中文摘要
健康老化與延長健康最大壽命，是近年來備受關注的議題。飲食熱量限制是增加壽命的方式之一，而進一步研究指出，減少蛋白質中蛋胺酸 (Methionine) 之攝取量更是增加壽命的關鍵因素之一。此外，若輔以耐力運動是否具有修飾的作用，有待進一步探討。目的:探討飲食中不同蛋胺酸含量於8週耐力運動訓練，對成長中大鼠體內胰島素/類胰島素生長因子-1軸（insulin/IGF-1 axis）、骨骼肌有氧代謝功能與氧化壓力的影響，同時亦將探討其間的關聯性。方法:將72隻7週大雄性SD大鼠，分為單純飲食控制之組別: 0.86%蛋胺酸 (0.86﹪Met) 組(n=12)、0.52%Met組(n=12)和0.17%Met組(n=12)，以及飲食控制同時進行運動訓練組，包括:0.86%Met+EXE組(n=12)、0.52%Met+EXE組(n=12)、0.17%Met+EXE組(n=12)共6組。於8週運動訓練結束後，取血液與骨骼肌組織進行分析。以two-way ANOVA (飲食x運動)進行組間考驗 (α=.05)，達顯著水準時 (p<.05) 以LSD方法進行事後比較。結果：於血液指標中，硫代巴比妥酸反應物質 (Thiobarbituric Acid Reactive Substances, TBARS)、胰島素（Insulin)、類胰島素連結蛋白-3 (Insulin-like growth factor binding protein- 3, IGFBP-3)、IGF-1/IGFBP-3比率等，均同時在飲食與運動的主要效果上達顯著差異 (TBARS：非運動組>運動組，0.86%組>0.17%組；Insulin：非運動組>運動組，0.52%>0.86%>0.17%；IGFBP-3：非運動組>運動組，0.52%>0.17%；IGF-1/IGFBP-3：非運動組>運動組，0.86%組>0.17%組、0.52%組>0.17%組)，瘦體素（Leptin)在運動的效果上達顯著差異(非運動組>運動組)，脫氫異雄固酮-硫酸鹽（Dehydroepiandrosterone sulfate, DHEA-S)在飲食的主要效果上達顯著差異(0.17%組>0.86%組)，IGF-1、IGFBP-1則於交互作用上達顯著水準 (IGF-1:在各種不同蛋胺酸飲食中運動的單純主要效果皆為非運動組>運動組；而在飲食的單純主要效果方面則為，非運動組：0.52%組>0.17%組、運動組:0.86%組>0.52%組>0.17%組)；於骨骼肌組織指標中，檸檬酸合成酶(citrate synthase,CS)同時在飲食與運動的主要效果上達顯著差異(運動組>非運動組，0.86%組>0.17%組、0.52%組>0.17%組)，IGF-1R、P-IGF-1R、IR於運動的主要效果上達顯著差異(皆為非運動組>運動組)，肌肉中的TBARS與GLUT-4則皆未達顯著水準。結論：減少飲食中80%蛋胺酸 (0.17%MET) 含量，對許多長壽指標的影響更勝於減少飲食中40%蛋胺酸含量 (0.52%MET)。長時間耐力運動訓練，對於蛋白質受器或激素的效應並不一定在於數量上以及濃度表現上的提高，而是在其敏感度與代謝效率上的增進。

Abstract

Recently, healthy aging and extending the maximum healthy life is one of the most popular issues. According to the caloric restriction-related studies, reduce dietary methionine intake can benefits on longevity. In addition, whether endurance exercise has modification effects on this methionine-restricted diet would be valuable for study. Purpose: To investigate the effects of different methionine-contained restriction diets (MetR) combined with 8 weeks endurance exercise training on insulin/IGF-1 axis, aerobic capacity and oxidative stress in skeletal muscles and Serum. Methods: male Sprague Dawley rats (7-week-old, n=72) were assigned to 6 groups (n=12 for each group), which were the 0.86% methionine (MET) group, the 0.52%MET group, the 0.17MET group, the 0.86%MET+exercise (EXE) group, the 0.52%MET+EXE group, the 0.17MET+EXE group. After 8 weeks diets and exercise intervension, animals were sacrificed, and skeletal muscle tissues and sera samples were collected for further analysis. Two-way ANOVA (Diet * Exercise) was used to compare the differences among groups (α=.05). When significant levels were reached, we used the LSD method for post hoc comparison. Result: In serum markers, Thiobarbituric Acid Reactive Substances (TBARS)、Insulin、Insulin-like growth factor-binding protein-3 (IGFBP-3)、IGF-1/IGFBP-3 ratio reached the significant level in the main effect of diet and exercise at the same time (TBARS：nonEXE>EXE，0.86%>0.17%；Insulin：nonEXE>EXE，0.52%>0.86%>0.17%；IGFBP-3：nonEXE>EXE，0.52%>0.17%；IGF-1/IGFBP-3：nonEXE>EXE，0.86%>0.17%、0.52%>0.17%)，leptin reached the significant level in the main effect of exercise (nonEXE>EXE)，Dehydroepiandrosterone sulfate (DHEAS) reached the significant level in the main effect of diet (0.17%>0.86%)，IGF-1、Insulin-like growth factor-binding protein -1 (IGFBP-1) reached the significant level in the interaction effect (IGF-1: the simple main effect of diet was nonEXE>EXE；the simple main effect of exercise was nonEXE：0.52%>0.17%、EXE:0.86%>0.52%>0.17%).In the skeletal muscle markers, CS reached the significant level in the main effect of diet and exercise at the same time (EXE>nonEXE，0.86%>0.17%、0.52%>0.17%)，IGF-1R、P-IGF-1R、IR all reached the significant level in the main effect of exercise (nonEXE>EXE ). TBARS and GLUT-4 in skeletal muscle did not show any significant levels. Conclusion: 0.17%Met diet showed a better effect on the longevity index as compared to the 0.52%Met diet. Possibly, the major beneficial of long-term endurance training on protein receptor and hormones is to improve their sensitivity rather than to increase their quantity or concentration.

