Effects of exercise training and resveratrol on vascular health in aging

Free Radical Biology and Medicine

Volumn 98, Issue , 2016, Pages 165-176

  Gliemann, Lasse ^a   Nyberg, Michael ^a   Hellsten, Ylva ^a  

^a UNIVERSITY OF COPENHAGEN   (Denmark)

Author keywords

Aging; Exercise training; Redox status; Resveratrol; Vascular function

Indexed keywords

NITRIC OXIDE; REACTIVE OXYGEN METABOLITE; RESVERATROL; STILBENE DERIVATIVE;

ADAPTATION; AGING; ANGIOGENESIS; ANTIOXIDANT ACTIVITY; ARTICLE; ATHEROSCLEROSIS; BIOAVAILABILITY; BLOOD PRESSURE; CARDIOVASCULAR FUNCTION; EXERCISE; HUMAN; INFLAMMATION; META ANALYSIS (TOPIC); MUSCLE BLOOD FLOW; MUSCLE CONTRACTION; NONHUMAN; PHYSICAL ACTIVITY; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); REDOX STRESS; REGULATORY MECHANISM; SENESCENCE; SKELETAL MUSCLE; VASCULARIZATION; ANIMAL; ARTERIAL STIFFNESS; CARDIOVASCULAR SYSTEM; DRUG EFFECTS; METABOLISM; OXIDATION REDUCTION REACTION; PHYSIOLOGY;

ADAPTATION, PHYSIOLOGICAL; AGING; ANIMALS; CARDIOVASCULAR PHYSIOLOGICAL PHENOMENA; CARDIOVASCULAR SYSTEM; EXERCISE; HUMANS; MUSCLE, SKELETAL; OXIDATION-REDUCTION; STILBENES; VASCULAR STIFFNESS;

EID: 84964668077     PISSN: 08915849     EISSN: 18734596     Source Type: Journal    
DOI: 10.1016/j.freeradbiomed.2016.03.037     Document Type: Article

References (176)

1. [1] Windecker, S., Alfonso, F., Collet, J.-P., Cremer, J., Falk, V., Filippatos, G., et al. ESC/EACTS Guidelines on myocardial revascularization: the Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur. J. Cardiothorac. Surg. 46:2014 (2014), 517–592, 10.1093/ejcts/ezu366.
2. [2] El Assar, M., Angulo, J., Rodríguez-Mañas, L., Oxidative stress and vascular inflammation in aging. Free Radic. Biol. Med. 65 (2013), 380–401, 10.1016/j.freeradbiomed.2013.07.003.
3. [3] Santos-Parker, J.R., LaRocca, T.J., Seals, D.R., Aerobic exercise and other healthy lifestyle factors that influence vascular aging. Adv. Physiol. Educ. 38 (2014), 296–307, 10.1152/advan.00088.2014.
4. [4] Wragg, J.W., Durant, S., McGettrick, H.M., Sample, K.M., Egginton, S., Bicknell, R., Shear stress regulated gene expression and angiogenesis in vascular endothelium. Microcirculation 21 (2014), 290–300, 10.1111/micc.12119.
5. [5] Newcomer, S.C., Thijssen, D.H.J., Green, D.J., Effects of exercise on endothelium and endothelium/smooth muscle cross talk: role of exercise-induced hemodynamics. J. Appl. Physiol. 111 (2011), 311–320, 10.1152/japplphysiol.00033.2011.
6. [6] Hansen, A.H., Nyberg, M., Bangsbo, J., Saltin, B., Hellsten, Y., Exercise training alters the balance between vasoactive compounds in skeletal muscle of individuals with essential hypertension. Hypertension 58 (2011), 943–949, 10.1161/HYPERTENSIONAHA.111.176529.
7. [7] Nyberg, M., Mortensen, S.P., Cabo, H., Gomez-Cabrera, M.-C., Viña, J., Hellsten, Y., Roles of sedentary aging and lifelong physical activity in exchange of glutathione across exercising human skeletal muscle. Free Radic. Biol. Med. 73 (2014), 166–173, 10.1016/j.freeradbiomed.2014.05.008.
8. [8] Andersen, P., Henriksson, J., Capillary supply of the quadriceps femoris muscle of man: adaptive response to exercise. J. Physiol. 270 (1977), 677–690.
9. [9] Bitterman, J.L., Chung, J.H., Metabolic effects of resveratrol: addressing the controversies. Cell. Mol. Life Sci. 72 (2015), 1473–1488, 10.1007/s00018-014-1808-8.
10. [10] Gliemann, L., Schmidt, J.F., Olesen, J., Biensø, R.S., Peronard, S.L., Grandjean, S.U., et al. Resveratrol blunts the positive effects of exercise training on cardiovascular health in aged men. J. Physiol. 591 (2013), 5047–5059.
11. [11] Gliemann, L., Olesen, J., Biensø, R.S., Biensø, R.S., Schmidt, J., Schmidt, J.F., et al. Resveratrol modulates the angiogenic response to exercise training in skeletal muscles of aged men. Am. J. Physiol. Heart Circ. Physiol. 307 (2014), H1111–H1119, 10.1152/ajpheart.00168.2014.
12. [12] Lakatta, E.G., Levy, D., Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part I: aging arteries: a “set up” for vascular disease. Circulation 107 (2003), 139–146.
13. [13] McEniery, C.M., Wallace, S., Mackenzie, I.S., McDonnell, B., Yasmin, Newby, D.E., et al. Endothelial function is associated with pulse pressure, pulse wave velocity, and augmentation index in healthy humans. Hypertension 48 (2006), 602–608, 10.1161/01.HYP.0000239206.64270.5f.
14. [14] Sun, Z., Aging, arterial stiffness, and hypertension. Hypertension 65 (2015), 252–256, 10.1161/HYPERTENSIONAHA.114.03617.
15. [15] Li, M., Fukagawa, N.K., Age-related changes in redox signaling and VSMC function. Antioxid. Redox Signal. 12 (2010), 641–655, 10.1089/ars.2009.2854.
16. [16] Widlansky, M.E., Gokce, N., Keaney, J.F., Vita, J.A., The clinical implications of endothelial dysfunction. J. Am. Coll. Cardiol. 42 (2003), 1149–1160.
17. [17] Taddei, S., Virdis, A., Ghiadoni, L., Salvetti, G., Bernini, G., Magagna, A., et al. Age-related reduction of NO availability and oxidative stress in humans. Hypertension 38 (2001), 274–279.
