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Vol. 54, No. 1, 2008
Issue release date: May 2008
Section title: Experimental Section
Free Access
Gerontology 2008;54:24–31
(DOI:10.1159/000113503)

The Aging Cardiomyocyte: A Mini-Review

Bernhard D. · Laufer G.
Cardiac Surgery Research Laboratory, Department of Cardiac Surgery, Innsbruck Medical University, Innsbruck, Austria
email Corresponding Author

Abstract

Background: Aging per se is a risk factor for reduced cardiac function and heart diseases, even when adjusted for aging-associated cardiovascular risk factors. Accordingly, aging-related biochemical and cell-biological changes lead to pathophysiological conditions, especially reduced heart function and heart disease. Objective: In this review, we summarize the changes that occur as the heart ages from youth to old age on the basis of the cardiac myocyte. Aging phenotypes and underlying mechanisms shall be discussed that affect cardiomyocyte repair, signaling, structure, and function. Methods: Review of the literature. Results: The following factors play vital roles in the aging of cardiomyocytes: oxidative stress, inflammation, cellular protection and repair, telomere integrity, survival and death, metabolism, post-translational modifications, and altered gene expression. Importantly, non-cardiomyocyte-based aging processes (vascular, fibroblast, extracellular matrix, etc.) in the heart will interfere with cardiomyocyte aging and cardiac function. Conclusion: Based on our analyses, we postulate that the physiological aging process of the heart and of the cardiomyocyte is primarily driven by intrinsic aging factors. However, extrinsic aging factors, e.g. smoking, also make an important contribution to pathologically accelerated aging of the heart.

© 2008 S. Karger AG, Basel


  

