Changes in the Heart That Accompany Advancing Age: Humans to Molecules

  • Edward G. LakattaEmail author
  • Harold A. Spurgeon
  • Andrzej M. Janczewski


Age per se is the major risk factor for cardiovascular disease. Elucidation of the age-associated alterations in cardiac and arterial structure and function at both the cellular and molecular levels provides valuable clues that may assist in the development of effective therapies to prevent, to delay, or to attenuate the cardiovascular changes that accompany aging and contribute to the clinical manifestations of chronic heart failure. Changes in cardiac cell phenotype that occur with normal aging, as well as in HF associated with aging, include deficits in β-adrenergic receptor (β-AR) signaling, increased generation of reactive oxygen species (ROS), and altered excitation–contraction (EC) coupling that involves prolongation of the action potential (AP), intracellular Ca2+ (Cai 2+) transient and contraction, and blunted force and relaxation-frequency responses. Evidence suggests that altered sarcoplasmic reticulum (SR) Ca2+ uptake, storage, and release play central role in these changes, which also involve sarcolemmal L-type Ca2+ channel (LCC), Na+−Ca2+ exchanger (NCX), and K + channels.

In spite of the interest in the physiology of the age-associated changes in cardiovascular structure and function, however, cardiovascular aging has remained, for the most part, outside of mainstream clinical medicine. This is largely because the pathophysiologic implications of these age-associated changes are largely underappreciated and are not well disseminated in the medical community. In fact, age has traditionally been considered a nonmodifiable risk factor. Policy makers, researchers, and clinicians need to intensify their efforts toward identification of novel pathways that could be targeted for interventions aiming at retardation or attenuation of these age-associated alterations that occur in the heart and arteries, particularly in individuals in whom these alterations are accelerated. Translational studies would then examine whether these strategies (i.e., those targeting cardiovascular aging) can have a salutary impact on the adverse cardiovascular effects of accelerated cardiovascular aging. As such, cardiovascular aging is a promising frontier in preventive cardiology.


Ventricular Myocytes Action Potential Duration Left Ventricle Wall Cardiovascular Aging Action Potential Prolongation 
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.


  1. 1.
    Lakatta EG. Cardiovascular regulatory mechanisms in advanced age. Physiol Rev. 1993;73:413.PubMedGoogle Scholar
  2. 2.
    Leinwand LA. Sex is a potent modifier of the cardiovascular system. J Clin Invest. 2003;112:302.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Konhilas JP, Leinwand LA. The effects of biological sex and diet on the development of heart failure. Circulation. 2007;116:2747.PubMedCrossRefGoogle Scholar
  4. 4.
    Fermin DR, Barac A, Lee S, et al. Sex and age dimorphism of myocardial gene expression in nonischemic human heart failure. Circ Cardiovasc Genet. 2008;1:117–25.PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Fleg JL, Schulman S, O’Connor FC, Becker LC, Gerstenblith G, Clulow JF, Renlund DG, Lakatta EG. Effects of acute β-adrenergic receptor blockade on age-associated changes in cardiovascular performance during dynamic exercise. Circulation. 1994;90:2333–41.PubMedCrossRefGoogle Scholar
  6. 6.
    Yin FCP, Weisfeldt ML, Milnor WR. Role of aortic input impedance in the decreased cardiovascular response to exercise with aging in dogs. J Clin Invest. 1981;68:28–38.PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Brodde OE, Konschak U, Becker K, et al. Cardiac muscarinic receptors decrease with age. In vitro and in vivo studies. J Clin Invest. 1998;101:471.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Fraticelli A, Josephson R, Danziger R, Lakatta E, Spurgeon H. Morphological and contractile characteristics of rat cardiac myocytes from maturation to senescence. Am J Physiol. 1989;257:H259–65.PubMedGoogle Scholar
  9. 9.
    Anversa P, Palackal T, Sonnenblick EH, Olivetti G, Meggs LG, Capasso JM. Myocyte cell loss and myocyte cellular hyperplasia in the hypertrophied aging rat heart. Circ Res. 1990;67:871–85.PubMedCrossRefGoogle Scholar
  10. 10.
    Lakatta EG. Cardiovascular aging research: the next horizons. J Am Geriatr Soc. 1999;47:613–25.PubMedGoogle Scholar
  11. 11.
    Cigola E, Kastura J, Li B, Meggs LG, Anversa P. Angiotensin II activates programmed myocyte cell death in vitro. Exp Cell Res. 1997;231:363–71.PubMedCrossRefGoogle Scholar
  12. 12.
