Skip to main content
SpringerLink
Log in
Book cover

The Comparative Biology of Aging pp 259–286Cite as

Cardiac Aging

  • Chapter
  • First Online:

Abstract

Cardiovascular diseases are the leading causes of death in the western world. The fact that cardiovascular mortality and morbidity rates increase exponentially in the elderly suggests that age per se is a major risk factor for cardiovascular diseases. Data from the Framingham Heart study and the Baltimore Longitudinal Study on Aging showed an age-dependent increase in left ventricular hypertrophy, diastolic dysfunction, atrial fibrillation, and decline in exercise capacity. Experimental evidence shows that cardiac aging in the mouse closely recapitulates that found in humans. The evolutionary conservation of intrinsic cardiac aging is demonstrated by studies in Drosophila melanogaster, and this model offers unique genetic insights into cardiac aging. In this chapter we summarize the biology of cardiac aging in humans, rodents, flies, dogs and primates. Murine and Drosophila models of cardiac aging have been valuable to elucidate the molecular mechanisms of cardiac aging and increase vulnerability in the aged heart. This chapter highlights the mechanistic role of mitochondrial oxidative stress, insulin-IGF1, the renin-angiotensin system and adrenergic signaling, as well as the aging of cardiac stem cells. The mechanism of progression to heart failure in aged hearts and the effect of dietary restriction are also discussed. As the number of elderly persons is predicted to double in the next 25 years and the prevalence of age-related cardiovascular disabilities continues to increase, there is an urgent need to understand the biology of the aging heart, the mechanisms for age-mediated cardiac vulnerability and to use these insights to develop strategies to ameliorate myocardial dysfunction in the elderly.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Rosamond WFK, Friday G et al. (2007). Heart disease and stroke statistics – 2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 115: e69–e171.

    PubMed  Google Scholar 

  2. Morbidity and Mortality: 2007 Chart Book on Cardiovascular, Lung and Blood Diseases (2007). Bethesda, MD: National Heart, Lung, and Blood Institute, National Institutes of Health.

    Google Scholar 

  3. Lakatta EG (2003). Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part III: cellular and molecular clues to heart and arterial aging. Circulation 107: 490–497.

    PubMed  Google Scholar 

  4. Lakatta EG and Levy D (2003). Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part II: the aging heart in health: links to heart disease. Circulation 107: 346–354.

    PubMed  Google Scholar 

  5. Lakatta EG and Levy D (2003). Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part I: aging arteries: a “set up” for vascular disease. Circulation 107: 139–146.

    PubMed  Google Scholar 

  6. Bursi F, Weston SA, Redfield MM, Jacobsen SJ, Pakhomov S, Nkomo VT, Meverden RA, and Roger VL (2006). Systolic and diastolic heart failure in the community. J Am Med Assoc 296: 2209–2216.

    CAS  Google Scholar 

  7. Fleg JL, O’Connor F, Gerstenblith G, Becker LC, Clulow J, Schulman SP, and Lakatta EG (1995). Impact of age on the cardiovascular response to dynamic upright exercise in healthy men and women. J Appl Physiol 78: 890–900.

    CAS  PubMed  Google Scholar 

  8. Correia LC, Lakatta EG, O’Connor FC, Becker LC, Clulow J, Townsend S, Gerstenblith G, and Fleg JL (2002). Attenuated cardiovascular reserve during prolonged submaximal cycle exercise in healthy older subjects. J Am Coll Cardiol 40: 1290–1297.

    PubMed  Google Scholar 

  9. Kosugi R, Shioi T, Watanabe-Maeda K, Yoshida Y, Takahashi K, Machida Y, and Izumi T (2006). Angiotensin II receptor antagonist attenuates expression of aging markers in diabetic mouse heart. Circ J 70: 482–488.

    CAS  PubMed  Google Scholar 

  10. Brodsky SV, Gealekman O, Chen J, Zhang F, Togashi N, Crabtree M, Gross SS, Nasjletti A, and Goligorsky MS (2004). Prevention and reversal of premature endothelial cell senescence and vasculopathy in obesity-induced diabetes by ebselen. Circ Res 94: 377–384.

    CAS  PubMed  Google Scholar 

  11. Hayashi T, Matsui-Hirai H, Miyazaki-Akita A, Fukatsu A, Funami J, Ding QF, Kamalanathan S, Hattori Y, Ignarro LJ, and Iguchi A (2006). Endothelial cellular senescence is inhibited by nitric oxide: implications in atherosclerosis associated with menopause and diabetes. Proc Natl Acad Sci U S A 103: 17018–17023.

    CAS  PubMed  Google Scholar 

  12. Tsirpanlis G (2008). Cellular senescence, cardiovascular risk, and CKD: a review of established and hypothetical interconnections. Am J Kidney Dis 51: 131–144.

    PubMed  Google Scholar 

  13. Orimo M, Minamino T, Miyauchi H, Tateno K, Okada S, Moriya J, and Komuro I (2009). Protective role of SIRT1 in diabetic vascular dysfunction. Arterioscler Thromb Vasc Biol 29: 889–894.

    CAS  PubMed  Google Scholar 

  14. Dai DF, Santana LF, Vermulst M, Tomazela DM, Emonds MJ, Maccoss MJ, Gollahon K, Martin GM, Loeb LA, Ladiges WC, and Rabinovitch PS (2009). Overexpression of catalase targeted to mitochondria attenuates murine cardiac aging. Circulation 119: 2789–2797.