Key Words

  • Myocyte
  • Aging
  • Senescence

References

  1. Chang KC, Peng YI, Dai SH, Tseng YZ: Age-related changes in pumping mechanical behavior of rat ventricle in terms of systolic elastance and resistance. J Gerontol [A] 2000;55:B440–B447.
  2. 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;78:890–900.
  3. Lakatta EG: Why cardiovascular function may decline with age. Geriatrics 1987;42:84–87.
  4. Anversa P, Leri A, Kajstura J: Cardiac regeneration. J Am Coll Cardiol 2006;47:1769–1776.
  5. Chimenti C, Kajstura J, Torella D, Urbanek K, Heleniak H, Colussi C, Di MF, Nadal-Ginard B, Frustaci A, Leri A, Maseri A, Anversa P: Senescence and death of primitive cells and myocytes lead to premature cardiac aging and heart failure. Circ Res 2003;93:604–613.
  6. 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;67:871–885.
  7. Chen X, Wilson RM, Kubo H, Berretta RM, Harris DM, Zhang X, Jaleel N, MacDonnell SM, Bearzi C, Tillmanns J, Trofimova I, Hosoda T, Mosna F, Cribbs L, Leri A, Kajstura J, Anversa P, Houser SR: Adolescent feline heart contains a population of small, proliferative ventricular myocytes with immature physiological properties. Circ Res 2007;100:536–544.
  8. Hacker TA, McKiernan SH, Douglas PS, Wanagat J, Aiken JM: Age-related changes in cardiac structure and function in Fischer 344 x Brown Norway hybrid rats. Am J Physiol 2006;290:H304–H311.
  9. Weber KT, Brilla CG: Pathological hypertrophy and cardiac interstitium. Fibrosis and renin-angiotensin-aldosterone system. Circulation 1991;83:1849–1865.
  10. Urbanek K, Quaini F, Tasca G, Torella D, Castaldo C, Nadal-Ginard B, Leri A, Kajstura J, Quaini E, Anversa P: Intense myocyte formation from cardiac stem cells in human cardiac hypertrophy. Proc Natl Acad Sci USA 2003;100:10440–10445.
  11. Rota M, Hosoda T, De AA, 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;101:387–399.
  12. Ishikawa F, Shimazu H, Shultz LD, Fukata M, Nakamura R, Lyons B, Shimoda K, Shimoda S, Kanemaru T, Nakamura K, Ito H, Kaji Y, Perry AC, Harada M: Purified human hematopoietic stem cells contribute to the generation of cardiomyocytes through cell fusion. FASEB J 2006;20:950–952.
  13. Leri A, Franco S, Zacheo A, Barlucchi L, Chimenti S, Limana F, Nadal-Ginard B, Kajstura J, Anversa P, Blasco MA: Ablation of telomerase and telomere loss leads to cardiac dilatation and heart failure associated with p53 upregulation. EMBO J 2003;22:131–139.
  14. Bodyak N, Kang PM, Hiromura M, Sulijoadikusumo I, Horikoshi N, Khrapko K, Usheva A: Gene expression profiling of the aging mouse cardiac myocytes. Nucl Acids Res 2002;30:3788–3794.
  15. Park SK, Prolla TA: Gene expression profiling studies of aging in cardiac and skeletal muscles. Cardiovasc Res 2005;66:205–212.
  16. Pandya K, Kim HS, Smithies O: Fibrosis, not cell size, delineates beta-myosin heavy chain reexpression during cardiac hypertrophy and normal aging in vivo. Proc Natl Acad Sci USA 2006;103:16864–16869.
  17. Nag AC, Cheng M: Biochemical evidence for cellular dedifferentiation in adult rat cardiac muscle cells in culture: expression of myosin isozymes. Biochem Biophys Res Commun 1986;137:855–862.
  18. Afilalo J, Sebag IA, Chalifour LE, Rivas D, Akter R, Sharma K, Duque G: Age-related changes in lamin A/C expression in cardiomyocytes. Am J Physiol 2007;293:H1451–H1456.
  19. Jones SA, Lancaster MK, Boyett MR: Ageing-related changes of connexins and conduction within the sinoatrial node. J Physiol 2004;560:429–437.
  20. Boengler K, Heusch G, Schulz R: Connexin 43 and ischemic preconditioning: effects of age and disease. Exp Gerontol 2006;41:485–488.
  21. Abbate A, Scarpa S, Santini D, Palleiro J, Vasaturo F, Miller J, Morales C, Vetrovec GW, Baldi A: Myocardial expression of survivin, an apoptosis inhibitor, in aging and heart failure. An experimental study in the spontaneously hypertensive rat. Int J Cardiol 2006;111:371–376.
  22. Fang CX, Doser TA, Yang X, Sreejayan N, Ren J: Metallothionein antagonizes aging-induced cardiac contractile dysfunction: role of PTP1B, insulin receptor tyrosine phosphorylation and Akt. Aging Cell 2006;5:177–185.
