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Mitochondria and oxidative stress in heart aging

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Abstract

As average lifespan of humans increases in western countries, cardiac diseases become the first cause of death. Aging is among the most important risk factors that increase susceptibility for developing cardiovascular diseases. The heart has very aerobic metabolism, and is highly dependent on mitochondrial function, since mitochondria generate more than 90 % of the intracellular ATP consumed by cardiomyocytes. In the last few decades, several investigations have supported the relevance of mitochondria and oxidative stress both in heart aging and in the development of cardiac diseases such as heart failure, cardiac hypertrophy, and diabetic cardiomyopathy. In the current review, we compile different studies corroborating this role. Increased mitochondria DNA instability, impaired bioenergetic efficiency, enhanced apoptosis, and inflammation processes are some of the events related to mitochondria that occur in aging heart, leading to reduced cellular survival and cardiac dysfunction. Knowing the mitochondrial mechanisms involved in the aging process will provide a better understanding of them and allow finding approaches to more efficiently improve this process.

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References

  • Abel ED, Doenst T (2011) Mitochondrial adaptations to physiological vs. pathological cardiac hypertrophy. Cardiovasc Res 90:234–242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aroor AR, Mandavia CH, Sowers JR (2012) Insulin resistance and heart failure: molecular mechanisms. Heart Fail Clin 8:609–617

    Article  PubMed  PubMed Central  Google Scholar 

  • Ashrafian H, Frenneaux MP, Opie LH (2007) Metabolic mechanisms in heart failure. Circulation 116:434–448

    Article  CAS  PubMed  Google Scholar 

  • Atkinson J (2008) Age-related medial elastocalcinosis in arteries: mechanisms, animal models, and physiological consequences. J Appl Physiol (1985) 105:1643–1651

    Article  CAS  Google Scholar 

  • Atkinson J, Kapralov AA, Yanamala N, Tyurina YY, Amoscato AA, Pearce L, Peterson J, Huang Z, Jiang J, Samhan-Arias AK, Maeda A, Feng W, Wasserloos K, Belikova NA, Tyurin VA, Wang H, Fletcher J, Wang Y, Vlasova II, Klein-Seetharaman J, Stoyanovsky DA, Bayir H, Pitt BR, Epperly MW, Greenberger JS, Kagan VE (2011) A mitochondria-targeted inhibitor of cytochrome c peroxidase mitigates radiation-induced death. Nat Commun 2:497

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Baris OR, Ederer S, Neuhaus JF, von Kleist-Retzow JC, Wunderlich CM, Pal M, Wunderlich FT, Peeva V, Zsurka G, Kunz WS, Hickethier T, Bunck AC, Stockigt F, Schrickel JW, Wiesner RJ (2015) Mosaic deficiency in mitochondrial oxidative metabolism promotes cardiac arrhythmia during aging. Cell Metab 21:667–677

    Article  CAS  PubMed  Google Scholar 

  • Barja G (1999) Mitochondrial oxygen radical generation and leak: sites of production in states 4 and 3, organ specificity, and relation to aging and longevity. J Bioenerg Biomembr 31:347–366

    Article  CAS  PubMed  Google Scholar 

  • Barja G (2013) Updating the mitochondrial free radical theory of aging: an integrated view, key aspects, and confounding concepts. Antioxid Redox Signal 19:1420–1445

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barja G (2014) The mitochondrial free radical theory of aging. Prog Mol Biol Transl Sci 127:1–27

    Article  CAS  PubMed  Google Scholar 

  • Battiprolu PK, Hojayev B, Jiang N, Wang ZV, Luo X, Iglewski M, Shelton JM, Gerard RD, Rothermel BA, Gillette TG, Lavandero S, Hill JA (2012) Metabolic stress-induced activation of FoxO1 triggers diabetic cardiomyopathy in mice. J Clin Invest 122:1109–1118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Beckman KB, Ames BN (1999) Endogenous oxidative damage of mtDNA. Mutat Res 424:51–58

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Beltrami AP, Urbanek K, Kajstura J, Yan SM, Finato N, Bussani R, Nadal-Ginard B, Silvestri F, Leri A, Beltrami CA, Anversa P (2001) Evidence that human cardiac myocytes divide after myocardial infarction. N Engl J Med 344:1750–1757

    Article  CAS  PubMed  Google Scholar 

  • Boluyt MO, Converso K, Hwang HS, Mikkor A, Russell MW (2004) Echocardiographic assessment of age-associated changes in systolic and diastolic function of the female F344 rat heart. J Appl Physiol (1985) 96:822–828

