Xu, Huailiang (Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University)
Yao, Yongfang (Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University)
Li, Diyan (Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University)
Publication Information
Biomolecules & Therapeutics / v.24, no.1, 2016 , pp. 1-8 More about this Journal
Abstract
Alpha-ketoglutarate (AKG) is a key molecule in the Krebs cycle determining the overall rate of the citric acid cycle of the organism. It is a nitrogen scavenger and a source of glutamate and glutamine that stimulates protein synthesis and inhibits protein degradation in muscles. AKG as a precursor of glutamate and glutamine is a central metabolic fuel for cells of the gastrointestinal tract as well. AKG can decrease protein catabolism and increase protein synthesis to enhance bone tissue formation in the skeletal muscles and can be used in clinical applications. In addition to these health benefits, a recent study has shown that AKG can extend the lifespan of adult Caenorhabditis elegans by inhibiting ATP synthase and TOR. AKG not only extends lifespan, but also delays age-related disease. In this review, we will summarize the advances in AKG research field, in the content of its physiological functions and applications.
Keywords
Alpha-ketoglutarate; Functions; Lifespan extension; Applications;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Tapiero, H., Mathe, G., Couvreur, P. and Tew, K. (2002) II. Glutamine and glutamate. Biomed. Pharmacother. 56, 446-457.   DOI
2 Tatara, M., Brodzki, A., Krupski, W., Silmanowicz, P., Majcher, P., Pierzynowski, S. and Studziński, T. (2005a) Effects of alpha-ketoglutarate on bone homeostasis and plasma amino acids in turkeys. Poult Sci. 84, 1604-1609.   DOI
3 Tatara, M., Tygesen, M. P., Sawa-Wojtanowicz, B., Krupski, W., Majcher, P. and Harrison, A. P. (2007) Bone development: The effect of short-term alpha-ketoglutarate administration on long-term mechanical properties of ribs in ram lambs. Small Ruminant Res. 67, 179-183.   DOI
4 Tatara, M. R., Silmanowicz, P., Majcher, P., Krupski, W. and Studziński, T. (2005b) Influence of alpha-ketoglutarate on cortical bone atrophy after denervation of the humerus in turkey. Bull. Vet. Inst. Pulawy 49, 113-116.
5 Taylor, A. (2002) Osteoblastic glutamate receptor function regulates bone formation and resorption. J. Musculoskelet. Neuronal Interact. 2, 285-290.
6 Tocaj, A., Filip, R., Lindergard, B., Wernerman, J., Studzinski, T., Ohman, K. and Pierzynowski, S. (2003) Alpha-ketoglutarate (AKG) inhibit osteoporosis development in postmenopausal women. In Journal of Bone and Mineral Research, Vol. 18, pp. S267-S267. Amer Soc Bone & Mineral Res 2025 M St, Nw, Ste 800, Washington, Dc 20036-3309 USA.
7 Toivonen, J. M., Walker, G. A., Martinez-Diaz, P., Bjedov, I., Driege, Y., Jacobs, H. T., Gems, D. and Partridge, L. (2007) No influence of Indy on lifespan in Drosophila after correction for genetic and cytoplasmic background effects. PLoS Genet. 3, e95.   DOI
8 Tritos, N. A. and Biller, B. M. (2009) Growth hormone and bone. Curr. Opin. Endocrinol. Diabetes Obes. 16, 415-422.   DOI
9 Tsang, W. Y., Sayles, L. C., Grad, L. I., Pilgrim, D. B. and Lemire, B. D. (2001) Mitochondrial respiratory chain deficiency in Caenorhabditis elegans results in developmental arrest and increased life span. J. Biol. Chem. 276, 32240-32246.   DOI
10 Urban, J., Soulard, A., Huber, A., Lippman, S., Mukhopadhyay, D., Deloche, O., Wanke, V., Anrather, D., Ammerer, G. and Riezman, H. (2007) Sch9 Is a Major Target of TORC1 in Saccharomyces cerevisiae. Mol. Cell 26, 663-674.   DOI
11 Vellai, T., Takacs-Vellai, K., Zhang, Y., Kovacs, A. L., Orosz, L. and Müller, F. (2003) Influence of TOR kinase on lifespan in C. elegans. Nature 426, 620.