    CAS  PubMed  Google Scholar 

  15. Zheng F, Plati AR, Potier M, Schulman Y, Berho M, Banerjee A, Leclercq B, Zisman A, Striker LJ, and Striker GE (2003). Resistance to glomerulosclerosis in B6 mice disappears after menopause. Am J Pathol 162: 1339–1348.

    PubMed  Google Scholar 

  16. Treuting PM, Linford NJ, Knoblaugh SE, Emond MJ, Morton JF, Martin GM, Rabinovitch PS, and Ladiges WC (2008). Reduction of age-associated pathology in old mice by overexpression of catalase in mitochondria. J Gerontol A Biol Sci Med Sci 63: 813–822.

    PubMed  Google Scholar 

  17. Yan L, Vatner DE, O’Connor JP, Ivessa A, Ge H, Chen W, Hirotani S, Ishikawa Y, Sadoshima J, and Vatner SF (2007). Type 5 adenylyl cyclase disruption increases longevity and protects against stress. Cell 130: 247–258.

    CAS  PubMed  Google Scholar 

  18. Khouri SJ, Maly GT, Suh DD, and Walsh TE (2004). A practical approach to the echocardiographic evaluation of diastolic function. J Am Soc Echocardiogr 17: 290–297.

    PubMed  Google Scholar 

  19. Barger JL, Kayo T, Vann JM, Arias EB, Wang J, Hacker TA, Wang Y, Raederstorff D, Morrow JD, Leeuwenburgh C, Allison DB, Saupe KW, Cartee GD, Weindruch R, and Prolla TA (2008). A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS ONE 3: e2264.

    PubMed  Google Scholar 

  20. Tei C, Nishimura RA, Seward JB, and Tajik AJ (1997). Noninvasive Doppler-derived myocardial performance index: correlation with simultaneous measurements of cardiac catheterization measurements. J Am Soc Echocardiogr 10: 169–178.

    CAS  PubMed  Google Scholar 

  21. Heineke J and Molkentin JD (2006). Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat Rev Mol Cell Biol 7: 589–600.

    CAS  PubMed  Google Scholar 

  22. Liang Q, Wiese RJ, Bueno OF, Dai YS, Markham BE, and Molkentin JD (2001). The transcription factor GATA4 is activated by extracellular signal-regulated kinase 1- and 2-mediated phosphorylation of serine 105 in cardiomyocytes. Mol Cell Biol 21: 7460–7469.

    CAS  PubMed  Google Scholar 

  23. Xu A and Narayanan N (1998). Effects of aging on sarcoplasmic reticulum Ca2+-cycling proteins and their phosphorylation in rat myocardium. Am J Physiol 275: H2087–H2094.

    CAS  PubMed  Google Scholar 

  24. Koban MU, Moorman AF, Holtz J, Yacoub MH, and Boheler KR (1998). Expressional analysis of the cardiac Na-Ca exchanger in rat development and senescence. Cardiovasc Res 37: 405–423.

    CAS  PubMed  Google Scholar 

  25. Adachi T, Weisbrod RM, Pimentel DR, Ying J, Sharov VS, Schoneich C, and Cohen RA (2004). S-Glutathiolation by peroxynitrite activates SERCA during arterial relaxation by nitric oxide. Nat Med 10: 1200–1207.

    CAS  PubMed  Google Scholar 

  26. Li SY, Du M, Dolence EK, Fang CX, Mayer GE, Ceylan-Isik AF, LaCour KH, Yang X, Wilbert CJ, Sreejayan N, and Ren J (2005). Aging induces cardiac diastolic dysfunction, oxidative stress, accumulation of advanced glycation endproducts and protein modification. Aging Cell 4: 57–64.

    CAS  PubMed  Google Scholar 

  27. Li Q, Ceylan-Isik AF, Li J, and Ren J (2008). Deficiency of insulin-like growth factor 1 reduces sensitivity to aging-associated cardiomyocyte dysfunction. Rejuvenation Res 11: 725–733.

    CAS  PubMed  Google Scholar 

  28. Josephson IR, Guia A, Stern MD, and Lakatta EG (2002). Alterations in properties of L-type Ca channels in aging rat heart. J Mol Cell Cardiol 34: 297–308.

    CAS  PubMed  Google Scholar 

  29. Janczewski AM, Spurgeon HA, and Lakatta EG (2002). Action potential prolongation in cardiac myocytes of old rats is an adaptation to sustain youthful intracellular Ca2+ regulation. J Mol Cell Cardiol 34: 641–648.

    CAS  PubMed  Google Scholar 

  30. Xiao RP, Tomhave ED, Wang DJ, Ji X, Boluyt MO, Cheng H, Lakatta EG, and Koch WJ (1998). Age-associated reductions in cardiac beta1- and beta2-adrenergic responses without changes in inhibitory G proteins or receptor kinases. J Clin Invest 101: 1273–1282.

    CAS  PubMed  Google Scholar 

  31. Kilts JD, Akazawa T, Richardson MD, and Kwatra MM (2002). Age increases cardiac Galpha(i2) expression, resulting in enhanced coupling to G protein-coupled receptors. J Biol Chem 277: 31257–31262.

    CAS  PubMed  Google Scholar 

  32. Pepe S, Xiao RP, Hohl C, Altschuld R, and Lakatta EG (1997). ‘Cross talk’ between opioid peptide and adrenergic receptor signaling in isolated rat heart. Circulation 95: 2122–2129.