    Younes A, Boluyt MO, O’Neill L, Meredith AL, Crow MT, Lakatta EG. Age-associated increase in rat ventricular ANP gene expression correlates with cardiac hypertrophy. Am J Physiol. 1995;38:H1003–8.Google Scholar
  13. 13.
    Caffrey JL, Boluyt MO, Younes A, Barron BA, O’Neill L, Crow MT, Lakatta EG. Aging, cardiac proenkephalin mRNA and enkephalin peptides in the Fisher 344 rat. J Mol Cell Cardiol. 1994;26:701–11.PubMedCrossRefGoogle Scholar
  14. 14.
    Grandy SA, Howlett SE. Cardiac excitation-contraction coupling is altered in myocytes from aged male mice but not in cells from aged female mice. Am J Physiol. 2006;291:H2362–70.Google Scholar
  15. 15.
    Lim CC, Apstein CS, Colucci WS, Liao R. Impaired cell shortening and relengthening with increased pacing frequency are intrinsic to the senescent mouse cardiomyocyte. J Mol Cell Cardiol. 2000;32:2075–82.PubMedCrossRefGoogle Scholar
  16. 16.
    Lim CC, Liao R, Varma N, Apstein CS. Impaired lusitropy-frequency in the aging mouse: role of Ca2+ handling proteins and effects of isoproterenol. Am J Physiol. 1999;277:H2083–90.PubMedGoogle Scholar
  17. 17.
    Spurgeon HA, Steinbach MF, Lakatta EG. Chronic exercise prevents characteristic age-related changes in rat cardiac contraction. Am J Physiol. 1983;244:H513–8.PubMedGoogle Scholar
  18. 18.
    Tate CA, Taffet GE, Hudson EK, Blaylock SL, McBride RP, Michael LH. Enhanced calcium uptake of cardiac sarcoplasmic reticulum in exercise-trained old rats. Am J Physiol. 1990;258:H431–5.PubMedGoogle Scholar
  19. 19.
    Zhu X, Altschafl BA, Hajjar RJ, Valdivia HH, Schmidt U. Altered Ca2+ sparks and gating properties of ryanodine receptors in aging cardiomyocytes. Cell Calcium. 2005;37:583–91.PubMedCrossRefGoogle Scholar
  20. 20.
    Dibb K, Rueckschloss U, Eisner D, Insberg G, Trafford A. Mechanisms underlying enhanced excitation contraction coupling observed in the senescent sheep myocardium. J Mol Cell Cardiol. 2004;37:1171–81.PubMedGoogle Scholar
  21. 21.
    Mace LC, Palmer BM, Brown DA, Jew KN, Lynch JM, Glunt JM, Parsons TA, Cheung JY, Moore RL. Influence of age and run training on cardiac Na+/Ca2+ exchange. J Appl Physiol. 2003;95:1994–2003.PubMedGoogle Scholar
  22. 22.
    Walker KE, Lakatta EG, Houser SR. Age associated changes in membrane currents in rat ventricular myocytes. Cardiovasc Res. 1993;27:1968–77.PubMedCrossRefGoogle Scholar
  23. 23.
    Wei JY, Spurgeon A, Lakatta EG. Excitation-contraction in rat myocardium: alterations with adult aging. Am J Physiol. 1984;246:H784–91.PubMedGoogle Scholar
  24. 24.
    Josephson IR, Guia A, Stern MD, Lakatta EG. Alterations in properties of L-type Ca channels in aging rat heart. J Mol Cell Cardiol. 2002;34:297–308.PubMedCrossRefGoogle Scholar
  25. 25.
    Xiao RP, Spurgeon HA, O’Connor F, Lakatta EG. Age-associated changes in beta-adrenergic modulation on rat cardiac excitation-contraction coupling. J Clin Invest. 1994;94:2051–9.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    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;94:514–24.PubMedCrossRefGoogle Scholar
  27. 27.
    Liu SJ, Wyeth RP, Melchert RB, Kennedy RH. Aging-associated changes in whole cell K+ and L-type Ca2+ currents in rat ventricular myocytes. Am J Physiol. 2000;279:H889–900.Google Scholar
  28. 28.
    Isenberg G, Borschke B, Rueckschloss U. Ca2+ transients in cardiomyocytes from senescent mice peak late and decay slowly. Cell Calcium. 2003;34:271–80.PubMedCrossRefGoogle Scholar
  29. 29.