參考文獻
戴桂英，王秀紅，林宜平，周麗端，翁惠瑛，王英偉,...林金定 (2009). 2020健康國民白皮書. 台北市: 行政院衛生署，財團法人國家衛生研究院.
Al-Regaiey, K. A., Masternak, M. M., Bonkowski, M., Sun, L., & Bartke, A. (2005). Long-lived growth hormone receptor knockout mice: interaction of reduced insulin-like growth factor i/insulin signaling and caloric restriction. Endocrinology, 146(2), 851-860.
Alleman, F., & Leclercq, B. (1997). Effect of dietary protein and environmental temperature on growth performance and water consumption of male broiler chickens. Br Poult Sci, 38(5), 607-610.
Barrett-Connor, E., Khaw, K. T., & Yen, S. S. (1986). A prospective study of dehydroepiandrosterone sulfate, mortality, and cardiovascular disease. N Engl J Med, 315(24), 1519-1524.
Barzilai, N., Banerjee, S., Hawkins, M., Chen, W., & Rossetti, L. (1998). Caloric restriction reverses hepatic insulin resistance in aging rats by decreasing visceral fat. J Clin Invest, 101(7), 1353-1361.
Bell, G. I., Burant, C. F., Takeda, J., & Gould, G. W. (1993). Structure and function of mammalian facilitative sugar transporters. J Biol Chem, 268(26), 19161-19164.
Berg, U., & Bang, P. (2004). Exercise and circulating insulin-like growth factor I. Horm Res, 62 Suppl 1, 50-58.
Bevilacqua, L., Ramsey, J. J., Hagopian, K., Weindruch, R., & Harper, M. E. (2005). Long-term caloric restriction increases UCP3 content but decreases proton leak and reactive oxygen species production in rat skeletal muscle mitochondria. Am J Physiol Endocrinol Metab, 289(3), E429-438.
Bjorntorp, P. (1991). Metabolic implications of body fat distribution. Diabetes Care, 14(12), 1132-1143.
Bogardus, C., Lillioja, S., Stone, K., & Mott, D. (1984). Correlation between muscle glycogen synthase activity and in vivo insulin action in man. J Clin Invest, 73(4), 1185-1190.
Boot, A. M., de Ridder, M. A., Pols, H. A., Krenning, E. P., & de Muinck Keizer-Schrama, S. M. (1997). Bone mineral density in children and adolescents: relation to puberty, calcium intake, and physical activity. J Clin Endocrinol Metab, 82(1), 57-62.
Boule, N. G., Weisnagel, S. J., Lakka, T. A., Tremblay, A., Bergman, R. N., Rankinen, T., et al. (2005). Effects of exercise training on glucose homeostasis: the HERITAGE Family Study. Diabetes Care, 28(1), 108-114.
Bourrin, S., Ammann, P., Bonjour, J. P., & Rizzoli, R. (2000). Dietary protein restriction lowers plasma insulin-like growth factor I (IGF-I), impairs cortical bone formation, and induces osteoblastic resistance to IGF-I in adult female rats. Endocrinology, 141(9), 3149-3155.
Breese, C. R., Ingram, R. L., & Sonntag, W. E. (1991). Influence of age and long-term dietary restriction on plasma insulin-like growth factor-1 (IGF-1), IGF-1 gene expression, and IGF-1 binding proteins. J Gerontol, 46(5), B180-187.
Brismar, K., Fernqvist-Forbes, E., Wahren, J., & Hall, K. (1994). Effect of insulin on the hepatic production of insulin-like growth factor-binding protein-1 (IGFBP-1), IGFBP-3, and IGF-I in insulin-dependent diabetes. J Clin Endocrinol Metab, 79(3), 872-878.
