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Metabolism 2000: the emperor needs new clothes

Published online by Cambridge University Press:  28 February 2007

Vernon R. Young  and
Alfred M. Ajami
Vernon R. Young*
Affiliation:
Laboratory of Human Nutrition, School of Science and Clinical Research Center, Massachusetts Institute of Technology, Cambridge, MA 02139, USA and Shriners Burns Hospital, Boston, MA 02114, USA
Alfred M. Ajami
Affiliation:
Phenome Sciences Inc., Woburn, MA 01801, USA
*
*Corresponding author: Professor Vernon R. Young, fax +1 617 253 9658, email vryoung@mit.edu
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Abstract

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Metabolism is one of the corner stones of nutritional science. As biology enters the post-genomic era and with functional genomics beginning to take off, we anticipate that the study of metabolism will play an increasingly important role in helping to link advances made via the reductionist paradigm, that has been so successful in molecular and cellular biology, with those emerging from observational studies in animals and human subjects. A reconstructive metabolically-focused approach offers a timely paradigm for enhancing the elegance of nutritional science. Here we give particular attention to the use of tracers as phenotyping tools and discuss the application of our metaprobe concepts with respect to some novel features of metabolism, including ‘underground metabolism’, ‘metabolic hijacking’, ‘catalytic promiscuity’ and ‘moonlighting proteins’. The opportunities for enhancing the study of metabolism by new and emerging technologies, and the importance of the interdisciplinary research enterprise are also touched upon. We conclude that: (1) the metaprobe concepts and approach, discussed herein, potentially yield a quantitative physiological (metabolic) phenotype against which to elaborate partial or focused genotypes; (2) physiological (metabolic) phenotypes which have a whole-body or kinetically-discernible inter-organ tissue-directed metabolic signature are an ideal target for this directed tracer-based definition of the ‘functional’ genotype; (3) metabolism, probed with tracer tool kits suitable for measuring rates of turnover, change and conversion, becomes in the current sociology of the ‘Net’, like AOL, Yahoo, Alta Vista, Lycos or Ask Jeeves, the portal for an exploration of the metabolic characteristics of the ‘Genomics Internet’.

Keywords

MetabolismMetaprobeTracersPhysiological (metabolic) phenotypes
Type
Plenary Lecture
Information
Proceedings of the Nutrition Society , Volume 60 , Issue 1 , February 2001 , pp. 27 - 44
Copyright
Copyright © The Nutrition Society 2001

References

Adams, MD, Celniker, SE, Holt, RA, Evas, CA et al. (2000) The genome sequence of Drosophila melanogaster . Science 287, 2185–2194.Google Scholar
Alonso de Vega, JM, Diaz, J, Serrano, E & Carbonell, LF (2000) Plasma redox status relates to severity in critically ill patients. Critical Care Medicine 28, 1812–1814.Google Scholar
Anderson, ME (1998) Glutathione: an overview of biosynthesis and modulation. Chemico-Biological Interactions 111–112, 1–14.Google Scholar
Arenkov, P, Kukhtin, A, Gemmell, A, Voloschchuk, S, Chupeeva, V & Mirabekov, A (2000) Protein microchips: use for immunoassay and enzymatic reactions. Analytical Biochemistry 278, 123–131.CrossRefGoogle ScholarPubMed
Arrigo, A-P (1999) Gene expression and the thiol redox state. Free Radical Biology and Medicine 27, 936–944.Google Scholar
Badman, ER & Cooks, RG (2000) Miniature mass analyzers. Journal of Mass Spectrometry 35, 659–671.Google Scholar