18. [18] Nyberg, M., Blackwell, J.R., Damsgaard, R., Jones, A.M., Hellsten, Y., Mortensen, S.P., Lifelong physical activity prevents an age-related reduction in arterial and skeletal muscle nitric oxide bioavailability in humans. J. Physiol. 590 (2012), 5361–5370, 10.1113/jphysiol.2012.239053.
19. [19] Vallance, P., Chan, N., Endothelial function and nitric oxide: clinical relevance. Heart 85 (2001), 342–350, 10.1136/heart.85.3.342.
20. [20] Kovacic, J.C., Moreno, P., Hachinski, V., Nabel, E.G., Fuster, V., Cellular senescence, vascular disease, and aging: part 1 of a 2-part review. Circulation 123 (2011), 1650–1660, 10.1161/CIRCULATIONAHA.110.007021.
21. [21] Stadtman, E.R., Protein oxidation in aging and age-related diseases. Ann. N. Y. Acad. Sci. 928 (2001), 22–38.
22. [22] Cosentino, F., Eto, M., De Paolis, P., van der Loo, B., Bachschmid, M., Ullrich, V., et al. High glucose causes upregulation of cyclooxygenase-2 and alters prostanoid profile in human endothelial cells: role of protein kinase C and reactive oxygen species. Circulation 107 (2003), 1017–1023.
23. [23] Seals, D.R., Jablonski, K.L., Donato, A.J., Aging and vascular endothelial function in humans. Clin. Sci. 120 (2011), 357–375, 10.1042/CS20100476.
24. [24] Bachschmid, M.M., Schildknecht, S., Matsui, R., Zee, R., Haeussler, D., Cohen, R.A., et al. Vascular aging: chronic oxidative stress and impairment of redox signaling-consequences for vascular homeostasis and disease. Ann. Med. 45 (2013), 17–36, 10.3109/07853890.2011.645498.
25. [25] Pillai, V.B., Sundaresan, N.R., Gupta, M.P., Regulation of Akt signaling by sirtuins: its implication in cardiac hypertrophy and aging. Circ. Res. 114 (2014), 368–378, 10.1161/CIRCRESAHA.113.300536.
26. [26] Rippe, C., Lesniewski, L., Connell, M., LaRocca, T., Donato, A., Seals, D., Short-term calorie restriction reverses vascular endothelial dysfunction in old mice by increasing nitric oxide and reducing oxidative stress. Aging Cell 9 (2010), 304–312, 10.1111/j.1474-9726.2010.00557.x.
27. [27] Kao, C.-L., Chen, L.-K., Chang, Y.-L., Yung, M.-C., Hsu, C.-C., Chen, Y.-C., et al. Resveratrol protects human endothelium from H(2)O(2)-induced oxidative stress and senescence via SirT1 activation. J. Atheroscler. Thromb. 17 (2010), 970–979.
28. [28] Gano, L.B., Donato, A.J., Pasha, H.M., Hearon, C.M., Sindler, A.L., Seals, D.R., The SIRT1 activator SRT1720 reverses vascular endothelial dysfunction, excessive superoxide production, and inflammation with aging in mice. Am. J. Physiol. Heart Circ. Physiol. 307 (2014), H1754–H1763, 10.1152/ajpheart.00377.2014.
29. [29] Ota, H., Akishita, M., Eto, M., Iijima, K., Kaneki, M., Ouchi, Y., Sirt1 modulates premature senescence-like phenotype in human endothelial cells. J. Mol. Cell. Cardiol. 43 (2007), 571–579, 10.1016/j.yjmcc.2007.08.008.
30. [30] Brunet, A., Sweeney, L.B., Sturgill, J.F., Chua, K.F., Greer, P.L., Lin, Y., et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303 (2004), 2011–2015, 10.1126/science.1094637.
31. [31] Lesniewski, L.A., Zigler, M.C., Durrant, J.R., Donato, A.J., Seals, D.R., Sustained activation of AMPK ameliorates age-associated vascular endothelial dysfunction via a nitric oxide-independent mechanism. Mech. Ageing Dev. 133 (2012), 368–371, 10.1016/j.mad.2012.03.011.
32. [32] Chen, Z., Peng, I.-C., Sun, W., Su, M.-I., Hsu, P.-H., Fu, Y., et al. AMP-activated protein kinase functionally phosphorylates endothelial nitric oxide synthase Ser633. Circ. Res. 104 (2009), 496–505, 10.1161/CIRCRESAHA.108.187567.
33. [33] Andersen, P., Saltin, B., Maximal perfusion of skeletal-muscle in man. J. Physiol. 366 (1985), 233–249.
34. [34] Nyberg, M., Piil, P., Egelund, J., Sprague, R.S., Mortensen, S.P., Hellsten, Y., Potentiation of cGMP signaling increases oxygen delivery and oxidative metabolism in contracting skeletal muscle of older but not young humans. Physiol. Rep., 3, 2015, e12508, 10.14814/phy2.12508.
35. [35] Nyberg, M., Hellsten, Y., Reduced blood flow to contracting skeletal muscle in ageing humans: is it all an effect of sand through the hourglass?. J. Physiol., 2015, 10.1113/JP270594.
36. [36] Proctor, D.N., Parker, B.A., Vasodilation and vascular control in contracting muscle of the aging human. Microcirculation 13 (2006), 315–327, 10.1080/10739680600618967.
37. [37] Kirby, B.S., Voyles, W.F., Simpson, C.B., Carlson, R.E., Schrage, W.G., Dinenno, F.A., Endothelium-dependent vasodilatation and exercise hyperaemia in ageing humans: impact of acute ascorbic acid administration. J. Physiol. 587 (2009), 1989–2003, 10.1113/jphysiol.2008.167320.
38. [38] Wray, D.W., Nishiyama, S.K., Monnet, A., Wary, C., Duteil, S.S., Carlier, P.G., et al. Antioxidants and aging: NMR-based evidence of improved skeletal muscle perfusion and energetics. Am. J. Physiol. Heart Circ. Physiol. 297 (2009), H1870–H1875, 10.1152/ajpheart.00709.2009.
39. [39] Bailey, D.M., McEneny, J., Mathieu-Costello, O., Henry, R.R., James, P.E., McCord, J.M., et al. Sedentary aging increases resting and exercise-induced intramuscular free radical formation. J. Appl. Physiol. 109 (2010), 449–456, 10.1152/japplphysiol.00354.2010.