Brown-Borg, H. M. (2003). Hormonal regulation of aging and life span. Trends Endocrinol Metab, 14(4), 151-153.
Bua, E., McKiernan, S. H., & Aiken, J. M. (2004). Calorie restriction limits the generation but not the progression of mitochondrial abnormalities in aging skeletal muscle. FASEB J, 18(3), 582-584.
Cappon, J., Brasel, J. A., Mohan, S., & Cooper, D. M. (1994). Effect of brief exercise on circulating insulin-like growth factor I. J Appl Physiol, 76(6), 2490-2496.
Carmeli, E., Coleman, R., & Reznick, A. Z. (2002). The biochemistry of aging muscle. Exp Gerontol, 37(4), 477-489.
Caro, P., Gomez, J., Lopez-Torres, M., Sanchez, I., Naudi, A., Portero-Otin, M., et al. (2008). Effect of every other day feeding on mitochondrial free radical production and oxidative stress in mouse liver. Rejuvenation Res, 11(3), 621-629.
Chicharro, J., Lopez-Calderon, A., Hoyos, J., Martin-Velasco, A., Villa, G., & Villanua, M. (2001). effect of an endurance cycling competiton on resting serum insulin-like growth factor I(IGF-I) and its binding proteins IGFBP-1 and IGFBP-3. Br J Sports Med, 35, 303-307.
Christ, C. Y., Hunt, D., Hancock, J., Garcia-Macedo, R., Mandarino, L. J., & Ivy, J. L. (2002). Exercise training improves muscle insulin resistance but not insulin receptor signaling in obese Zucker rats. J Appl Physiol, 92(2), 736-744.
Civitarese, A. E., Carling, S., Heilbronn, L. K., Hulver, M. H., Ukropcova, B., Deutsch, W. A., et al. (2007). Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS Med, 4(3), e76.
Clark, R. P., Schuenke, M., Keeton, S. M., Staron, R. S., & Kopchick, J. J. (2006). Effects of growth hormone and insulin-like growth factor I on muscle in mouse models of human growth disorders. Horm Res, 66 Suppl 1, 26-34.
Clemmons, D. R. (2009). Role of IGF-I in skeletal muscle mass maintenance. Trends Endocrinol Metab, 20(7), 349-356.
Coleman, R. A., & Herrmann, T. S. (1999). Nutritional regulation of leptin in humans. Diabetologia, 42(6), 639-646.
Cortez, M. Y., Torgan, C. E., Brozinick, J. T., Jr., & Ivy, J. L. (1991). Insulin resistance of obese Zucker rats exercise trained at two different intensities. Am J Physiol, 261(5 Pt 1), E613-619.
Cortright, R. N., Chandler, M. P., Lemon, P. W., & DiCarlo, S. E. (1997). Daily exercise reduces fat, protein and body mass in male but not female rats. Physiol Behav, 62(1), 105-111.
Coschigano, K. T., Clemmons, D., Bellush, L. L., & Kopchick, J. J. (2000). Assessment of growth parameters and life span of GHR/BP gene-disrupted mice. Endocrinology, 141(7), 2608-2613.
Dean, D. J., Brozinick, J. T., Jr., Cushman, S. W., & Cartee, G. D. (1998). Calorie restriction increases cell surface GLUT-4 in insulin-stimulated skeletal muscle. Am J Physiol, 275(6 Pt 1), E957-964.
DeFronzo, R. A., Jacot, E., Jequier, E., Maeder, E., Wahren, J., & Felber, J. P. (1981). The effect of insulin on the disposal of intravenous glucose. Results from indirect calorimetry and hepatic and femoral venous catheterization. Diabetes, 30(12), 1000-1007.
Dela, F., Mikines, K. J., von Linstow, M., Secher, N. H., & Galbo, H. (1992). Effect of training on insulin-mediated glucose uptake in human muscle. Am J Physiol, 263(6 Pt 1), E1134-1143.
Delafontaine, P. (1995). Insulin-like growth factor I and its binding proteins in the cardiovascular system. Cardiovasc Res, 30, 825-834.
Dohm, G. L., Sinha, M. K., & Caro, J. F. (1987). Insulin receptor binding and protein kinase activity in muscles of trained rats. Am J Physiol, 252(2 Pt 1), E170-175.
Douen, A. G., Ramlal, T., Cartee, G. D., & Klip, A. (1990). Exercise modulates the insulin-induced translocation of glucose transporters in rat skeletal muscle. FEBS Lett, 261(2), 256-260.
Eliakim, A., Brasel, J. A., Mohan, S., Barstow, T. J., Berman, N., & Cooper, D. M. (1996). Physical fitness, endurance training, and the growth hormone-insulin-like growth factor I system in adolescent females. J Clin Endocrinol Metab, 81(11), 3986-3992.
Eliakim, A., Brasel, J. A., Mohan, S., Wong, W. L., & Cooper, D. M. (1998). Increased physical activity and the growth hormone-IGF-I axis in adolescent males. Am J Physiol, 275(1 Pt 2), R308-314.