  23. Yang X, Doser TA, Fang CX, Nunn JM, Janardhanan R, Zhu M, Sreejayan N, Quinn MT, Ren J: Metallothionein prolongs survival and antagonizes senescence-associated cardiomyocyte diastolic dysfunction: role of oxidative stress. FASEB J 2006;20:1024–1026.
  24. Purcell NH, Wilkins BJ, York A, Saba-El-Leil MK, Meloche S, Robbins J, Molkentin JD: Genetic inhibition of cardiac ERK1/2 promotes stress-induced apoptosis and heart failure but has no effect on hypertrophy in vivo. Proc Natl Acad Sci USA 2007;104:14074–14079.
  25. Tsujita Y, Muraski J, Shiraishi I, Kato T, Kajstura J, Anversa P, Sussman MA: Nuclear targeting of Akt antagonizes aspects of cardiomyocyte hypertrophy. Proc Natl Acad Sci USA 2006;103:11946–11951.
  26. Lieber SC, Aubry N, Pain J, Diaz G, Kim SJ, Vatner SF: Aging increases stiffness of cardiac myocytes measured by atomic force microscopy nanoindentation. Am J Physiol 2004;287:H645–H651.
  27. Terman A, Brunk UT: Autophagy in cardiac myocyte homeostasis, aging, and pathology. Cardiovasc Res 2005;68:355–365.
  28. Domenighetti AA, Wang Q, Egger M, Richards SM, Pedrazzini T, Delbridge LM: Angiotensin II-mediated phenotypic cardiomyocyte remodeling leads to age-dependent cardiac dysfunction and failure. Hypertension 2005;46:426–432.
  29. Bokov A, Chaudhuri A, Richardson A: The role of oxidative damage and stress in aging. Mech Age Dev 2004;125:811–826.
  30. Di LF, Bernardi P: Mitochondrial function and myocardial aging: a critical analysis of the role of permeability transition. Cardiovasc Res 2005;66:222–232.
  31. Thompson LV: Oxidative stress, mitochondria and mtDNA-mutator mice. Exp Gerontol 2006;41:1220–1222.
  32. Judge S, Leeuwenburgh C: Cardiac mitochondrial bioenergetics, oxidative stress, and aging. Am J Physiol 2007;292:C1983–C1992.
  33. Li SY, Du M, Dolence EK, Fang CX, Mayer GE, Ceylan-Isik AF, LaCour KH, Yang X, Wilbert CJ, Sreejayan N, Ren J: Aging induces cardiac diastolic dysfunction, oxidative stress, accumulation of advanced glycation endproducts and protein modification. Aging Cell 2005;4:57–64.
  34. Bernhard D, Rossmann A, Wick G: Metals in cigarette smoke. IUBMB Life 2005;57:805–809.
  35. Bernhard D, Moser C, Backovic A, Wick G: Cigarette smoke – an aging accelerator? Exp Gerontol 2007;42:160–165.
  36. Bernhard D, Wang XL: Smoking, oxidative stress and cardiovascular diseases – do anti-oxidative therapies fail? Curr Med Chem 2007;14:1703–1712.
  37. 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;94:514–524.
  38. Fulop N, Mason MM, Dutta K, Wang P, Davidoff AJ, Marchase RB, Chatham JC: Impact of Type 2 diabetes and aging on cardiomyocyte function and O-linked N-acetylglucosamine levels in the heart. Am J Physiol 2007;292:C1370–C1378.
  39. Terman A, Gustafsson B, Brunk UT: The lysosomal-mitochondrial axis theory of postmitotic aging and cell death. Chem Biol Interact 2006;163:29–37.
  40. Fuster JJ, Andres V: Telomere biology and cardiovascular disease. Circ Res 2006;99:1167–1180.
  41. Ancey C, Menet E, Corbi P, Fredj S, Garcia M, Rucker-Martin C, Bescond J, Morel F, Wijdenes J, Lecron JC, Potreau D: Human cardiomyocyte hypertrophy induced in vitro by gp130 stimulation. Cardiovasc Res 2003;59:78–85.
  42. Maestri R, Milia AF, Salis MB, Graiani G, Lagrasta C, Monica M, Corradi D, Emanueli C, Madeddu P: Cardiac hypertrophy and microvascular deficit in kinin B2 receptor knockout mice. Hypertension 2003;41:1151–1155.
  43. Kim YK, Suarez J, Hu Y, McDonough PM, Boer C, Dix DJ, Dillmann WH: Deletion of the inducible 70-kDa heat shock protein genes in mice impairs cardiac contractile function and calcium handling associated with hypertrophy. Circulation 2006;113:2589–2597.
  44. Ren J, Li Q, Wu S, Li SY, Babcock SA: Cardiac overexpression of antioxidant catalase attenuates aging-induced cardiomyocyte relaxation dysfunction. Mech Age Dev 2007;128:276–285.
  45. Oh H, Taffet GE, Youker KA, Entman ML, Overbeek PA, Michael LH, Schneider MD: Telomerase reverse transcriptase promotes cardiac muscle cell proliferation, hypertrophy, and survival. Proc Natl Acad Sci USA 2001;98:10308–10313.