    Janczewski AM, Spurgeon HA, Lakatta EG. Action potential prolongation in cardiac myocytes of old rats is an adaptation to sustain youthful intracellular Ca2+ regulation. J Mol Cell Cardiol. 2002;34:641–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Bito V, Heinzel FR, Biesmans L, Antoons G, Sipido KR. Crosstalk between L-type Ca2+ channels and the sarcoplasmic reticulum: alterations during cardiac remodeling. Cardiovasc Res. 2008;77:315–24.PubMedCrossRefGoogle Scholar
  31. 31.
    Bassani RA. Transient outward potassium current and Ca2+ homeostasis in the heart: beyond the action potential. Braz J Med Biol Res. 2006;39:393–403.PubMedCrossRefGoogle Scholar
  32. 32.
    Froehlich JP, Lakatta EG, Beard E, Spurgeon HA, Weisfeldt ML, Gerstenblith G. Studies of sarcoplasmic reticulum function and contraction duration in young and aged rat myocardium. J Mol Cell Cardiol. 1978;10:427–38.PubMedCrossRefGoogle Scholar
  33. 33.
    Kaplan P, Jurkovicova D, Babusikova E, Hudecova S, Racay P, Sirova M, Lehotsky J, Drgova A, Dobrota D, Krizanova O. Effect of aging on the expression of intracellular Ca2+ transport proteins in a rat heart. Mol Cell Biochem. 2007;301:219–26.PubMedCrossRefGoogle Scholar
  34. 34.
    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 Ca2+-ATPase. Circulation. 2000;101:790–6.PubMedCrossRefGoogle Scholar
  35. 35.
    Taffet GE, Tate CA. CaATPase content is lower in cardiac sarcoplasmic reticulum isolated from old rats. Am J Physiol. 1993;264:H1609–14.PubMedGoogle Scholar
  36. 36.
    Xu A, Narayanan N. Effects of aging on sarcoplasmic reticulum Ca2+-cycling proteins and their phosphorylation in rat myocardium. Am J Physiol. 1998;275:H2087–94.PubMedGoogle Scholar
  37. 37.
    Jiang MT, Moffat MP, Narayanan N. Age-related alterations in the phosphorylation of sarcoplasmic reticulum and myofibrillar proteins and diminished contractile response to isoproterenol in intact rat ventricle. Circ Res. 1993;72:102–11.PubMedCrossRefGoogle Scholar
  38. 38.
    Xu A, Hawkins C, Narayanan N. Phosphorylation and activation of the Ca2+-ATPase of cardiac sarcoplasmic reticulum by Ca2+/calmodulin-dependent protein kinase. J Biol Chem. 1993;268:8394–7.PubMedGoogle Scholar
  39. 39.
    Assayag P, Charlemagne D, Marty I, de Leiris J, Lompre AM, Boucher F, Valere PE, Lortet S, Swynghedauw B, Besse S. Effects of sustained low-flow ischemia on myocardial function and calcium-regulating proteins in adult and senescent rat hearts. Cardiovasc Res. 1998;38:169–80.PubMedCrossRefGoogle Scholar
  40. 40.
    Slack JP, Grupp IL, Dash R, Holder D, Schmidt A, Gerst MJ, Tamura T, Tilgmann C, James PF, Johnson R, Gerdes AM, Kranias EG. The enhanced contractility of the phospholamban-deficient mouse heart persists with aging. J Mol Cell Cardiol. 2001;33:1031–40.PubMedCrossRefGoogle Scholar
  41. 41.
    MacLennan DH, Kranias EG. Phospholamban: a crucial regulator of cardiac contractility. Nat Rev Mol Cell Biol. 2003;4:566–77.PubMedCrossRefGoogle Scholar
  42. 42.
    del Monte F, Harding SE, Dec GW, Gwathmey JK, Hajjar RJ. Targeting phospholamban by gene transfer in human heart failure. Circulation. 2002;105:904–7.PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Armand A-S, De Windt LJ. Calcium cycling in heart failure: how the fast became too furious. Cardiovasc Res. 2004;62:439–41.PubMedCrossRefGoogle Scholar
  44. 44.
    Sipido KR, Eisner D. Something old, something new: changing views on the cellular mechanisms of heart failure. Cardiovasc Res. 2005;68:167–74.PubMedCrossRefGoogle Scholar
  45. 45.