Balagopal, P, Rooyackers, OE, Adey, DB, Ades, PA & Nair, KS (1997) Effects of aging on in vivo synthesis of skeletal muscle myosin heavy-chain and sarcoplasmic protein in humans. American Journal of Physiology 273, E790–E800.Google ScholarPubMed
Barrett, PHR, Bell, BM, Cobelli, C, Glode, H, Schumitzky, A, Vicini, P & Foster, DM (1998) SAAM II: Simulation, analysis and modeling software for tracer and pharmacokinetic studies. Metabolism 47, 484–493.CrossRefGoogle ScholarPubMed
Boger, RH, Bode-Boger, SM, Sydow, K, Heistd, DD & Lentz, SR (2000) Plasma concentration of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, is elevated in monkeys with hyperhomocyst(e)inemia or hypercholesterolemia. Arteriosclerosis, Thrombosis and Vascular Biology 20, 1557–1564.Google Scholar
Boucher, JL, Moali, C & Tenu, JP (1999) Nitric oxide biosynthesis, nitric oxide synthesis inhibitors and arginase competition for L-arginine utilization. Cellular and Molecular Life Sciences 55, 1015–1028.CrossRefGoogle ScholarPubMed
Brattström, L & Wilcken, DEL (2000) Homocysteine and cardiovascular disease: cause or effect? American Journal of Clinical Nutrition 72, 315–323.CrossRefGoogle ScholarPubMed
Breullie, D, Farges, MC, Rose, F, Arnal, M, Attaix, D & Obled, C (1993) Pentoxifylline decreases body weight loss and muscle protein wasting characteristics of sepsis. American Journal of Physiology 265, E660–E666.Google Scholar
Butler, D (2000) Souped-up search engines. Nature 405, 112–115.CrossRefGoogle ScholarPubMed
Castillo, L, Beaumier, L, Ajami, AM & Young, VR (1996) Whole body nitric oxide synthesis in healthy men determined from [15N\arginine-to-[15N\citrulline labeling. Proceedings of the National Academy of Sciences USA 93, 11460–11465.CrossRefGoogle ScholarPubMed
Chambers, JC, McGregor, A, Jean-Marie, J, Obeid, OA & Kooner, JS (1999) Demonstration of rapid onset vascular endothelial dysfunction after hyperhomocysteinemia: an effect reversible with vitamin C therapy. Circulation 99, 1156–1160.CrossRefGoogle ScholarPubMed
Chang, CI, Lia, JC & Kuo, L (1998) Arginase modulates nitric oxide production in activated macrophages. American Journal of Physiology 274, H342–H348.Google ScholarPubMed
Cheng, H, Jusko, WHJ & Gillespie, WR (1991) Relationships between the area under the first moment curve after single bolus injection and the integral of plasma concentrations after constant-rate intravenous infusion. Journal of Pharmacological Sciences 80, 507–510.CrossRefGoogle ScholarPubMed
Chow, K, Cheung, F, Lao, TT & OK, (1999) Effect of homocysteine on the production of nitric oxide in endothelial cells. Clinical and Experimental Pharmacology and Physiology 26, 817–818.Google Scholar
Cobelli, C, Saccomani, MP, Tessari, P, Biolo, G, Luzi, L & Matthews, DE (1991) Compartmental model of leucine kinetics in humans. American Journal of Physiology 261, E539–E550.Google ScholarPubMed
Cunningham, DF & O'Connor, BD (1997) Proline specific peptidases. Biochimica et Biophysica Acta 1343, 160–186.Google Scholar
Cyrano(tm) Sciences (2000) A Tour of the Cyranose 320. http://www.cyranosciences.com Google Scholar
D'Ari, R & Casadesus, J (1998) Underground metabolism. Bioessays 20, 181–186.Google Scholar
Dröge, W (1999) Cysteine and glutathione in catabolic conditions and immunological dysfunction. Current Opinion in Clinical Nutrition and Metabolic Care 2, 227–233.Google Scholar
Dröge, W & Holm, E (1997) Role of cysteine and glutathione in HIV infection and other diseases associated with muscle wasting and immunologial dysfunction. FASEB Journal 11, 1077–1089.Google Scholar
Dudman, NPB (1999) An alternative view of homocysteine. Lancet 354, 2072–2074.Google Scholar