40. [40] Donato, A.J., Gano, L.B., Eskurza, I., Silver, A.E., Gates, P.E., Jablonski, K., et al. Vascular endothelial dysfunction with aging: endothelin-1 and endothelial nitric oxide synthase. Am. J. Physiol. Heart Circ. Physiol. 297 (2009), H425–H432, 10.1152/ajpheart.00689.2008.
41. [41] Nyberg, M., Gliemann, L., Thaning, P., Hellsten, Y., Mortensen, S.P., Role of nitric oxide and prostanoids in the regulation of leg blood flow and blood pressure in humans with essential hypertension: effect of high-intensity aerobic training. J. Physiol. 590 (2012), 1481–1494, 10.1113/jphysiol.2011.225136.
42. [42] Copp, S.W., Schwagerl, P.J., Hirai, D.M., Poole, D.C., Musch, T.I., Acute ascorbic acid and hindlimb skeletal muscle blood flow distribution in old rats: rest and exercise. Can. J. Physiol. Pharmacol. 90 (2012), 1498–1505, 10.1139/y2012-109.
43. [43] Vasilaki, A., Mansouri, A., Remmen, H., van der Meulen, J.H., Larkin, L., Richardson, A.G., et al. Free radical generation by skeletal muscle of adult and old mice: effect of contractile activity. Aging Cell 5 (2006), 109–117, 10.1111/j.1474-9726.2006.00198.x.
44. [44] Palomero, J., Vasilaki, A., Pye, D., McArdle, A., Jackson, M.J., Aging increases the oxidation of dichlorohydrofluorescein in single isolated skeletal muscle fibers at rest, but not during contractions. Am. J. Physiol. Regul. Integr. Comp. Physiol. 305 (2013), R351–R358, 10.1152/ajpregu.00530.2012.
45. [45] Fleenor, B.S., Marshall, K.D., Durrant, J.R., Lesniewski, L.A., Seals, D.R., Arterial stiffening with ageing is associated with transforming growth factor-β1-related changes in adventitial collagen: reversal by aerobic exercise. J. Physiol. 588 (2010), 3971–3982, 10.1113/jphysiol.2010.194753.
46. [46] Tanaka, H., Dinenno, F.A., Monahan, K.D., Clevenger, C.M., DeSouza, C.A., Seals, D.R., Aging, habitual exercise, and dynamic arterial compliance. Circulation 102 (2000), 1270–1275.
47. [47] Moreau, K.L., Donato, A.J., Seals, D.R., DeSouza, C.A., Tanaka, H., Regular exercise, hormone replacement therapy and the age-related decline in carotid arterial compliance in healthy women. Cardiovasc. Res. 57 (2003), 861–868.
48. [48] Gando, Y., Yamamoto, K., Kawano, H., Murakami, H., Ohmori, Y., Kawakami, R., et al. Attenuated age-related carotid arterial remodeling in adults with a high level of cardiorespiratory fitness. J. Atheroscler. Thromb. 18 (2011), 248–254.
49. [49] Csiszar, A., Ungvari, Z., Edwards, J.G., Kaminski, P., Wolin, M.S., Koller, A., et al. Aging-induced phenotypic changes and oxidative stress impair coronary arteriolar function. Circ. Res. 90 (2002), 1159–1166.
50. [50] Durrant, J.R., Seals, D.R., Connell, M.L., Russell, M.J., Lawson, B.R., Folian, B.J., et al. Voluntary wheel running restores endothelial function in conduit arteries of old mice: direct evidence for reduced oxidative stress, increased superoxide dismutase activity and down-regulation of NADPH oxidase. J. Physiol. 587 (2009), 3271–3285, 10.1113/jphysiol.2009.169771.
51. [51] Taddei, S., Galetta, F., Virdis, A., Ghiadoni, L., Salvetti, G., Franzoni, F., et al. Physical activity prevents age-related impairment in nitric oxide availability in elderly athletes. Circulation 101 (2000), 2896–2901.
52. [52] Gu, Q., Wang, B., Zhang, X.-F., Ma, Y.-P., Liu, J.-D., Wang, X.-Z., Chronic aerobic exercise training attenuates aortic stiffening and endothelial dysfunction through preserving aortic mitochondrial function in aged rats. Exp. Gerontol. 56 (2014), 37–44, 10.1016/j.exger.2014.02.014.
53. [53] Pierce, G.L., Donato, A.J., LaRocca, T.J., Eskurza, I., Silver, A.E., Seals, D.R., Habitually exercising older men do not demonstrate age-associated vascular endothelial oxidative stress. Aging Cell 10 (2011), 1032–1037, 10.1111/j.1474-9726.2011.00748.x.
54. [54] Kröller-Schön, S., Jansen, T., Hauptmann, F., Schüler, A., Heeren, T., Hausding, M., et al. α1AMP-activated protein kinase mediates vascular protective effects of exercise. Arterioscler. Thromb. Vasc. Biol. 32 (2012), 1632–1641, 10.1161/ATVBAHA.111.243980.
55. [55] Gliemann, L., Nyberg, M., Hellsten, Y., Nitric oxide and reactive oxygen species in limb vascular function: what is the effect of physical activity?. Free Radic. Res. 48 (2014), 71–83, 10.3109/10715762.2013.835045.
56. [56] Suwa, M., Nakano, H., Radak, Z., Kumagai, S., Endurance exercise increases the SIRT1 and peroxisome proliferator-activated receptor gamma coactivator-1alpha protein expressions in rat skeletal muscle. Metab. Clin. Exp. 57 (2008), 986–998, 10.1016/j.metabol.2008.02.017.
57. [57] Behnke, B.J., Ramsey, M.W., Stabley, J.N., Dominguez, J.M., Davis, R.T., McCullough, D.J., et al. Effects of aging and exercise training on skeletal muscle blood flow and resistance artery morphology. J. Appl. Physiol. 113 (2012), 1699–1708, 10.1152/japplphysiol.01025.2012.
58. [58] Muller-Delp, J.M., Heterogeneous ageing of skeletal muscle microvascular function. J. Physiol., 2015, 10.1113/JP271005.
59. [59] Cobley, J.N., Sakellariou, G.K., Owens, D.J., Murray, S., Waldron, S., Gregson, W., et al. Lifelong training preserves some redox-regulated adaptive responses after an acute exercise stimulus in aged human skeletal muscle. Free Radic. Biol. Med. 70 (2014), 23–32, 10.1016/j.freeradbiomed.2014.02.004.
60. [60] Baur, J.A., Biochemical effects of SIRT1 activators. Biochim. Biophys. Acta 1804 (2010), 1626–1634, 10.1016/j.bbapap.2009.10.025.