Eliakim, A., Scheett, T. P., Newcomb, R., Mohan, S., & Cooper, D. M. (2001). Fitness, training, and the growth hormone-->insulin-like growth factor I axis in prepubertal girls. J Clin Endocrinol Metab, 86(6), 2797-2802.
Flores, M. B., Fernandes, M. F., Ropelle, E. R., Faria, M. C., Ueno, M., Velloso, L. A., et al. (2006). Exercise improves insulin and leptin sensitivity in hypothalamus of Wistar rats. Diabetes, 55(9), 2554-2561.
Fontana, L., Weiss, E. P., Villareal, D. T., Klein, S., & Holloszy, J. O. (2008). Long-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3 concentration in humans. Aging Cell, 7(5), 681-687.
Frankiewicz-Jozko, A., Faff, J., & Sieradzan-Gabelska, B. (1996). Changes in concentrations of tissue free radical marker and serum creatine kinase during the post-exercise period in rats. Eur J Appl Physiol Occup Physiol, 74(5), 470-474.
Gazdag, A. C., Sullivan, S., Kemnitz, J. W., & Cartee, G. D. (2000). Effect of long-term caloric restriction on GLUT4, phosphatidylinositol-3 kinase p85 subunit, and insulin receptor substrate-1 protein levels in rhesus monkey skeletal muscle. J Gerontol A Biol Sci Med Sci, 55(1), B44-46; discussion B47-48.
Gollnick, P. D. (1986). Metabolic regulation in skeletal muscle: influence of endurance training as exerted by mitochondrial protein concentration. Acta Physiol Scand Suppl, 556, 53-66.
Gudbrandsen, O. A., Wergedahl, H., Liaset, B., Espe, M., & Berge, R. K. (2005). Dietary proteins with high isoflavone content or low methionine-glycine and lysine-arginine ratios are hypocholesterolaemic and lower the plasma homocysteine level in male Zucker fa/fa rats. Br J Nutr, 94(3), 321-330.
Hansen, P. A., Nolte, L. A., Chen, M. M., & Holloszy, J. O. (1998). Increased GLUT-4 translocation mediates enhanced insulin sensitivity of muscle glucose transport after exercise. J Appl Physiol, 85(4), 1218-1222.
Hawrylewicz, E. J., Huang, H. H., & Blair, W. H. (1991). Dietary soybean isolate and methionine supplementation affect mammary tumor progression in rats. J Nutr, 121(10), 1693-1698.
Hayashi, H., Yamaza, H., Komatsu, T., Park, S., Chiba, T., Higami, Y., et al. (2008). Calorie restriction minimizes activation of insulin signaling in response to glucose: potential involvement of the growth hormone-insulin-like growth factor 1 axis. Exp Gerontol, 43(9), 827-832.
Hebbelinck, M., Clarys, P., & De Malsche, A. (1999). Growth, development, and physical fitness of Flemish vegetarian children, adolescents, and young adults. Am J Clin Nutr, 70(3 Suppl), 579S-585S.
Heilbronn, L. K., de Jonge, L., Frisard, M. I., DeLany, J. P., Larson-Meyer, D. E., Rood, J., et al. (2006). Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: a randomized controlled trial. JAMA, 295(13), 1539-1548.
Helge, J. W., & Kiens, B. (1997). Muscle enzyme activity in humans: role of substrate availability and training. Am J Physiol, 272(5 Pt 2), R1620-1624.
Helmrich, S. P., Ragland, D. R., Leung, R. W., & Paffenbarger, R. S., Jr. (1991). Physical activity and reduced occurrence of non-insulin-dependent diabetes mellitus. N Engl J Med, 325(3), 147-152.
Holloszy, J. O., & Coyle, E. F. (1984). Adaptations of skeletal muscle to endurance exercise and their metabolic consequences. J Appl Physiol, 56(4), 831-838.
Holzenberger, M., Dupont, J., Ducos, B., Leneuve, P., Geloen, A., Even, P. C., et al. (2003). IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature, 421(6919), 182-187.
Huang, T. H., Chang, F. L., Lin, S. C., Liu, S. H., Hsieh, S. S., & Yang, R. S. (2008). Endurance treadmill running training benefits the biomaterial quality of bone in growing male Wistar rats. J Bone Miner Metab, 26(4), 350-357.
Huang, T. H., Lin, S. C., Chang, F. L., Hsieh, S. S., Liu, S. H., & Yang, R. S. (2003). Effects of different exercise modes on mineralization, structure, and biomechanical properties of growing bone. J Appl Physiol, 95(1), 300-307.
Huffman, D. M., Moellering, D. R., Grizzle, W. E., Stockard, C. R., Johnson, M. S., & Nagy, T. R. (2008). Effect of exercise and calorie restriction on biomarkers of aging in mice. Am J Physiol Regul Integr Comp Physiol, 294(5), R1618-1627.
