Healthy ageing: the beneficial effect of dietary supplementation with alpha-ketoglutarate on arterial elasticity in elderly mice
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Department of Animal and Veterinary Basic Sciences, Faculty of Life Sciences, Copenhagen University, Frederiksberg, Denmark
Department of Food Science, Faculty of Life Sciences, Copenhagen University, Frederiksberg, Denmark
Copenhagen University Library and The Parker Institute, Frederiksberg Hospital, Denmark
Institute of Agricultural Medicine, Department of Medical Biology, Lublin, Poland, Department of Cell and Organism Biology, Lund University, Sweden
Adrian P. Harrison   

IBHV, LIFE, Copenhagen University, Grønnegaardsvej 7, 1870 Frederiksberg C, Denmark.
J Pre Clin Clin Res. 2009;3(1):24–30
The study employed mechanical stretching in vitro of sections of abdominal aorta of elderly mice to investigate any benefi ts of oral treatment with alpha-ketoglutarate (AKG) on arterial elasticity. Eighteen female mice (50-weeks-old) were assigned to a control (2% w/v) Na2-AKG or (2% w/v) a Ca-AKG group, and treated for 182 days before being humanely killed. Aorta sections were exposed to increases in force (0.09 N) giving approx. 6 kPa of pressure, after which elastic recoil (N ms-1 mg-1 wet wt.) was measured. Na2-AKG treatment for 182 days induced a 30% (P <0.01) improvement, while Ca-AKG induced a 93% (P <0.001) improvement in the elastic recoil compared to controls (3.30 ± 0.08 × 10-5 N ms-1 mg-1 wet wt). AKG administered orally improved arterial elasticity in elderly mice, a change that occurred despite an increase in total collagen content. Alpha-ketoglutarate warrants further investigation as a candidate for therapies targeting arterial stiff ening with age.
Booth ML, Macaskill P, Owen N, Oldenburg B, Marcus BH, Bauman A: Population prevalence and correlates of stages of change in physical-activity. Health Educ Quart 1993, 20, 431-440.
Ishikawa J, Kario K, Matsui Y, Shibasaki S, Morinari M, Kaneda R, Hoshide S, Eguchi K, Hojo Y, Shimada K: Collagen metabolism in extracellular matrix may be involved in arterial stiff ness in olderhypertensive patients with left ventricular hypertrophy. Hypertens Res 2005, 28, 995-1001.
Shekhonin BV, Domogatsky SP, Idelson GL, Koteliansky VE, Rukosuev VS: Relative distribution of fi bronectin and type-I, Type-III, type- IV, type-V collagens in normal and atherosclerotic intima of human arteries. Atheroscler 1987, 67, 9-16.
Bruggemann D, Risbo J, Pierzynowski SG, Harrison AP: Muscle contraction and force: the importance of an ancillary network, nutrient supply and waste removal. Int J Mol Sci 2008, 9, 1472-1488.
Lewis RA: Medical phase contrast x-ray imaging: current status and mfuture prospects. Phys Med Biol 2004, 49, 3573-3583.
Safar ME, London GM, Asmar R, Frohlich ED: Recent advances on large arteries in hypertension. Hypertens 1998, 32, 156-161.
McEniery CM, Wilkinson IB, Avolio AP: Age, hypertension and arterial function. Clin Exp Pharmacol Physiol 2007, 34, 665-671.
Jones C, Palmer TEA, Griffi ths RD: Randomized clinical outcome study of critically ill patients given glutamine-supplemented enteral nutrition. Nutrition 1999, 15, 108-115.
Kristensen L, Therkildsen M, Riis B, Sorensen MT, Oksbjerg N, Purslow PP, Ertbjerg P: Dietary-induced changes of muscle growth rate in pigs: Eff ects on in vivo and postmortem muscle proteolysis and meat quality. J Anim Sci 2002, 80, 2862-2871.
Diegelmann RF: Analysis of collagen synthesis. Met Mol Med 2003, 78, 349-358.
Lambert BD, Filip R, Stoll B, Junghans P, Derno M, Hennig U, Souff rant WB, Pierzynowski S, Burrin DG: First-pass metabolism limits the intestinal absorption of enteral 〈-ketoglutarate in young pigs. J Nutr 2006, 136, 2779-2784.
Harrison AP, Pierzynowski SG: Biological eff ects of 2-oxoglutarate with particularemphasis 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 2008, 59, 91-106.
Mudge GH: Studies on potassium accumulation by rabbit kidney slices – eff ect of metabolic activity. Am J Physiol 1951, 165, 113-127.
Harrison AP, Nielsen OB, Clausen T: Role of Na+-K+ pump and Na+ channel concentrations in the contractility of rat soleus muscle. Am J Physiol Reg Int Comp Physiol 1997, 41, R1402-R1408.
Harrison AP, Flatman JA: Measurement of force and both surface and deep M wave properties in isolated rat soleus muscles. Am J Physiol Reg Int Comp Physiol 1990, 277, R1646-R1653.
Kolar K: Colorimetric determination of hydroxyproline as measure of collagen content in meat and meat-products – NMKL collaborative study. J Ass Anal Chem 1990, 73, 54-57.
Durant RR: Blood pressure in the rat. Am J Physiol 1927, 81, 679-685.
Carroll JF, Zenebe WJ, Strange TB: Cardiovascular function in a rat model of diet-induced obesity. Hypertension 2006, 48, 65-72.
Duka A, Duka I, Gao GH, Shenouda S, Gavras I, Gavras H: Role of bradykinin B-1 and B-2 receptors in normal blood pressure regulation. Am J Physiol Endoc M 2006, 291, E268-E274.