12 Velvizhi, S., Dakshayani, K. B. and Subramanian, P. (2002) Effects of ${\alpha}$-ketoglutarate on antioxidants and lipid peroxidation products in rats treated with ammonium acetate. Nutrition 18, 747-750.   DOI
13 Wang, Y., Zhou, Y. and Graves, D. T. (2014) FOXO transcription factors: their clinical significance and regulation. Biomed. Res. Int. 2014, 925350.
14 Webb, A. E. and Brunet, A. (2014) FOXO transcription factors: key regulators of cellular quality control. Trends Biochem. Sci. 39, 159-169.   DOI
15 Welborn, J. R., Shpun, S., Dantzler, W. H. and Wright, S. H. (1998) Effect of ${\alpha}$-ketoglutarate on organic anion transport in single rabbit renal proximal tubules. Am. J. Physiol. Renal Physiol. 274, F165- F174.   DOI
16 Wernerman, J., Hammarqvist, F. and Vinnars, E. (1990) ${\alpha}$-Ketoglutarate and postoperative muscle catabolism. Lancet 335, 701-703.   DOI
17 Wiren, M. and Permert, J. (2002) ${\alpha}$-ketoglutarate-supplemented enteral nutrition: effects on postoperative nitrogen balance and muscle catabolism. Nutrition 18, 725-728.   DOI
18 Yeh, S. L., Lai, Y. N., Shang, H. F., Lin, M. T. and Chen, W. J. (2004) Effects of glutamine supplementation on innate immune response in rats with gut-derived sepsis. Br. J. Nutr. 91, 423-430.   DOI
19 Wu, G., Fang, Y. Z., Yang, S., Lupton, J. R. and Turner, N. D. (2004) Glutathione metabolism and its implications for health. J. Nutr. 134, 489-492.   DOI
20 Wullschleger, S., Loewith, R. and Hall, M. N. (2006) TOR signaling in growth and metabolism. Cell 124, 471-484.   DOI
21 Ziegler, T. R. and Daignault, N. M. (2000) Glutamine regulation of human immune cell function. Nutrition 16, 458-459.   DOI
22 Zimmerman, J. J. and Ringer, T. V. (1992) Inflammatory host responses in sepsis. Crit. Care Clin. 8, 163-189.   DOI
23 Barthel, A., Schmoll, D. and Unterman, T. G. (2005) FoxO proteins in insulin action and metabolism. Trends Endocrinol. Metab. 16, 183-189.   DOI
24 Abcouwer, S. F. (2000) Effects of glutamine on immune cells. Nutrition 16, 67-69.
25 Abrahams, J. P., Leslie, A. G., Lutter, R. and Walker, J. E. (1994) Structure at 2.8 A resolution of F1-ATPase from bovine heart mitochondria. Nature 370, 621-628.   DOI
26 Alpers, D. H. (2006) Glutamine: do the data support the cause for glutamine supplementation in humans? Gastroenterology 130, S106- S116.   DOI
27 Andersen, N. K., Tatara, M. R., Krupski, W., Majcher, P. and Harrison, A. P. (2008) The long-term effect of alpha-ketoglutarate, given early in postnatal life, on both growth and various bone parameters in pigs. J. Anim. Physiol. Anim. Nutr. 92, 519-528.   DOI
28 Ashkanazi, J., Carpertier, Y. and Michelsen, C. (1980) Muscle and plasma amino acids following injury. Ann. Surg. 192, 78-85.   DOI
29 Bellon, G., Chaqour, B., Wegrowski, Y., Monboisse, J. C. and Borel, J. P. (1995) Glutamine increases collagen gene transcription in cultured human fibroblasts. Biochim. Biophys. Acta 1268, 311-323.javascript:checkRefBr('', 'next');   DOI
30 Bienko, M., Radzki, R., Puzio, I., Filip, R., Pierzynowski, S. and Studzinski, T. (2002) The influence of alpha-ketoglutarate (AKG) on mineralization of femur in rats with established osteopenia. Acta Orthop. Scand. 73, 52.
