Overview of Cardiovascular Aging

  • José Marín-García
  • Michael J. Goldenthal
  • Gordon W. Moe


Telomere Length Replicative Senescence Dwarf Mouse Aging Heart Cardiovascular Aging 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Wolf MJ, Amrein H, Izatt JA, Choma MA, Reedy MC, Rockman HA. Drosophila as a model for the identification of genes causing adult human heart disease. Proc Natl Acad Sci USA 2006;103:1394–1399PubMedGoogle Scholar
  2. 2.
    Roman MJ, Ganau A, Saba PS, Pini R, Pickering TG, Devereux RB. Impact of arterial stiffening on left ventricular structure. Hypertension 2000;36:489–494PubMedGoogle Scholar
  3. 3.
    Taddei S, Virdis A, Mattei P, Ghiadoni L, Gennari A, Fasolo CB, Sudano I, Salvetti A. Aging and endothelial function in normotensive subjects and patients with essential hypertension. Circulation 1995;91: 1981–1987PubMedGoogle Scholar
  4. 4.
    Lakatta EG, Gerstenblith G, Angell CS, Shock NW, Weisfeldt ML. Prolonged contraction duration in aged myocardium. J Clin Invest 1975;55:61–68PubMedGoogle Scholar
  5. 5.
    Schulman SP, Lakatta EG, Fleg JL, Lakatta L, Becker LC, Gerstenblith G. Age-related decline in left ventricular filling at rest and exercise. Am J Physiol 1992;263:H1932–H1938PubMedGoogle Scholar
  6. 6.
    Merillon JP, Motte G, Masquet C, Azancot I, Aumont MC, Guiomard A, Gourgon R. Changes in the physical properties of the arterial system and left ventricular performance with age and in permanent arterial hypertension: their interrelation. Arch Mal Coeur Vaiss 1982;75:127–132PubMedGoogle Scholar
  7. 7.
    Lakatta EG. Cardiovascular regulatory mechanisms in advanced age. Physiol Rev 1993;73:413–467PubMedGoogle Scholar
  8. 8.
    Edo MD, Andrés V. Aging, telomeres, and atherosclerosis. Cardiovasc Res 2005;66:213–221PubMedGoogle Scholar
  9. 9.
    Aviv H, Khan MY, Skurnick J, Okuda K, Kimura M, Gardner J, Priolo L, Aviv A. Age dependent aneuploidy and telomere length of the human vascular endothelium. Atherosclerosis 2001;159:281–287PubMedGoogle Scholar
  10. 10.
    Chang E, Harley CB. Telomere length and replicative aging in human vascular tissues. Proc Natl Acad Sci USA 1995;92:11190–11194PubMedGoogle Scholar
  11. 11.
    Okuda K, Khan MY, Skurnick J, Kimura M, Aviv H, Aviv A. Telomere attrition of the human abdominal aorta: relationships with age and atherosclerosis. Atherosclerosis 2000;152:391–398PubMedGoogle Scholar
  12. 12.
    Matthews C, Gorenne I, Scott S, Figg N, Kirkpatrick P, Ritchie A, Goddard M, Bennett M. Vascular smooth muscle cells undergo telomere-based senescence in human atherosclerosis: effects of telomerase and oxidative stress. Circ Res 2006;99:156–164PubMedGoogle Scholar
  13. 13.
    Samani NJ, Boultby R, Butler R, Thompson JR, Goodall AH. Telomere shortening in atherosclerosis. Lancet 2001;358:472–473PubMedGoogle Scholar
  14. 14.
    Benetos A, Gardner JP, Zureik M, Labat C, Xiaobin L, Adamopoulos C, Temmar M, Bean KE, Thomas F, Aviv A. Short telomeres are associated with increased carotid atherosclerosis in hypertensive subjects. Hypertension 2004;43:182–185PubMedGoogle Scholar
  15. 15.
    Collerton J, Martin-Ruiz C, Kenny A, Barrass K, von Zglinicki T, Kirkwood T, Keavney B. Telomere length is associated with left ventricular function in the oldest old: the Newcastle 85+ study. Eur Heart J 2007;28:172–176Google Scholar
  16. 16.
    von Zglinicki T. Oxidative stress shortens telomeres. Trends Biochem Sci 2002;27:339–344Google Scholar
  17. 17.
    Kurz DJ, Decary S, Hong Y, Trivier E, Akhmedov A, Erusalimsky JD. Chronic oxidative stress compromises telomere integrity and accelerates the onset of senescence in human endothelial cells. J Cell Sci 2004;117: 2417–2426PubMedGoogle Scholar
  18. 18.
    Haendeler J, Hoffmann J, Diehl JF, Vasa M, Spyridopoulos I, Zeiher AM, Dimmeler S. Antioxidants inhibit nuclear export of telomerase reverse transcriptase and delay replicative senescence of endothelial cells. Circ Res 2004;94:768–775PubMedGoogle Scholar
  19. 19.
    Spyridopoulos I, Haendeler J, Urbich C, Brummendorf TH, Oh H, Schneider MD, Zeiher AM, Dimmeler S. Statins enhance migratory capacity by upregulation of the telomere repeat-binding factor TRF2 in endothelial progenitor cells. Circulation 2004;110:3136–3142PubMedGoogle Scholar
  20. 20.
    Imanishi T, Hano T, Nishio I. Estrogen reduces endothelial progenitor cell senescence through augmentation of telomerase activity. J Hypertens 2005;23:1699–1706PubMedGoogle Scholar
  21. 21.
    Simoncini T, Hafezi-Moghadam A, Brazil DP, Ley K, Chin WW, Liao JK. Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature 2000;407:538–541PubMedGoogle Scholar
  22. 22.
    Vasa M, Breitschopf K, Zeiher AM, Dimmeler S. Nitric oxide activates telomerase and delays endothelial cell senescence. Circ Res 2000;87:540–542PubMedGoogle Scholar
  23. 23.
    Imanishi T, Hano T, Sawamura T, Nishio I. Oxidized low-density lipoprotein induces endothelial progenitor cell senescence, leading to cellular dysfunction. Clin Exp Pharmacol Physiol 2004;31:407–413PubMedGoogle Scholar
  24. 24.
    Serrano AL, Andres V. Telomeres and cardiovascular disease: does size matter? Circ Res 2004;94:575–584PubMedGoogle Scholar
  25. 25.
    von Zglinicki T, Pilger R, Sitte N. Accumulation of single-strand breaks is the major cause of telomere shortening in human fibroblasts. Free Radic Biol Med 2000;28:64–74Google Scholar
  26. 26.
    Forsyth NR, Evans AP, Shay JW, Wright WE. Developmental differences in the immortalization of lung fibroblasts by telomerase. Aging Cell 2003;2:235–243PubMedGoogle Scholar
  27. 27.
    Serra V, von Zglinicki T, Lorenz M, Saretzki G. Extracellular superoxide dismutase is a major antioxidant in human fibroblasts and slows telomere shortening. J Biol Chem 2003;278:6824–6830Google Scholar
  28. 28.