El-Khoury, AE, Fukagawa, NK, Sánchez, M, Tsay, RH, Gleason, RE, Chapman, TE & Young, VR (1994 a) Validation of the tracer balance concept with reference to leucine. 24-h Intravenous tracer studies with L-[1-13C\leucine and [15N-15N\urea. American Journal of Clinical Nutrition 59, 1000–1011.Google Scholar
El-Khoury, AE, Fukagawa, NK, Sánchez, M, Tsay, RH, Gleason, RE, Chapman, TE & Young, VR (1994 b) The 24 hour pattern and rate of leucine oxidation, with particular reference to tracer estimates of leucine requirements in healthy adults. American Journal of Clinical Nutrition 59, 1012–1020.Google Scholar
ENSEMBL: The European Bioinformatics Institute (2000) Gene Sweepstake. http://www.ensembl.org/genesweep.html Google Scholar
Evans, WJ (1998) Exercise and nutritional needs of elderly people. Gerontology 15, 15–24.Google ScholarPubMed
Figeys, D & Pinto, D (2000) Lab-on-a-chip: A revolution in biological and medical sciences. Analytical Chemistry 72, 330A–335A.Google Scholar
Finkelstein, JD (2000) Homocysteine: a history of progress. Nutrition Reviews 58, 193–204.Google Scholar
Finkelstein, JD & Martin, JJ (2000) Homocysteine. International Journal of Biochemistry and Cell Biology 32, 385–389.Google Scholar
Fodinger, M, Buchmayer, H & Sunder-Plassmann, G (1999) Molecular genetics of homocysteine metabolism. Mineral and Electrolyte Metabolism 25, 269–278.Google Scholar
Fodinger, M, Horl, WH & Sunder-Plassmann, G (2000) Molecular biology of 5,10-methylenetetrahydrafolate reductase. Journal of Nephrology 13, 20–33.Google Scholar
France, J, Hanigan, MD, Reynolds, CK, Dijkstra, J, Compton, LA, Maas, JA, Bequette, BJ, Metcalf, JA, Lobley, GE, MacRae, JC & Beever, DE (1999) An isotope dilution model for partitioning leucine uptake by the liver of the lactating dairy cow. Journal of Theoretical Biology 198, 121–133.Google Scholar
Fukagawa, NK, Hercules, E & Ajami, AM (2000 a) L-2-[13C\oxothiazolidine-4-carboxylic acid: A probe for precursor mobilization for glutathione synthesis. American Journal of Physiology 278, E171–E176.Google Scholar
Fukagawa, NK, Martin, JJ, Wurthmann, A, Prue, AH, Ebenstein, D & O'Rourke, B (2000 b) Sex related differences in methionine metabolism and plasma homocysteine concentrations. American Journal of Clinical Nutrition 72, 22–29.Google Scholar
Griffith, OW (1999) Biologic and pharmacologic regulation of mammalian glutathione synthesis. Free Radical Biology and Medicine 27, 922–935.CrossRefGoogle ScholarPubMed
Griffith, OW & Mulcahy, RT (1999) The enzymes of glutathione synthesis: γ-glutamylcysteine synthetase. Advances in Enzymology and Related Areas of Molecular Biology 73, 209–267.Google Scholar
Guetens, G, van CaurvenGerghe, K, De Boeck, G, Maes, R, Tjaden, UR, van der Greef, J, Highley, M, Van Oosterom, AT & de Bruijn, EA (2000) Nanotechnology in bio/clinical analysis. Journal of Chromatography 739B, 139–150.Google Scholar
Harper, ME, Monemdjou, S, Ramsey, JJ & Weindruch, R (1998) Age related increase in mitochondrial proton leak and decrease in ATP turnover reactions in mouse hepatocytes. American Journal of Physiology 275, E197–E206.Google ScholarPubMed
Harris, ED (2000) Differential CR and DNA microarrays: the modern era of nutritional investigations. Nutrition 16, 714–715.Google Scholar
Heidelberg, JF, Eisen, JA, Nelson, WC, Clayton, RA et al. . (2000) DNA sequence of both chromosomes of cholera pathogen Vibrio cholerae . Nature 406, 477–483.Google Scholar
Heyman, MB, Young, VR, Fuss, B, Tsay, R, Joseph, L & Roberts, SB (1992) Underfeeding and body weight regulation in normal weight young men. American Journal of Physiology 263, R250–R257.Google Scholar
Ikeda, U, Ikeda, M, Minota, S & Shimada, K (1999) Homocysteine increases nitric oxide synthesis in cytokine-stimulated vascular smooth muscle cells. Circulation 99, 1230–1235.CrossRefGoogle ScholarPubMed