31 Bissonnette, R., Friedmann, D., Giroux, J. M., Dolenga, M., Hechtman, P., Der Kaloustian, V. M. and Dubuc, R. (1993) Prolidase deficiency: a multisystemic hereditary disorder. J. Am. Acad. Dermatol. 29, 818-821.   DOI
32 Blagosklonny, M. V. (2006) Aging and immortality: quasi-programmed senescence and its pharmacologic inhibition. Cell Cycle 5, 2087- 2102.   DOI
33 Boyer, P. D. (1997) The ATP synthase-a splendid molecular machine. Annu. Rev. Biochem. 66, 717-749.   DOI
34 Brauer, M. J., Yuan, J., Bennett, B. D., Lu, W., Kimball, E., Botstein, D. and Rabinowitz, J. D. (2006) Conservation of the metabolomic response to starvation across two divergent microbes. Proc. Natl. Acad. Sci. U.S.A. 103, 19302-19307.   DOI
35 Chenu, C. (2002b) Glutamatergic regulation of bone remodeling. J. Musculoskelet Neuronal Interact. 2, 282-284.
36 Brugnara, L., Vinaixa, M., Murillo, S., Samino, S., Rodriguez, M. A., Beltran, A., Lerin, C., Davison, G., Correig, X. and Novials, A. (2012) Metabolomics approach for analyzing the effects of exercise in subjects with type 1 diabetes mellitus. PloS one 7, e40600.   DOI
37 Brunet, A. (2004) [The multiple roles of FOXO transcription factors]. Med. Sci. 20, 856-859.
38 Chenu, C. (2002a) Glutamatergic innervation in bone. Microsc. Res. Tech. 58, 70-76.   DOI
39 Chin, R. M., Fu, X., Pai, M. Y., Vergnes, L., Hwang, H., Deng, G., Diep, S., Lomenick, B., Meli, V. S. and Monsalve, G. C. (2014) The metabolite a-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature 510, 397-401.   DOI
40 Colomb, V., Dabbas, M., Goulet, O., Talbotec, C., Corriol, O. and Ricour, C. (2004) Prepubertal growth in children with long-term parenteral nutrition. Horm. Res. Paediatr. 58, 2-6.
41 Curran, S. P. and Ruvkun, G. (2007) Lifespan regulation by evolutionarily conserved genes essential for viability. PLoS Genet. 3, e56.   DOI
42 Cynober, L. (2004) Ornithine ${\alpha}$-ketoglutarate as a potent precursor of arginine and nitric oxide: a new job for an old friend. J. Nutr. 134, 2858S-2862S.   DOI
43 Dabek, M., Kruszewska, D., Filip, R., Hotowy, A., Pierzynowski, L., Wojtasz-Pajak, A., Szymanczyk, S., Valverde Piedra, J., Werpachowska, E. and Pierzynowski, S. (2005) ${\alpha}$-Ketoglutarate (AKG) absorption from pig intestine and plasma pharmacokinetics. J. Anim. Physiol. Anim. Nutr. 89, 419-426.   DOI
44 Dobrowolski, P. J., Piersiak, T., Surve, V. V., Kruszewska, D., Gawron, A., Pacuska, P., Hakanson, R. and Pierzynowski, S. G. (2008) Dietary ${\alpha}$-ketoglutarate reduces gastrectomy-evoked loss of calvaria and trabecular bone in female rats. Scand J. Gastroenterol. 43, 551-558.   DOI
45 Dakshayani, K. and Subramanian, P. (2006) ${\alpha}$-ketoglutarate modulates the circadian patterns of lipid peroxidation and antioxidant status during N-nitrosodiethylamine-induced hepatocarcinogenesis in rats. J. Med. Food 9, 90-97.   DOI