    CAS  PubMed  Google Scholar 

  33. Brodde OE, Konschak U, Becker K, Ruter F, Poller U, Jakubetz J, Radke J, and Zerkowski HR (1998). Cardiac muscarinic receptors decrease with age. In vitro and in vivo studies. J Clin Invest 101: 471–478.

    CAS  PubMed  Google Scholar 

  34. Leosco D, Rengo G, Iaccarino G, Filippelli A, Lymperopoulos A, Zincarelli C, Fortunato F, Golino L, Marchese M, Esposito G, Rapacciuolo A, Rinaldi B, Ferrara N, Koch WJ, and Rengo F (2007). Exercise training and beta-blocker treatment ameliorate age-dependent impairment of beta-adrenergic receptor signaling and enhance cardiac responsiveness to adrenergic stimulation. Am J Physiol Heart Circ Physiol 293: H1596–H1603.

    CAS  PubMed  Google Scholar 

  35. Tani M, Suganuma Y, Hasegawa H, Shinmura K, Ebihara Y, Hayashi Y, Guo X, and Takayama M (1997). Decrease in ischemic tolerance with aging in isolated perfused Fischer 344 rat hearts: relation to increases in intracellular Na+ after ischemia. J Mol Cell Cardiol 29: 3081–3089.

    CAS  PubMed  Google Scholar 

  36. Isoyama S and Nitta-Komatsubara Y (2002). Acute and chronic adaptation to hemodynamic overload and ischemia in the aged heart. Heart Fail Rev 7: 63–69.

    PubMed  Google Scholar 

  37. Juhaszova M, Rabuel C, Zorov DB, Lakatta EG, and Sollott SJ (2005). Protection in the aged heart: preventing the heart-break of old age?. Cardiovasc Res 66: 233–244.

    CAS  PubMed  Google Scholar 

  38. Nitta Y, Abe K, Aoki M, Ohno I, and Isoyama S (1994). Diminished heat shock protein 70 mRNA induction in aged rat hearts after ischemia. Am J Physiol 267: H1795–H1803.

    CAS  PubMed  Google Scholar 

  39. Bolli R (2001). Cardioprotective function of inducible nitric oxide synthase and role of nitric oxide in myocardial ischemia and preconditioning: an overview of a decade of research. J Mol Cell Cardiol 33: 1897–1918.

    CAS  PubMed  Google Scholar 

  40. Chou TC, Yen MH, Li CY, and Ding YA (1998). Alterations of nitric oxide synthase expression with aging and hypertension in rats. Hypertension 31: 643–648.

    CAS  PubMed  Google Scholar 

  41. Korzick DH, Holiman DA, Boluyt MO, Laughlin MH, and Lakatta EG (2001). Diminished alpha1-adrenergic-mediated contraction and translocation of PKC in senescent rat heart. Am J Physiol Heart Circ Physiol 281: H581–H589.

    CAS  PubMed  Google Scholar 

  42. Tani M, Honma Y, Hasegawa H, and Tamaki K (2001). Direct activation of mitochondrial K(ATP) channels mimics preconditioning but protein kinase C activation is less effective in middle-aged rat hearts. Cardiovasc Res 49: 56–68.

    CAS  PubMed  Google Scholar 

  43. Hsieh PC, Segers VF, Davis ME, MacGillivray C, Gannon J, Molkentin JD, Robbins J, and Lee RT (2007). Evidence from a genetic fate-mapping study that stem cells refresh adult mammalian cardiomyocytes after injury. Nat Med 13: 970–974.

    CAS  PubMed  Google Scholar 

  44. Beltrami AP, Barlucchi L, Torella D, Baker M, Limana F, Chimenti S, Kasahara H, Rota M, Musso E, Urbanek K, Leri A, Kajstura J, Nadal-Ginard B, and Anversa P (2003). Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 114: 763–776.

    CAS  PubMed  Google Scholar 

  45. Reinecke H, Minami E, Zhu WZ, and Laflamme MA (2008). Cardiogenic differentiation and transdifferentiation of progenitor cells. Circ Res 103: 1058–1071.

    CAS  PubMed  Google Scholar 

  46. Oh H, Bradfute SB, Gallardo TD, Nakamura T, Gaussin V, Mishina Y, Pocius J, Michael LH, Behringer RR, Garry DJ, Entman ML, and Schneider MD (2003). Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. Proc Natl Acad Sci U S A 100: 12313–12318.

    CAS  PubMed  Google Scholar 

  47. Matsuura K, Wada H, Nagai T, Iijima Y, Minamino T, Sano M, Akazawa H, Molkentin JD, Kasanuki H, and Komuro I (2004). Cardiomyocytes fuse with surrounding noncardiomyocytes and reenter the cell cycle. J Cell Biol 167: 351–363.

    CAS  PubMed  Google Scholar 

  48. Anversa P, Rota M, Urbanek K, Hosoda T, Sonnenblick EH, Leri A, Kajstura J, and Bolli R (2005). Myocardial aging – a stem cell problem. Basic Res Cardiol 100: 482–493.

    CAS  PubMed  Google Scholar 

  49. Rota M, LeCapitaine N, Hosoda T, Boni A, De Angelis A, Padin-Iruegas ME, Esposito G, Vitale S, Urbanek K, Casarsa C, Giorgio M, Luscher TF, Pelicci PG, Anversa P, Leri A, and Kajstura J (2006). Diabetes promotes cardiac stem cell aging and heart failure, which are prevented by deletion of the p66shc gene. Circ Res 99: 42–52.