61. [61] Xia, N., Förstermann, U., Li, H., Resveratrol and endothelial nitric oxide. Molecules 19 (2014), 16102–16121, 10.3390/molecules191016102.
62. [62] Trela, B.C., Waterhouse, A.L., Resveratrol: isomeric molar absorptivities and stability. J. Agric. Food Chem. 44 (1996), 1253–1257.
63. [63] Mikulski, D., Górniak, R., Molski, M., A theoretical study of the structure-radical scavenging activity of trans-resveratrol analogues and cis-resveratrol in gas phase and water environment. Eur. J. Med. Chem. 45 (2010), 1015–1027, 10.1016/j.ejmech.2009.11.044.
64. [64] Mikulski, D., Molski, M., Quantitative structure-antioxidant activity relationship of trans-resveratrol oligomers, trans-4,4“-dihydroxystilbene dimer, trans-resveratrol-3-O-glucuronide, glucosides: trans-piceid, cis-piceid, trans-astringin and trans-resveratrol-4-”O-beta-D-glucopyranoside. Eur. J. Med. Chem. 45 (2010), 2366–2380, 10.1016/j.ejmech.2010.02.016.
65. [65] Basly, J.P., Marre-Fournier, F., Le Bail, J.C., Habrioux, G., Chulia, A.J., Estrogenic/antiestrogenic and scavenging properties of (E)- and (Z)-resveratrol. Life Sci. 66 (2000), 769–777.
66. [66] Novelle, M.G., Wahl, D., Diéguez, C., Bernier, M., de Cabo, R., Resveratrol supplementation: where are we now and where should we go?. Ageing Res. Rev. 21 (2015), 1–15, 10.1016/j.arr.2015.01.002.
67. [67] Poulsen, M.M., Jørgensen, J.O.L., Jessen, N., Richelsen, B., Pedersen, S.B., Resveratrol in metabolic health: an overview of the current evidence and perspectives. Ann. N. Y. Acad. Sci. 1290 (2013), 74–82, 10.1111/nyas.12141.
68. [68] Vang, O., Ahmad, N., Baile, C.A., Baur, J.A., Brown, K., Csiszar, A., et al. What is new for an old molecule? Systematic review and recommendations on the use of resveratrol. PLoS One, 6, 2011, e19881, 10.1371/journal.pone.0019881.
69. [69] Lin, S.J., Defossez, P.A., Guarente, L., Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 289 (2000), 2126–2128.
70. [70] Howitz, K.T., Bitterman, K.J., Cohen, H.Y., Lamming, D.W., Lavu, S., Wood, J.G., et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425 (2003), 191–196, 10.1038/nature01960.
71. [71] Wood, J.G., Rogina, B., Lavu, S., Howitz, K., Helfand, S.L., Tatar, M., et al. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 430 (2004), 686–689, 10.1038/nature02789.
72. [72] Bauer, J.H., Goupil, S., Garber, G.B., Helfand, S.L., An accelerated assay for the identification of lifespan-extending interventions in Drosophila melanogaster. Proc. Natl. Acad. Sci. USA 101 (2004), 12980–12985, 10.1073/pnas.0403493101.
73. [73] Gerhart-Hines, Z., Rodgers, J.T., Bare, O., Lerin, C., Kim, S.-H., Mostoslavsky, R., et al. Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha. Embo. J. 26 (2007), 1913–1923, 10.1038/sj.emboj.7601633.
74. [74] Winnik, S., Auwerx, J., Sinclair, D.A., Matter, C.M., Protective effects of sirtuins in cardiovascular diseases: from bench to bedside. Eur. Heart J., 36, 2015, 10.1093/eurheartj/ehv290.
75. [75] Oliva, J., French, B.A., Li, J., Bardag-Gorce, F., Fu, P., French, S.W., Sirt1 is involved in energy metabolism: the role of chronic ethanol feeding and resveratrol. Exp. Mol. Pathol. 85 (2008), 155–159, 10.1016/j.yexmp.2008.08.002.
76. [76] Timmers, S., Hesselink, M.K.C., Schrauwen, P., Therapeutic potential of resveratrol in obesity and type 2 diabetes: new avenues for health benefits?. Ann. N. Y. Acad. Sci. 1290 (2013), 83–89, 10.1111/nyas.12185.
77. [77] Agrawal, N.K., Kant, S., Targeting inflammation in diabetes: newer therapeutic options. World J. Diabetes. 5 (2014), 697–710, 10.4239/wjd.v5.i5.697.
78. [78] Olholm, J., Paulsen, S.K., Cullberg, K.B., Richelsen, B., Pedersen, S.B., Anti-inflammatory effect of resveratrol on adipokine expression and secretion in human adipose tissue explants. Int. J. Obes. 34 (2010), 1546–1553, 10.1038/ijo.2010.98.
79. [79] Cullberg, K.B., Olholm, J., Paulsen, S.K., Foldager, C.B., Lind, M., Richelsen, B., et al. Resveratrol has inhibitory effects on the hypoxia-induced inflammation and angiogenesis in human adipose tissue in vitro. Eur. J. Pharm. Sci. 49 (2013), 251–257, 10.1016/j.ejps.2013.02.014.
80. [80] Gómez-Zorita, S., Fernández-Quintela, A., Lasa, A., Hijona, E., Bujanda, L., Portillo, M.P., Effects of resveratrol on obesity-related inflammation markers in adipose tissue of genetically obese rats. Nutrition 29 (2013), 1374–1380, 10.1016/j.nut.2013.04.014.
81. [81] Hubbard, B.P., Sinclair, D.A., Small molecule SIRT1 activators for the treatment of aging and age-related diseases. Trends Pharmacol. Sci. 35 (2014), 146–154, 10.1016/j.tips.2013.12.004.
82. [82] Kulkarni, S.S., Cantó, C., The molecular targets of resveratrol. Biochim. Biophys. Acta 1852 (2015), 1114–1123, 10.1016/j.bbadis.2014.10.005.
83. [83] Frémont, L., Biological effects of resveratrol. Life Sci. 66 (2000), 663–673.
84. [84] Liu, G.-S., Zhang, Z.-S., Yang, B., He, W., Resveratrol attenuates oxidative damage and ameliorates cognitive impairment in the brain of senescence-accelerated mice. Life Sci. 91 (2012), 872–877, 10.1016/j.lfs.2012.08.033.