Calabresi C, Arosio B, Galimberti L, Scanziani E, Bergottini R, Annoni G, Vergani C: Natural aging, expression of fi brosis-related genes and collagen deposition in rat lung. Exp Gerontol 2007, 42, 1003-1011.
Marin J, Rodriguez-Martinez MA: Age-related changes in vascular responses. Exp Gerontol 1999, 34, 503-512.
Dao HH, Essalihi R, Bouvet C, Moreau P: Evolution and modulation of age-related medial elastocalcinosis: Impact on large artery stiff ness and isolated systolic hypertension. Cardiovasc Res 2005, 66, 307-317.
Hajdu MA, Heistad DD, Siems JE, Baumbach GL: Eff ects of aging on mechanics and composition of cerebral arterioles in rats. Circ Res 1990, 66, 1747-1754.
Moreau P, d’Uscio LV, Luscher TF: Structure and reactivity of small arteries in aging. Cardiovas Res 1998, 37, 247-253.
Laurant P, Adrian M, Berthelot A: Eff ect of age on mechanical properties of rat mesenteric small arteries. Can J Physiol Pharmacol 2004, 82, 269-275.
Bruel A, Oxlund H: Changes in biomechanical properties, composition of collagen and elastin, and advanced glycation endproducts of the rat aorta in relation to age. Atherosclerv 1996, 127, 155-165.
Jacob MP: Extracellular matrix remodeling and matrix metalloproteinases in the vascular wall during aging and in pathological conditions. Biomed Pharmacother 2003, 57, 195-202.
Briones AM, Salaices M, Vila E: Mechanisms underlying hypertrophic remodeling and increased stiff ness of mesenteric resistance arteries from aged rats. J Gerontol Series A 2007, 62, 696-706
Cliff WJ: Aortic Tunica Media in Aging Rats. Exp Mol Pathol 1970, 13,.172-189
Orlandi A, Mauriello A, Marino B, Spagnoli LG: Age-related modifi cations of aorta and coronaries in the rabbit – a morphological and morphometrical assessment. Archiv Gerontol Geriatr 1993, 17, 37-53.
Marin J: Age-related-changes in vascular-responses – a Review. Mech Age Develop 1995, 79,71-114
Robert L: Aging of the vascular wall and atherogenesis: Role of the elastin-laminin receptor. Atheroscler 1996, 123, 169-179
Meyer A, Verzar F: Age-changes of the hydroxyproline release during thermic contraction of collagen fi bers. Gerontol 1959, 3, 184-203.
Hammarqvist F, Wernerman J, Vonderdecken A, Vinnars E: Alphaketoglutarate preserves protein synthesis and free glutamine in skeletal-muscle after surgery. Surgery 1991, 109, 28-36.
Son E, Kim H, Choi H, Chang I, Hwang J: Alpha-ketoglutarate stimulates collagen production in cultured human dermal fi broblasts, and decreases UVB-induced wrinkle formation following topical application on the dorsal skin of hairless mice. J Invest Dermatol 2007, 127, 37.
Noma T, Mizushige K, Yao L, Yu Y, Kiyomoto H, Hosomi N, Kimura S, Abe Y, Ohmori K, Matsuo H: Alteration in aortic wall stiff ness and accumulation of collagen during the prediabetic stage of type II diabetes mellitus in rats. Japan Circ J 1999, 63, 988-993.
He WH, Miao FJP, Lin DCH, Schwandner RT, Wang ZL, Gao JH, Chen JL, Tian H, Ling L: Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors. Nature 2004, 429, 188-193.
Schmidt A, Lorkowski S, Seidler D, Breithardt G, Buddecke E: TGFbeta( 1) generates a specifi c multicomponent extracellular matrix in human coronary SMC. Eur J Clin Invest 2006, 36, 473-482.
Schnoor M, Cullen P, Lorkowski J, Stolle K, Robenek H, Troyer D, Rauterberg J, Lorkowski S: Production of type VI collagen by human macrophages: A new dimension in macrophage functional heterogeneity. J Immunol 2008, 180, 5707-5719.
Tatara MR, Brodzki A, Krupski W, Śliwa E, Silmanowicz P, Majcher P, Pierzynowski SG, Studziński T: Eff ects of alpha-ketoglutarate on bone homeostasis and plasma amino acids in turkeys. Poultry Sci 2005, 84, 1604-1609.
Harrison AP, Tygesen MP, Sawa-Wojtanowicz B, Husted S, Tatara MR: Alpha-ketoglutarate treatment early in postnatal life improves bone density in lambs at slaughter. Bone 2004, 35, 204-209.
Coudray-Lucas C, Le Bever H, Cynober L, De Bandt JP, Carsin H: Ornithine alpha-ketoglutarate improves wound healing in severe burn patients: a prospective randomized double-blind trial versus isonitrogenous controls. Crit Care Med 2000, 28, 1772-1776.
Wernerman J, Hammarqvist F, von der Decken A, Vinnars E: Ornithinealpha- ketoglutarate improves skeletal muscle protein synthesis as assessed by ribosome analysis and nitrogen use after surgery. Ann Surg 1987, 206, 674-678.
Cynober L, Lasnier E, le Boucher J, Jardel A, Coudray-Lucas C: Eff ect of ornithine alpha-ketoglutarate on glutamin pools in burn injury: evidence of component interaction. Intens Care Med 2007, 33, 538- 541.
Filip SR, Pierzynowski SG, Lindegard B, Wernerman J, Haratym- Maj A, Podgurniak M: 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 Vit Nutr Res 2007, 77, 89-97.
Koike T, Vernon RB, Gooden MD, Sadoun E, Reed MJ: Inhibited angiogenesis in aging: A role for TIMP-2. J Gerontol Series A 2003, 58, 798-805.
Verzar F: The ageing of connective tissue. Gerontologia 1957, 1, 363.