    CAS  PubMed  Google Scholar 

  50. Gonzalez A, Rota M, Nurzynska D, Misao Y, Tillmanns J, Ojaimi C, Padin-Iruegas ME, Muller P, Esposito G, Bearzi C, Vitale S, Dawn B, Sanganalmath SK, Baker M, Hintze TH, Bolli R, Urbanek K, Hosoda T, Anversa P, Kajstura J, and Leri A (2008). Activation of cardiac progenitor cells reverses the failing heart senescent phenotype and prolongs lifespan. Circ Res 102: 597–606.

    CAS  PubMed  Google Scholar 

  51. Bergmann O, Bhardwaj RD, Bernard S, Zdunek S, Barnabe-Heider F, Walsh S, Zupicich J, Alkass K, Buchholz BA, Druid H, Jovinge S, and Frisen J (2009). Evidence for cardiomyocyte renewal in humans. Science 324: 98–102.

    CAS  PubMed  Google Scholar 

  52. Harman D (1956). Aging: a theory based on free radical and radiation chemistry. J Gerontol 11: 298–300.

    CAS  PubMed  Google Scholar 

  53. Balaban RS, Nemoto S, and Finkel T (2005). Mitochondria, oxidants, and aging. Cell 120: 483–495.

    CAS  PubMed  Google Scholar 

  54. Schriner SE, Linford NJ, Martin GM, Treuting P, Ogburn CE, Emond M, Coskun PE, Ladiges W, Wolf N, Van Remmen H, Wallace DC, and Rabinovitch PS (2005). Extension of murine life span by overexpression of catalase targeted to mitochondria. Science 308: 1909–1911.

    CAS  PubMed  Google Scholar 

  55. Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CE, Bohlooly YM, Gidlof S, Oldfors A, Wibom R, Tornell J, Jacobs HT, and Larsson NG (2004). Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429: 417–423.

    CAS  PubMed  Google Scholar 

  56. 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, and Prolla TA (2005). Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309: 481–484.

    CAS  PubMed  Google Scholar 

  57. Vermulst M, Wanagat J, Kujoth GC, Bielas JH, Rabinovitch PS, Prolla TA, and Loeb LA (2008). DNA deletions and clonal mutations drive premature aging in mitochondrial mutator mice. Nat Genet 40: 392–394.

    CAS  PubMed  Google Scholar 

  58. Migliaccio E, Giorgio M, Mele S, Pelicci G, Reboldi P, Pandolfi PP, Lanfrancone L, and Pelicci PG (1999). The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature 402: 309–313.

    CAS  PubMed  Google Scholar 

  59. 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, and Pelicci PG (2004). 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 279: 25689–25695.

    CAS  PubMed  Google Scholar 

  60. Pinton P, Rimessi A, Marchi S, Orsini F, Migliaccio E, Giorgio M, Contursi C, Minucci S, Mantovani F, Wieckowski MR, Del Sal G, Pelicci PG, and Rizzuto R (2007). Protein kinase C beta and prolyl isomerase 1 regulate mitochondrial effects of the life-span determinant p66Shc. Science 315: 659–663.

    CAS  PubMed  Google Scholar 

  61. Domenighetti AA, Wang Q, Egger M, Richards SM, Pedrazzini T, and Delbridge LM (2005). Angiotensin II-mediated phenotypic cardiomyocyte remodeling leads to age-dependent cardiac dysfunction and failure. Hypertension 46: 426–432.

    CAS  PubMed  Google Scholar 

  62. Groban L, Pailes NA, Bennett CD, Carter CS, Chappell MC, Kitzman DW, and Sonntag WE (2006). Growth hormone replacement attenuates diastolic dysfunction and cardiac angiotensin II expression in senescent rats. J Gerontol A Biol Sci Med Sci 61: 28–35.

    PubMed  Google Scholar 

  63. Basso N, Cini R, Pietrelli A, Ferder L, Terragno NA, and Inserra F (2007). Protective effect of long-term angiotensin II inhibition. Am J Physiol Heart Circ Physiol 293: H1351–H1358.

    CAS  PubMed  Google Scholar 

  64. Benigni A, Corna D, Zoja C, Sonzogni A, Latini R, Salio M, Conti S, Rottoli D, Longaretti L, Cassis P, Morigi M, Coffman TM, and Remuzzi G (2009). Disruption of the Ang II type 1 receptor promotes longevity in mice. J Clin Invest 119: 524–530.

    CAS  PubMed  Google Scholar 

  65. Okumura S, Vatner DE, Kurotani R, Bai Y, Gao S, Yuan Z, Iwatsubo K, Ulucan C, Kawabe J, Ghosh K, Vatner SF, and Ishikawa Y (2007). Disruption of type 5 adenylyl cyclase enhances desensitization of cyclic adenosine monophosphate signal and increases Akt signal with chronic catecholamine stress. Circulation 116: 1776–1783.

    CAS  PubMed  Google Scholar 

  66. Okumura S, Takagi G, Kawabe J, Yang G, Lee MC, Hong C, Liu J, Vatner DE, Sadoshima J, Vatner SF, and Ishikawa Y (2003). Disruption of type 5 adenylyl cyclase gene preserves cardiac function against pressure overload. Proc Natl Acad Sci U S A 100: 9986–9990.

    CAS  PubMed  Google Scholar 

  67. Holzenberger M, Dupont J, Ducos B, Leneuve P, Geloen A, Even PC, Cervera P, and Le Bouc Y (2003). IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421: 182–187.

    CAS  PubMed  Google Scholar 

  68. Wessells RJ, Fitzgerald E, Cypser JR, Tatar M, and Bodmer R (2004). Insulin regulation of heart function in aging fruit flies. Nat Genet 36: 1275–1281.