  

Author Contacts

PD Dr. David Bernhard
Department of Cardiac Surgery, Innsbruck Medical University
Innrain 66, AT–6020 Innsbruck (Austria)
Tel. +43 512 5042 7815 or 7804, Fax +43 512 5042 7805
E-Mail david.bernhard@i-med.ac.at

  

Article Information

Published online: January 15, 2008
Number of Print Pages : 8
Number of Figures : 2, Number of Tables : 0, Number of References : 45

  

Publication Details

Gerontology (International Journal of Experimental, Clinical, Behavioural and Technological Gerontology)

Vol. 54, No. 1, Year 2008 (Cover Date: May 2008)

Journal Editor: Meier-Ruge W. (Basel)
ISSN: 0304–324X (Print), eISSN: 1423–0003 (Online)

For additional information: http://www.karger.com/GER


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Background: Aging per se is a risk factor for reduced cardiac function and heart diseases, even when adjusted for aging-associated cardiovascular risk factors. Accordingly, aging-related biochemical and cell-biological changes lead to pathophysiological conditions, especially reduced heart function and heart disease. Objective: In this review, we summarize the changes that occur as the heart ages from youth to old age on the basis of the cardiac myocyte. Aging phenotypes and underlying mechanisms shall be discussed that affect cardiomyocyte repair, signaling, structure, and function. Methods: Review of the literature. Results: The following factors play vital roles in the aging of cardiomyocytes: oxidative stress, inflammation, cellular protection and repair, telomere integrity, survival and death, metabolism, post-translational modifications, and altered gene expression. Importantly, non-cardiomyocyte-based aging processes (vascular, fibroblast, extracellular matrix, etc.) in the heart will interfere with cardiomyocyte aging and cardiac function. Conclusion: Based on our analyses, we postulate that the physiological aging process of the heart and of the cardiomyocyte is primarily driven by intrinsic aging factors. However, extrinsic aging factors, e.g. smoking, also make an important contribution to pathologically accelerated aging of the heart.

© 2008 S. Karger AG, Basel


  

Author Contacts

PD Dr. David Bernhard
Department of Cardiac Surgery, Innsbruck Medical University
Innrain 66, AT–6020 Innsbruck (Austria)
Tel. +43 512 5042 7815 or 7804, Fax +43 512 5042 7805
E-Mail david.bernhard@i-med.ac.at

  

Article Information

Published online: January 15, 2008
Number of Print Pages : 8
Number of Figures : 2, Number of Tables : 0, Number of References : 45

  

Publication Details

Gerontology (International Journal of Experimental, Clinical, Behavioural and Technological Gerontology)

Vol. 54, No. 1, Year 2008 (Cover Date: May 2008)

Journal Editor: Meier-Ruge W. (Basel)
ISSN: 0304–324X (Print), eISSN: 1423–0003 (Online)

For additional information: http://www.karger.com/GER


Article / Publication Details

First-Page Preview
Abstract of Experimental Section

Published online: 1/15/2008
Issue release date: May 2008

Number of Print Pages: 8
Number of Figures: 2
Number of Tables: 0

ISSN: 0304-324X (Print)
eISSN: 1423-0003 (Online)