    Saretzki G, Murphy MP, von Zglinicki T. MitoQ counteracts telomere shortening and elongates life span of fibroblasts under mild oxidative stress. Aging Cell 2003;2:141–143PubMedGoogle Scholar
  29. 29.
    Passos JF, von Zglinicki T. Mitochondria, telomeres and cell senescence. Exp Gerontol 2005;40:466–472PubMedGoogle Scholar
  30. 30.
    Kirkwood TB. Understanding the odd science of aging. Cell 2005;120:437–447PubMedGoogle Scholar
  31. 31.
    Cook SA, Sugden PH, Clerk A. Regulation of Bcl-2 family proteins during development and in response to oxidative stress in cardiac myocytes: association with changes in mitochondrial membrane potential. Circ Res 1999;85:940–949PubMedGoogle Scholar
  32. 32.
    Long X, Goldenthal MJ, Wu GM, Marín-García J. Mitochondrial Ca2+ flux and respiratory enzyme activity decline are early events in cardiomyocyte response to H_2O_2. J Mol Cell Cardiol 2004;37:63–70Google Scholar
  33. 33.
    Pollack M, Phaneuf S, Dirks A, Leeuwenburgh C. The role of apoptosis in the normal aging brain, skeletal muscle, and heart. Ann NY Acad Sci 2002;959:93–107PubMedGoogle Scholar
  34. 34.
    Marin-Garcia J, Pi Y, Goldenthal MJ. Mitochondrial-nuclear cross-talk in the aging and failing heart. Cardiovasc Drugs Ther 2006;20:477–491PubMedGoogle Scholar
  35. 35.
    Narula J, Haider N, Arbustini E, Chandrashekhar Y. Mechanisms of disease: apoptosis in heart failure–seeing hope in death. Nat Clin Pract Cardiovasc Med 2006;3:681–688PubMedGoogle Scholar
  36. 36.
    Madamanchi NR, Runge MS. Mitochondrial dysfunction in atherosclerosis. Circ Res 2007;100:460–473PubMedGoogle Scholar
  37. 37.
    Webster KA, Graham RM, Thompson JW, Spiga MG, Frazier DP, Wilson A, Bishopric NH. Redox stress and the contributions of BH3-only proteins to infarction. Antioxid Redox Signal 2006;8:1667–1676PubMedGoogle Scholar
  38. 38.
    Danial NN, Korsmeyer SJ. Cell death: critical control points. Cell 2004;116:205–219PubMedGoogle Scholar
  39. 39.
    Li LY, Luo X, Wang X. Endonuclease G is an apoptotic DNase when released from mitochondria. Nature 2001;412:95–99PubMedGoogle Scholar
  40. 40.
    Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E, Costantini P, Loeffler M, Larochette N, Goodlett DR, Aebersold R, Siderovski DP, Penninger JM, Kroemer G. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 1999;397:441–446PubMedGoogle Scholar
  41. 41.
    Joza N, Oudit GY, Brown D, Benit P, Kassiri Z, Vahsen N, Benoit L, Patel MM, Nowikovsky K, Vassault A, Backx PH, Wada T, Kroemer G, Rustin P, Penninger JM. Muscle-specific loss of apoptosis-inducing factor leads to mitochondrial dysfunction, skeletal muscle atrophy, and dilated cardiomyopathy. Mol Cell Biol 2005;25:10261–10272PubMedGoogle Scholar
  42. 42.
    Vahsen N, Cande C, Briere JJ, Benit P, Joza N, Larochette N, Mastroberardino PG, Pequignot MO, Casares N, Lazar V, Feraud O, Debili N, Wissing S, Engelhardt S, Madeo F, Piacentini M, Penninger JM, Schagger H, Rustin P, Kroemer G. AIF deficiency compromises oxidative phosphorylation. EMBO J 2004;23:4679–4689PubMedGoogle Scholar
  43. 43.
    Bahi N, Zhang J, Llovera M, Ballester M, Comella JX, Sanchis D. Switch from caspase-dependent to caspase-independent death during heart development: essential role of endonuclease G in ischemia-induced DNA processing of differentiated cardiomyocytes. J Biol Chem 2006;281:22943–22952PubMedGoogle Scholar
  44. 44.
    Liu X, Kim CN, Yang J, Jemmerson R, Wang X. Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell 1996;86:147–157PubMedGoogle Scholar
  45. 45.
    Acehan D, Jiang X, Morgan DG, Heuser JE, Wang X, Akey CW. Three-dimensional structure of the apoptosome: implications for assembly, procaspase-9 binding, and activation. Mol Cell 2002;9:423–432PubMedGoogle Scholar
  46. 46.
    Kinnally KW, Antonsson B. A tale of two mitochondrial channels, MAC and PTP, in apoptosis. Apoptosis 2007 Feb 6Google Scholar
  47. 47.
    Kroemer G. Mitochondrial control of apoptosis: an introduction. Biochem Biophys Res Commun 2003;304:433–435PubMedGoogle Scholar
  48. 48.
    Correa F, Soto V, Zazueta C. Mitochondrial permeability transition relevance for apoptotic triggering in the post-ischemic heart. Int J Biochem Cell Biol 2007 Jan 21Google Scholar
  49. 49.
    Marzo I, Brenner C, Zamzami N, Susin SA, Beutner G, Brdiczka D, Remy R, Xie ZH, Reed JC, Kroemer G. The permeability transition pore complex: a target for apoptosis regulation by caspases and Bcl-2 related proteins. J Exp Med 1998;187:1261–1267PubMedGoogle Scholar
  50. 50.
    Scorrano L, Ashiya M, Buttle K, Weiler S, Oakes S, Mannella CA, Korsmeyer SJ. A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis. Dev Cell 2002;2:55–67PubMedGoogle Scholar
  51. 51.
    Ekhterae D, Lin Z, Lundberg MS, Crow MT, Brosius FC 3rd, Nunez G. ARC inhibits cytochrome c release from mitochondria and protects against hypoxia-induced apoptosis in heart-derived H9c2 cells. Circ Res 1999;85:e70–e77PubMedGoogle Scholar
  52. 52.
    Scorrano L, Oakes SA, Opferman JT, Cheng EH, Sorcinelli MD, Pozzan T, Korsmeyer SJ. BAX and BAK regulation of endoplasmic reticulum Ca2+: a control point for apoptosis. Science 2003;300:135–139Google Scholar
  53. 53.
    Hajnoczky G, Csordas G, Das S, Garcia-Perez C, Saotome M, Sinha Roy S, Yi M. Mitochondrial calcium signalling and cell death: approaches for assessing the role of mitochondrial Ca2+ uptake in apoptosis. Cell Calcium 2006;40:553–560PubMedGoogle Scholar
  54. 54.
    Jacobson J, Duchen MR. Mitochondrial oxidative stress and cell death in astrocytes—requirement for stored Ca2+ and sustained opening of the permeability transition pore. J Cell Sci 2002;115:1175–1188PubMedGoogle Scholar
  55. 55.