    Article  Google Scholar 

  • Boudina S, Bugger H, Sena S, O’Neill BT, Zaha VG, Ilkun O, Wright JJ, Mazumder PK, Palfreyman E, Tidwell TJ, Theobald H, Khalimonchuk O, Wayment B, Sheng X, Rodnick KJ, Centini R, Chen D, Litwin SE, Weimer BE, Abel ED (2009) Contribution of impaired myocardial insulin signaling to mitochondrial dysfunction and oxidative stress in the heart. Circulation 119:1272–1283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brand MD (2010) The sites and topology of mitochondrial superoxide production. Exp Gerontol 45:466–472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bratic A, Larsson NG (2013) The role of mitochondria in aging. J Clin Invest 123:951–957

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bratic I, Trifunovic A (2010) Mitochondrial energy metabolism and ageing. Biochim Biophys Acta 1797:961–967

    Article  CAS  PubMed  Google Scholar 

  • Campbell SG, Haynes P, Kelsey Snapp W, Nava KE, Campbell KS (2013) Altered ventricular torsion and transmural patterns of myocyte relaxation precede heart failure in aging F344 rats. Am J Physiol Heart Circ Physiol 305:H676–H686

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carnes CA, Geisbuhler TP, Reiser PJ (2004) Age-dependent changes in contraction and regional myocardial myosin heavy chain isoform expression in rats. J Appl Physiol (1985) 97:446–453

    Article  CAS  Google Scholar 

  • Conceicao G, Heinonen I, Lourenco AP, Duncker DJ, Falcao-Pires I (2016) Animal models of heart failure with preserved ejection fraction. Neth Heart J 24:275–286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen L, Knowlton AA (2011) Mitochondrial dynamics in heart failure. Congest Heart Fail 17:257–261

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chen XJ (2013) Mechanism of homologous recombination and implications for aging-related deletions in mitochondrial DNA. Microbiol Mol Biol Rev 77:476–496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dai DF, Chen T, Wanagat J, Laflamme M, Marcinek DJ, Emond MJ, Ngo CP, Prolla TA, Rabinovitch PS (2010) Age-dependent cardiomyopathy in mitochondrial mutator mice is attenuated by overexpression of catalase targeted to mitochondria. Aging Cell 9:536–544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dai DF, Hsieh EJ, Liu Y, Chen T, Beyer RP, Chin MT, MacCoss MJ, Rabinovitch PS (2012) Mitochondrial proteome remodelling in pressure overload-induced heart failure: the role of mitochondrial oxidative stress. Cardiovasc Res 93:79–88

    Article  CAS  PubMed  Google Scholar 

  • Dai DF, Karunadharma PP, Chiao YA, Basisty N, Crispin D, Hsieh EJ, Chen T, Gu H, Djukovic D, Raftery D, Beyer RP, MacCoss MJ, Rabinovitch PS (2014) Altered proteome turnover and remodeling by short-term caloric restriction or rapamycin rejuvenate the aging heart. Aging Cell 13:529–539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dai DF, Rabinovitch PS (2009) Cardiac aging in mice and humans: the role of mitochondrial oxidative stress. Trends in cardiovascular medicine 19:213–220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Davidson SM, Duchen MR (2007) Endothelial mitochondria: contributing to vascular function and disease. Circ Res 100:1128–1141

    Article  CAS  PubMed  Google Scholar 

  • De Meyer GR, De Keulenaer GW, Martinet W (2010) Role of autophagy in heart failure associated with aging. Heart Fail Rev 15:423–430

    Article  PubMed  Google Scholar 

  • de Souza RR (2002) Aging of myocardial collagen. Biogerontology 3:325–335

    Article  PubMed  Google Scholar 

  • Dei Cas A, Khan SS, Butler J, Mentz RJ, Bonow RO, Avogaro A, Tschoepe D, Doehner W, Greene SJ, Senni M, Gheorghiade M, Fonarow GC (2015) Impact of diabetes on epidemiology, treatment, and outcomes of patients with heart failure. JACC Heart Fail 3:136–145

    Article  PubMed  Google Scholar 

  • Demissie S, Levy D, Benjamin EJ, Cupples LA, Gardner JP, Herbert A, Kimura M, Larson MG, Meigs JB, Keaney JF, Aviv A (2006) Insulin resistance, oxidative stress, hypertension, and leukocyte telomere length in men from the Framingham Heart Study. Aging Cell 5:325–330

    Article  CAS  PubMed  Google Scholar 

  • Dhingra A, Garg A, Kaur S, Chopra S, Batra JS, Pandey A, Chaanine AH, Agarwal SK (2014) Epidemiology of heart failure with preserved ejection fraction. Curr Heart Fail Rep 11:354–365

    Article  PubMed  Google Scholar 

  • Dillin A, Hsu AL, Arantes-Oliveira N, Lehrer-Graiwer J, Hsin H, Fraser AG, Kamath RS, Ahringer J, Kenyon C (2002) Rates of behavior and aging specified by mitochondrial function during development. Science 298:2398–2401

    Article  CAS  PubMed  Google Scholar 

  • Doenst T, Nguyen TD, Abel ED (2013) Cardiac metabolism in heart failure: implications beyond ATP production. Circ Res 113:709–724