46 Danbolt, N. C. (2001) Glutamate uptake. Prog. Neurobiol. 65, 1-105.   DOI
47 Dillin, A., Hsu, A. L., Arantes-Oliveira, N., Lehrer-Graiwer, J., Hsin, H., Fraser, A. G., Kamath, R. S., Ahringer, J. and Kenyon, C. (2002) Rates of behavior and aging specified by mitochondrial function during development. Science 298, 2398-2401.   DOI
48 Espat, N. J., Watkins, K. T., Lind, D. S., Weis, J. K., Copeland, E. M. and Souba, W. W. (1996) Dietary modulation of amino acid transport in rat and human liver. J. Surg. Res. 63, 263-268.   DOI
49 Fayh, A. P., Friedman, R., Sapata, K. B. and Oliveira, A. R. (2007) [Effect of L-arginine supplementation on secretion of human growth hormone and insulin-like growth factor in adults]. Arq. Bras. Endocrinol. Metabol. 51, 587-592.   DOI
50 Furukawa, S., Saito, H., Inoue, T., Matsuda, T., Fukatsu, K., Han, I., Ikeda, S. and Hidemura, A. (2000) Supplemental glutamine augments phagocytosis and reactive oxygen intermediate production by neutrophils and monocytes from postoperative patients in vitro. Nutrition 16, 323-329.   DOI
51 Gianotti, L., Alexander, J. W., Gennari, R., Pyles, T. and Babcock, G. F. (1995) Oral glutamine decreases bacterial translocation and improves survival in experimental gut-origin sepsis. J. Parenter. Enteral Nutr. 19, 69-74.   DOI
52 Hammarqvist, F., Wernerman, J., Ali, R., von der Decken, A. and Vinnars, E. (1989) Addition of glutamine to total parenteral nutrition after elective abdominal surgery spares free glutamine in muscle, counteracts the fall in muscle protein synthesis, and improves nitrogen balance. Ann. Surg. 209, 455-461.   DOI
53 Giustina, A., Mazziotti, G. and Canalis, E. (2008) Growth hormone, insulin-like growth factors, and the skeleton. Endocr. Rev. 29, 535- 559.   DOI
54 Gross, D. N., van den Heuvel, A. P. and Birnbaum, M. J. (2008) The role of FoxO in the regulation of metabolism. Oncogene 27, 2320- 2336.   DOI
55 Gu, Y., Genever, P., Skerry, T. and Publicover, S. (2002) The NMDA type glutamate receptors expressed by primary rat osteoblasts have the same electrophysiological characteristics as neuronal receptors. Calcif. Tissue Int. 70, 194-203.   DOI
56 Hansen, M., Taubert, S., Crawford, D., Libina, N., Lee, S. J. and Kenyon, C. (2007) Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans. Aging Cell 6, 95-110.   DOI
57 Hardie, D. G., Ross, F. A. and Hawley, S. A. (2012) AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat. Rev. Mol. Cell Biol. 13, 251-262.
58 Harrison, A. P. and Pierzynowski, S. (2008) 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. 59, 91-106.
59 Harrison, A. P., Tygesen, M. P., Sawa-Wojtanowicz, B., Husted, S. and Tatara, M. (2004) ${\alpha}$-Ketoglutarate treatment early in postnatal life improves bone density in lambs at slaughter. Bone 35, 204-209.   DOI
60 Hixt, U. and Muller, H. (1996) L-alanyl-glutamine-a glutamine dipeptide for paraenteral nutrition. Environ. Health Perspect. 2, 72-76.