Hughes, V. A., Fiatarone, M. A., Fielding, R. A., Kahn, B. B., Ferrara, C. M., Shepherd, P., et al. (1993). Exercise increases muscle GLUT-4 levels and insulin action in subjects with impaired glucose tolerance. Am J Physiol, 264(6 Pt 1), E855-862.
Janssen, J. A., & Lamberts, S. W. (2004). Igf-I and longevity. Horm Res, 62 Suppl 3, 104-109.
Jones, J., & Clemmons, D. (1995). Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev., 16, 3-34.
Juul, A., Scheike, T., Davidsen, M., Gyllenborg, J., & Jorgensen, T. (2002). Low serum insulin-like growth factor I is associated with increased risk of ischemic heart disease: a population-based case-control study. Circulation, 106(8), 939-944.
Kapahi, P., Boulton, M. E., & Kirkwood, T. B. (1999). Positive correlation between mammalian life span and cellular resistance to stress. Free Radic Biol Med, 26(5-6), 495-500.
Keizer, H., Janssen, G. M., Menheere, P., & Kranenburg, G. (1989). Changes in basal plasma testosterone, cortisol, and dehydroepiandrosterone sulfate in previously untrained males and females preparing for a marathon. Int J Sports Med, 10 Suppl 3, S139-145.
Kim, J. H., Kwak, H. B., Leeuwenburgh, C., & Lawler, J. M. (2008). Lifelong exercise and mild (8%) caloric restriction attenuate age-induced alterations in plantaris muscle morphology, oxidative stress and IGF-1 in the Fischer-344 rat. Exp Gerontol, 43(4), 317-329.
King, N. A., Burley, V. J., & Blundell, J. E. (1994). Exercise-induced suppression of appetite: effects on food intake and implications for energy balance. Eur J Clin Nutr, 48(10), 715-724.
Klip, A., & Paquet, M. R. (1990). Glucose transport and glucose transporters in muscle and their metabolic regulation. Diabetes Care, 13(3), 228-243.
Kraemer, R. R., Durand, R. J., Acevedo, E. O., Johnson, L. G., Kraemer, G. R., Hebert, E. P., et al. (2004). Rigorous running increases growth hormone and insulin-like growth factor-I without altering ghrelin. Exp Biol Med (Maywood), 229(3), 240-246.
Lane, M. A., Ingram, D. K., & Roth, G. S. (1995). Effects of aging and long-term calorie restriction on DHEA and DHEA sulfate in rhesus monkeys. Ann N Y Acad Sci, 774, 319-322.
Lass, A., Sohal, B. H., Weindruch, R., Forster, M. J., & Sohal, R. S. (1998). Caloric restriction prevents age-associated accrual of oxidative damage to mouse skeletal muscle mitochondria. Free Radic Biol Med, 25(9), 1089-1097.
Lawrence, M. C., McKern, N. M., & Ward, C. W. (2007). Insulin receptor structure and its implications for the IGF-1 receptor. Curr Opin Struct Biol, 17(6), 699-705.
Linnamo, V., Hakkinen, K., & Komi, P. V. (1998). Neuromuscular fatigue and recovery in maximal compared to explosive strength loading. Eur J Appl Physiol Occup Physiol, 77(1-2), 176-181.
Maffei, M., Halaas, J., Ravussin, E., Pratley, R. E., Lee, G. H., Zhang, Y., et al. (1995). Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med, 1(11), 1155-1161.
Mai, V., Colbert, L. H., Berrigan, D., Perkins, S. N., Pfeiffer, R., Lavigne, J. A., et al. (2003). Calorie restriction and diet composition modulate spontaneous intestinal tumorigenesis in Apc(Min) mice through different mechanisms. Cancer Res, 63(8), 1752-1755.
Malloy, V. L., Krajcik, R. A., Bailey, S. J., Hristopoulos, G., Plummer, J. D., & Orentreich, N. (2006). Methionine restriction decreases visceral fat mass and preserves insulin action in aging male Fischer 344 rats independent of energy restriction. Aging Cell, 5(4), 305-314.
Masoro, E. J. (2005). Overview of caloric restriction and ageing. Mech Ageing Dev, 126(9), 913-922.
Masoro, E. J., McCarter, R. J., Katz, M. S., & McMahan, C. A. (1992). Dietary restriction alters characteristics of glucose fuel use. J Gerontol, 47(6), B202-208.
Matsakas, A., Nikolaidis, M. G., Kokalas, N., Mougios, V., & Diel, P. (2004). Effect of voluntary exercise on the expression of IGF-I and androgen receptor in three rat skeletal muscles and on serum IGF-I and testosterone levels. Int J Sports Med, 25(7), 502-508.
Mattison, J. A., Lane, M. A., Roth, G. S., & Ingram, D. K. (2003). Calorie restriction in rhesus monkeys. Exp Gerontol, 38(1-2), 35-46.