85. [85] Park, S.-J., Ahmad, F., Philp, A., Baar, K., Williams, T., Luo, H., et al. Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell 148 (2012), 421–433, 10.1016/j.cell.2012.01.017.
86. [86] Lan, F., Cacicedo, J.M., Ruderman, N., Ido, Y., SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1. Possible role in AMP-activated protein kinase activation. J. Biol. Chem. 283 (2008), 27628–27635, 10.1074/jbc.M805711200.
87. [87] Cantó, C., Jiang, L.Q., Deshmukh, A.S., Mataki, C., Coste, A., Lagouge, M., et al. Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell Metab. 11 (2010), 213–219, 10.1016/j.cmet.2010.02.006.
88. [88] Hou, X., Xu, S., Maitland-Toolan, K.A., Sato, K., Jiang, B., Ido, Y., et al. SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase. J. Biol. Chem. 283 (2008), 20015–20026.
89. [89] Dasgupta, B., Milbrandt, J., Resveratrol stimulates AMP kinase activity in neurons. Proc. Natl. Acad. Sci. USA 104 (2007), 7217–7222, 10.1073/pnas.0610068104.
90. [90] Bowers, J.L., Tyulmenkov, V.V., Jernigan, S.C., Klinge, C.M., Resveratrol acts as a mixed agonist/antagonist for estrogen receptors alpha and beta. Endocrinology 141 (2000), 3657–3667, 10.1210/endo.141.10.7721.
91. [91] Robb, E.L., Stuart, J.A., Resveratrol interacts with estrogen receptor-β to inhibit cell replicative growth and enhance stress resistance by upregulating mitochondrial superoxide dismutase. Free Radic. Biol. Med. 50 (2011), 821–831, 10.1016/j.freeradbiomed.2010.12.038.
92. [92] Klinge, C.M., Wickramasinghe, N.S., Ivanova, M.M., Dougherty, S.M., Resveratrol stimulates nitric oxide production by increasing estrogen receptor alpha-Src-caveolin-1 interaction and phosphorylation in human umbilical vein endothelial cells. Faseb J. 22 (2008), 2185–2197, 10.1096/fj.07-103366.
93. [93] Mitchell, J.H., Gardner, P.T., McPhail, D.B., Morrice, P.C., Collins, A.R., Duthie, G.G., Antioxidant efficacy of phytoestrogens in chemical and biological model systems. Arch. Biochem. Biophys. 360 (1998), 142–148, 10.1006/abbi.1998.0951.
94. [94] Burkitt, M.J., Duncan, J., Effects of trans-resveratrol on copper-dependent hydroxyl-radical formation and DNA damage: evidence for hydroxyl-radical scavenging and a novel, glutathione-sparing mechanism of action. Arch. Biochem. Biophys. 381 (2000), 253–263, 10.1006/abbi.2000.1973.
95. [95] Bors, W., Michel, C., Antioxidant capacity of flavanols and gallate esters: pulse radiolysis studies. Free Radic. Biol. Med. 27 (1999), 1413–1426.
96. [96] Gambini, J., Inglés, M., Olaso, G., Lopez-Grueso, R., Bonet-Costa, V., Gimeno-Mallench, L., et al. Properties of resveratrol: in vitro and in vivo studies about metabolism, bioavailability, and biological effects in animal models and humans. Oxid. Med. Cell Longev., 2015, 2015, 10.1155/2015/837042.
97. [97] Nguyen, T., Nioi, P., Pickett, C.B., The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J. Biol. Chem. 284 (2009), 13291–13295, 10.1074/jbc.R900010200.
98. [98] Buendia, I., Michalska, P., Navarro, E., Gameiro, I., Egea, J., León, R., Nrf2–ARE pathway: an emerging target against oxidative stress and neuroinflammation in neurodegenerative diseases. Pharmacol. Ther. 157 (2016), 84–104, 10.1016/j.pharmthera.2015.11.003.
99. [99] Carrizzo, A., Puca, A., Damato, A., Marino, M., Franco, E., Pompeo, F., et al. Resveratrol improves vascular function in patients with hypertension and dyslipidemia by modulating NO metabolism. Hypertension 62 (2013), 359–366, 10.1161/HYPERTENSIONAHA.111.01009.
100. [100] Ungvari, Z., Bagi, Z., Feher, A., Recchia, F.A., Sonntag, W.E., Pearson, K., et al. Resveratrol confers endothelial protection via activation of the antioxidant transcription factor Nrf2. Am. J. Physiol. Heart Circ. Physiol. 299 (2010), H18–H24, 10.1152/ajpheart.00260.2010.
101. [101] Zarzuelo, M.J., López-Sepúlveda, R., Sánchez, M., Romero, M., Gómez-Guzmán, M., Ungvary, Z., et al. SIRT1 inhibits NADPH oxidase activation and protects endothelial function in the rat aorta: implications for vascular aging. Biochem. Pharmacol. 85 (2013), 1288–1296, 10.1016/j.bcp.2013.02.015.
102. [102] Park, D.W., Baek, K., Kim, J.R., Lee, J.J., Ryu, S.H., Chin, B.R., et al. Resveratrol inhibits foam cell formation via NADPH oxidase 1-mediated reactive oxygen species and monocyte chemotactic protein-1. Exp. Mol. Med. 41 (2009), 171–179, 10.3858/emm.2009.41.3.020.
103. [103] Li, H., Horke, S., Förstermann, U., Vascular oxidative stress, nitric oxide and atherosclerosis. Atherosclerosis 237 (2014), 208–219, 10.1016/j.atherosclerosis.2014.09.001.
104. [104] Thomas, G.D., Functional muscle ischemia in Duchenne and Becker muscular dystrophy. Front. Physiol., 4, 2013, 381, 10.3389/fphys.2013.00381.
105. [105] Copp, S.W., Holdsworth, C.T., Ferguson, S.K., Hirai, D.M., Poole, D.C., Musch, T.I., Muscle fibre-type dependence of neuronal nitric oxide synthase-mediated vascular control in the rat during high speed treadmill running. J. Physiol. 591 (2013), 2885–2896, 10.1113/jphysiol.2013.251082.
106. [106] Copp, S.W., Hirai, D.M., Musch, T.I., Poole, D.C., Critical speed in the rat: implications for hindlimb muscle blood flow distribution and fibre recruitment. J. Physiol. 588 (2010), 5077–5087.
107. [107] Wallerath, T., Deckert, G., Ternes, T., Anderson, H., Li, H., Witte, K., et al. Resveratrol, a polyphenolic phytoalexin present in red wine, enhances expression and activity of endothelial nitric oxide synthase. Circulation 106 (2002), 1652–1658.