Institute for Clinical Research, Kyoto University and the Human Genome Center of the University of Tokyo (2000) GenomeNet Database. http://www.genome.ad.jp Google Scholar
Ishii, Y, Asai, S, Kohno, T, Suzuki, S, Ishii, M, Hosoi, I, Fujii, M, Iwai, S & Ishikawa, K (1999) 13CO2 peak value of L-[1-13C\phenylalanine breath test reflects hepatopathy. Journal of Surgical Research 86, 130–135.Google Scholar
Jahoor, F, Jackson, A, Gazzard, B, Philips, G, Sharpstone, D, Frazer, ME & Heird, W (1999) Erythrocyte glutathione deficiency in symptom-free HIV infection is associated with decreased synthesis rate. American Journal of Physiology 276, E205–E211.Google Scholar
Jahoor, F, Wykes, LJ, Reeds, PJ, Henry, JF, del Rosario, MP & Frazer, ME (1995) Protein-deficient pigs cannot maintain reduced glutathione homeostasis when subjected to the stress of inflammation. Journal of Nutrition 125, 1462–1472.Google Scholar
Jasny, BR (2000) The universe of Drosophila genes. Science 287, 2181.Google Scholar
Jeffery, CJ (1999) Moonlighting proteins. Trends in Biochemical Sciences 24, 8–11.Google Scholar
Jones, WHS (editor) (1931 a) Hippocrates Nature of Man, pp. 1–42. Cambridge, MA: Harvard University Press.Google Scholar
Jones, WHS (editor) (1931 b) Heracleitus On the Universe, pp. 449–509. Cambridge, MA: Harvard University Press.Google Scholar
Jucker, BM, Dufour, S, Ren, J, Cao, X, Previs, SF, Underhill, B, Cadman, KS & Shulman, GL (2000) Assessment of mitochondrial energy coupling in vivo by 13C/31P NMR. Proceedings of the National Academy of Sciences USA 97, 6880–6884.CrossRefGoogle Scholar
Kanani, PM, Sinkey, CA, Browning, RL, Allaman, M, Knapp, HR & Haynes, WG (1999) Role of oxidant stress in endothelial dysfunction produced by experimental hyperhomocyst(e)inemia in humans. Circulation 100, 1161–1168.CrossRefGoogle ScholarPubMed
Kato, T & Sano, M (1993) Effect of ammonium chloride on homocitrulline and homoarginine synthesis. Journal of Inherited Metabolic Disease 16, 906–907.CrossRefGoogle ScholarPubMed
Kato, T, Sano, M & Mizutani, N (1989) Homocitrullinuria and homoargininuria in lysinuric protein intolerance. Journal of Inherited Metabolic Disease 12, 906–907.Google Scholar
Kato, T, Sano, M, Mizutani, N & Hayakawa, C (1988) Homocitrullinuria and homoargininuria in hyper-argininaemia. Journal of Inherited Metabolic Disease 11, 261–265.CrossRefGoogle Scholar
Katz, J (1989) The determination of mass of metabolites with tracers. Metabolism 38, 728–733.CrossRefGoogle ScholarPubMed
Kaufman, S (1991) Some metabolic relationships between biopterin and folate: Implications for the 'methyl trap hypothesis'. Neurochemical Research 16, 1031–1036.Google Scholar
Kay, BK, Williamson, MP & Sudal, M (2000) The importance of being proline: the interaction of proline-rich motifs in signaling proteins with their cognate domains. FASEB Journal 14, 231–241.CrossRefGoogle ScholarPubMed
Kohno, T, Hosoi, I, Oshima, J & Shibata, K (1998) Diagnostic agent for diabetics. European Patent Application EP0826377A1.Google Scholar
Krumdieck, CL & Prince, CW (2000) Mechanisms of homocysteine toxicity on connective tissues: implications for the morbidity of aging. Journal of Nutrition 130, 365S–368S.Google Scholar
Kuhn, TS (1970) The Structure of Scientific Revolutions, 2nd ed., pp. 15–16. Chicago, IL: The University of Chicago Press.Google Scholar
Lander, ES (1999) Array of hope. Nature Genetics 21, Suppl., 3–4.CrossRefGoogle ScholarPubMed
Lander, ES & Weinberg, RA (2000) Journey to the center of biology. Science 287, 1777–1782.Google Scholar