McCarty, M. F., Barroso-Aranda, J., & Contreras, F. (2009). The low-methionine content of vegan diets may make methionine restriction feasible as a life extension strategy. Med Hypotheses, 72(2), 125-128.
McKoy, G., Leger, M. E., Bacou, F., & Goldspink, G. (1998). Differential expression of myosin heavy chain mRNA and protein isoforms in four functionally diverse rabbit skeletal muscles during pre- and postnatal development. Dev Dyn, 211(3), 193-203.
Mero, A. A., Huovinen, H., Matintupa, O., Hulmi, J. J., Puurtinen, R., Hohtari, H., et al. (2010). Moderate energy restriction with high protein diet results in healthier outcome in women. J Int Soc Sports Nutr, 7(1), 4.
Merry, B. J. (2002). Molecular mechanisms linking calorie restriction and longevity. Int J Biochem Cell Biol, 34(11), 1340-1354.
Miller, R. A., Buehner, G., Chang, Y., Harper, J. M., Sigler, R., & Smith-Wheelock, M. (2005). Methionine-deficient diet extends mouse lifespan, slows immune and lens aging, alters glucose, T4, IGF-I and insulin levels, and increases hepatocyte MIF levels and stress resistance. Aging Cell, 4(3), 119-125.
Moses, A. C., Young, S. C., Morrow, L. A., O'Brien, M., & Clemmons, D. R. (1996). Recombinant human insulin-like growth factor I increases insulin sensitivity and improves glycemic control in type II diabetes. Diabetes, 45(1), 91-100.
Moskovitz, J., Bar-Noy, S., Williams, W. M., Requena, J., Berlett, B. S., & Stadtman, E. R. (2001). Methionine sulfoxide reductase (MsrA) is a regulator of antioxidant defense and lifespan in mammals. Proc Natl Acad Sci U S A, 98(23), 12920-12925.
Nair, K. S. (2000). Age-related changes in muscle. Mayo Clin Proc, 75 Suppl, S14-18.
Orentreich, N., Matias, J. R., DeFelice, A., & Zimmerman, J. A. (1993). Low methionine ingestion by rats extends life span. J Nutr, 123(2), 269-274.
Pi-Sunyer, F. X., & Woo, R. (1985). Effect of exercise on food intake in human subjects. Am J Clin Nutr, 42(5 Suppl), 983-990.
Ploug, T., Galbo, H., & Richter, E. A. (1984). Increased muscle glucose uptake during contractions: no need for insulin. Am J Physiol, 247(6 Pt 1), E726-731.
Ploug, T., Stallknecht, B. M., Pedersen, O., Kahn, B. B., Ohkuwa, T., Vinten, J., et al. (1990). Effect of endurance training on glucose transport capacity and glucose transporter expression in rat skeletal muscle. Am J Physiol, 259(6 Pt 1), E778-786.
Poehlman, E. T., & Copeland, K. C. (1990). Influence of physical activity on insulin-like growth factor-I in healthy younger and older men. J Clin Endocrinol Metab, 71(6), 1468-1473.
Rayhill, S. C., Kirby, P. A., Voigt, M. D., La Brecque, D. R., Lutz, C. T., Katz, D. A., et al. (2005). Positive serum cryoglobulin is associated with worse outcome after liver transplantation for chronic hepatitis C. Transplantation, 80(4), 448-456.
Remer, T., Pietrzik, K., & Manz, F. (1998). Short-term impact of a lactovegetarian diet on adrenocortical activity and adrenal androgens. J Clin Endocrinol Metab, 83(6), 2132-2137.
Reseland, J. E., Anderssen, S. A., Solvoll, K., Hjermann, I., Urdal, P., Holme, I., et al. (2001). Effect of long-term changes in diet and exercise on plasma leptin concentrations. Am J Clin Nutr, 73(2), 240-245.
Richie, J. P., Jr., Leutzinger, Y., Parthasarathy, S., Malloy, V., Orentreich, N., & Zimmerman, J. A. (1994). Methionine restriction increases blood glutathione and longevity in F344 rats. FASEB J, 8(15), 1302-1307.
Rikken, B., van Doorn, J., Ringeling, A., Van den Brande, J. L., Massa, G., & Wit, J. M. (1998). Plasma levels of insulin-like growth factor (IGF)-I, IGF-II and IGF-binding protein-3 in the evaluation of childhood growth hormone deficiency. Horm Res, 50(3), 166-176.
Roberts, C. K., Vaziri, N. D., & Barnard, R. J. (2002). Effect of diet and exercise intervention on blood pressure, insulin, oxidative stress, and nitric oxide availability. Circulation, 106(20), 2530-2532.
Rodnick, K. J., Holloszy, J. O., Mondon, C. E., & James, D. E. (1990). Effects of exercise training on insulin-regulatable glucose-transporter protein levels in rat skeletal muscle. Diabetes, 39(11), 1425-1429.