    CAS  PubMed  Google Scholar 

  69. Corpas E, Harman SM, and Blackman MR (1993). Human growth hormone and human aging. Endocr Rev 14: 20–39.

    CAS  PubMed  Google Scholar 

  70. Vasan RS, Sullivan LM, D’Agostino RB, Roubenoff R, Harris T, Sawyer DB, Levy D, and Wilson PW (2003). 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 139: 642–648.

    CAS  PubMed  Google Scholar 

  71. Giustina A, Lorusso R, Borghetti V, Bugari G, Misitano V, and Alfieri O (1996). Impaired spontaneous growth hormone secretion in severe dialated cardiomyopathy. Am Heart J 131: 620–622.

    CAS  PubMed  Google Scholar 

  72. Broglio F, Fubini A, Morello M, Arvat E, Aimaretti G, Gianotti L, Boghen MF, Deghenghi R, Mangiardi L, and Ghigo E (1999). Activity of GH/IGF-I axis in patients with dilated cardiomyopathy. Clin Endocrinol (Oxf) 50: 417–430.

    CAS  Google Scholar 

  73. Yang R, Bunting S, Gillett N, Clark R, and Jin H (1995). Growth hormone improves cardiac performance in experimental heart failure. Circulation 92: 262–267.

    CAS  PubMed  Google Scholar 

  74. Tajima M, Weinberg EO, Bartunek J, Jin H, Yang R, Paoni NF, and Lorell BH (1999). Treatment with growth hormone enhances contractile reserve and intracellular calcium transients in myocytes from rats with postinfarction heart failure. Circulation 99: 127–134.

    CAS  PubMed  Google Scholar 

  75. Cittadini A, Grossman JD, Napoli R, Katz SE, Stromer H, Smith RJ, Clark R, Morgan JP, and Douglas PS (1997). Growth hormone attenuates early left ventricular remodeling and improves cardiac function in rats with large myocardial infarction. J Am Coll Cardiol 29: 1109–1116.

    CAS  PubMed  Google Scholar 

  76. Oka T and Komuro I (2008). Molecular mechanisms underlying the transition of cardiac hypertrophy to heart failure. Circulation J Supp.A: A13–A16.

    Google Scholar 

  77. Nadal-Ginard B, Kajstura J, Leri A, and Anversa P (2003). Myocyte death, growth, and regeneration in cardiac hypertrophy and failure. Circ Res 92: 139–150.

    CAS  PubMed  Google Scholar 

  78. Foo RS, Mani K, and Kitsis RN (2005). Death begets failure in the heart. J Clin Invest 115: 565–571.

    CAS  PubMed  Google Scholar 

  79. Nakayama H, Chen X, Baines CP, Klevitsky R, Zhang X, Zhang H, Jaleel N, Chua BH, Hewett TE, Robbins J, Houser SR, and Molkentin JD (2007). Ca2+- and mitochondrial-dependent cardiomyocyte necrosis as a primary mediator of heart failure. J Clin Invest 117: 2431–2444.

    CAS  PubMed  Google Scholar 

  80. Wencker D, Chandra M, Nguyen K, Miao W, Garantziotis S, Factor SM, Shirani J, Armstrong RC, and Kitsis RN (2003). A mechanistic role for cardiac myocyte apoptosis in heart failure. J Clin Invest 111: 1497–1504.

    CAS  PubMed  Google Scholar 

  81. Kostin S, Pool L, Elsasser A, Hein S, Drexler HC, Arnon E, Hayakawa Y, Zimmermann R, Bauer E, Klovekorn WP, and Schaper J (2003). Myocytes die by multiple mechanisms in failing human hearts. Circ Res 92: 715–724.

    CAS  PubMed  Google Scholar 

  82. Akazawa H, Komazaki S, Shimomura H, Terasaki F, Zou Y, Takano H, Nagai T, and Komuro I (2004). Diphtheria toxin-induced autophagic cardiomyocyte death plays a pathogenic role in mouse model of heart failure. J Biol Chem 279: 41095–41103.

    CAS  PubMed  Google Scholar 

  83. Nakai A, Yamaguchi O, Takeda T, Higuchi Y, Hikoso S, Taniike M, Omiya S, Mizote I, Matsumura Y, Asahi M, Nishida K, Hori M, Mizushima N, and Otsu K (2007). The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress. Nat Med 13: 619–624.

    CAS  PubMed  Google Scholar 

  84. Zhu H, Tannous P, Johnstone JL, Kong Y, Shelton JM, Richardson JA, Le V, Levine B, Rothermel BA, and Hill JA (2007). Cardiac autophagy is a maladaptive response to hemodynamic stress. J Clin Invest 117: 1782–1793.

    CAS  PubMed  Google Scholar 

  85. Ducharme A, Frantz S, Aikawa M, Rabkin E, Lindsey M, Rohde LE, Schoen FJ, Kelly RA, Werb Z, Libby P, and Lee RT (2000). Targeted deletion of matrix metalloproteinase-9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction. J Clin Invest 106: 55–62.

    CAS  PubMed  Google Scholar 

  86. Lindsey ML, Gannon J, Aikawa M, Schoen FJ, Rabkin E, Lopresti-Morrow L, Crawford J, Black S, Libby P, Mitchell PG, and Lee RT (2002). Selective matrix metalloproteinase inhibition reduces left ventricular remodeling but does not inhibit angiogenesis after myocardial infarction. Circulation 105: 753–758.

