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Reduced Oxidative Stress as a Mechanism for Increased Longevity, Exercise and Heart Failure Protection with Adenylyl Cyclase Type 5 Inhibition

  • Stephen F. VatnerEmail author
  • Jie Zhang
  • Dorothy E. Vatner
Chapter
Part of the Advances in Biochemistry in Health and Disease book series (ABHD, volume 16)

Abstract

One common mechanism mediating longevity and healthful aging is the protection against oxidative stress. Most serious diseases that limit aging, in general, and healthful aging, in particular, are linked to increased oxidative stress and increased sympathetic stimulation. Conversely, inhibition of sympathetic tone at any level in the β-adrenergic receptor/adenylyl cyclase/G-protein signaling pathway is a major mechanism protecting against oxidative stress. Disruption of adenylyl cyclase type 5 (AC5), one of the two major isoforms of AC in the heart, protects against oxidative stress resulting in enhanced longevity and more importantly healthful aging as exemplified by increased exercise performance, and protection against diabetes, obesity, cardiomyopathy and cancer, all related to oxidative stress. Despite the overwhelming evidence in animal models that increased oxidative stress is a major mechanism in limiting healthful aging, disappointing clinical trials have impaired the translation to patients. Inhibition of AC5 is a potential novel therapeutic modality, since it extends longevity and protects against diabetes, obesity, cardiomyopathy and cancer, while improving exercise tolerance, with all having an oxidative stress component.

Keywords

Oxidative stress Human longevity Healthful human aging Cardiomyopathy Sympathetic tone Adenylyl cyclase type 5 

References

  1. 1.
    Yan L, Vatner SF, Vatner DE (2014) Disruption of type 5 adenylyl cyclase prevents beta adrenergic receptor cardiomyopathy: a novel approach to beta-adrenergic receptor blockade. Am J Physiol Heart Circ Physiol 307:H1521–H1528CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Yan L, Vatner DE, O’Connor JP et al (2007) Type 5 adenylyl cyclase disruption increases longevity and protects against stress. Cell 130:247–258CrossRefPubMedGoogle Scholar
  3. 3.
    Vatner DE, Yan L, Lai L et al (2015) Type 5 adenylyl cyclase disruption leads to enhanced exercise performance. Aging Cell 14:1075–1084CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Okumura S, Takagi G, Kawabe J et al (2003) Disruption of type 5 adenylyl cyclase gene preserves cardiac function against pressure overload. Proc Natl Acad Sci U S A 100:9986–9990CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Ho D, Zhao X, Yan L et al (2015) Adenylyl cyclase type 5 deficiency protects against diet-induced obesity and insulin resistance. Diabetes 64:2636–2645CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    De Lorenzo MS, Chen W, Baljinnyam E (2014) Reduced malignancy as a mechanism for longevity in mice with adenylyl cyclase type 5 disruption. Aging Cell 13:102–110CrossRefPubMedGoogle Scholar
  7. 7.
    Lai L, Yan L, Gao S et al (2013) Type 5 adenylyl cyclase increases oxidative stress by transcriptional regulation of manganese superoxide dismutase via the SIRT1/FoxO3a pathway. Circulation 127:1692–1701CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Yan L, Park JY, Dillinger JG et al (2012) Common mechanisms for calorie restriction and adenylyl cyclase type 5 knockout models of longevity. Aging Cell 11:1110–1120CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Vatner SF, Park M, Yan L et al (2013) Adenylyl cyclase type 5 in cardiac disease, metabolism, and aging. Am J Physiol Heart Circ Physiol 305:H1–H8CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Bravo C, Vatner DE, Pachon R et al (2016) An FDA approved anti-viral agent which inhibits adenylyl cyclase type 5 protects the ischemic heart even when administered after reperfusion. J Pharmacol Exp Ther 357:331–336CrossRefPubMedGoogle Scholar
  11. 11.
    Iwatsubo K, Bravo C, Uechi M et al (2012) Prevention of heart failure in mice by an antiviral agent that inhibits type 5 cardiac adenylyl cyclase. Am J Physiol Heart Circ Physiol 302:H2622–H2628CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Qiu X, Brown K, Hirschey MD et al (2010) Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. Cell Metab 12:662–667CrossRefPubMedGoogle Scholar
  13. 13.