For additional information: http://www.karger.com/GER


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Chang KC, Peng YI, Dai SH, Tseng YZ: Age-related changes in pumping mechanical behavior of rat ventricle in terms of systolic elastance and resistance. J Gerontol [A] 2000;55:B440–B447.
  2. 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;78:890–900.
  3. Lakatta EG: Why cardiovascular function may decline with age. Geriatrics 1987;42:84–87.
  4. Anversa P, Leri A, Kajstura J: Cardiac regeneration. J Am Coll Cardiol 2006;47:1769–1776.
  5. Chimenti C, Kajstura J, Torella D, Urbanek K, Heleniak H, Colussi C, Di MF, Nadal-Ginard B, Frustaci A, Leri A, Maseri A, Anversa P: Senescence and death of primitive cells and myocytes lead to premature cardiac aging and heart failure. Circ Res 2003;93:604–613.
  6. 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;67:871–885.
  7. Chen X, Wilson RM, Kubo H, Berretta RM, Harris DM, Zhang X, Jaleel N, MacDonnell SM, Bearzi C, Tillmanns J, Trofimova I, Hosoda T, Mosna F, Cribbs L, Leri A, Kajstura J, Anversa P, Houser SR: Adolescent feline heart contains a population of small, proliferative ventricular myocytes with immature physiological properties. Circ Res 2007;100:536–544.
  8. Hacker TA, McKiernan SH, Douglas PS, Wanagat J, Aiken JM: Age-related changes in cardiac structure and function in Fischer 344 x Brown Norway hybrid rats. Am J Physiol 2006;290:H304–H311.
  9. Weber KT, Brilla CG: Pathological hypertrophy and cardiac interstitium. Fibrosis and renin-angiotensin-aldosterone system. Circulation 1991;83:1849–1865.
  10. Urbanek K, Quaini F, Tasca G, Torella D, Castaldo C, Nadal-Ginard B, Leri A, Kajstura J, Quaini E, Anversa P: Intense myocyte formation from cardiac stem cells in human cardiac hypertrophy. Proc Natl Acad Sci USA 2003;100:10440–10445.
  11. Rota M, Hosoda T, De AA, 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;101:387–399.
  12. Ishikawa F, Shimazu H, Shultz LD, Fukata M, Nakamura R, Lyons B, Shimoda K, Shimoda S, Kanemaru T, Nakamura K, Ito H, Kaji Y, Perry AC, Harada M: Purified human hematopoietic stem cells contribute to the generation of cardiomyocytes through cell fusion. FASEB J 2006;20:950–952.
  13. Leri A, Franco S, Zacheo A, Barlucchi L, Chimenti S, Limana F, Nadal-Ginard B, Kajstura J, Anversa P, Blasco MA: Ablation of telomerase and telomere loss leads to cardiac dilatation and heart failure associated with p53 upregulation. EMBO J 2003;22:131–139.
  14. Bodyak N, Kang PM, Hiromura M, Sulijoadikusumo I, Horikoshi N, Khrapko K, Usheva A: Gene expression profiling of the aging mouse cardiac myocytes. Nucl Acids Res 2002;30:3788–3794.
  15. Park SK, Prolla TA: Gene expression profiling studies of aging in cardiac and skeletal muscles. Cardiovasc Res 2005;66:205–212.
  16. Pandya K, Kim HS, Smithies O: Fibrosis, not cell size, delineates beta-myosin heavy chain reexpression during cardiac hypertrophy and normal aging in vivo. Proc Natl Acad Sci USA 2006;103:16864–16869.
  17. Nag AC, Cheng M: Biochemical evidence for cellular dedifferentiation in adult rat cardiac muscle cells in culture: expression of myosin isozymes. Biochem Biophys Res Commun 1986;137:855–862.
  18. Afilalo J, Sebag IA, Chalifour LE, Rivas D, Akter R, Sharma K, Duque G: Age-related changes in lamin A/C expression in cardiomyocytes. Am J Physiol 2007;293:H1451–H1456.
  19. Jones SA, Lancaster MK, Boyett MR: Ageing-related changes of connexins and conduction within the sinoatrial node. J Physiol 2004;560:429–437.
  20. Boengler K, Heusch G, Schulz R: Connexin 43 and ischemic preconditioning: effects of age and disease. Exp Gerontol 2006;41:485–488.
  21. Abbate A, Scarpa S, Santini D, Palleiro J, Vasaturo F, Miller J, Morales C, Vetrovec GW, Baldi A: Myocardial expression of survivin, an apoptosis inhibitor, in aging and heart failure. An experimental study in the spontaneously hypertensive rat. Int J Cardiol 2006;111:371–376.
  22. Fang CX, Doser TA, Yang X, Sreejayan N, Ren J: Metallothionein antagonizes aging-induced cardiac contractile dysfunction: role of PTP1B, insulin receptor tyrosine phosphorylation and Akt. Aging Cell 2006;5:177–185.