108. [108] Wallerath, T., Li, H., Gödtel-Ambrust, U., Schwarz, P.M., Förstermann, U., A blend of polyphenolic compounds explains the stimulatory effect of red wine on human endothelial NO synthase. Nitric Oxide 12 (2005), 97–104, 10.1016/j.niox.2004.12.004.
109. [109] Xia, N., Strand, S., Schlufter, F., Siuda, D., Reifenberg, G., Kleinert, H., et al. Role of SIRT1 and FOXO factors in eNOS transcriptional activation by resveratrol. Nitric Oxide 32 (2013), 29–35, 10.1016/j.niox.2013.04.001.
110. [110] Csiszar, A., Labinskyy, N., Jiménez, R., Pinto, J.T., Ballabh, P., Losonczy, G., et al. Anti-oxidative and anti-inflammatory vasoprotective effects of caloric restriction in aging: role of circulating factors and SIRT1. Mech. Ageing Dev. 130 (2009), 518–527, 10.1016/j.mad.2009.06.004.
111. [111] Takahashi, S., Nakashima, Y., Repeated and long-term treatment with physiological concentrations of resveratrol promotes NO production in vascular endothelial cells. Br. J. Nutr. 107 (2012), 774–780, 10.1017/S0007114511003588.
112. [112] Xu, Q., Hao, X., Yang, Q., Si, L., Resveratrol prevents hyperglycemia-induced endothelial dysfunction via activation of adenosine monophosphate-activated protein kinase. Biochem. Biophys. Res. Commun. 388 (2009), 389–394, 10.1016/j.bbrc.2009.08.021.
113. [113] Förstermann, U., Janus-faced role of endothelial NO synthase in vascular disease: uncoupling of oxygen reduction from NO synthesis and its pharmacological reversal. Biol. Chem. 387 (2006), 1521–1533, 10.1515/BC.2006.190.
114. [114] Xia, N., Daiber, A., Habermeier, A., Closs, E.I., Thum, T., Spanier, G., et al. Resveratrol reverses endothelial nitric-oxide synthase uncoupling in apolipoprotein E knockout mice. J. Pharmacol. Exp. Ther. 335 (2010), 149–154, 10.1124/jpet.110.168724.
115. [115] Crow, J.P., Beckman, J.S., Reactions between nitric oxide, superoxide, and peroxynitrite: footprints of peroxynitrite in vivo. Adv. Pharmacol. 34 (1995), 17–43.
116. [116] Mortensen, S.P., Nyberg, M., Thaning, P., Saltin, B., Hellsten, Y., Adenosine contributes to blood flow regulation in the exercising human leg by increasing prostaglandin and nitric oxide formation. Hypertension 53 (2009), 993–999, 10.1161/HYPERTENSIONAHA.109.130880.
117. [117] Hellsten, Y., Nyberg, M., Jensen, L.G., Mortensen, S.P., Vasodilator interactions in skeletal muscle blood flow regulation. J. Physiol. 590 (2012), 6297–6305, 10.1113/jphysiol.2012.240762.
118. [118] Nicholson, W.T., Vaa, B., Hesse, C., Eisenach, J.H., Joyner, M.J., Aging is associated with reduced prostacyclin-mediated dilation in the human forearm. Hypertension 53 (2009), 973–978, 10.1161/HYPERTENSIONAHA.108.121483.
119. [119] Jang, M., Cai, L., Udeani, G.O., Slowing, K.V., Thomas, C.F., Beecher, C.W., et al. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275 (1997), 218–220.
120. [120] Kutil, Z., Temml, V., Maghradze, D., Pribylova, M., Dvorakova, M., Schuster, D., et al. Impact of wines and wine constituents on cyclooxygenase-1, cyclooxygenase-2, and 5-lipoxygenase catalytic activity. Med. Inflamm. 2014 (2014), 178931–178938, 10.1155/2014/178931.
121. [121] Murias, M., Handler, N., Erker, T., Pleban, K., Ecker, G., Saiko, P., et al. Resveratrol analogues as selective cyclooxygenase-2 inhibitors: synthesis and structure-activity relationship. Bioorg. Med. Chem. 12 (2004), 5571–5578, 10.1016/j.bmc.2004.08.008.
122. [122] Yar, A.S., Menevse, S., Alp, E., The effects of resveratrol on cyclooxygenase-1 and −2, nuclear factor kappa beta, matrix metalloproteinase-9, and sirtuin 1 mRNA expression in hear. Genet. Mol. Res. 10 (2011), 2962–2975, 10.4238/2011.November.29.7.
123. [123] Yar, A.S., Menevse, S., Alp, E., Helvacioglu, F., Take, G., The effects of resveratrol on cyclooxygenase-1 and cyclooxygenase-2 mRNA and protein levels in diabetic rat kidneys. Mol. Biol. Rep. 37 (2009), 2323–2331, 10.1007/s11033-009-9737-6.
124. [124] Rader, D.J., Human genetics of atherothrombotic disease and its risk factors. Arterioscler. Thromb. Vasc. Biol. 35 (2015), 741–747, 10.1161/ATVBAHA.115.305492.
125. [125] Kullo, I.J., Leeper, N.J., The genetic basis of peripheral arterial disease: current knowledge, challenges, and future directions. Circ. Res. 116 (2015), 1551–1560, 10.1161/CIRCRESAHA.116.303518.
126. [126] Manea, A., Simionescu, M., Nox enzymes and oxidative stress in atherosclerosis. Front. Biosci. 4 (2012), 651–670.
127. [127] Sahebkar, A., Effects of resveratrol supplementation on plasma lipids: a systematic review and meta-analysis of randomized controlled trials. Nutr. Rev. 71 (2013), 822–835, 10.1111/nure.12081.
128. [128] Donnelly, L.E., Newton, R., Kennedy, G.E., Fenwick, P.S., Leung, R.H.F., Ito, K., et al. Anti-inflammatory effects of resveratrol in lung epithelial cells: molecular mechanisms. Am. J. Physiol. Lung Cell Mol. Physiol. 287 (2004), L774–L783, 10.1152/ajplung.00110.2004.
129. [129] Ikeda, U., Ito, T., Shimada, K., Interleukin-6 and acute coronary syndrome. Clin. Cardiol. 24 (2001), 701–704.