    Migliaccio E, Giorgio M, Mele S, Pelicci G, Reboldi P, Pandolfi PP, Lanfrancone L, Pelicci PG. The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature 1999;402:309–313PubMedGoogle Scholar
  56. 56.
    Orsini F, Migliaccio E, Moroni M, Contursi C, Raker VA, Piccini D, Martin-Padura I, Pelliccia G, Trinei M, Bono M, Puri C, Tacchetti C, Ferrini M, Mannucci R, Nicoletti I, Lanfrancone L, Giorgio M, Pelicci PG. The life span determinant p66Shc localizes to mitochondria where it associates with mitochondrial heat shock protein 70 and regulates trans-membrane potential, J Biol Chem 2004;279:25689–25695PubMedGoogle Scholar
  57. 57.
    Trinei M, Giorgio M, Cicalese A, Barozzi S, Ventura A, Migliaccio E, Milia E, Padura IM, Raker VA, Maccarana M, Petronilli V, Minucci S, Bernardi P, Lanfrancone L, Pelicci PG. A p53–p66Shc signalling pathway controls intracellular redox status, levels of oxidation-damaged DNA and oxidative stress-induced apoptosis. Oncogene 2002;21:3872–3878PubMedGoogle Scholar
  58. 58.
    Giorgio M, Migliaccio E, Orsini F, Paolucci D, Moroni M, Contursi C, Pelliccia G, Luzi L, Minucci S, Marcaccio M, Pinton P, Rizzuto R, Bernardi P, Paolucci F, Pelicci PG. Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis. Cell 2005;122:221–233PubMedGoogle Scholar
  59. 59.
    Zaccagnini G, Martelli F, Fasanaro P, Magenta A, Gaetano C, Di Carlo A, Biglioli P, Giorgio M, Martin-Padura I, Pelicci PG, Capogrossi MC. p66ShcA modulates tissue response to hindlimb ischemia. Circulation 2004;109:2917–2923PubMedGoogle Scholar
  60. 60.
    Napoli C, Martin-Padura I, de Nigris F, Giorgio M, Mansueto G, Somma P, Condorelli M, Sica G, De Rosa G, Pelicci P. Deletion of the p66Shc longevity gene reduces systemic and tissue oxidative stress, vascular cell apoptosis, and early atherogenesis in mice fed a high-fat diet. Proc Natl Acad Sci USA 2003;100:2112–2116PubMedGoogle Scholar
  61. 61.
    Torella D, Rota M, Nurzynska D, Musso E, Monsen A, Shiraishi I, Zias E, Walsh K, Rosenzweig A, Sussman MA, Urbanek K, Nadal-Ginard B, Kajstura J, Anversa P, Leri A. Cardiac stem cell and myocyte aging, heart failure, and insulin-like growth factor-1 overexpression. Circ Res 2004; 94:514–524PubMedGoogle Scholar
  62. 62.
    Kujoth GC, Hiona A, Pugh TD, Someya S, Panzer K, Wohlgemuth SE, Hofer T, Seo AY, Sullivan R, Jobling WA, Morrow JD, Van Remmen H, Sedivy JM, Yamasoba T, Tanokura M, Weindruch R, Leeuwenburgh C, Prolla TA. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 2005;309:481–484PubMedGoogle Scholar
  63. 63.
    Ball AJ, Levine F. Telomere-independent cellular senescence in human fetal cardiomyocytes. Aging Cell 2005;4:21–30PubMedGoogle Scholar
  64. 64.
    Uhrbom L, Nister M, Westermark B. Induction of senescence in human malignant glioma cells by p16INK4A. Oncogene 1997;15:505–514PubMedGoogle Scholar
  65. 65.
    Melov S. Mitochondrial oxidative stress. Physiologic consequences and potential for a role in aging. Ann NY Acad Sci 2000;908:219–225PubMedGoogle Scholar
  66. 66.
    Lenaz G, D’Aurelio M, Merlo Pich M, Genova ML, Ventura B, Bovina C, Formiggini G, Parenti Castelli G. Mitochondrial bioenergetics in aging. Biochim Biophys Acta 2000;1459:397–404PubMedGoogle Scholar
  67. 67.
    Pepe S. Effect of dietary polyunsaturated fatty acids on age-related changes in cardiac mitochondrial membranes. Exp Gerontol 2005;40:751–758PubMedGoogle Scholar
  68. 68.
    Hansford RG, Tsuchiya N, Pepe S. Mitochondria in heart ischaemia and aging. Biochem Soc Symp 1999; 66:141–7; Harper ME, Bevilacqua L, Hagopian K, Weindruch R, Ramsey JJ. Ageing, oxidative stress, and mitochondrial uncoupling. Acta Physiol Scand 2004;182:321–331PubMedGoogle Scholar
  69. 69.
    Di Lisa F, Bernardi P. Mitochondrial function and myocardial aging. A critical analysis of the role of permeability transition. Cardiovasc Res 2005;66:222–232PubMedGoogle Scholar
  70. 70.
    Jahangir A, Ozcan C, Holmuhamedov EL, Terzic A. Increased calcium vulnerability of senescent cardiac mitochondria: protective role for a mitochondrial potassium channel opener. Mech Ageing Dev 2001;122:1073–1086PubMedGoogle Scholar
  71. 71.
    Russell LK, Finck BN, Kelly DP. Mouse models of mitochondrial dysfunction and heart failure. J Mol Cell Cardiol 2005;38:81–91PubMedGoogle Scholar
  72. 72.
    Chakravarti B, Chakravarti DN. Oxidative modification of proteins: age-related changes. Gerontology 2006;53:128–139PubMedGoogle Scholar
  73. 73.
    Levine RL, Stadtman ER. Oxidative modification of proteins during aging. Exp Gerontol 2001;36:1495–1502PubMedGoogle Scholar
  74. 74.
    Stadtman ER, Levine RL. Protein oxidation. Ann. NY Acad.Sci 2000;899:191–208PubMedGoogle Scholar
  75. 75.
    Yarian CS, Rebrin I, Sohal RS. Aconitase and ATP synthase are targets of malondialdehyde modification and undergo an age-related decrease in activity in mouse heart mitochondria. Biochem Biophys Res Commun 2005;330:151–156PubMedGoogle Scholar
  76. 76.
    Yan LJ, Sohal RS. Mitochondrial adenine nucleotide translocase is modified oxidatively during aging. Proc Natl Acad Sci USA 1998;95:12896–12890PubMedGoogle Scholar
  77. 77.
    Choksi KB, Boylston WH, Rabek JP, Widger WR, Papaconstantinou J. Oxidatively damaged proteins of heart mitochondrial electron transport complexes. Biochim Biophys Acta 2004;1688:95–101PubMedGoogle Scholar
  78. 78.
    Vasquez-Vivar J, Kalyanaraman B, Kennedy MC. Mitochondrial aconitase is a source of hydroxyl radical. An electron spin resonance investigation. J Biol Chem 2000;2751:4064–4069Google Scholar
  79. 79.
    Viner RI, Ferrington DA, Williams TD, Bigelow DJ, Schoneich C. Protein modification during biological aging: selective tyrosine nitration of the SERCA2a isoform of the sarcoplasmic reticulum Ca2+-ATPase in skeletal muscle. Biochem J 1999;340:657–669PubMedGoogle Scholar
  80. 80.