Lau, T, Owen, W, Ya, YM, Noviski, N, Lyons, J, Zurakowski, D, Tsay, R, Ajami, A, Young, VR & Castillo, L (2000) Arginine, citrulline, and nitric oxide metabolism in end-stage renal disease patients. Journal of Clinical Investigation 105, 1217–1225.Google Scholar
Laughlin, RB & Pines, D (2000) The theory of everything. Proceedings of the National Academy of Sciences USA 97, 28–31.CrossRefGoogle ScholarPubMed
Lee, B, Yu, H, Jahoor, F, O'Brien, W, Beaudet, AL & Reeds, P (2000) In vivo urea cycle flux distinguishes and correlates with phenotypic severity in disorders of the urea cycle. Proceedings of the National Academy of Sciences USA 97, 8021–8026.CrossRefGoogle ScholarPubMed
Lee, C-K, Klopp, RG, Weindruch, R & Prolia, TA (1999) Gene expression profile of aging and its retardation by caloric restriction. Science 285, 1390–1393.CrossRefGoogle ScholarPubMed
Liaudet, L, Soriano, FG & Szabó, C (2000) Biology of nitric oxide signaling. Critical Care Medicine 28, N37–N52.CrossRefGoogle ScholarPubMed
Linder, E & Buck, RP (2000) Microfabricated potentiometric electrodes and their in vivo applications. Analytical Chemistry 72, 336A–345A.Google Scholar
Lockhart, DJ & Winzeler, EA (2000) Genomics, gene expression and DNA arrays. Nature 405, 827–836.Google Scholar
Loscalzo, J (2000) What we know and don't know about L-arginine and NO. Circulation 101, 2126–2129.Google Scholar
Lowell, BB & Spiegelman, BM (2000) Toward a molecular understanding of adaptive thermogenesis. Nature 404, 652–660.Google Scholar
Lu, SC (1999) Regulation of hepatic glutathione synthesis: Current concepts and controversies. FASEB Journal 13, 1169–1183.Google Scholar
Lucky, R (2000) The quickening of science communication. Science 289, 259–264.Google Scholar
Lyons, J, Rauh-Pfeiffer, A, Yu, YM, Lu, X-M, Zurakowski, D, Curley, M, Collier, S, Duggan, C, Nurko, S, Thompson, J, Ajami, A, Borgonha, S, Young, VR & Castillo, L (2001) Cysteine metabolism and whole blood glutathione synthesis in septic pediatric patients. Critical Care Medicine (In the Press).CrossRefGoogle ScholarPubMed
Lyons, J, Rauh-Pfeiffer, A, Yu, YM, Lu, X-M, Zurakowski, D, Tsay, R, Ajami, A, Young, VR & Costillo, L (2000) Blood glutathione synthesis rates in healthy adults receiving a sulfur amino acid-free diet. Proceedings of the National Academy of Sciences USA 97, 5071–5076.Google Scholar
McNamara, PJ, Fleishaker, JC & Hayden, TL (1987) Mean residence time in peripheral tissues. Journal of Pharmacokinetics and Biopharmacology 15, 439–450.Google Scholar
Magistretti, PJ, Pellerin, L, Rothman, DL & Shulman, RG (1999) Energy on demand. Science 283, 496–497.Google Scholar
Malmezat, T, Breuille, D, Capitan, P, Mirand, PP & Obled, C (2000) Glutathione turnover is increased during the acute phase of sepsis in rats. Journal of Nutrition 130, 1239–1246.Google Scholar
Matthews, RG & Kaufman, S (1980) Characterization of dihydropterin reductase activity of pig liver methylenetetrahydrofolate reductase. Journal of Biological Chemistry 255, 6014–6017.Google Scholar
Marescau, B, DeDeyn, PP, Holvoet, J, Possemiers, I, Nagels, G, Saxenn, V & Mahler, C (1995) Guandinino compounds in serum and urine of cirrhotic patients. Metabolism 44, 584–588.Google Scholar
Marescau, B, Deshmukh, D, Kockx, M, Possemiers, I, Qureski, IA, Wiechert, P & DeDeyn, PP (1992) Guanidino compounds in serum, urine, liver, kidney, and brain of man and some ureotelic animals. Metabolism 41, 526–532.Google Scholar
Marx, J (2000) Interfering with gene expression. Science 288, 1370–1372.Google Scholar
Melanson, KJ, Saltzman, E, Vinken, AG, Russel, R & Roberts, SB (1998) The effects of age on post-prandial thermogenesis at four graded energetic challenges: findings in young and older men. Journal of Gerontology 53, B409–B414.Google Scholar