130. [130] Rotondo, S., Rajtar, G., Manarini, S., Celardo, A., Rotillo, D., de Gaetano, G., et al. Effect of trans-resveratrol, a natural polyphenolic compound, on human polymorphonuclear leukocyte function. Br. J. Pharmacol. 123 (1998), 1691–1699, 10.1038/sj.bjp.0701784.
131. [131] Olas, B., Wachowicz, B., Resveratrol, a phenolic antioxidant with effects on blood platelet functions. Platelets 16 (2005), 251–260, 10.1080/09537100400020591.
132. [132] Egginton, S., Invited review: activity-induced angiogenesis. Pflugers Arch. - Eur. J. Physiol. 457 (2009), 963–977, 10.1007/s00424-008-0563-9.
133. [133] Bonner, J.S., Lantier, L., Hasenour, C.M., James, F.D., Bracy, D.P., Wasserman, D.H., Muscle-specific vascular endothelial growth factor deletion induces muscle capillary rarefaction creating muscle insulin resistance. Diabetes 62 (2013), 572–580, 10.2337/db12-0354.
134. [134] Akerstrom, T., Laub, L., Vedel, K., Brand, C.L., Pedersen, B.K., Lindqvist, A.K., et al. Increased skeletal muscle capillarization enhances insulin sensitivity. Am. J. Physiol. Endocrinol. Metab. 307 (2014), E1105–E1116, 10.1152/ajpendo.00020.2014.
135. [135] Yu, H.-B., Zhang, H.-F., Zhang, X., Li, D.-Y., Xue, H.-Z., Pan, C.-E., et al. Resveratrol inhibits VEGF expression of human hepatocellular carcinoma cells through a NF-kappa B-mediated mechanism. Hepatogastroenterology 57 (2010), 1241–1246.
136. [136] Zhang, M., Li, W., Yu, L., Wu, S., The suppressive effect of resveratrol on HIF-1α and VEGF expression after warm ischemia and reperfusion in rat liver. PLoS One, 9, 2014, e109589, 10.1371/journal.pone.0109589.
137. [137] Kraft, T.E., Parisotto, D., Schempp, C., Efferth, T., Fighting cancer with red wine? Molecular mechanisms of resveratrol. Crit Rev. Food Sci. Nutr. 49 (2009), 782–799, 10.1080/10408390802248627.
138. [138] Taubert, D., Berkels, R., Upregulation and activation of eNOS by resveratrol. Circulation 107 (2003), e78–e79.
139. [139] Lagouge, M., Argmann, C., Gerhart-Hines, Z., Meziane, H., Lerin, C., Daussin, F., et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell 127 (2006), 1109–1122, 10.1016/j.cell.2006.11.013.
140. [140] Dolinsky, V.W., Jones, K.E., Sidhu, R.S., Haykowsky, M., Czubryt, M.P., Gordon, T., et al. Improvements in skeletal muscle strength and cardiac function induced by resveratrol during exercise training contribute to enhanced exercise performance in rats. J. Physiol. 590 (2012), 2783–2799, 10.1113/jphysiol.2012.230490.
141. [141] da Luz, P.L., Tanaka, L., Brum, P.C., Dourado, P.M.M., Favarato, D., Krieger, J.E., et al. Red wine and equivalent oral pharmacological doses of resveratrol delay vascular aging but do not extend life span in rats. Atherosclerosis 224 (2012), 136–142, 10.1016/j.atherosclerosis.2012.06.007.
142. [142] Matos, R.S., Baroncini, L.A.V., Précoma, L.B., Winter, G., Lambach, P.H., Caron, E.Y., et al. Resveratrol causes antiatherogenic effects in an animal model of atherosclerosis. Arq. Bras. Cardiol. 98 (2012), 136–142.
143. [143] Fleg, J.L., Lakatta, E.G., Prevalence and significance of postexercise hypotension in apparently healthy subjects. Am. J. Cardiol. 57 (1986), 1380–1384.
144. [144] Kenney, M.J., Seals, D.R., Postexercise hypotension. Key features, mechanisms, and clinical significance. Hypertension 22 (1993), 653–664, 10.1161/01.HYP.22.5.653.
145. [145] Halliwill, J.R., Buck, T.M., Lacewell, A.N., Romero, S.A., Postexercise hypotension and sustained postexercise vasodilatation: what happens after we exercise?. Exp. Physiol. 98 (2013), 7–18, 10.1113/expphysiol.2011.058065.
146. [146] Anunciação, P.G., Polito, M.D., A review on post-exercise hypotension in hypertensive individuals. Arq. Bras. Cardiol. 96 (2011), e100–e109.
147. [147] Cornelissen, V.A., Smart, N.A., Exercise training for blood pressure: a systematic review and meta-analysis. J. Am. Heart Assoc., 2, 2013, 10.1161/JAHA.112.004473.
148. [148] Schmitt, C.A., Heiss, E.H., Dirsch, V.M., Effect of resveratrol on endothelial cell function: molecular mechanisms. Biofactors 36 (2010), 342–349, 10.1002/biof.109.
149. [149] Miatello, R., Vázquez, M., Renna, N., Cruzado, M., Zumino, A.P., Risler, N., Chronic administration of resveratrol prevents biochemical cardiovascular changes in fructose-fed rats*. Am. J. Hypertens. 18 (2005), 864–870, 10.1016/j.amjhyper.2004.12.012.
150. [150] Khandelwal, A.R., Hebert, V.Y., Dugas, T.R., Essential role of ER-alpha-dependent NO production in resveratrol-mediated inhibition of restenosis. Am. J. Physiol. Heart Circ. Physiol. 299 (2010), H1451–H1458, 10.1152/ajpheart.00369.2010.
151. [151] Mortensen, S.P., Askew, C.D., Walker, M., Nyberg, M., Hellsten, Y., The hyperaemic response to passive leg movement is dependent on nitric oxide: a new tool to evaluate endothelial nitric oxide function. J. Physiol. 590 (2012), 4391–4400, 10.1113/jphysiol.2012.235952.
152. [152] Liu, Y., Ma, W., Zhang, P., He, S., Huang, D., Effect of resveratrol on blood pressure: a meta-analysis of randomized controlled trials. Clin. Nutr. 34 (2015), 27–34, 10.1016/j.clnu.2014.03.009.
153. [153] Sahebkar, A., Serban, C., Ursoniu, S., Wong, N.D., Muntner, P., Graham, I.M., et al. Lack of efficacy of resveratrol on C-reactive protein and selected cardiovascular risk factors–Results from a systematic review and meta-analysis of randomized controlled trials. Int. J. Cardiol. 189 (2015), 47–55, 10.1016/j.ijcard.2015.04.008.