    Howlett SE, Grandy SA, Ferrier GR. Calcium spark properties in ventricular myocytes are altered in aged mice. Am J Physiol. 2006;290:H1566–74.Google Scholar
  46. 46.
    Hano O, Bogdanov KY, Sakai M, Danziger RG, Spurgeon HA, Lakatta EG. Reduced threshold for myocardial cell calcium intolerance in the rat heart with aging. Am J Physiol. 1995;269:H1607–12.PubMedGoogle Scholar
  47. 47.
    Lakatta EG. Functional implications of spontaneous sarcoplasmic reticulum Ca2+ release in the heart. Cardiovasc Res. 1992;26:193–214.PubMedCrossRefGoogle Scholar
  48. 48.
    Marks AR. Cardiac intracellular calcium release channels: role in heart failure. Circ Res. 2000;87:8–11.PubMedCrossRefGoogle Scholar
  49. 49.
    Guo T, Zhang T, Mestril R, Bers DM. Ca/calmodulin-dependent protein kinase II phosphorylation of ryanodine receptor does affect calcium sparks in mouse ventricular myocytes. Circ Res. 2006;99:398–406.PubMedCrossRefGoogle Scholar
  50. 50.
    Li Y, Kranias EG, Mignery GA, Bers DM. Protein kinase a phosphorylation of the ryanodine receptor does not affect calcium sparks in mouse ventricular myocytes. Circ Res. 2002;90:309–16.PubMedCrossRefGoogle Scholar
  51. 51.
    Li Q, Wu S, Li S-Y, Lopez FL, Du M, Kajstura J, Anversa P, Ren J. Cardiac-specific overexpression of insulin-like growth factor 1 attenuates aging-associated cardiac diastolic contractile dysfunction and protein damage. Am J Physiol. 2007;292:H1398–403.CrossRefGoogle Scholar
  52. 52.
    Janapati V, Wu A, Davis N, Derrico CA, Levengood J, Schummers J, Colvin RA. Post-transcriptional regulation of the Na+/Ca2+ exchanger in aging rat heart. Mech Ageing Dev. 1995;84:195–208.PubMedCrossRefGoogle Scholar
  53. 53.
    Heyliger C, Prakash A, McNeill J. Alterations in membrane Na+–Ca2+ exchange in the aging myocardium. Age. 1988;1988:1–6.CrossRefGoogle Scholar
  54. 54.
    Frolkis VV, Frolkis RA, Mkhitarian LS, Shevchuk VG, Fraifeld VE, Vakulenko LG, Syrovy I. Contractile function and Ca2+ transport system of myocardium in ageing. Gerontology. 1988;34:64–74.PubMedCrossRefGoogle Scholar
  55. 55.
    Abete P, Ferrara N, Cioppa A, Ferrara P, Bianco S, Calabrese C, Napoli C, Rengo F. The role of aging on the control of contractile force by Na+–Ca2+ exchange in rat papillary muscle. J Gerontol A Biol Sci Med Sci. 1996;51:M251–9.PubMedCrossRefGoogle Scholar
  56. 56.
    Schmidt U, Zhu X, Lebeche D, Huq F, Guerrero JL, Hajjar RJ. In vivo gene transfer of parvalbumin improves diastolic function in aged rat hearts. Cardiovasc Res. 2005;66:318–23.PubMedCrossRefGoogle Scholar
  57. 57.
    Xiao R-P, Tomhave ED, Wang DJ, Ji X, Boluyt MO, Cheng H, Lakatta EG, Koch WJ. Age-associated reductions in cardiac β1- and β2-adrenoceptor responses without changes in inhibitory G proteins or receptor kinases. J Clin Invest. 1998;101:1273–82.PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    Sakai M, Danziger RS, Staddon JM, Lakatta EG, Hansford RG. Decrease with senescence in the norepinephrine-induced phosphorylation of myofilament proteins in isolated rat cardiac myocytes. J Mol Cell Cardiol. 1989;21:1327–36.PubMedCrossRefGoogle Scholar
  59. 59.
    Lakatta EG, Sollott SJ, Pepe S. The old heart: operating on the edge. In: Bock G, Goode JA, editors. Ageing vulnerability: causes and interventions, Novartis Foundation Symposium, vol. 235. New York, NY: Wiley; 2001. p. 172–201.CrossRefGoogle Scholar
  60. 60.
    Brenner DA, Apstein CS, Saupe KW. Exercise training attenuates age-associated diastolic dysfunction in rats. Circulation. 2001;104:221–6.PubMedCrossRefGoogle Scholar
  61. 61.