    Flurkey K, Papaconstantinou J, Harrison DE (2002) The snell dwarf mutation pit1(dw) can increase life span in mice. Mech Ageing Dev 123:121–130CrossRefPubMedGoogle Scholar
  14. 14.
    Salmon AB, Murakami S, Bartke A et al (2005) Fibroblast cell lines from young adult mice of long-lived mutant strains are resistant to multiple forms of stress. Am J Physiol Endocrinol Metab 289:E23–E29CrossRefPubMedGoogle Scholar
  15. 15.
    Flurkey K, Papaconstantinou J, Miller RA et al (2001) Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production. Proc Natl Acad Sci U S A 98:6736–6741CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Holzenberger M, Dupont J, Ducos B et al (2003) IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421:182–187CrossRefPubMedGoogle Scholar
  17. 17.
    Kurosu H, Yamamoto M, Clark JD et al (2005) Suppression of aging in mice by the hormone klotho. Science 309:1829–1833CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Migliaccio E, Giorgio M, Mele S et al (1999) The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature 402:309–313CrossRefPubMedGoogle Scholar
  19. 19.
    Mitsui A, Hamuro J, Nakamura H et al (2002) Overexpression of human thioredoxin in transgenic mice controls oxidative stress and life span. Antioxid Redox Signal 4:693–696CrossRefPubMedGoogle Scholar
  20. 20.
    Schriner SE, Linford NJ, Martin GM et al (2005) Extension of murine life span by overexpression of catalase targeted to mitochondria. Science 308:1909–1911CrossRefPubMedGoogle Scholar
  21. 21.
    Yang X, Doser TA, Fang CX et al (2006) Metallothionein prolongs survival and antagonizes senescence-associated cardiomyocyte diastolic dysfunction: role of oxidative stress. FASEB J 20:1024–1026CrossRefPubMedGoogle Scholar
  22. 22.
    Benigni A, Corna D, Zoja C et al (2009) Disruption of the Ang II type 1 receptor promotes longevity in mice. J Clin Invest 119:524–530CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Selman C, Lingard S, Choudhury AI et al (2008) Evidence for lifespan extension and delayed age-related biomarkers in insulin receptor substrate 1 null mice. FASEB J 22:807–818CrossRefPubMedGoogle Scholar
  24. 24.
    Sadagurski M, Cheng Z, Rozzo A et al (2011) IRS2 increases mitochondrial dysfunction and oxidative stress in a mouse model of Huntington disease. J Clin Invest 121:4070–4081CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Dell’agnello C, Leo S, Agostino A et al (2007) Increased longevity and refractoriness to Ca(2+)-dependent neurodegeneration in surf1 knockout mice. Hum Mol Genet 16:431–444CrossRefPubMedGoogle Scholar
  26. 26.
    Lapointe J, Stepanyan Z, Bigras E et al (2009) Reversal of the mitochondrial phenotype and slow development of oxidative biomarkers of aging in long-lived Mclk1+/− mice. J Biol Chem 284:20364–20374CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Gerschman R, Gilbert DL, Nye SW et al (1954) Oxygen poisoning and x-irradiation: a mechanism in common. Science 119:623–626CrossRefPubMedGoogle Scholar
  28. 28.
    Forman HJ, Maiorino M, Ursini F (2010) Signaling functions of reactive oxygen species. Biochemistry 49:835–842CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    ZelkoIN MTJ, Folz RJ (2002) Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression. Free Radic Biol Med 33:337–349CrossRefGoogle Scholar
  30. 30.
    Miriyala S, Spasojevic I, Tovmasyan A et al (2012) Manganese superoxide dismutase and its mimics. Biochim Biophys Acta 1822:794–814CrossRefPubMedGoogle Scholar
  31. 31.
    Dhalla NS, Temsah RM, Netticadan T (2000) Role of oxidative stress in cardiovascular diseases. J Hypertens 18:655–673CrossRefPubMedGoogle Scholar
  32. 32.
    Valko M, Rhodes CJ, Moncol J et al (2006) Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact 160:1–40CrossRefPubMedGoogle Scholar
  33. 33.