    Knyushko TV, Sharov VS, Williams TD, Schoneich C, Bigelow DJ. 3-Nitrotyrosine modification of SERCA2a in the aging heart: a distinct signature of the cellular redox environment. Biochemistry 2005;44:13071–13081PubMedGoogle Scholar
  81. 81.
    Xu S, Ying J, Jiang B, Guo W, Adachi T, Sharov V, Lazar H, Menzoian J, Knyushko TV, Bigelow D, Schoneich C, Cohen RA. Detection of sequence-specific tyrosine nitration of manganese SOD and SERCA in cardiovascular disease and aging. Am J Physiol Heart Circ Physiol 2006;290:H2220–H2227PubMedGoogle Scholar
  82. 82.
    Murray J, Taylor SW, Zhang B, Ghosh SS, Capaldi RA. Oxidative damage to mitochondrial complex I due to peroxynitrite: identification of reactive tyrosines by mass spectrometry. J Biol Chem 2003;278:37223–37230PubMedGoogle Scholar
  83. 83.
    Kanski J, Behring A, Pelling J, Schoneich C. Proteomic identification of 3-nitrotyrosine-containing rat cardiac proteins: effects of biological aging. Am J Physiol Heart Circ Physiol 2005;288:H371–H381PubMedGoogle Scholar
  84. 84.
    LeDoux SP, Wilson GL. Base excision repair of mitochondrial DNA damage in mammalian cells. Prog Nucleic Acid Res Mol Biol 2001;68:273–284PubMedGoogle Scholar
  85. 85.
    Yakes FM, Van Houten B. Mitochondrial DNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress. Proc Natl Acad Sci USA 1997;94:514–519PubMedGoogle Scholar
  86. 86.
    Yowe DL, Ames BN. Quantitation of age-related mitochondrial DNA deletions in rat tissues shows that their pattern of accumulation differs from that of humans. Gene 1998;209:23–30PubMedGoogle Scholar
  87. 87.
    Zhang C, Bills M, Quigley A, Maxwell RJ, Linnane AW, Nagley P. Varied prevalence of age-associated mitochondrial DNA deletions in different species and tissues: a comparison between human and rat. Biochem Biophys Res Commun 1997;230:630–635PubMedGoogle Scholar
  88. 88.
    Muscari C, Giaccari A, Stefanelli C, Viticchi C, Giordano E, Guarnieri C, Caldarera CM. Presence of a DNA-4236 bp deletion and 8-hydroxy-deoxyguanosine in mouse cardiac mitochondrial DNA during aging. Aging (Milano) 1996;8:429–433Google Scholar
  89. 89.
    Wanagat J, Wolff MR, Aiken JM. Age-associated changes in function, structure and mitochondrial genetic and enzymatic abnormalities in the Fischer 344 -Brown Norway F(1) hybrid rat heart. J Mol Cell Cardiol 2002;34:17–28PubMedGoogle Scholar
  90. 90.
    Pak JW, Vang F, Johnson C, McKenzie D, Aiken JM. MtDNA point mutations are associated with deletion mutations in aged rat. Exp Gerontol 2005;40:209–218PubMedGoogle Scholar
  91. 91.
    Wang Y, Michikawa Y, Mallidis C, Bai Y, Woodhouse L, Yarasheski KE, Miller CA, Askanas V, Engel WK, Bhasin S, Attardi G. Muscle-specific mutations accumulate with aging in critical human mtDNA control sites for replication. Proc Natl Acad Sci USA 2001;98:4022–4027PubMedGoogle Scholar
  92. 92.
    Michikawa Y, Mazzucchelli F, Bresolin N, Scarlato G, Attardi G. Aging-dependent large accumulation of point mutations in the human mtDNA control region for replication. Science 1999;286:774–779PubMedGoogle Scholar
  93. 93.
    Marín-García J, Zoubenko O, Goldenthal MJ. Mutations in the cardiac mtDNA control region associated with cardiomyopathy and aging. J Card Fail 2002;8:93–100PubMedGoogle Scholar
  94. 94.
    Song X, Deng JH, Liu CJ, Bai Y. Specific point mutations may not accumulate with aging in the mouse mitochondrial DNA control region. Gene 2005;350:193–199PubMedGoogle Scholar
  95. 95.
    Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CE, Bohlooly-Y M, Gidlof S, Oldfors A, Wibom R, Tornell J, Jacobs HT, Larsson NG. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 2004;27:417–423Google Scholar
  96. 96.
    Trifunovic A, Hansson A, Wredenberg A, Rovio AT, Dufour E, Khvorostov I, Spelbrink JN, Wibom R, Jacobs HT, Larsson NG. Somatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production. Proc Natl Acad Sci USA 2005;102:17993–17998PubMedGoogle Scholar
  97. 97.
    Loeb LA, Wallace DC, Martin GM. The mitochondrial theory of aging and its relationship to reactive oxygen species damage and somatic mtDNA mutations. Proc Natl Acad Sci USA 2005;102:18769–18770PubMedGoogle Scholar
  98. 98.
    Suh JH, Heath SH, Hagen T. Two subpopulations of mitochondria in the aging rat heart display heterogenous levels of oxidative stress. Free Radic Biol Med 2003;35:1064–1072PubMedGoogle Scholar
  99. 99.
    Judge S, Jang YM, Smith A, Hagen T, Leeuwenburgh C. Age-associated increases in oxidative stress and antioxidant enzyme activities in cardiac interfibrillar mitochondria: implications for the mitochondrial theory of aging. FASEB J 2005;19:419–421PubMedGoogle Scholar
  100. 100.
    Zhao K, Zhao GM, Wu D, Soong Y, Birk AV, Schiller PW, Szeto HH. Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death and reperfusion injury. J Biol Chem 2004;279:34682–34690PubMedGoogle Scholar
  101. 101.
    Smith RA, Porteous CM, Gane AM, Murphy MP. Delivery of bioactive molecules to mitochondria in vivo. Proc Natl Acad Sci USA 2003;100:5407–5412PubMedGoogle Scholar
  102. 102.
    Schriner SE, Linford NJ, Martin GM, Treuting P, Ogburn CE, Emond M, Coskun PE, Ladiges W, Wolf N, Van Remmen H, Wallace DC, Rabinovitch PS. Extension of murine life span by overexpression of catalase targeted to mitochondria. Science 2005;308:1909–1911PubMedGoogle Scholar
  103. 103.
    Ren J, Li Q, Wu S, Li SY, Babcock SA. Cardiac overexpression of antioxidant catalase attenuates aging-induced cardiomyocyte relaxation dysfunction. Mech Ageing Dev 2007;128:276–285PubMedGoogle Scholar
  104. 104.
    Chung HY, Sung B, Jung KJ, Zou Y, Yu BP. The molecular inflammatory process in aging. Antioxid Redox Signal 2006;8:572–581PubMedGoogle Scholar
  105. 105.