    Zhang SJ, Zhou YY, Xiao RP, et al. Age-associated reduction in recovery of the equilibrium state of myocyte length during reduced interstimulus intervals at higher stimulation rates. Biophys J. 2000;78:227A (Abstract).CrossRefGoogle Scholar
  62. 62.
    Pepe S, Tsuchiya N, Lakatta EG, Hansford RG. PUFA and aging modulate cardiac mitochondrial membrane lipid composition and Ca2+ activation of PDH. Am J Physiol. 1999;276:H149–58.PubMedGoogle Scholar
  63. 63.
    Lucas D, Sweda L. Cardiac reperfusion injury, aging, lipid peroxidation, and mitochondrial dysfunction. Proc Natl Acad Sci USA. 1998;95:510–4.PubMedCrossRefGoogle Scholar
  64. 64.
    Van der Loo B, Labugger R, Skepper JN, Bachschmid M, Kilo J, Powell JM, Palacios-Callendere M, Erusalimsky JD, Quaschning T, Malinski T, Gygi D, Ullrich V, Luscher TF. Enhanced peroxynitrite formation is associated with vascular aging. J Exp Med. 2000;192:1731–43.PubMedCentralPubMedCrossRefGoogle Scholar
  65. 65.
    Anversa P, Rota M, Urbanek K, Hosoda T, Sonnenblick EH, Leri A, Kajstura J, Bolli R. Myocardial aging-a stem cell problem. Basic Res Cardiol. 2005;100:482–93.PubMedCrossRefGoogle Scholar
  66. 66.
    Chimenti C, Kajstura J, Torella D, Urbanek K, Heleniak H, Colussi C, Di Meglio F, Nadal-Ginard B, Frustaci A, Leri A, Maseri A, Anversa P. Senescence and death of primitive cells and myocytes leads to premature cardiac aging and heart failure. Circ Res. 2003;93:604–13.PubMedCrossRefGoogle Scholar
  67. 67.
    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, Anganalmath SK, Baker M, Hintze TH, Bolli R, Urbanek K, Hosoda T, Anversa P, Kajstura J, Leri A. Activation of cardiac progenitor cells reverses the failing heart senescent phenotype and prolongs lifespan. Circ Res. 2008;102:597–606.PubMedCrossRefGoogle Scholar
  68. 68.
    Kajstura J, Urbanek K, Rota M, Bearzi C, Hosoda T, Bolli R, Anversa P, Leri A. Cardiac stem cells and myocardial disease. J Mol Cell Cardiol. 2008;45:505–13.PubMedCrossRefGoogle Scholar
  69. 69.
    Rota M, Hosoda T, De Angelis A, Arcarese ML, Esposito G, Rizzi R, Tillmanns J, Tugal D, Musso E, Rimoldi O, Bearzi C, Urbanek K, Anversa P, Leri A, Kajstura J. The young mouse heart is composed of myocytes heterogeneous in age and function. Circ Res. 2007;101:387–99.PubMedCrossRefGoogle Scholar
  70. 70.
    Bergmann O, Bhardwaj RD, Bernard S, Zdunek S, Barnabe-Heider F, Walsh S, Zupicich J, Alkass K, Buchholz BA, Druid H, Jovinge S, Frisen J. Evidence for cardiomyocyte renewal in humans. Science. 2009;324:98–102.PubMedCentralPubMedCrossRefGoogle Scholar
  71. 71.
    Kajstura J, Rota M, Cappetta D, Ogorek B, Arranto C, Bai Y, Ferreira-Martins J, Signore S, Sanada F, Matsuda A, Kostyla J, Caballero M-V, Fiorini C, D’Alessandro DA, Michler RE, del Monte F, Hosoda T, Perrella MA, Leri A, Buchholz BA, Loscalzo J, Anversa P. Cardiomyogenesis in the aging and failing human heart. Circulation. 2012;126:1869–81.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Edward G. Lakatta
    • 1
    Email author
  • Harold A. Spurgeon
    • 2
  • Andrzej M. Janczewski
    • 3
  1. 1.National Institute on Aging/NIHBaltimoreUSA
  2. 2.Laboratory of Cardiovascular ScienceNational Institute on Aging, National Institutes of HealthBaltimoreUSA
  3. 3.Department of Internal MedicinePCK Marine HospitalGdyniaPoland

Personalised recommendations