    Rahman I (2005) The role of oxidative stress in the pathogenesis of COPD: implications for therapy. Treat Respir Med 4:175–200CrossRefPubMedGoogle Scholar
  34. 34.
    El Kossi MM, Zakhary MM (2000) Oxidative stress in the context of acute cerebrovascular stroke. Stroke 31:1889–1892CrossRefPubMedGoogle Scholar
  35. 35.
    Markesbery WR (1997) Oxidative stress hypothesis in Alzheimer’s disease. Free Radic Biol Med 23:134–147CrossRefPubMedGoogle Scholar
  36. 36.
    Karunakaran U, Park KG (2013) A systematic review of oxidative stress and safety of antioxidants in diabetes: focus on islets and their defense. Diabetes Metab J 37:106–112CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Oberg BP, McMenamin E, Lucas FL et al (2004) Increased prevalence of oxidant stress and inflammation in patients with moderate to severe chronic kidney disease. Kidney Int 65:1009–1016CrossRefPubMedGoogle Scholar
  38. 38.
    De Sandre-Giovannoli A, Bernard R, Cau P et al (2003) Lamin a truncation in Hutchinson-Gilford progeria. Science 300:2055–2056CrossRefPubMedGoogle Scholar
  39. 39.
    Eriksson M, Brown WT, Gordon LB et al (2003) Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 423:293–298CrossRefPubMedGoogle Scholar
  40. 40.
    McClintock D, Gordon LB, Djabali K (2006) Hutchinson-Gilford progeria mutant lamin A primarily targets human vascular cells as detected by an anti-lamin A G608G antibody. Proc Natl Acad Sci U S A 103:2154–2159CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Viteri G, Chung YW, Stadtman ER (2010) Effect of progerin on the accumulation of oxidized proteins in fibroblasts from Hutchinson-Gilford progeria patients. Mech Ageing Dev 131:2–8CrossRefPubMedGoogle Scholar
  42. 42.
    Hennekam RC (2006) Hutchinson-Gilford progeria syndrome: review of the phenotype. Am J Med Genet A 140:2603–2624CrossRefPubMedGoogle Scholar
  43. 43.
    Singal PK, Yates JC, Beamish RE et al (1981) Influence of reducing agents on adrenochrome-induced changes in the heart. Arch Pathol Lab Med 105:664–669PubMedGoogle Scholar
  44. 44.
    Obata T, Hosokawa H, Yamanaka Y (1994) In vivo monitoring of norepinephrine and HO•. generation on myocardial ischemic injury by dialysis technique. Am J Physiol 266:H903–H908PubMedGoogle Scholar
  45. 45.
    Obata T, Yamanaka Y (1996) Cardiac microdialysis of salicylic acid to detect hydroxyl radical generation associated with sympathetic nerve stimulation. Neurosci Lett 211:216–318CrossRefPubMedGoogle Scholar
  46. 46.
    Kukin ML, Kalman J, Charney RH et al (1999) Prospective, randomized comparison of effect of long-term treatment with metoprolol or carvedilol on symptoms, exercise, ejection fraction, and oxidative stress in heart failure. Circulation 99:2645–2651CrossRefPubMedGoogle Scholar
  47. 47.
    Nakamura K, Kusano K, Nakamura Y et al (2002) Carvedilol decreases elevated oxidative stress in human failing myocardium. Circulation 105:2867–2871CrossRefPubMedGoogle Scholar
  48. 48.
    Mehdi MM, Rizvi SI (2013) N, N-Dimethyl-p-phenylenediamine dihydrochloride-based method for the measurement of plasma oxidative capacity during human aging. Anal Biochem 436:165–167CrossRefPubMedGoogle Scholar
  49. 49.
    Sastre J, Pallardo FV, Vina J (2003) The role of mitochondrial oxidative stress in aging. Free Radic Biol Med 35:1–8CrossRefPubMedGoogle Scholar
  50. 50.
    Slater AF, Stefan C, Nobel I et al (1995) Signalling mechanisms and oxidative stress in apoptosis. Toxicol Lett 82–83:149–153CrossRefPubMedGoogle Scholar
  51. 51.
    Finkel T, Holbrook NJ (2000) Oxidants, oxidative stress and the biology of ageing. Nature 408:239–247CrossRefPubMedGoogle Scholar
  52. 52.