    CAS  PubMed  Google Scholar 

  87. Rohde LE, Ducharme A, Arroyo LH, Aikawa M, Sukhova GH, Lopez-Anaya A, McClure KF, Mitchell PG, Libby P, and Lee RT (1999). Matrix metalloproteinase inhibition attenuates early left ventricular enlargement after experimental myocardial infarction in mice. Circulation 99: 3063–3070.

    CAS  PubMed  Google Scholar 

  88. Lindsey ML, Escobar GP, Dobrucki LW, Goshorn DK, Bouges S, Mingoia JT, McClister DM, Jr., Su H, Gannon J, MacGillivray C, Lee RT, Sinusas AJ, and Spinale FG (2006). Matrix metalloproteinase-9 gene deletion facilitates angiogenesis after myocardial infarction. Am J Physiol Heart Circ Physiol 290: H232–H239.

    CAS  PubMed  Google Scholar 

  89. Lee RT (2001). Matrix metalloproteinase inhibition and the prevention of heart failure. Trends Cardiovasc Med 11: 202–205.

    CAS  PubMed  Google Scholar 

  90. Berk BC, Fujiwara K, and Lehoux S (2007). ECM remodeling in hypertensive heart disease. J Clin Invest 117: 568–575.

    CAS  PubMed  Google Scholar 

  91. Spinale FG (2007). Myocardial matrix remodeling and the matrix metalloproteinases: influence on cardiac form and function. Physiol Rev 87: 1285–1342.

    CAS  PubMed  Google Scholar 

  92. O’Rourke B, Kass DA, Tomaselli GF, Kaab S, Tunin R, and Marban E (1999). Mechanisms of altered excitation-contraction coupling in canine tachycardia-induced heart failure. I: experimental studies. Circ Res 84: 562–570.

    PubMed  Google Scholar 

  93. Hobai IA and O’Rourke B (2001). Decreased sarcoplasmic reticulum calcium content is responsible for defective excitation-contraction coupling in canine heart failure. Circulation 103: 1577–1584.

    CAS  PubMed  Google Scholar 

  94. Bers DM (2006). Altered cardiac myocyte Ca regulation in heart failure. Physiology (Bethesda) 21: 380–387.

    CAS  Google Scholar 

  95. Miyamoto MI, del Monte F, Schmidt U, DiSalvo TS, Kang ZB, Matsui T, Guerrero JL, Gwathmey JK, Rosenzweig A, and Hajjar RJ (2000). Adenoviral gene transfer of SERCA2a improves left-ventricular function in aortic-banded rats in transition to heart failure. Proc Natl Acad Sci U S A 97: 793–798.

    CAS  PubMed  Google Scholar 

  96. Minamisawa S, Hoshijima M, Chu G, Ward CA, Frank K, Gu Y, Martone ME, Wang Y, Ross J, Jr., Kranias EG, Giles WR, and Chien KR (1999). Chronic phospholamban-sarcoplasmic reticulum calcium ATPase interaction is the critical calcium cycling defect in dilated cardiomyopathy. Cell 99: 313–322.

    CAS  PubMed  Google Scholar 

  97. Hoshijima M, Ikeda Y, Iwanaga Y, Minamisawa S, Date MO, Gu Y, Iwatate M, Li M, Wang L, Wilson JM, Wang Y, Ross J, Jr., and Chien KR (2002). Chronic suppression of heart-failure progression by a pseudophosphorylated mutant of phospholamban via in vivo cardiac rAAV gene delivery. Nat Med 8: 864–871.

    CAS  PubMed  Google Scholar 

  98. Shiojima I, Sato K, Izumiya Y, Schiekofer S, Ito M, Liao R, Colucci WS, and Walsh K (2005). Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure. J Clin Invest 115: 2108–2118.

    CAS  PubMed  Google Scholar 

  99. Izumiya Y, Shiojima I, Sato K, Sawyer DB, Colucci WS, and Walsh K (2006). Vascular endothelial growth factor blockade promotes the transition from compensatory cardiac hypertrophy to failure in response to pressure overload. Hypertension 47: 887–893.

    CAS  PubMed  Google Scholar 

  100. Heineke J, Auger-Messier M, Xu J, Oka T, Sargent MA, York A, Klevitsky R, Vaikunth S, Duncan SA, Aronow BJ, Robbins J, Crombleholme TM, and Molkentin JD (2007). Cardiomyocyte GATA4 functions as a stress-responsive regulator of angiogenesis in the murine heart. J Clin Invest 117: 3198–3210.

    CAS  PubMed  Google Scholar 

  101. Rabinowitz M and Zak R (1975). Mitochondria and cardiac hypertrophy. Circ Res 36: 367–376.

    CAS  PubMed  Google Scholar 

  102. Beer M, Seyfarth T, Sandstede J, Landschutz W, Lipke C, Kostler H, von Kienlin M, Harre K, Hahn D, and Neubauer S (2002). Absolute concentrations of high-energy phosphate metabolites in normal, hypertrophied, and failing human myocardium measured noninvasively with (31)P-SLOOP magnetic resonance spectroscopy. J Am Coll Cardiol 40: 1267–1274.

    CAS  PubMed  Google Scholar 

  103. Weiss RG, Gerstenblith G, and Bottomley PA (2005). ATP flux through creatine kinase in the normal, stressed, and failing human heart. Proc Natl Acad Sci U S A 102: 808–813.

