Cardiac aging in mice and humans: the role of mitochondrial oxidative stress.

Age is a major risk factor for cardiovascular diseases, not only because it prolongs exposure to several other cardiovascular risks, but also owing to intrinsic cardiac aging, which reduces cardiac functional reserve, predisposes the heart to stress, and contributes to increased cardiovascular mortality in the elderly. Intrinsic cardiac aging in the murine model closely recapitulates age-related cardiac changes in humans, including left ventricular hypertrophy, fibrosis, and diastolic dysfunction. Cardiac aging in mice is accompanied by accumulation of mitochondrial protein oxidation, increased mitochondrial DNA mutations, increased mitochondrial biogenesis, as well as decreased cardiac SERCA2 protein. All of these age-related changes are significantly attenuated in mice overexpressing catalase targeted to mitochondria. These findings demonstrate the critical role of mitochondrial reactive oxygen species in cardiac aging and support the potential application of mitochondrial antioxidants to cardiac aging and age-related cardiovascular diseases.

[1]  M. Emond,et al.  Extension of Murine Life Span by Overexpression of Catalase Targeted to Mitochondria , 2005, Science.

[2]  S. Isoyama,et al.  Acute and Chronic Adaptation to Hemodynamic Overload and Ischemia in the Aged Heart , 2004, Heart Failure Reviews.

[3]  Robert S. Balaban,et al.  Mitochondria, Oxidants, and Aging , 2005, Cell.

[4]  B. Lorell,et al.  Treatment with growth hormone enhances contractile reserve and intracellular calcium transients in myocytes from rats with postinfarction heart failure. , 1999, Circulation.

[5]  D. Ingram,et al.  Caloric restriction and aging in primates: Relevance to humans and possible CR mimetics , 2002, Microscopy research and technique.

[6]  E. Lakatta,et al.  Diminished alpha1-adrenergic-mediated contraction and translocation of PKC in senescent rat heart. , 2001, American journal of physiology. Heart and circulatory physiology.

[7]  A. Bartke,et al.  Genes that prolong life: relationships of growth hormone and growth to aging and life span. , 2001, The journals of gerontology. Series A, Biological sciences and medical sciences.

[8]  A. Moorman,et al.  Expressional analysis of the cardiac Na-Ca exchanger in rat development and senescence. , 1998, Cardiovascular research.

[9]  T. Chou,et al.  Alterations of nitric oxide synthase expression with aging and hypertension in rats. , 1998, Hypertension.

[10]  C. Wilbert,et al.  Aging induces cardiac diastolic dysfunction, oxidative stress, accumulation of advanced glycation endproducts and protein modification , 2005, Aging cell.

[11]  D. Torella,et al.  Adult Cardiac Stem Cells Are Multipotent and Support Myocardial Regeneration , 2003, Cell.

[12]  Karen Ocorr,et al.  Age-related cardiac disease model of Drosophila , 2007, Mechanisms of Ageing and Development.

[13]  J B Seward,et al.  Noninvasive Doppler-derived myocardial performance index: correlation with simultaneous measurements of cardiac catheterization measurements. , 1997, Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography.

[14]  A. Navarro,et al.  The mitochondrial energy transduction system and the aging process. , 2007, American journal of physiology. Cell physiology.

[15]  Reiko Kurotani,et al.  Disruption of Type 5 Adenylyl Cyclase Enhances Desensitization of Cyclic Adenosine Monophosphate Signal and Increases Akt Signal With Chronic Catecholamine Stress , 2007, Circulation.

[16]  E. Sonnenblick,et al.  Myocardial aging--a stem cell problem. , 2005, Basic research in cardiology.

[17]  Mary Ann Ottinger,et al.  Aging in Rhesus Monkeys: Relevance to Human Health Interventions , 2004, Science.

[18]  P. Bernardi,et al.  Mitochondria and ischemia–reperfusion injury of the heart: Fixing a hole , 2006 .

[19]  K. Furie,et al.  Heart disease and stroke statistics--2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. , 2008, Circulation.

[20]  Serguei V. S. Pakhomov,et al.  Systolic and diastolic heart failure in the community. , 2006, JAMA.

[21]  Lin Yan,et al.  Type 5 Adenylyl Cyclase Disruption Increases Longevity and Protects Against Stress , 2007, Cell.

[22]  Daniel Levy,et al.  Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part II: the aging heart in health: links to heart disease. , 2003, Circulation.

[23]  A Xu,et al.  Effects of aging on sarcoplasmic reticulum Ca2+-cycling proteins and their phosphorylation in rat myocardium. , 1998, American journal of physiology. Heart and circulatory physiology.

[24]  E. Lakatta,et al.  Protection in the aged heart: preventing the heart-break of old age? , 2005, Cardiovascular research.

[25]  D. Harman.  Aging: a theory based on free radical and radiation chemistry. , 1956, Journal of gerontology.

[26]  R. Wiesner,et al.  Regulation of mitochondrial proliferation in the heart: power-plant failure contributes to cardiac failure in hypertrophy. , 2004, Cardiovascular research.

[27]  Edward G Lakatta,et al.  Arterial and Cardiac Aging: Major Shareholders in Cardiovascular Disease Enterprises: Part III: Cellular and Molecular Clues to Heart and Arterial Aging , 2003, Circulation.

[28]  D. Ingram,et al.  Calorie restriction in nonhuman primates: effects on diabetes and cardiovascular disease risk. , 1999, Toxicological sciences : an official journal of the Society of Toxicology.