    Yoon SO, Yun CH, Chung AS (2002) Dose effect of oxidative stress on signal transduction in aging. Mech Ageing Develop 123:1597–1604CrossRefGoogle Scholar
  53. 53.
    Lorenzini A, Tresini M, Mawal-Dewan M et al (2002) Role of the Raf/MEK/ERK and the PI3K/Akt(PKB) pathways in fibroblast senescence. Exp Gerontol 37:1149–1156CrossRefPubMedGoogle Scholar
  54. 54.
    Hutter D, Yo Y, Chen W et al (2000) Age-related decline in Ras/ERK mitogen-activated protein kinase cascade is linked to a reduced association between Shc and EGF receptor. J Gerontol A Biol Sci Med Sci 55:B125–B134CrossRefPubMedGoogle Scholar
  55. 55.
    Torres C, Francis MK, Lorenzini A et al (2003) Metabolic stabilization of MAP kinase phosphatase-2 in senescence of human fibroblasts. Exp Cell Res 290:195–206CrossRefPubMedGoogle Scholar
  56. 56.
    Meloche S, Gopalbhai K, Beatty BG et al (2000) Chromosome mapping of the human genes encoding the MAP kinase kinase MEK1 (MAP2K1) to 15q21 and MEK2 (MAP2K2) to 7q32. Cytogenet Cell Genet 88:249–252CrossRefPubMedGoogle Scholar
  57. 57.
    Romero-Alvira D, Roche E, Placer L (1996) Cardiomyopathies and oxidative stress. Med Hypotheses 47:137–144CrossRefPubMedGoogle Scholar
  58. 58.
    Cesselli D, Jakoniuk I, Barlucchi L et al (2001) Oxidative stress-mediated cardiac cell death is a major determinant of ventricular dysfunction and failure in dog dilated cardiomyopathy. Circ Res 89:279–286CrossRefPubMedGoogle Scholar
  59. 59.
    Wold LE, Ceylan-Isik AF, Ren J (2005) Oxidative stress and stress signaling: menace of diabetic cardiomyopathy. Acta Pharmacol Sin 26:908–917CrossRefPubMedGoogle Scholar
  60. 60.
    Bandyopadhyay D, Chattopadhyay A, Ghosh G et al (2004) Oxidative stress-induced ischemic heart disease: protection by antioxidants. Curr Med Chem 11:369–387CrossRefPubMedGoogle Scholar
  61. 61.
    Jacob MH, Pontes MR, Araujo AS et al (2006) Aortic-banding induces myocardial oxidative stress and changes in concentration and activity of antioxidants in male Wistar rats. Life Sci 79:2187–2193CrossRefPubMedGoogle Scholar
  62. 62.
    Okumura S, Vatner DE, Kurotani R et al (2007) Disruption of type 5 adenylyl cyclase enhances desensitization of cyclic adenosine monophosphate signal and increases Akt signal with chronic catecholamine stress. Circulation 116:1776–1783Google Scholar
  63. 63.
    Brunet A, Sweeney LB, Sturgill JF et al (2004) Stress-dependent regulation of FoxO transcription factors by the SIRT1 deacetylase. Science 303:2011–2015CrossRefPubMedGoogle Scholar
  64. 64.
    Salih DA, Brunet A (2008) FoxO transcription factors in the maintenance of cellular homeostasis during aging. Curr Opin Cell Biol 20:126–136CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Sengupta A, Molkentin JD, Yutzey KE (2009) FoxO transcription factors promote autophagy in cardiomyocytes. J Biol Chem 284:28319–28331CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Eaton CB (1992) Relation of physical activity and cardiovascular fitness to coronary heart disease: a meta-analysis of the independent relation of physical activity and coronary heart disease. J Am Board Fam Pract 5:31–42PubMedGoogle Scholar
  67. 67.
    Eaton CB (1992) Relation of physical activity and cardiovascular fitness to coronary heart disease: cardiovascular fitness and the safety and efficacy of physical activity prescription. J Am Board Fam Pract 5:157–165PubMedGoogle Scholar
  68. 68.
    Agress CM (1978) Energetics. Grosset & Dunlap, New York, 166 pGoogle Scholar
  69. 69.