  23. Yang X, Doser TA, Fang CX, Nunn JM, Janardhanan R, Zhu M, Sreejayan N, Quinn MT, Ren J: Metallothionein prolongs survival and antagonizes senescence-associated cardiomyocyte diastolic dysfunction: role of oxidative stress. FASEB J 2006;20:1024–1026.
  24. Purcell NH, Wilkins BJ, York A, Saba-El-Leil MK, Meloche S, Robbins J, Molkentin JD: Genetic inhibition of cardiac ERK1/2 promotes stress-induced apoptosis and heart failure but has no effect on hypertrophy in vivo. Proc Natl Acad Sci USA 2007;104:14074–14079.
  25. Tsujita Y, Muraski J, Shiraishi I, Kato T, Kajstura J, Anversa P, Sussman MA: Nuclear targeting of Akt antagonizes aspects of cardiomyocyte hypertrophy. Proc Natl Acad Sci USA 2006;103:11946–11951.
  26. Lieber SC, Aubry N, Pain J, Diaz G, Kim SJ, Vatner SF: Aging increases stiffness of cardiac myocytes measured by atomic force microscopy nanoindentation. Am J Physiol 2004;287:H645–H651.
  27. Terman A, Brunk UT: Autophagy in cardiac myocyte homeostasis, aging, and pathology. Cardiovasc Res 2005;68:355–365.
  28. Domenighetti AA, Wang Q, Egger M, Richards SM, Pedrazzini T, Delbridge LM: Angiotensin II-mediated phenotypic cardiomyocyte remodeling leads to age-dependent cardiac dysfunction and failure. Hypertension 2005;46:426–432.
  29. Bokov A, Chaudhuri A, Richardson A: The role of oxidative damage and stress in aging. Mech Age Dev 2004;125:811–826.
  30. Di LF, Bernardi P: Mitochondrial function and myocardial aging: a critical analysis of the role of permeability transition. Cardiovasc Res 2005;66:222–232.
  31. Thompson LV: Oxidative stress, mitochondria and mtDNA-mutator mice. Exp Gerontol 2006;41:1220–1222.
  32. Judge S, Leeuwenburgh C: Cardiac mitochondrial bioenergetics, oxidative stress, and aging. Am J Physiol 2007;292:C1983–C1992.
  33. Li SY, Du M, Dolence EK, Fang CX, Mayer GE, Ceylan-Isik AF, LaCour KH, Yang X, Wilbert CJ, Sreejayan N, Ren J: Aging induces cardiac diastolic dysfunction, oxidative stress, accumulation of advanced glycation endproducts and protein modification. Aging Cell 2005;4:57–64.
  34. Bernhard D, Rossmann A, Wick G: Metals in cigarette smoke. IUBMB Life 2005;57:805–809.
  35. Bernhard D, Moser C, Backovic A, Wick G: Cigarette smoke – an aging accelerator? Exp Gerontol 2007;42:160–165.
  36. Bernhard D, Wang XL: Smoking, oxidative stress and cardiovascular diseases – do anti-oxidative therapies fail? Curr Med Chem 2007;14:1703–1712.
  37. 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;94:514–524.
  38. Fulop N, Mason MM, Dutta K, Wang P, Davidoff AJ, Marchase RB, Chatham JC: Impact of Type 2 diabetes and aging on cardiomyocyte function and O-linked N-acetylglucosamine levels in the heart. Am J Physiol 2007;292:C1370–C1378.
  39. Terman A, Gustafsson B, Brunk UT: The lysosomal-mitochondrial axis theory of postmitotic aging and cell death. Chem Biol Interact 2006;163:29–37.
  40. Fuster JJ, Andres V: Telomere biology and cardiovascular disease. Circ Res 2006;99:1167–1180.
  41. Ancey C, Menet E, Corbi P, Fredj S, Garcia M, Rucker-Martin C, Bescond J, Morel F, Wijdenes J, Lecron JC, Potreau D: Human cardiomyocyte hypertrophy induced in vitro by gp130 stimulation. Cardiovasc Res 2003;59:78–85.
  42. Maestri R, Milia AF, Salis MB, Graiani G, Lagrasta C, Monica M, Corradi D, Emanueli C, Madeddu P: Cardiac hypertrophy and microvascular deficit in kinin B2 receptor knockout mice. Hypertension 2003;41:1151–1155.
  43. Kim YK, Suarez J, Hu Y, McDonough PM, Boer C, Dix DJ, Dillmann WH: Deletion of the inducible 70-kDa heat shock protein genes in mice impairs cardiac contractile function and calcium handling associated with hypertrophy. Circulation 2006;113:2589–2597.
  44. Ren J, Li Q, Wu S, Li SY, Babcock SA: Cardiac overexpression of antioxidant catalase attenuates aging-induced cardiomyocyte relaxation dysfunction. Mech Age Dev 2007;128:276–285.
  45. Oh H, Taffet GE, Youker KA, Entman ML, Overbeek PA, Michael LH, Schneider MD: Telomerase reverse transcriptase promotes cardiac muscle cell proliferation, hypertrophy, and survival. Proc Natl Acad Sci USA 2001;98:10308–10313.