154. [154] Gomez-Cabrera, M.-C., Domenech, E., Viña, J., Moderate exercise is an antioxidant: upregulation of antioxidant genes by training. Free Radic. Biol. Med. 44 (2008), 126–131, 10.1016/j.freeradbiomed.2007.02.001.
155. [155] Ji, L.L., Antioxidant enzyme response to exercise and aging. Med. Sci. Sports Exerc. 25 (1993), 225–231.
156. [156] Hollander, J., Fiebig, R., Gore, M., Ookawara, T., Ohno, H., Ji, L., Superoxide dismutase gene expression is activated by a single bout of exercise in rat skeletal muscle. Pflugers Arch. - Eur. J. Physiol. 442 (2001), 426–434, 10.1007/s004240100539.
157. [157] Spanier, G., Xu, H., Xia, N., Tobias, S., Deng, S., Wojnowski, L., et al. Resveratrol reduces endothelial oxidative stress by modulating the gene expression of superoxide dismutase 1 (SOD1), glutathione peroxidase 1 (GPx1) and NADPH oxidase subunit (Nox4). J. Physiol. Pharmacol. 60:Suppl. 4 (2009), S111–S116.
158. [158] Ungvari, Z., Orosz, Z., Rivera, A., Labinskyy, N., Xiangmin, Z., Olson, S., et al. Resveratrol increases vascular oxidative stress resistance. Am. J. Physiol. Heart Circ. Physiol. 292 (2007), H2417–H2424, 10.1152/ajpheart.01258.2006.
159. [159] Olesen, J., Gliemann, L., Biensø, R., Schmidt, J., Hellsten, Y., Pilegaard, H., Exercise training, but not resveratrol, improves metabolic and inflammatory status in skeletal muscle of aged men. J. Physiol. 592 (2014), 1873–1886, 10.1113/jphysiol.2013.270256.
160. [160] Lin, X., Zhang, X., Guo, J., Roberts, C.K., McKenzie, S., Wu, W.-C., et al. Effects of exercise training on cardiorespiratory fitness and biomarkers of cardiometabolic health: a systematic review and meta-analysis of randomized controlled trials. J. Am. Heart Assoc., 4, 2015, 10.1161/JAHA.115.002014.
161. [161] Scribbans, T.D., Ma, J.K., Edgett, B.A., Vorobej, K.A., Mitchell, A.S., Zelt, J.G.E., et al. Resveratrol supplementation does not augment performance adaptations or fibre-type–specific responses to high-intensity interval training in humans. Appl. Physiol. Nutr. Metab. 39 (2014), 1305–1313, 10.1139/apnm-2014-0070.
162. [162] Murase, T., Haramizu, S., Ota, N., Hase, T., Suppression of the aging-associated decline in physical performance by a combination of resveratrol intake and habitual exercise in senescence-accelerated mice. Biogerontology 10 (2009), 423–434, 10.1007/s10522-008-9177-z.
163. [163] Ventura-Clapier, R., Potentiating exercise training with resveratrol. J. Physiol. 590 (2012), 3215–3216, 10.1113/jphysiol.2012.237743.
164. [164] Voduc, N., la Porte, C., Tessier, C., Mallick, R., Cameron, D.W., Effect of resveratrol on exercise capacity: a randomized placebo-controlled crossover pilot study. Appl. Physiol. Nutr. Metab., 2014, 1–5, 10.1139/apnm-2013-0547.
165. [165] Hart, N., Sarga, L., Csende, Z., Koltai, E., Koch, L.G., Britton, S.L., et al. Resveratrol enhances exercise training responses in rats selectively bred for high running performance. Food Chem. Toxicol. 61 (2013), 53–59, 10.1016/j.fct.2013.01.051.
166. [166] Gomez-Cabrera, M.-C., Domenech, E., Romagnoli, M., Arduini, A., Borras, C., Pallardo, F.V., et al. Oral administration of vitamin C decreases muscle mitochondrial biogenesis and hampers training-induced adaptations in endurance performance. Am. J. Clin. Nutr. 87 (2008), 142–149.
167. [167] Ristow, M., Zarse, K., Oberbach, A., Klöting, N., Birringer, M., Kiehntopf, M., et al. Antioxidants prevent health-promoting effects of physical exercise in humans. Proc. Natl. Acad. Sci. USA 106 (2009), 8665–8670, 10.1073/pnas.0903485106.
168. [168] Menzies, K.J., Singh, K., Saleem, A., Hood, D.A., Sirtuin 1-mediated effects of exercise and resveratrol on mitochondrial biogenesis. J. Biol. Chem. 288 (2013), 6968–6979, 10.1074/jbc.M112.431155.
169. [169] Richter, E.A., Ruderman, N.B., AMPK and the biochemistry of exercise: implications for human health and disease. Biochem. J., 418, 2009, 261, 10.1042/BJ20082055.
170. [170] Olesen, J., Kiilerich, K., Pilegaard, H., PGC-1alpha-mediated adaptations in skeletal muscle. Pflugers Arch. - Eur. J. Physiol. 460 (2010), 153–162, 10.1007/s00424-010-0834-0.
171. [171] Williams, C.B., Gurd, B.J., Skeletal muscle SIRT1 and the genetics of metabolic health: therapeutic activation by pharmaceuticals and exercise. Appl. Clin. Genet. 5 (2012), 81–91, 10.2147/TACG.S31276.
172. [172] Perel, P., Roberts, I., Sena, E., Wheble, P., Briscoe, C., Sandercock, P., et al. Comparison of treatment effects between animal experiments and clinical trials: systematic review. BMJ, 334, 2007, 10.1136/bmj.39048.407928.BE.
173. [173] Sena, E.S., van der Worp, H.B., Bath, P.M.W., Howells, D.W., Macleod, M.R., Publication bias in reports of animal stroke studies leads to major overstatement of efficacy. PLoS Biol., 8, 2010, e1000344, 10.1371/journal.pbio.1000344.
174. [174] Hackam, D.G., Redelmeier, D.A., Translation of research evidence from animals to humans. JAMA 296 (2006), 1731–1732, 10.1001/jama.296.14.1731.
175. [175] FDA, Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products. 2004, Food and Drug Administration, Washington, DC.
176. [176] Pound, P., Ebrahim, S., Sandercock, P., Bracken, M.B., Roberts, I., Reviewing Animal Trials Systematically (RATS) Group, where is the evidence that animal research benefits humans?. BMJ 328 (2004), 514–517, 10.1136/bmj.328.7438.514.