    Kruk J, Duchnik E (2014) Oxidative stress and skin diseases: possible role of physical activity. Asian Pac J Cancer Prev 15:561–568CrossRefPubMedGoogle Scholar
  70. 70.
    Rockl KS, Hirshman MF, Brandauer J et al (2007) Skeletal muscle adaptation to exercise training: AMP-activated protein kinase mediates muscle fiber type shift. Diabetes 56:2062–2069CrossRefPubMedGoogle Scholar
  71. 71.
    Yamamoto H, Williams EG, Mouchiroud L et al (2011) NCoR1 is a conserved physiological modulator of muscle mass and oxidative function. Cell 147:827–839CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Kops GJ, Dansen TB, Polderman PE et al (2002) Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature 419:316–321CrossRefPubMedGoogle Scholar
  73. 73.
    Dufresne SD, Bjorbaek C, El-Haschimi K et al (2001) Altered extracellular signal-regulated kinase signaling and glycogen metabolism in skeletal muscle from p90 ribosomal S6 kinase 2 knockout mice. Mol Cell Biol 21:81–87CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Chalkiadaki A, Igarashi M, Nasamu AS et al (2014) Muscle-specific SIRT1 gain-of-function increases slow-twitch fibers and ameliorates pathophysiology in a mouse model of Duchenne muscular dystrophy. PLoS Genet 10(7):e1004490CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Onda T, Hashimoto Y, Nagai M et al (2001) Type-specific regulation of adenylyl cyclase. selective pharmacological stimulation and inhibition of adenylyl cyclase isoforms. J Biol Chem 276:47785–47793PubMedGoogle Scholar
  76. 76.
    Defer N, Best-Belpomme M, Hanoune J (2000) Tissue specificity and physiological relevance of various isoforms of adenylyl cyclase. Am J Physiol Renal Physiol 279:F400–F416PubMedGoogle Scholar
  77. 77.
    Takahashi T, Tang T, Lai NC et al (2006) Increased cardiac adenylyl cyclase expression is associated with increased survival after myocardial infarction. Circulation 114:388–396CrossRefPubMedGoogle Scholar
  78. 78.
    Lai NC, Tang T, Gao MH et al (2008) Activation of cardiac adenylyl cyclase expression increases function of the failing ischemic heart in mice. J Am Coll Cardiol 51:1490–1497CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Roth DM, Bayat H, Drumm JD et al (2002) Adenylyl cyclase increases survival in cardiomyopathy. Circulation 105:1989–1994CrossRefPubMedGoogle Scholar
  80. 80.
    Roth DM, Gao MH, Lai NC et al (1999) Cardiac-directed adenylyl cyclase expression improves heart function in murine cardiomyopathy. Circulation 99:3099–3102CrossRefPubMedGoogle Scholar
  81. 81.
    Wang Z, Li V, Chan GC et al (2009) Adult type 3 adenylyl cyclase-deficient mice are obese. PLoS One 4(9):e6979CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Stephens NG, Parsons A, Schofield PM et al (1996) Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet 347:781–786CrossRefPubMedGoogle Scholar
  83. 83.
    Sesso HD, Buring JE, Christen WG et al (2008) Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians’ Health Study II randomized controlled trial. JAMA 300:2123–2133CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Cook NR, Albert CM, Gaziano JM et al (2007) A randomized factorial trial of vitamins C and E and beta carotene in the secondary prevention of cardiovascular events in women: results from the Women’s Antioxidant Cardiovascular Study. Arch Intern Med 167:1610–1618CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Bjelakovic G, Nikolova D, Gluud LL et al (2007) Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA 297:842–857CrossRefPubMedGoogle Scholar
  86. 86.
    Lonn E, Bosch J, Yusuf S et al (2005) Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA 293:1338–1347CrossRefPubMedGoogle Scholar
  87. 87.
    Myung SK, Ju W, Cho B et al (2013) Efficacy of vitamin and antioxidant supplements in prevention of cardiovascular disease: systematic review and meta-analysis of randomised controlled trials. BMJ 346:f10–f22CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Stephen F. Vatner
    • 1
    Email author
  • Jie Zhang
    • 1
  • Dorothy E. Vatner
    • 1
  1. 1.Department of Cell Biology and Molecular MedicineRutgers, New Jersey Medical SchoolNewarkUSA

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