    Kritchevsky SB, Cesari M, Pahor M. Inflammatory markers and cardiovascular health in older adults. Cardiovasc Res 2005;66:265–275PubMedGoogle Scholar
  106. 106.
    Deten A, Marx G, Briest W, Volz HC, Zimmer H-G. Heart function and molecular biological parameters are comparable in young adult and aged rats after chronic myocardial infarction. Cardiovasc Res 2005;66:364–373PubMedGoogle Scholar
  107. 107.
    Antonicelli R, Olivieri F, Bonafe M, Cavallone L, Spazzafumo L, Marchegiani F, Cardelli M, Recanatini A, Testarmata P, Boemi M, Parati G, Franceschi C. The interleukin-6 -174 G>C promoter polymorphism is associated with a higher risk of death after an acute coronary syndrome in male elderly patients. Int J Cardiol 2005;103:266–271PubMedGoogle Scholar
  108. 108.
    White M, Roden R, Minobe W, Khan MF, Larrabee P, Wollmering M, Port JD, Anderson F, Campbell D, Feldman AM. Age-related changes in beta-adrenergic neuroeffector systems in the human heart. Circulation 1994;90:1225–1238PubMedGoogle Scholar
  109. 109.
    Brodde OE, Konschak U, Becker K, Ruter F, Poller U, Jakubetz J, Radke J, Zerkowski H. Cardiac muscarinic receptors decrease with age. In vitro and in vivo studies. J Clin Invest 1998;101:471–478PubMedGoogle Scholar
  110. 110.
    Giraldo E, Martos F, Gomez A, Garcia A, Vigano MA, Ladinsky H, Sanchez de la Cuesta F. Characterization of muscarinic receptor subtypes in human tissues. Life Sci 1988;43:1507–1515Google Scholar
  111. 111.
    Deighton NM, Motomura S, Borquez D, Zerkowski, HR, Doetsch N, Brodde OE. Muscarinic cholinoceptors in the human heart: demonstration, subclassification, and distribution. Naunyn-Schmiedeberg’s Arch Pharmacol 1990;341:414–421Google Scholar
  112. 112.
    Böhm M, Gierschik P, Jakobs KH, Piesk B, Schnabel P, Ungerer PM, Erdmann E. Increase of Gi in human hearts with dilated but not ischemic cardiomyopathy. Circulation 1990;82:1249–1265PubMedGoogle Scholar
  113. 113.
    Von Scheidt W, Böhm M, Stäblein A, Autenrieth G, Erdmann E. Antiadrenergic effect of M-cholinoceptor stimulation on human ventricular contractility in vivo. Am J Physiol 1992;263:H1927–H1931Google Scholar
  114. 114.
    Landzberg JS, Parker JD, Gauthier DF, Colucci WS. Effect of intracoronary acetylcholine and atropine on basal and dobutamine-stimulated left ventricular contractility. Circulation 1994;89:164–168PubMedGoogle Scholar
  115. 115.
    Turner MJ, Mier CM, Spina RJ, Ehsani AA. Effects of age and gender on cardiovascular responses to phenylephrine. J Gerontol A Biol Sci Med Sci 1999;54:M17–M24PubMedGoogle Scholar
  116. 116.
    Hees PS, Fleg JL, Mirza ZA, Ahmed S, Siu CO, Shapiro EP. Effects of normal aging on left ventricular lusitropic, inotropic, and chronotropic responses to dobutamine. J Am Coll Cardiol 2006;47:1440–1447PubMedGoogle Scholar
  117. 117.
    Korzick DH, Holiman DA, Boluyt MO, Laughlin MH, Lakatta EG. Diminished alpha1-adrenergic-mediated contraction and translocation of PKC in senescent rat heart. Am J Physiol Heart Circ Physiol 2001;281: H581–H589PubMedGoogle Scholar
  118. 118.
    Korzick DH, Hunter JC, McDowell MK, Delp MD, Tickerhoof MM, Carson LD. Chronic exercise improves myocardial inotropic reserve capacity through alpha1-adrenergic and protein kinase C-dependent effects in Senescent rats. J Gerontol A Biol Sci Med Sci 2004;59:1089–1098PubMedGoogle Scholar
  119. 119.
    Hunter JC, Korzick DH. Age- and sex-dependent alterations in protein kinase C (PKC) and extracellular regulated kinase 1/2 (ERK1/2) in rat myocardium. Mech Ageing Dev 2005;126:535–550PubMedGoogle Scholar
  120. 120.
    Montagne O, Le Corvoisier P, Guenoun T, Laplace M, Crozatier B. Impaired alpha1-adrenergic responses in aged rat hearts. Fundam Clin Pharmacol 2005;19:331–339Google Scholar
  121. 121.
    Esler M, Kaye D. Sympathetic nervous system activation in essential hypertension, cardiac failure and psychosomatic heart disease. J Cardiovasc Pharmacol 2000;35:S1–S7PubMedGoogle Scholar
  122. 122.
    Kaye D, Esler M. Sympathetic neuronal regulation of the heart in aging and heart failure. Cardiovasc Res 2005;66:256–64PubMedGoogle Scholar
  123. 123.
    Kilts JD, Akazawa T, El-Moalem HE, Mathew JP, Newman MF, Kwatra MM. Age increases expression and receptor-mediated activation of Galpha i in human atria. J Cardiovasc Pharmacol 2003;42:662–670PubMedGoogle Scholar
  124. 124.
    Kilts JD, Akazawa T, Richardson MD, Kwatra MM. Age increases cardiac Galpha (i2) expression, resulting in enhanced coupling to G protein-coupled receptors. J Biol Chem 2002;277:31257–31262PubMedGoogle Scholar
  125. 125.
    Brodde O-E, Michel MC. Adrenergic and muscarinic receptors in the human heart. Pharmacol Rev 1999;51:651–689PubMedGoogle Scholar
  126. 126.
    Richardson MD, Kilts JD, Kwatra MM. Increased expression of Gi-coupled muscarinic acetylcholine receptor and Gi in atrium of elderly diabetic subjects. Diabetes 2004;53:2392–2396PubMedGoogle Scholar
  127. 127.
    Brodde O-E, Konschack U, Becker K, Rüter F, Poller U, Jakubetz J, Radke J, Zerkowski H-R. Cardiac muscarinic receptors decrease with age:in vitro and in vivo studies. J Clin Invest 1998;101:471–478PubMedGoogle Scholar
  128. 128.
    Oberhauser V, Schwertfeger E, Rutz T, Beyersdorf F, Rump LC. Acetylcholine release in human heart atrium: influence of muscarinic autoreceptors, diabetes, and age. Circulation 2001;103:1638–1643PubMedGoogle Scholar
  129. 129.
    Halls ML, van der Westhuizen ET, Bathgate RA, Summers RJ. Relaxin Family Peptide Receptors – former orphans reunite with their parent ligands to activate multiple signalling pathways. Br J Pharmacol. 2007 Feb 12Google Scholar
  130. 130.
    Hisaw FL. Experimental relaxation of the pubic ligament of the guinea pig. Proc Soc Exp Biol Med 1926;23:661–663Google Scholar
  131. 131.