61 Huang, X., Liu, J., Withers, B. R., Samide, A. J., Leggas, M. and Dickson, R. C. (2013) Reducing signs of aging and increasing lifespan by drug synergy. Aging Cell 12, 652-660.   DOI
62 Inoki, K. and Guan, K.-L. (2006) Complexity of the TOR signaling network. Trends Cell Biol. 16, 206-212.   DOI
63 Isemura, M., Hanyu, T., Gejyo, F., Nakazawa, R., Igarashi, R., Matsuo, S., Ikeda, K. and Sato, Y. (1979) Prolidase deficiency with imidodipeptiduria. A familial case with and without clinical symptoms. Clin. Chim. Acta 93, 401-407.   DOI
64 Jones, C., Allan Palmer, T. and Griffiths, R. (1999) Randomized clinical outcome study of critically ill patients given glutamine-supplemented enteral nutrition. Nutrition 15, 108-115.   DOI
65 Junghans, P., Derno, M., Pierzynowski, S., Hennig, U., Eberhard Rudolph, P. and Souffrant, W. B. (2006) Intraduodenal infusion of ${\alpha}$-ketoglutarate decreases whole body energy expenditure in growing pigs. Clin. Nutr. 25, 489-496.   DOI
66 Kaeberlein, M., Burtner, C. R. and Kennedy, B. K. (2007) Recent developments in yeast aging. PLoS Genet. 3, e84.   DOI
67 Kaminsky, Y. G., Kosenko, E. A. and Kondrashova, M. N. (1982) Metabolites of citric acid cycle, carbohydrate and phosphorus metabolism, and related reactions, redox and phosphorylating states of hepatic tissue, liver mitochondria and cytosol of the pigeon, under normal feeding and natural nocturnal fasting conditions. Comp. Biochem. Physiol. B. 73, 957-963.   DOI
68 Kapahi, P. and Zid, B. (2004) TOR pathway: linking nutrient sensing to life span. Sci. Aging Knowledge Environ. 2004, pe34.
69 Karna, E., Szoka, L. and Palka, J. A. (2013) The mechanism of hydralazine- induced collagen biosynthesis in cultured fibroblasts. Naunyn Schmiedebergs Arch.Pharmacol. 386, 303-309.   DOI
70 Kapahi, P., Zid, B. M., Harper, T., Koslover, D., Sapin, V. and Benzer, S. (2004) Regulation of lifespan in drosophila by modulation of genes in the TOR signaling pathway. Curr. Biol. 14, 885-890.   DOI
71 Katewa, S. D. and Kapahi, P. (2011) Role of TOR signaling in aging and related biological processes in Drosophila melanogaster. Exp Gerontol. 46, 382-390.   DOI
72 Korkmaz, A., Yurdakok, M., Yigit, S. and Tekinalp, G. (2007) Long-term enteral glutamine supplementation in very low birth weight infants: effects on growth parameters. Turk J. Pediatr. 49, 37-44.
73 Kowalik, S., Sliwa, E., Tatara, M. R., Krupski, W., Majcher, P. and Studzinski, T. (2005) Influence of alpha-ketoglutarate on mineral density and geometrical and mechanical parameters of femora during postnatal life in piglets. Bull. Vet. Inst. Pulawy 49, 107-111.
74 Kristensen, N. B., Jungvid, H., Fernandez, J. A. and Pierzynowski, S. (2002) Absorption and metabolism of ${\alpha}$-ketoglutarate in growing pigs. J. Anim. Physiol. Anim. Nutr. 86, 239-245.   DOI
75 Lamande, S. R. and Bateman, J. F. (1999) Procollagen folding and assembly: the role of endoplasmic reticulum enzymes and molecular chaperones. Semin. Cell Dev. Biol. 10, 455-464.   DOI
76 Lambert, B. D., Filip, R., Stoll, B., Junghans, P., Derno, M., Hennig, U., Souffrant, W. B., Pierzynowski, S. and Burrin, D. G. (2006) First-pass metabolism limits the intestinal absorption of enteral ${\alpha}$-ketoglutarate in young pigs. J. Nutr. 136, 2779-2784.   DOI
77 Lomenick, B., Hao, R., Jonai, N., Chin, R. M., Aghajan, M., Warburton, S., Wang, J., Wu, R. P., Gomez, F. and Loo, J. A. (2009) Target identification using drug affinity responsive target stability (DARTS) Proc. Natl. Acad. Sci. U.S.A. 106, 21984-21989.   DOI
78 Le Boucher, J., Coudray-Lucas, C., Lasnier, E., Jardel, A., Ekindjian, O. G. and Cynober, L. A. (1997) Enteral administration of ornithine alpha-ketoglutarate or arginine alpha-ketoglutarate: a comparative study of their effects on glutamine pools in burn-injured rats. Crit. Care Med. 25, 293-298.   DOI