Rosen, C. J., Dimai, H. P., Vereault, D., Donahue, L. R., Beamer, W. G., Farley, J., et al. (1997). Circulating and skeletal insulin-like growth factor-I (IGF-I) concentrations in two inbred strains of mice with different bone mineral densities. Bone, 21(3), 217-223.
Rosendal, L., Langberg, H., Flyvbjerg, A., Frystyk, J., Orskov, H., & Kjaer, M. (2002). Physical capacity influences the response of insulin-like growth factor and its binding proteins to training. J Appl Physiol, 93(5), 1669-1675.
Rossetti, L., & Giaccari, A. (1990). Relative contribution of glycogen synthesis and glycolysis to insulin-mediated glucose uptake. A dose-response euglycemic clamp study in normal and diabetic rats. J Clin Invest, 85(6), 1785-1792.
Roth, G. S., Lane, M. A., Ingram, D. K., Mattison, J. A., Elahi, D., Tobin, J. D., et al. (2002). Biomarkers of caloric restriction may predict longevity in humans. Science, 297(5582), 811.
Roy, D., & Marette, A. (1996). Exercise induces the translocation of GLUT4 to transverse tubules from an intracellular pool in rat skeletal muscle. Biochem Biophys Res Commun, 223(1), 147-152.
Salomon, F., Cuneo, R. C., Hesp, R., & Sonksen, P. H. (1989). The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency. N Engl J Med, 321(26), 1797-1803.
Sanz, A., Caro, P., Ayala, V., Portero-Otin, M., Pamplona, R., & Barja, G. (2006). Methionine restriction decreases mitochondrial oxygen radical generation and leak as well as oxidative damage to mitochondrial DNA and proteins. FASEB J, 20(8), 1064-1073.
Sanz, A., Caro, P., & Barja, G. (2004). Protein restriction without strong caloric restriction decreases mitochondrial oxygen radical production and oxidative DNA damage in rat liver. J Bioenerg Biomembr, 36(6), 545-552.
Sanz, A., Caro, P., Sanchez, J. G., & Barja, G. (2006). Effect of lipid restriction on mitochondrial free radical production and oxidative DNA damage. Ann N Y Acad Sci, 1067, 200-209.
Sanz, A., Gomez, J., Caro, P., & Barja, G. (2006). Carbohydrate restriction does not change mitochondrial free radical generation and oxidative DNA damage. J Bioenerg Biomembr, 38(5-6), 327-333.
Saunderson, C. L., & Mackinlay, J. (1990). Changes in body-weight, composition and hepatic enzyme activities in response to dietary methionine, betaine and choline levels in growing chicks. Br J Nutr, 63(2), 339-349.
Schantz, P., Henriksson, J., & Jansson, E. (1983). Adaptation of human skeletal muscle to endurance training of long duration. Clin Physiol, 3(2), 141-151.
Schurch, M. A., Rizzoli, R., Slosman, D., Vadas, L., Vergnaud, P., & Bonjour, J. P. (1998). Protein supplements increase serum insulin-like growth factor-I levels and attenuate proximal femur bone loss in patients with recent hip fracture. A randomized, double-blind, placebo-controlled trial. Ann Intern Med, 128(10), 801-809.
Schwarz, A. J., Brasel, J. A., Hintz, R. L., Mohan, S., & Cooper, D. M. (1996). Acute effect of brief low- and high-intensity exercise on circulating insulin-like growth factor (IGF) I, II, and IGF-binding protein-3 and its proteolysis in young healthy men. J Clin Endocrinol Metab, 81(10), 3492-3497.
Shimokawa, I., Higami, Y., Tsuchiya, T., Otani, H., Komatsu, T., Chiba, T., et al. (2003). Life span extension by reduction of the growth hormone-insulin-like growth factor-1 axis: relation to caloric restriction. FASEB J, 17(9), 1108-1109.
Smith, W. J., Nam, T. J., Underwood, L. E., Busby, W. H., Celnicker, A., & Clemmons, D. R. (1993). Use of insulin-like growth factor-binding protein-2 (IGFBP-2), IGFBP-3, and IGF-1 for assessing growth hormone status in short children. J Clin Endocrinol
Metab Syndr Relat Disord, 77, 1294-1299.
Sreekumar, R., Unnikrishnan, J., Fu, A., Nygren, J., Short, K. R., Schimke, J., et al. (2002). Effects of caloric restriction on mitochondrial function and gene transcripts in rat muscle. Am J Physiol Endocrinol Metab, 283(1), E38-43.
Sugimoto, T., Nishiyama, K., Kuribayashi, F., & Chihara, K. (1997). Serum levels of insulin-like growth factor (IGF) I, IGF-binding protein (IGFBP)-2, and IGFBP-3 in osteoporotic patients with and without spinal fractures. J Bone Miner Res, 12(8), 1272-1279.
Sun, L., Sadighi Akha, A. A., Miller, R. A., & Harper, J. M. (2009). Life-span extension in mice by preweaning food restriction and by methionine restriction in middle age. J Gerontol A Biol Sci Med Sci, 64(7), 711-722.