    Bathgate RAD, Hsueh AJW, Sherwood OD. Physiology and molecular biology of the relaxin peptide family. In: Neill JD, editor. Knobil and Neill’s physiology of reproduction 3rd edn. New York: Academic Press; 2006.Google Scholar
  132. 132.
    Bathgate RA, Ivell R, Sanborn BM, Sherwood OD, Summers RJ. International Union of Pharmacology LVII: recommendations for the nomenclature of receptors for relaxin family peptides. Pharmacol Rev 2006;58:7–31PubMedGoogle Scholar
  133. 133.
    Long X, Boluyt MO, O’Neill L, Zheng JS, Wu G, Nitta YK, Crow MT, Lakatta EG. Myocardial retinoid X receptor, thyroid hormone receptor, and myosin heavy chain gene expression in the rat during adult aging. J Gerontol A Biol Sci Med Sci 1999;54:B23–B27PubMedGoogle Scholar
  134. 134.
    Iemitsu M, Miyauchi T, Maeda S, Tanabe T, Takanashi M, Matsuda M, Yamaguchi I. Exercise training improves cardiac function-related gene levels through thyroid hormone receptor signaling in aged rats. Am J Physiol Heart Circ Physiol 2004;286:H1696–H1705PubMedGoogle Scholar
  135. 135.
    Tang F. Effect of sex and age on serum aldosterone and thyroid hormones in the laboratory rat. Horm Metab Res 1985;17:507–509PubMedGoogle Scholar
  136. 136.
    Buttrick P, Malhotra A, Factor S, Greenen D, Leinwand L, Scheuer J. Effect of aging and hypertension on myosin biochemistry and gene expression in the rat heart. Circ Res 1991;68:645–652PubMedGoogle Scholar
  137. 137.
    Schmidt U, del Monte F, Miyamoto MI, Matsui T, Gwathmey JK, Rosenzweig A, Hajjar RJ. Restoration of diastolic function in senescent rat hearts through adenoviral gene transfer of sarcoplasmic reticulum Ca(2+)-ATPase. Circulation 2000;101:790–796PubMedGoogle Scholar
  138. 138.
    Cain BS, Meldrum DR, Joo KS, Wang JF, Meng X, Cleveland JC Jr, Banerjee A, Harken AH. Human SERCA2a levels correlate inversely with age in senescent human myocardium. J Am Coll Cardiol 1998;32:458–467PubMedGoogle Scholar
  139. 139.
    Tatar M, Bartke A, Antebi A. The endocrine regulation of aging by insulin-like signals. Science 2003;299: 1346–1351PubMedGoogle Scholar
  140. 140.
    Muller EE, Cella SG, De Gennaro Colonna V, Parenti M, Cocchi D, Locatelli V. Aspects of the neuroendocrine control of growth hormone secretion in ageing mammals. J Reprod Fertil Suppl 1993;46:99–114PubMedGoogle Scholar
  141. 141.
    Bartke A. Minireview: role of the growth hormone/insulin-like growth factor system in mammalian aging. Endocrinology 2005;146:3718–3723PubMedGoogle Scholar
  142. 142.
    Brown-Borg HM, Borg KF, Meliska CJ, Bartke A. Dwarf mice and the ageing process. Nature 1996;384:33Google Scholar
  143. 143.
    Hsieh CC, de Ford JH, Flurkey K, Harrison DE, Papaconstantinou J. Effects of the Pit1 mutation on the insulin signaling pathway: implication on the longevity of the long lived Snell dwarf mouse. Mech Ageing Dev 2002;123:1254–1255Google Scholar
  144. 144.
    Barbieri M, Bonafe M, Franceschi C, Paolisso G. Insulin/IGF-1-signaling pathway: an evolutionarily conserved mechanism of longevity from yeast to humans. Am J Physiol Endocrinol Metab 2003;285:E1064–E1071PubMedGoogle Scholar
  145. 145.
    Bluher M, Kahn BB, Kahn CR. Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 2003;299:572–574PubMedGoogle Scholar
  146. 146.
    Steger RW, Bartke A, Cecim M. Premature ageing in transgenic mice expressing different growth hormone genes. J Reprod Fertil Suppl 1993;46:61–75PubMedGoogle Scholar
  147. 147.
    Muller F. Growth hormone receptor knockout (Laron) mice.;2002/8/tg1Google Scholar
  148. 148.
    Holzenberger M, Dupont J, Ducos B, Leneuve P, Geloen A, Even PC, Cervera P, Le Bouc Y. IGF-1 receptor regulates life span and resistance to oxidative stress in mice. Nature 2003;421:182–186Google Scholar
  149. 149.
    Goodman-Gruen D, Barrett-Connor E. Epidemiology of insulin-like growth factor-I in elderly men and women. The Rancho Bernardo Study. Am J Epidemiol 1997;145:970–976PubMedGoogle Scholar
  150. 150.
    Lieberman SA, Mitchell AM, Marcus R, Hintz RL, Hoffman AR. The insulin-like growth factor I generation test: resistance to growth hormone with aging and estrogen replacement therapy. Horm Metab Res 1994;26: 229–233PubMedGoogle Scholar
  151. 151.
    Khan AS, Sane DC, Wannenburg T, Sonntag WE. Growth hormone, insulin-like growth factor-1 and the aging cardiovascular system. Cardiovasc Res 2002;54:25–35PubMedGoogle Scholar
  152. 152.
    Vasan RS, Sullivan LM, D’Agostino RB, Roubenoff R, Harris T, Sawyer DB, Levy D, Wilson PW. Serum insulin-like growth factor I and risk for heart failure in elderly individuals without a previous myocardial infarction: the Framingham Heart Study. Ann Intern Med 2003;139:642–648PubMedGoogle Scholar
  153. 153.
    Roubenoff R, Parise H, Payette HA, Abad LW, D’Agostino R, Jacques PF, Wilson PW, Dinarello CA, Harris TB. Cytokines, insulin-like growth factor 1, sarcopenia, and mortality in very old community-dwelling men and women: the Framingham Heart Study. Am J Med 2003;115:429–435PubMedGoogle Scholar
  154. 154.
    Ghigo E, Arvat E, Gianotti L, Ramunni J, DiVito L, Maccagno B, Grottoli S, Camanni F. Human aging and the GH-IGF-1 axis. J Pediatr Endocrinol Metab 1996;9:271–278PubMedGoogle Scholar
  155. 155.
    Takahashi S, Meites J. GH binding to liver in young and old female rats: relation to somatomedin-C secretion. Proc Soc Exp Biol Med 1987;186:229–233PubMedGoogle Scholar
  156. 156.
    Xu X, Bennett SA, Ingram RL, Sonntag WE. Decreases in growth hormone receptor signal transduction contribute to the decline in insulin-like growth factor I gene expression with age. Endocrinology 1995;136: 4551–4557PubMedGoogle Scholar
  157. 157.
    Khan AS, Sane DC, Wannenburg T, Sonntag WE. Growth hormone, insulin-like growth factor-1 and the aging cardiovascular system. Cardiovasc Res 2002;54:25–35PubMedGoogle Scholar
  158. 158.