79 Le Boucher, J. and Cynober, L. A. (1997) Ornithine alpha-ketoglutarate: the puzzle. Nutrition 14, 870-873.
80 Lee, S. S., Lee, R. Y., Fraser, A. G., Kamath, R. S., Ahringer, J. and Ruvkun, G. (2003) A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity. Nat. Genet. 33, 40-48.
81 Luong, N., Davies, C. R., Wessells, R. J., Graham, S. M., King, M. T., Veech, R., Bodmer, R. and Oldham, S. M. (2006) Activated FOXOmediated insulin resistance is blocked by reduction of TOR activity. Cell Metab. 4, 133-142.   DOI
82 MacFie, J. and McNaught, C. (2002) Glutamine and gut barrier function. Nutrition 18, 433-434.   DOI
83 Melendez, A., Talloczy, Z., Seaman, M., Eskelinen, E. L., Hall, D. H. and Levine, B. (2003) Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science 301, 1387-1391.   DOI
84 Mentaverri, R., Kamel, S., Wattel, A., Prouillet, C., Sevenet, N., Petit, J., Tordjmann, T. and Brazier, M. (2003) Regulation of bone resorption and osteoclast survival by nitric oxide: Possible involvement of NMDA-receptor. J. Cell. Biochem. 88, 1145-1156.   DOI
85 Ogle, C. K., Ogle, J. D., Mao, J. X., Simon, J., Noel, J. G., Li, B.-G. and Alexander, J. W. (1994) Effect of glutamine on phagocytosis and bacterial killing by normal and pediatric burn patient neutrophils. J. Parenter. Enteral Nutr. 18, 128-133.   DOI
86 Myara, I., Charpentier, C. and Lemonnier, A. (1984) Prolidase and prolidase deficiency. Life Sci. 34, 1985-1998.   DOI
87 Myllyharju, J. (2003) Prolyl 4-hydroxylases, the key enzymes of collagen biosynthesis. Matrix Biol. 22, 15-24.   DOI
88 Neu, J., Shenoy, V. and Chakrabarti, R. (1996) Glutamine nutrition and metabolism: where do we go from here? FASEB J. 10, 829-837.   DOI
89 Palka, J. A. and Phang, J. M. (1997) Prolidase activity in fibroblasts is regulated by interaction of extracellular matrix with cell surface integrin receptors. J. Cell. Biochem. 67, 166-175.   DOI
90 Panosyan, E. H., Grigoryan, R. S., Avramis, I. A., Seibel, N. L., Gaynon, P. S., Siegel, S. E., Fingert, H. J. and AVRAMIS, V. I. (2004) Deamination of glutamine is a prerequisite for optimal asparagine deamination by asparaginases in vivo (CCG-1961) Anticancer Res. 24, 1121-1126.
91 Parry-Billings, M., Calder, P., Newsholme, E. and Evans, J. (1990) Does glutamine contribute to immunosuppression after major burns? Lancet 336, 523-525.   DOI
92 Pesty, F. H., Sultan, F. and Braun, B. (1997) Glutamine homologues and derivatives: A limiting factor in current artificial nutrition? Nutrition 13, 575-577.   DOI
93 Pierzynowski, S. and Sjodin, A. (1998) Perspectives of glutamine and its derivatives as feed additives for farm animals. J. Anim. Feed Sci. 7, 79-91.   DOI
94 Riedel, E., Nundel, M. and Hampl, H. (1996) alpha-Ketoglutarate application in hemodialysis patients improves amino acid metabolism. Nephron 74, 261-265.   DOI
95 Pierzynowski, S. G., Filip, R. and Harrison, A. (2007) Effect of feed supplementation with alpha-ketoglutarate, combined with vitamin B-6 or C, on the performance and haemoglobin and amino acid levels in growing rats. Bull. Vet. Inst. Pulawy 51, 289-296.