[29]  M. Crabtree,et al.  Prevention and Reversal of Premature Endothelial Cell Senescence and Vasculopathy in Obesity-Induced Diabetes by Ebselen , 2004, Circulation research.

[30]  M. Talan,et al.  Oxygen consumption in adult and aged C57BL/6J mice during acute treadmill exercise of different intensity , 1996, Experimental Gerontology.

[31]  Elina Minami,et al.  Cardiogenic Differentiation and Transdifferentiation of Progenitor Cells , 2008, Circulation research.

[32]  Ralph D'Agostino,et al.  Serum Insulin-like Growth Factor I and Risk for Heart Failure in Elderly Individuals without a Previous Myocardial Infarction: The Framingham Heart Study , 2003, Annals of Internal Medicine.

[33]  Jing Liu,et al.  Disruption of type 5 adenylyl cyclase gene preserves cardiac function against pressure overload , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[34]  E. Lakatta,et al.  Alterations in properties of L-type Ca channels in aging rat heart. , 2002, Journal of molecular and cellular cardiology.

[35]  D. Ingram,et al.  Calorie restriction in rhesus monkeys , 2003, Experimental Gerontology.

[36]  S. Khouri,et al.  A practical approach to the echocardiographic evaluation of diastolic function. , 2004, Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography.

[37]  Martin Holzenberger,et al.  IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice , 2003, Nature.

[38]  A. Ceylan-isik,et al.  Deficiency of insulin-like growth factor 1 reduces sensitivity to aging-associated cardiomyocyte dysfunction. , 2008, Rejuvenation research.

[39]  D. Wallace,et al.  The pathophysiology of mitochondrial disease as modeled in the mouse. , 2009, Genes & development.

[40]  Jeffrey Robbins,et al.  Evidence from a genetic fate-mapping study that stem cells refresh adult mammalian cardiomyocytes after injury , 2007, Nature Medicine.

[41]  R. Bodmer,et al.  Insulin regulation of heart function in aging fruit flies , 2004, Nature Genetics.

[42]  Keiko Takahashi,et al.  Angiotensin II receptor antagonist attenuates expression of aging markers in diabetic mouse heart. , 2006, Circulation journal : official journal of the Japanese Circulation Society.

[43]  Qing Wang,et al.  Angiotensin II–Mediated Phenotypic Cardiomyocyte Remodeling Leads to Age-Dependent Cardiac Dysfunction and Failure , 2005, Hypertension.

[44]  D. Wallace,et al.  Hypoxemia is associated with mitochondrial DNA damage and gene induction. Implications for cardiac disease. , 1991, JAMA.

[45]  Samuel Bernard,et al.  Evidence for Cardiomyocyte Renewal in Humans , 2008, Science.

[46]  O. Alfieri,et al.  Impaired spontaneous growth hormone secretion in severe dialated cardiomyopathy. , 1996, American heart journal.

[47]  A. Pietrelli,et al.  Protective effect of long-term angiotensin II inhibition. , 2007, American journal of physiology. Heart and circulatory physiology.

[48]  J. Molkentin,et al.  Regulation of cardiac hypertrophy by intracellular signalling pathways , 2006, Nature Reviews Molecular Cell Biology.

[49]  H. Hasegawa,et al.  Direct activation of mitochondrial K(ATP) channels mimics preconditioning but protein kinase C activation is less effective in middle-aged rat hearts. , 2001, Cardiovascular research.

[50]  S. Rafii,et al.  Adult cardiac stem cells--where do we go from here? , 2003, Science of Aging Knowledge Environment.

[51]  G. Remuzzi,et al.  Disruption of the Ang II type 1 receptor promotes longevity in mice. , 2009, The Journal of clinical investigation.

[52]  T. D. Pugh,et al.  Mitochondrial DNA Mutations, Oxidative Stress, and Apoptosis in Mammalian Aging , 2005, Science.

[53]  P. Nagley,et al.  Varied prevalence of age-associated mitochondrial DNA deletions in different species and tissues: a comparison between human and rat. , 1997, Biochemical and biophysical research communications.

[54]  M. MacCoss,et al.  Overexpression of Catalase Targeted to Mitochondria Attenuates Murine Cardiac Aging , 2009, Circulation.

[55]  福家 聡,et al.  DNA deletions and clonal mutations drive premature aging in mitochondrial mutator mice , 2008 .

[56]  M. Emond,et al.  Reduction of age-associated pathology in old mice by overexpression of catalase in mitochondria. , 2008, The journals of gerontology. Series A, Biological sciences and medical sciences.

[57]  G. Radda,et al.  Uncoupling proteins in human heart , 2004, The Lancet.

[58]  D. Kitzman,et al.  Growth hormone replacement attenuates diastolic dysfunction and cardiac angiotensin II expression in senescent rats. , 2006, The journals of gerontology. Series A, Biological sciences and medical sciences.

[59]  A. Garnier,et al.  Transcriptional control of mitochondrial biogenesis: the central role of PGC-1alpha. , 2008, Cardiovascular research.

[60]  E. Lakatta,et al.  Action potential prolongation in cardiac myocytes of old rats is an adaptation to sustain youthful intracellular Ca2+ regulation. , 2002, Journal of molecular and cellular cardiology.

[61]  Howard T. Jacobs,et al.  Premature ageing in mice expressing defective mitochondrial DNA polymerase , 2004, Nature.

[62]  D. Pimentel,et al.  S-Glutathiolation by peroxynitrite activates SERCA during arterial relaxation by nitric oxide , 2004, Nature Medicine.