    CAS  PubMed  Google Scholar 

  104. Nakae I, Mitsunami K, Omura T, Yabe T, Tsutamoto T, Matsuo S, Takahashi M, Morikawa S, Inubushi T, Nakamura Y, Kinoshita M, and Horie M (2003). Proton magnetic resonance spectroscopy can detect creatine depletion associated with the progression of heart failure in cardiomyopathy. J Am Coll Cardiol 42: 1587–1593.

    CAS  PubMed  Google Scholar 

  105. Neubauer S, Horn M, Cramer M, Harre K, Newell JB, Peters W, Pabst T, Ertl G, Hahn D, Ingwall JS, and Kochsiek K (1997). Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy. Circulation 96: 2190–2196.

    CAS  PubMed  Google Scholar 

  106. Mattson MP and Wan R (2005). Beneficial effects of intermittent fasting and caloric restriction on the cardiovascular and cerebrovascular systems. J Nutr Biochem 16: 129–137.

    CAS  PubMed  Google Scholar 

  107. Meyer TE, Kovacs SJ, Ehsani AA, Klein S, Holloszy JO, and Fontana L (2006). Long-term caloric restriction ameliorates the decline in diastolic function in humans. J Am Coll Cardiol 47: 398–402.

    CAS  PubMed  Google Scholar 

  108. Riordan MM, Weiss EP, Meyer TE, Ehsani AA, Racette SB, Villareal DT, Fontana L, Holloszy JO, and Kovacs SJ (2008). The effects of caloric restriction- and exercise-induced weight loss on left ventricular diastolic function. Am J Physiol Heart Circ Physiol 294: H1174–H1182.

    CAS  PubMed  Google Scholar 

  109. Taffet GE, Pham TT, and Hartley CJ (1997). The age-associated alterations in late diastolic function in mice are improved by caloric restriction. J Gerontol A Biol Sci Med Sci 52: B285–B290.

    CAS  PubMed  Google Scholar 

  110. Seymour EM, Parikh RV, Singer AA, and Bolling SF (2006). Moderate calorie restriction improves cardiac remodeling and diastolic dysfunction in the Dahl-SS rat. J Mol Cell Cardiol 41: 661–668.

    CAS  PubMed  Google Scholar 

  111. Wessells RJ and Bodmer R (2004). Screening assays for heart function mutants in Drosophila. Biotechniques 37: 58–60.

    CAS  PubMed  Google Scholar 

  112. Taghli-Lamallem O, Akasaka T, Hogg G, Nudel U, Yaffe D, Chamberlain JS, Ocorr K, and Bodmer R (2008). Dystrophin deficiency in Drosophila reduces lifespan and causes a dilated cardiomyopathy phenotype. Aging Cell 7: 237–249.

    CAS  PubMed  Google Scholar 

  113. Ocorr K, Akasaka T, and Bodmer R (2007). Age-related cardiac disease model of Drosophila. Mech Ageing Dev 128: 112–116.

    CAS  PubMed  Google Scholar 

  114. Wolf MJ, Amrein H, Izatt JA, Choma MA, Reedy MC, and Rockman HA (2006). Drosophila as a model for the identification of genes causing adult human heart disease. Proc Natl Acad Sci U S A 103: 1394–1399.

    CAS  PubMed  Google Scholar 

  115. Dowse H, Ringo J, Power J, Johnson E, Kinney K, and White L (1995). A congenital heart defect in Drosophila caused by an action-potential mutation. J Neurogenet 10: 153–168.

    CAS  PubMed  Google Scholar 

  116. Johnson E, Ringo J, and Dowse H (1997). Modulation of Drosophila heartbeat by neurotransmitters. J Comp Physiol [B] 167: 89–97.

    CAS  Google Scholar 

  117. Dulcis D and Levine RB (2003). Innervation of the heart of the adult fruit fly, Drosophila melanogaster. J Comp Neurol 465: 560–578.

    PubMed  Google Scholar 

  118. Ocorr K, Reeves NL, Wessells RJ, Fink M, Chen HS, Akasaka T, Yasuda S, Metzger JM, Giles W, Posakony JW, and Bodmer R (2007). KCNQ potassium channel mutations cause cardiac arrhythmias in Drosophila that mimic the effects of aging. Proc Natl Acad Sci U S A 104: 3943–3948.

    CAS  PubMed  Google Scholar 

  119. Curtis NJ, Ringo JM, and Dowse HB (1999). Morphology of the pupal heart, adult heart, and associated tissues in the fruit fly, Drosophila melanogaster. J Morphol. 240: 225–235.

    CAS  PubMed  Google Scholar 

  120. Molina MR and Cripps RM (2001). Ostia, the inflow tracts of the Drosophila heart, develop from a genetically distinct subset of cardial cells. Mech Dev 109: 51–59.

    CAS  PubMed  Google Scholar 

  121. Cammarato A, Dambacher CM, Knowles AF, Kronert WA, Bodmer R, Ocorr K, and Bernstein SI (2008). Myosin transducer mutations differentially affect motor function, myofibril structure, and the performance of skeletal and cardiac muscles. Mol Biol Cell 19: 553–562.

    CAS  PubMed  Google Scholar 

  122. Ocorr K, Perrin L, Lim HY, Qian L, Wu X, and Bodmer R (2007). Genetic control of heart function and aging in Drosophila. Trends Cardiovasc Med 17: 177–182.

    CAS  PubMed  Google Scholar 

  123. Luong N, Davies CR, Wessells RJ, Graham SM, King MT, Veech R, Bodmer R, and Oldham SM (2006). Activated FOXO-mediated insulin resistance is blocked by reduction of TOR activity. Cell Metab 4: 133–142.