Metges, CC, Yu, Y-M, Cai, W, Lu, X-M, Wong, S, Ajami, AM & Young, VR (1999) Plasma L-5-oxoproline carbon and nitrogen kinetics in healthy young adults. Journal of Nutrition 129, 1998–2004.Google Scholar
Metges, CC, Yu, Y-M, Cai, W, Lu, X-M, Wong, S, Ajami, AM & Young, VR (2000) Oxoproline kinetics and oxoproline excretion during glycine- or sulfur amino acid-free diets in adults. American Journal of Physiology 278, E868–E876.Google Scholar
Metzger, N & Zare, RN (1999) Interdisciplinary research: From belief to reality. Science 283, 642–643.Google Scholar
Michikawa, Y, Mazzucchelli, F, Bresolin, N, Scarlato, G & Attardi, G (1999) Age-dependent large accumulation of point mutations in the human mtDNA control region for replication. Science 286, 774–779.Google Scholar
Moali, C, Boucher, JL, Sari, MA, Stuehr, DJ & Mansuy, D (1998) Substrate specificity of NO synthetases: detailed comparison of L-arginine, homo-L-arginine, their N omega-hydroxy derivatives, and omega-hydroxynor-L-arginine. Biochemistry 37, 10453–10460.CrossRefGoogle Scholar
Morley, JE (1997) Anorexia of aging: physiologic and pathologic. American Journal of Clinical Nutrition 66, 760–773.Google Scholar
O'Brien, PJ & Henshlag, D (1999) Catalytic promiscuity and the evolution of new enzyme activities. Chemistry and Biology 6, R91–R105.Google Scholar
Ogbourne, S & Antalis, TM (1998) Transcriptional control and the role of silencers in transcriptional regulation in eukaryotes. Biochemical Journal 331, 1–14.Google Scholar
Ortiz de Montellano, PR, Nishida, C, Rodriguez-Crespo, I & Gerber, N (1998) Nitric oxide synthase structure and electron transfer. Drug Metabolism and Disposition 26, 1223–1231.Google Scholar
Pennisi, E (1999) Aging research. Do mitochondrial mutations dim the fire of life? Science 286, 664.CrossRefGoogle ScholarPubMed
Phelps, ME (2000) Positron emission tomography provides molecular imaging of biological processes. Proceedings of the National Academy of Sciences USA 97, 9226–9233.CrossRefGoogle ScholarPubMed
Pennisi, E (2000) Human Genome Project. And the gene number is … ? Science 288, 1146–1147.Google Scholar
Powis, G, Briehl, M & Oblong, J (1995) Redox signaling and the control of cell growth and death. Pharmacology and Therapeutics 68, 149–173.Google Scholar
Reid, M, Badalloo, A, Forrester, T, Morlese, JF, Frazer, M, Heird, WC & Jahoor, F (2000) In vivo rates of erythrocyte glutathione synthesis in children with severe protein-energy malnutrition. American Journal of Physiology 278, E405–E412.Google Scholar
Rennie, MJ (1999) An introduction to the use of tracers in nutrition metabolism. Proceedings of the Nutrition Society 58, 935–944.Google Scholar
Ridley, A (2000) Molecular switches in metastasis. Nature 406, 466–467.Google Scholar
Roberts, SB (2000) Energy regulation and aging: recent findings and their implications. Nutritional Reviews 58, 91–97.Google Scholar
Roberts, SB, Fuss, P, Dallal, GE, Atkinson, A, Evans, WJ, Joseph, L, Fiatarone, MA, Greenberg, GS & Young, VR (1996 a) Effects of age on energy expenditure and substrate oxidation during experimental overfeeding in healthy men. Journal of Gerontology 51, B148–B157.Google Scholar
Roberts, SB, Fuss, P, Heyman, MB, Dallal, GE & Young, VR (1996 b) Effects of age on energy expenditure and substrate oxidation during experimental underfeeding in healthy men. Journal of Gerontology 51, B158–B166.Google Scholar
Roberts, SB, Fuss, P, Heyman, MB, Evans, WJ, Tsay, R, Rasmussen, H, Fiatarone, M, Cortiella, J, Dallol, GE & Young, VR (1994) Control of food intake in older men. Journal of the American Medical Association 272, 1601–1606.Google Scholar