Takahashi, S., Kajikawa, M., Umezawa, T., Kato, H., Miura, Y., Nam, T. J., et al. (1990). Effect of dietary proteins on the plasma immunoreactive insulin-like growth factor-1/somatomedin C concentration in the rat. Br J Nutr, 63(3), 521-534.
Takenaka, A., Oki, N., Takahashi, S. I., & Noguchi, T. (2000). Dietary restriction of single essential amino acids reduces plasma insulin-like growth factor-I (IGF-I) but does not affect plasma IGF-binding protein-1 in rats. J Nutr, 130(12), 2910-2914.
Tsao, T. S., Katz, E. B., Pommer, D., & Charron, M. J. (2000). Amelioration of insulin resistance but not hyperinsulinemia in obese mice overexpressing GLUT4 selectively in skeletal muscle. Metabolism, 49(3), 340-346.
Vincent, A. M., & Feldman, E. L. (2002). Control of cell survival by IGF signaling pathways. Growth Horm IGF Res, 12(4), 193-197.
Wadden, T. A., Considine, R. V., Foster, G. D., Anderson, D. A., Sarwer, D. B., & Caro, J. S. (1998). Short- and long-term changes in serum leptin dieting obese women: effects of caloric restriction and weight loss. J Clin Endocrinol Metab, 83(1), 214-218.
Waly, M., Olteanu, H., Banerjee, R., Choi, S. W., Mason, J. B., Parker, B. S., et al. (2004). Activation of methionine synthase by insulin-like growth factor-1 and dopamine: a target for neurodevelopmental toxins and thimerosal. Mol Psychiatry, 9(4), 358-370.
Wang, C., Weindruch, R., Fernandez, J. R., Coffey, C. S., Patel, P., & Allison, D. B. (2004). Caloric restriction and body weight independently affect longevity in Wistar rats. Int J Obes Relat Metab Disord, 28(3), 357-362.
Wang, K., Li, D., & Sun, F. (2004). Dietary caloric restriction may delay the development of cataract by attenuating the oxidative stress in the lenses of Brown Norway rats. Exp Eye Res, 78(1), 151-158.
Warram, J. H., Martin, B. C., Krolewski, A. S., Soeldner, J. S., & Kahn, C. R. (1990). Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the offspring of diabetic parents. Ann Intern Med, 113(12), 909-915.
Welle, S. (2002). Cellular and molecular basis of age-related sarcopenia. Can J Appl Physiol, 27(1), 19-41.
Westerterp-Plantenga, M. S., Verwegen, C. R., Ijedema, M. J., Wijckmans, N. E., & Saris, W. H. (1997). Acute effects of exercise or sauna on appetite in obese and nonobese men. Physiol Behav, 62(6), 1345-1354.
Wetter, T. J., Gazdag, A. C., Dean, D. J., & Cartee, G. D. (1999). Effect of calorie restriction on in vivo glucose metabolism by individual tissues in rats. Am J Physiol, 276(4 Pt 1), E728-738.
Wojtaszewski, J. F., Higaki, Y., Hirshman, M. F., Michael, M. D., Dufresne, S. D., Kahn, C. R., et al. (1999). Exercise modulates postreceptor insulin signaling and glucose transport in muscle-specific insulin receptor knockout mice. J Clin Invest, 104(9), 1257-1264.
Xu, S., Gu, X., Pan, H., Zhu, H., Gong, F., Li, Y., et al. (2010). Reference Ranges for Serum IGF-1 and IGFBP-3 Levels in Chinese Children During Childhood and Adolescence. ENDOCRINE JOURNAL ADVANCE PUBLICATION, 57(3), 221-228.
Yakar, S., Rosen, C. J., Beamer, W. G., Ackert-Bicknell, C. L., Wu, Y., Liu, J. L., et al. (2002). Circulating levels of IGF-1 directly regulate bone growth and density. J Clin Invest, 110(6), 771-781.
Zachwieja, J. J., Hendry, S. L., Smith, S. R., & Harris, R. B. (1997). Voluntary wheel running decreases adipose tissue mass and expression of leptin mRNA in Osborne-Mendel rats. Diabetes, 46(7), 1159-1166.
Zainal, T. A., Oberley, T. D., Allison, D. B., Szweda, L. I., & Weindruch, R. (2000). Caloric restriction of rhesus monkeys lowers oxidative damage in skeletal muscle. FASEB J, 14(12), 1825-1836.
Zierath, J. R. (2002). Invited review: Exercise training-induced changes in insulin signaling in skeletal muscle. J Appl Physiol, 93(2), 773-781.
Zoll, J., Sanchez, H., N'Guessan, B., Ribera, F., Lampert, E., Bigard, X., et al. (2002). Physical activity changes the regulation of mitochondrial respiration in human skeletal muscle. J Physiol, 543(Pt 1), 191-200.