    CAS  PubMed  Google Scholar 

  124. Robbins J (2001). KCNQ potassium channels: physiology, pathophysiology, and pharmacology. Pharmacol Ther 90: 1–19.

    CAS  PubMed  Google Scholar 

  125. Piazza N, Hayes M, Martin I, Duttaroy A, Grotewiel M, and Wessells R (2009). Multiple measures of functionality exhibit progressive decline in a parallel, stochastic fashion in Drosophila Sod2 null mutants. Biogerontology 10: 637–648.

    CAS  PubMed  Google Scholar 

  126. Judge LM, Haraguchiln M, and Chamberlain JS (2006). Dissecting the signaling and mechanical functions of the dystrophin-glycoprotein complex. J Cell Sci 119: 1537–1546.

    CAS  PubMed  Google Scholar 

  127. Morrow G and Tanguay RM (2008). Mitochondria and ageing in Drosophila. Biotechnol J 3: 728–739.

    CAS  PubMed  Google Scholar 

  128. Kenyon C (2005). The plasticity of aging: insights from long-lived mutants. Cell 120: 449–460.

    CAS  PubMed  Google Scholar 

  129. Kim SK (2007). Common aging pathways in worms, flies, mice and humans. J Exp Biol 210: 1607–1612.

    CAS  PubMed  Google Scholar 

  130. Wessells RJ and Bodmer R (2007). Age-related cardiac deterioration: insights from Drosophila. Front Biosci 12: 39–48.

    CAS  PubMed  Google Scholar 

  131. Hamlin RL (2007). Animal models of ventricular arrhythmias. Pharmacol Ther 113: 276–295.

    CAS  PubMed  Google Scholar 

  132. Koh GY, Soonpaa MH, Klug MG, Pride HP, Cooper BJ, Zipes DP, and Field LJ (1995). Stable fetal cardiomyocyte grafts in the hearts of dystrophic mice and dogs. J Clin Invest 96: 2034–2042.

    CAS  PubMed  Google Scholar 

  133. Jugdutt BI (2002). The dog model of left ventricular remodeling after myocardial infarction. J Card Fail 8: S472–S475.

    PubMed  Google Scholar 

  134. Hamlin RL and Smith CR (1960). Anatomical and physiologic basis for interpretation of the electrocardiogram. Am J Vet Res 21: 701–718.

    CAS  PubMed  Google Scholar 

  135. Guglielmini C (2003). Cardiovascular diseases in the ageing dog: diagnostic and therapeutic problems. Vet Res Commun 27(Suppl 1): 555–560.

    PubMed  Google Scholar 

  136. Eichelberg H and Seine R (1996). [Life expectancy and cause of death in dogs. I. The situation in mixed breeds and various dog breeds]. Berl Munch Tierarztl Wochenschr 109: 292–303.

    CAS  PubMed  Google Scholar 

  137. Van Vleet JF (2001). Age-related non-neoplastic lesions of the heart. In Patholbiology of the Ageing Dog. (U Mohr et al., ed.). Ames: ISU Press, pp. 101–107.

    Google Scholar 

  138. Kwart C and Haggstrom J (2000). Acquired valvular heart disease. In Textbook of Veterinary Internal Medicine. (SJ Ettinger, EC Feldman, ed.). Philadelphia: W.B. Saunders.

    Google Scholar 

  139. Lane MA, Ingram DK, and Roth GS (1999). Calorie restriction in nonhuman primates: effects on diabetes and cardiovascular disease risk. Toxicol Sci 52: 41–48.

    CAS  PubMed  Google Scholar 

  140. Lane MA, Mattison J, Ingram DK, and Roth GS (2002). Caloric restriction and aging in primates: relevance to humans and possible CR mimetics. Microsc Res Tech 59: 335–338.

    PubMed  Google Scholar 

  141. Mattison JA, Lane MA, Roth GS, and Ingram DK (2003). Calorie restriction in rhesus monkeys. Exp Gerontol 38: 35–46.

    PubMed  Google Scholar 

  142. Roth GS, Mattison JA, Ottinger MA, Chachich ME, Lane MA, and Ingram DK (2004). Aging in rhesus monkeys: relevance to human health interventions. Science 305: 1423–1426.

    CAS  PubMed  Google Scholar 

  143. Bodmer R, Wessells RJ, Johnson EC, Dowse H (2005). Heart development and function. In: Comprehensive Molecular Insect Science (volumes 1–7). (eds. Gilbert LI, Iatrou K, and Gill S.), Elsevier, vol. 2, p. 199–250.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, University of Washington, Seattle, WA, USA

    Dao-Fu Dai & Peter S. Rabinovitch

  2. Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA

    Robert J. Wessells

  3. Burnham Institute, Development and Aging Program, La Jolla, CA, USA

    Rolf Bodmer

Authors
  1. Dao-Fu Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert J. Wessells
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rolf Bodmer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peter S. Rabinovitch
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter S. Rabinovitch .

Editor information

Editors and Affiliations

  1. 98195-7470 98195-7470, Seattle, 98195-7470, U.S.A.

    Norman S. Wolf

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer Science+Business Media B.V.

About this chapter

Cite this chapter

Dai, DF., Wessells, R.J., Bodmer, R., Rabinovitch, P.S. (2010). Cardiac Aging. In: Wolf, N. (eds) The Comparative Biology of Aging. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-3465-6_12

Download citation

Publish with us

Policies and ethics

Search

Navigation