96 Radzki, R., Bienko, M., Puzio, I., Filip, R., Pierzynowski, S. and Studzinski, T. (2002) The effect of alpha-ketoglutarate (AKG) on mineralization of femur in ovariectomized rats. Acta Orthop. Scand. 73, 52.
97 Rani, R. S., Leela, A. C. and Rao, G. N. (2012) Effect of dielectric constant on protonation equilibria of l-aspartic acid and ethylenediamine in 1, 2-propanediol-water mixtures. P. Natl A Sci. India A. 82, 313-316.   DOI
98 Roth, E., Funovics, J., Mühlbacher, F., Schemper, M., Mauritz, W., Sporn, P. and Fritsch, A. (1982) Metabolic disorders in severe abdominal sepsis: glutamine deficiency in skeletal muscle. Clin. Nutr. 1, 25-41.   DOI
99 Salvalaggio, P. R. and Campos, A. C. (2002) Bacterial translocation and glutamine. Nutrition 18, 435-437.   DOI
100 Sawyer, D. W., Donowitz, G. R. and Mandell, G. L. (1989) Polymorphonuclear neutrophils: an effective antimicrobial force. 11, S1532- S1544.   DOI
101 Schlegel, L., Coudray-Lucas, C., Barbut, F., Le Boucher, J., Jardel, A., Zarrabian, S. and Cynober, L. (2000) Bacterial dissemination and metabolic changes in rats induced by endotoxemia following intestinal E. coli overgrowth are reduced by ornithine ${\alpha}$-ketoglutarate administration. J. Nutr. 130, 2897-2902.   DOI
102 Sliwa, E., Dobrowolski, P., Tatara, M., Piersiak, T., Siwicki, A., Rokita, E. and Pierzynowski, S. (2009) Alpha-ketoglutarate protects the liver of piglets exposed during prenatal life to chronic excess of dexamethasone from metabolic and structural changes. J. Anim. Physiol. Anim. Nutr. 93, 192-202.   DOI
103 Selman, C., Tullet, J. M., Wieser, D., Irvine, E., Lingard, S. J., Choudhury, A. I., Claret, M., Al-Qassab, H., Carmignac, D. and Ramadani, F. (2009) Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 326, 140-144.   DOI
104 Sheaffer, K. L., Updike, D. L. and Mango, S. E. (2008) The target of rapamycin pathway antagonizes pha-4/FoxA to control development and aging. Curr. Biol. 18, 1355-1364.   DOI
105 Sliwa, E. (2010) 2-Oxoglutaric acid administration diminishes fundectomy- induced osteopenia in pigs. J. Anim. Physiol. Anim. Nutr. 94, e86-e95.   DOI
106 Son, E. D., Choi, G. H., Kim, H., Lee, B., Chang, I. S. and Hwang, J. S. (2007) 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.   DOI
107 Spencer, G. J., McGrath, C. J. and Genever, P. G. (2007) Current perspectives on NMDA-type glutamate signalling in bone. Int. J. Biochem. Cell Biol. 39, 1089-1104.   DOI
108 Stanfel, M. N., Shamieh, L. S., Kaeberlein, M. and Kennedy, B. K. (2009) The TOR pathway comes of age. Biochim. Biophys. Acta 1790, 1067-1074.   DOI
109 Stoll, B., McNelly, S., Buscher, H. P. and Häussinger, D. (1991) Functional hepatocyte heterogeneity in glutamate, aspartate and ${\alpha}$-ketoglutarate uptake: A histoautoradiographical study. Hepatology 13, 247-253.   DOI