    Colao A, Marzullo P, Di Somma C, Lombardi G. Growth hormone and the heart. Clin Endocrinol 2001;54: 137–154Google Scholar
  159. 159.
    Osterziel KJ, Strohm O, Schuler J, Friedrich M, Hänlein D, Willenbrock R, Anker SD, Poole-Wilson PA, Ranke MB, Dietz R. Randomised, double-blind, placebo-controlled trial of human recombinant growth hormone in patients with chronic heart failure due to dilated cardiomyopathy. Lancet 1998;351:1233–1237PubMedGoogle Scholar
  160. 160.
    Wang PH. Roads to survival: insulin-like growth factor-1 signaling pathways in cardiac muscle. Circ Res 2001;88:552–554PubMedGoogle Scholar
  161. 161.
    Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P, McGuinness OP, Chikuda H, Yamaguchi M, Kawaguchi H, Shimomura I, Takayama Y, Herz J, Kahn CR, Rosenblatt KP, Kuro-o M. Suppression of aging in mice by the hormone Klotho. Science 2005;309:1829–1833PubMedGoogle Scholar
  162. 162.
    Bartke A. Long-lived Klotho mice: new insights into the roles of IGF-1 and insulin in aging. Trends Endocrinol Metab 2006;17:33–35PubMedGoogle Scholar
  163. 163.
    Yamamoto M, Clark JD, Pastor JV, Gurnani P, Nandi A, Kurosu H, Miyoshi M, Ogawa Y, Castrillon DH, Rosenblatt KP, Kuro-o M. Regulation of oxidative stress by the anti-aging hormone klotho. J Biol Chem 2005;280:38029–33834PubMedGoogle Scholar
  164. 164.
    Brunt UT, Terman A. The mitochondrial-lysosomal axis theory of aging: accumulation of damaged mitochondria as a result of imperfect autophagocytosis. Eur J Biochem 2002;269:1996–2002Google Scholar
  165. 165.
    Rooyackers OE, Adey DB, Ades PA, Nair KS. Effect of age on in vivo rates of mitochondrial protein synthesis in human skeletal muscle. Proc Natl Acad Sci USA 1996;93:15364–15369PubMedGoogle Scholar
  166. 166.
    Hamacher-Brady A, Brady NR, Gottlieb RA. The interplay between pro-death and pro-survival signaling pathways in myocardial ischemia/reperfusion injury: apoptosis meets autophagy. Cardiovasc Drugs Ther 2006;20:445–462PubMedGoogle Scholar
  167. 167.
    Klionsky DJ, Emr SD. Autophagy as a regulated pathway of cellular degradation. Science 2000;290:1717–1721PubMedGoogle Scholar
  168. 168.
    Breckenridge DG, Germain M, Mathai JP, Nguyen M, Shore GC. Regulation of apoptosis by endoplasmic reticulum pathways. Oncogene 2003;22:8608–8618PubMedGoogle Scholar
  169. 169.
    Ravikumar B, Berger Z, Vacher C, O’Kane CJ, Rubinsztein DC. Rapamycin pre-treatment protects against apoptosis. Hum Mol Genet 2006;15:1209–1216PubMedGoogle Scholar
  170. 170.
    Canu N, Tufi R, Serafino AL, Amadoro G, Ciotti MT, Calissano P. Role of the autophagic-lysosomal system on low potassium-induced apoptosis in cultured cerebellar granule cells. J Neurochem 2005;92:1228–1242PubMedGoogle Scholar
  171. 171.
    Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, Packer M, Schneider MD, Levine B. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 2005;122:927–939PubMedGoogle Scholar
  172. 172.
    Shimizu S, Kanaseki T, Mizushima N, Mizuta T, Arakawa-Kobayashi S, Thompson CB, Tsujimoto Y. Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nat Cell Biol 2004;6:1221–1228PubMedGoogle Scholar
  173. 173.
    Fleg JL, O’Connor F, Gerstenblith G, Becker LC, Clulow J, Schulman SP, Lakatta EG. Impact of age on the cardiovascular response to dynamic upright exercise in healthy men and women. J Appl Physiol 1995;78: 890–900PubMedGoogle Scholar
  174. 174.
    Redfield MM, Jacobsen SJ, Borlaug BA, Rodeheffer RJ, Kass DA. Age- and gender-related ventricular-vascular stiffening: a community-based study. Circulation 2005;112:2254–2262PubMedGoogle Scholar
  175. 175.
    Abbott RD, Curb JD, Rodriguez BL, Masaki KH, Yano K, Schatz IJ, Ross GW, Petrovitch H. Age-related changes in risk factor effects on the incidence of coronary heart disease. Ann Epidemiol 2002;12:173–181PubMedGoogle Scholar
  176. 176.
    Saito H, Papaconstantinou J. Age-associated differences in cardiovascular inflammatory gene induction during endotoxic stress. J Biol Chem 2001;276:29307–29312PubMedGoogle Scholar
  177. 177.
    Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S, Nagai R, Nabeshima YI. Mutation of the mouse klotho gene leads to a syndrome resembling aging. Nature 1997;390:45–51PubMedGoogle Scholar
  178. 178.
    Masuda H, Chikuda H, Suga T, Kawaguchi H, Kuro-o M. Regulation of multiple ageing-like phenotypes by inducible klotho gene expression in klotho mutant mice. Mech Ageing Dev 2005;126:1274–1283PubMedGoogle Scholar
  179. 179.
    Arking DE, Krebsova A, Macek M Sr, Macek M Jr, Arking A, Mian IS, Fried L, Hamosh A, Dey S, McIntosh I, Dietz HC. Association of human aging with a functional variant of klotho. Proc Natl Acad Sci USA 2002;99:856–861Google Scholar
  180. 180.
    Arking DE, Becker DM, Yanek LR, Fallin D, Judge DP, Moy TF, Becker LC, Dietz HC. KLOTHO allele status and the risk of early-onset occult coronary artery disease. Am J Hum Genet 2003;2:1154–1161Google Scholar
  181. 181.
    Arking DE, Atzmon G, Arking A, Barzilai N, Dietz HC. Association between a functional variant of the KLOTHO gene and high-density lipoprotein cholesterol, blood pressure, stroke, and longevity. Circ Res 2005;96:412–418PubMedGoogle Scholar
  182. 182.
    Paternostro G, Vignola C, Bartsch DU, Omens JH, McCulloch AD, Reed JC. Age-associated cardiac dysfunction in Drosophila melanogaster. Circ Res 2001;88:1053–1058PubMedGoogle Scholar
  183. 183.
    Wessells RJ, Fitzgerald E, Cypser JR, Tatar M, Bodmer R. Insulin regulation of heart function in aging fruit flies. Nat Genet 2004;36:1275–1281PubMedGoogle Scholar
  184. 184.
    Ocorr K, Akasaka T, Bodmer R. Age-related cardiac disease model of Drosophila. Mech Ageing Dev 2007;128:112–116PubMedGoogle Scholar
  185. 185.