Roberts, SB, Young, VR, Fuss, P, Fiatarone, MA, Richard, B, Rasmussen, H, Wagner, D, Holehouse, JH & Evans, WJ (1990) Energy expenditure and subsequent nutrient intakes in overfed young men. American Journal of Physiology 259, R461–R469.Google Scholar
Rooyackers, OE, Adey, JB, Ades, PA & Nair, KS (1996) Effect of age on in vivo rates of mitochondrial protein synthesis in human skeletal muscle. Proceedings of the National Academy of Sciences USA 93, 15364–15369.Google Scholar
Rubanyi, GM (editor) (1999 a) Pathophysiology and Clinical Applications of Nitric Oxide, part A. Amsterdam, The Netherlands: Harwood Academic Publishers.Google Scholar
Rubanyi, GM (editor) (1999 b) Pathophysiology and Clinical Applications of Nitric Oxide, part B. Amsterdam, The Netherlands: Harwood Academic Publishers.Google Scholar
Rubin, GM, Yandell, MD, Wortman, JR, Miklos, GLG, Nelson, CR, Hariharan, IK et al. . (2000) Comparative genomics of the eukaryotes. Science 287, 2204–2215.Google Scholar
Said, HM, Chenoweth, M & Dunn, A (1989) Metabolism of 3H- and 14C-labeled glutamate, proline, and alanine in normal and adrenalectomized rats using different sites of tracer administration and sampling. Metabolism 38, 718–727.Google Scholar
Schindler, K, Zouner, C, Buchmeyer, H, Födinger, M, Wölfe, G, Bieglmeyer, C, Heinz, G, Wilfing, A, Hörl, WH & Sunder-Plassmann, G (2000) High prevalence of hyperhomocysteinemia in critically ill patients. Critical Care Medicine 28, 991–995.Google Scholar
Schwartz, MW, Woods, SC, Porte, D Jr, Seeley, RJ & Baskin, DG (2000) Central nervous system control of food intake. Nature 404, 652–660.Google Scholar
Scott, JM (2000) Homocysteine and cardiovascular risk. American Journal of Clinical Nutrition 72, 333–334.Google Scholar
Selhub, J (1999) Homocysteine metabolism. Annual Reviews of Nutrition 19, 217–246.Google Scholar
Seshardi, N & Robinson, K (2000) Homocysteine, B vitamins, and coronary artery disease. Medical Clinics of North America 84, 215–237.Google Scholar
Sies, H (1999) Glutathione and its role in cellular functions. Free Radical Biology and Medicine 27, 916–921.Google Scholar
Simpson, AJG, Reinach, FC, Arruda, P, Abreu, FA et al. . (2000) The genome sequence of the plant pathogen Xylella fastidiosa . Nature 406, 151–157.Google Scholar
Stroes, E, Kastelein, J, Cosentino, F, Erkelens, W, Wever, R, Koomans, H, Luscher, T & Rabelink, T (1997) Tetrahydrobiopterin restores endothelial function in hypercholesterolemia. Journal of Clinical Investigation 99, 41–46.Google Scholar
Ubbink, JB & Delport, R (2000) Homocysteine as atherothrombotic agent: is the bark worse than the bite? Nutrition 16, 672–674.Google Scholar
Ueland, PM, Refsum, H, Beresford, SAA & Vollset, SE (2000) The controversy over homocysteine and cardiovascular risk. American Journal of Clinical Nutrition 72, 324–332.Google Scholar
Verhaar, MC, Wever, RMF, Kastelein, JP, Van Dam, T, Koomans, HA & Rabelink, TJ (1998) 5-Methyltetrahydrofolate, the active form of folic acid, restores endothelial function in familial hypercholesterolemia. Circulation 97, 237–241.Google Scholar
Verhaar, MC, Wever, RMF, Kastelein, JP, Van Loon, D, Milstien, S, Koomans, HA & Rabelink, TJ (1999) Effects of oral folic acid supplementation on endothelial function in familial hypercholesterolemia. A randomized placebo-controlled trial. Circulation 100, 335–338.Google Scholar
Voehringer, DW (1999) BCL-2 and glutathione: Alterations in cellular redox state that regulate apoptosis sensitivity. Free Radical Biology and Medicine 27, 945–950.Google Scholar
Voet, D & Voet, JG (1995) Biochemistry, 2nd ed., p. 143. New York: John Wiley & Sons, Inc. Google Scholar
Volpi, E, Ferrando, AA, Yeckel, CW, Tipton, KD & Wolfe, RR (1998) Exogenous amino acids stimulate net muscle protein synthesis in the elderly. Journal of Clinical Investigation 101, 2000–2007.Google Scholar