    Roth DA, White CD, Podolin DA, Mazzeo RS. Alterations in myocardial signal transduction due to aging and chronic dynamic exercise. J Appl Physiol 1998;84:177–184PubMedGoogle Scholar
  186. 186.
    Iemitsu M, Miyauchi T, Maeda S, Tanabe T, Takanashi M, Irukayama-Tomobe Y, Sakai S, Ohmori H, Matsuda M, Yamaguchi I. Aging-induced decrease in the PPAR-alpha level in hearts is improved by exercise training. Am J Physiol Heart Circ Physiol 2002;283:H1750–H1760PubMedGoogle Scholar
  187. 187.
    Maeda S, Tanabe T, Miyauchi T, Otsuki T, Sugawara J, Iemitsu M, Kuno S, Ajisaka R, Yamaguchi I, Matsuda M. Aerobic exercise training reduce plasma endothelin-1 concentration in older women. J Appl Physiol 2003;95: 336–341PubMedGoogle Scholar
  188. 188.
    Maeda S, Tanabe T, Otsuki T, Sugawara J, Iemitsu M, Miyauchi T, Kuno S, Ajisaka R, Matsuda M. Moderate regular exercise increases basal production of nitric oxide in elderly women. Hypertens Res 2004;27:947–953PubMedGoogle Scholar
  189. 189.
    DeSouza CA, Shapiro LF, Clevenger CM, Dinenno FA, Monahan KD, Tanaka H, Seals DR. Regular aerobic exercise prevents and restores age-related declines in endothelium-dependent vasodilation in healthy men. Circulation 2000;102:1351–1357PubMedGoogle Scholar
  190. 190.
    Smith DT, Hoetzer GL, Greiner JJ, Stauffer BL, DeSouza CA. Effects of ageing and regular aerobic exercise on endothelial fibrinolytic capacity in humans. J Physiol 2003;546:289–298PubMedGoogle Scholar
  191. 191.
    DeSouza CA, Van Guilder GP, Greiner JJ, Smith DT, Hoetzer GL, Stauffer BL. Basal endothelial nitric oxide release is preserved in overweight and obese adults. Obes Res 2005;13:1303–1306PubMedGoogle Scholar
  192. 192.
    Van Guilder GP, Hoetzer GL, Smith DT, Irmiger HM, Greiner JJ, Stauffer BL, Desouza CA. Endothelial t-PA release is impaired in overweight and obese adults but can be improved with regular aerobic exercise. Am J Physiol Endocrinol Metab 2005;289:E807–E813PubMedGoogle Scholar
  193. 193.
    Quindry J, French J, Hamilton K, Lee Y, Mehta JL, Powers S. Exercise training provides cardioprotection against ischemia-reperfusion induced apoptosis in young and old animals. Exp Gerontol 2005;40:416–425PubMedGoogle Scholar
  194. 194.
    French JP, Quindry JC, Falk DJ, Staib JL, Lee Y, Wang KK, Powers SK. Ischemia-reperfusion induced calpain activation and SERCA2a degradation are attenuated by exercise training and calpain inhibition. Am J Physiol Heart Circ Physiol 2005;290:H128–H136PubMedGoogle Scholar
  195. 195.
    Gielen S, Adams V, Niebauer J, Schuler G, Hambrecht R. Aging and heart failure – similar syndromes of exercise intolerance? Implications for exercise-based interventions. Heart Fail Monit 2005;4:130–136PubMedGoogle Scholar
  196. 196.
    Musch TI, Eklund KE, Hageman KS, Poole DC. Altered regional blood flow responses to submaximal exercise in older rats. J Appl Physiol 2004;96:81–88PubMedGoogle Scholar
  197. 197.
    Eklund KE, Hageman KS, Poole DC, Musch TI. Impact of aging on muscle blood flow in chronic heart failure. J Appl Physiol 2005;99:505–514PubMedGoogle Scholar
  198. 198.
    Terry DF, Wilcox M, McCormick MA, Lawler E, Perls TT. Cardiovascular advantages among the offspring of centenarians. J Gerontol A Biol Sci Med Sci 2003;58:M425–M431PubMedGoogle Scholar
  199. 199.
    Perls T, Terry D. Genetics of exceptional longevity. Exp Gerontol 2003;38:725–730PubMedGoogle Scholar
  200. 200.
    Atzmon G, Schechter C, Greiner W, Davidson D, Rennert G, Barzilai N. Clinical phenotype of families with longevity. J Am Geriatr Soc 2004;52:274–277PubMedGoogle Scholar
  201. 201.
    Terry DF, McCormick M, Andersen S, Pennington J, Schoenhofen E, Palaima E, Bausero M, Ogawa K, Perls TT, Asea A. Cardiovascular disease delay in centenarian offspring: role of heat shock proteins. Ann NY Acad Sci 2004;1019:502–505PubMedGoogle Scholar
  202. 202.
    Terry DF, Wyszynski DF, Nolan VG, Atzmon G, Schoenhofen EA, Pennington JY, Andersen SL, Wilcox MA, Farrer LA, Barzilai N, Baldwin CT, Asea A. Serum heat shock protein 70 level as a biomarker of exceptional longevity. Mech Ageing Dev 2006;127:862–868PubMedGoogle Scholar
  203. 203.
    Dominguez LJ, Galioto A, Ferlisi A, Pineo A, Putignano E, Belvedere M, Costanza G, Barbagallo M. Ageing, lifestyle modifications, and cardio-vascular disease in developing countries. J Nutr Health Aging 2006;10: 143–149PubMedGoogle Scholar
  204. 204.
    Daviglus ML, Lloyd-Jones DM, Pirzada A. Preventing cardiovascular disease in the 21st century: therapeutic and preventive implications of current evidence. Am J Cardiovasc Drugs 2006;6:87–101PubMedGoogle Scholar
  205. 205.
    Daviglus ML, Stamler J, Pirzada A, Yan LL, Garside DB, Liu K, Wang R, Dyer AR, Lloyd-Jones DM, Greenland P. Favorable cardiovascular risk profile in young women and long-term risk of cardiovascular and all-cause mortality. JAMA 2004;292:1588–1592PubMedGoogle Scholar
  206. 206.
    Orlic D, Kajstura J, Chimenti S, Limana F, Jakoniuk I, Quaini F, Nadal-Ginard B, Bodine DM, Leri A, Anversa P. Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proc Natl Acad Sci USA 2001;98:10344–10349PubMedGoogle Scholar
  207. 207.
    Quaini F, Urbanek K, Beltrami AP, Finato N, Beltrami CA, Nadal-Ginard B, Kajstura J, Leri A, Anversa P. Chimerism of the transplanted heart. N Engl J Med 2002;346:5–15PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • José Marín-García
    • 1
  • Michael J. Goldenthal
    • 2
  • Gordon W. Moe
    • 3
  1. 1.The Molecular Cardiology and Neuromuscular InstituteHighland Park
  2. 2.The Molecular Cardiology and Neuromuscular InstituteHighland Park
  3. 3.University of TorontoTorontoCanada

Personalised recommendations