Volpi, E, Mittendorfer, B, Wolfe, SE & Wolfe, RR (1999) Oral amino acids stimulate muscle protein anobolism in the elderly despite higher first-pass splanchnic extraction. American Journal of Physiology 277, E513–E520.Google Scholar
Vukmirovic, OG & Tilghman, SM (2000) Exploring genome space. Nature 405, 820–822.Google Scholar
Wagner, JG (1976) Linear pharmacokinetic equations allowing direct calculation of many needed pharmacokinetic parameters from the coefficients and exponents of polyexponential equations which have been fitted to the data. Journal of Pharmacokinetics and Biopharmacology 4, 443–467.Google Scholar
Wagner, JG (1993) Pharmacokinetics for the Pharmaceutical Scientist, pp. 1–316. Lancaster, PA: Technomic Publishing Co. Google Scholar
Waterlow, JC (1995) Whole-body protein turnover in humans – past, present and future. Annual Reviews of Nutrition 15, 57–92.Google Scholar
Weindrich, R & Sohal, RS (1997) Seminars in medicine of the Beth Israel Deaconess Medical Center: Caloric intake and aging. New England Journal of Medicine 337, 986–994.Google Scholar
Weir, DG & Scott, JM (1998) Homocysteine as a risk factor for cardiovascular and related disease: nutritional implications. Nutrition Research Reviews 11, 311–338.Google Scholar
Welch, CN & Loscalzo, J (1998) Homocysteine and atherothrombosis. New England Journal of Medicine 338, 1042–1050.Google Scholar
Welle, SC, Thornton, C, Jozefowicz, R & Statt, M (1993) Myofibrillar protein synthesis in young and old men. American Journal of Physiology 264, E693–E698.Google Scholar
Wickware, P (2000) Next-generation biologists must straddle computation and biology. Nature 404, 683–684.Google Scholar
Yarasheski, KE, Zachwieja, JJ & Bier, DM (1993) Acute effects of resistance exercise on muscle protein synthesis in young and elderly men and women. American Journal of Physiology 265, E210–E214.Google Scholar
Young, VR (1992) Macronutrient needs in the elderly. Nutrition Reviews 50, 454–462.Google Scholar
Young, VR & Ajami, AM (1999 a) 1999 Jonathan E Rhoads Lecture. Isotopic metaprobes, nutrition and the roads ahead. Journal of Parental and Enteral Nutrition 23, 175–194.Google Scholar
Young, VR & Ajami, AM (1999 b) Isotopes in nutritional research. Proceedings of the Nutrition Society 58, 15–32.Google Scholar
Young, VR & Ajami, AM (2000) Glutamate: An amino acid of particular distinction. Journal of Nutrition 130, 892S–900S.Google Scholar
Young, VR, Borgonha, S & Ajami, AM (2000) Trends in tracer techniques, including use of positron emission tomography. Diabetes, Nutrition and Metabolism 13, 35–45.Google Scholar
Yu, Y-M, Ryan, CM, Burke, JF, Tompkins, RG & Young, VR (1995 a) Relations among arginine, citrulline, ornithine, and leucine kinetics in adult burn patients. American Journal of Clinical Nutrition 62, 960–968.CrossRefGoogle ScholarPubMed
Yu, Y-M, Ryan, CM, Castillo, L, Lu, X-M, Beaumier, L, Tompkins, RG & Young, VR (2000) Arginine and ornithine kinetics in severely burned patients: Increased rate of arginine disposal. American Journal of Physiology (In the Press).Google Scholar
Yu, Y-M, Young, VR, Castillo, L, Chapman, TE, Tompkins, RG, Ryan, CM & Burke, JF (1995 b) Plasma arginine and leucine kinetics and urea production rates in burn patients. Metabolism 44, 659–666.Google Scholar
Yu, Y-M, Sheridan, RL, Burke, JF, Chapman, TE, Tompkins, RG & Young, VR (1996) Kinetics of plasma arginine and leucine in pediatric burn patients. American Journal of Clinical Nutrition 64, 60–66.Google Scholar
Yu, Y-M, Tompkins, RG, Ryan, CM & Young, VR (1999) The metabolic basis of the rise in severely burned patients. Journal of Parenteral and Enteral Nutrition 23, 160–168.Google Scholar