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Doi R, Masuyama T, Yamamoto K, Doi Y, Mano T, Sakata Y, Ono K, Kuzuya T, Hirota S, Koyama T, Miwa T, Hori M (2000) Development of different phenotypes of hypertensive heart failure: systolic versus diastolic failure in Dahl salt-sensitive rats. J Hypertens 18:111–120

    Article  CAS  PubMed  Google Scholar 

  • Domenighetti AA, Danes VR, Curl CL, Favaloro JM, Proietto J, Delbridge LM (2010) Targeted GLUT-4 deficiency in the heart induces cardiomyocyte hypertrophy and impaired contractility linked with Ca(2+) and proton flux dysregulation. J Mol Cell Cardiol 48:663–672

    Article  CAS  PubMed  Google Scholar 

  • Drew B, Leeuwenburgh C (2004) Ageing and subcellular distribution of mitochondria: role of mitochondrial DNA deletions and energy production. Acta Physiol Scand 182:333–341

    Article  CAS  PubMed  Google Scholar 

  • Dutta D, Calvani R, Bernabei R, Leeuwenburgh C, Marzetti E (2012) Contribution of impaired mitochondrial autophagy to cardiac aging mechanisms and therapeutic opportunities. Circ Res 110:1125–1138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Edgar D, Shabalina I, Camara Y, Wredenberg A, Calvaruso MA, Nijtmans L, Nedergaard J, Cannon B, Larsson NG, Trifunovic A (2009) Random point mutations with major effects on protein-coding genes are the driving force behind premature aging in mtDNA mutator mice. Cell Metab 10:131–138

    Article  CAS  PubMed  Google Scholar 

  • Fang EF, Scheibye-Knudsen M, Chua KF, Mattson MP, Croteau DL, Bohr VA (2016) Nuclear DNA damage signalling to mitochondria in ageing. Nat Rev Mol Cell Biol 17:308–321

    Article  CAS  PubMed  Google Scholar 

  • Finck BN, Kelly DP (2007) Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) regulatory cascade in cardiac physiology and disease. Circulation 115:2540–2548

    Article  PubMed  Google Scholar 

  • Frey N, Olson EN (2003a) Cardiac hypertrophy: the good, the bad and the ugly. Annu Rev Physiol 65:45–79

    Article  CAS  PubMed  Google Scholar 

  • Frey N, Olson EN (2003b) Cardiac hypertrophy: the good, the bad, and the ugly. Annu Rev Physiol 65:45–79

    Article  CAS  PubMed  Google Scholar 

  • Fulop N, Mason MM, Dutta K, Wang P, Davidoff AJ, Marchase RB, Chatham JC (2007) Impact of type 2 diabetes and aging on cardiomyocyte function and O-linked N-acetylglucosamine levels in the heart. Am J Physiol Cell Physiol 292:C1370–C1378

    Article  CAS  PubMed  Google Scholar 

  • Garinis GA, van der Horst GT, Vijg J, Hoeijmakers JH (2008) DNA damage and ageing: new-age ideas for an age-old problem. Nat Cell Biol 10:1241–1247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gazoti Debessa CR, Mesiano Maifrino LB, Rodrigues de Souza R (2001) Age related changes of the collagen network of the human heart. Mech Ageing Dev 122:1049–1058

    Article  CAS  PubMed  Google Scholar 

  • Gonzalez-Freire M, de Cabo R, Bernier M, Sollott SJ, Fabbri E, Navas P, Ferrucci L (2015) Reconsidering the role of mitochondria in aging. J Gerontol A Biol Sci Med Sci 70:1334–1342

    Article  PubMed  Google Scholar 

  • Gottdiener JS, Arnold AM, Aurigemma GP, Polak JF, Tracy RP, Kitzman DW, Gardin JM, Rutledge JE, Boineau RC (2000) Predictors of congestive heart failure in the elderly: the Cardiovascular Health Study. J Am Coll Cardiol 35:1628–1637

    Article  CAS  PubMed  Google Scholar 

  • Gredilla R, Barja G (2005) Minireview: the role of oxidative stress in relation to caloric restriction and longevity. Endocrinology 146:3713–3717

    Article  CAS  PubMed  Google Scholar 

  • Gredilla R, Bohr VA, Stevnsner T (2010) Mitochondrial DNA repair and association with aging—an update. Exp Gerontol 45:478–488

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Green DR, Galluzzi L, Kroemer G (2011) Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science 333:1109–1112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grollman AP, Moriya M (1993) Mutagenesis by 8-oxoguanine: an enemy within. Trends Genet 9:246–249

    Article  CAS  PubMed  Google Scholar 

  • Gruber J, Schaffer S, Halliwell B (2008) The mitochondrial free radical theory of ageing—where do we stand? Front Biosci 13:6554–6579

    Article  CAS  PubMed  Google Scholar 

  • Gutstein DE, Morley GE, Fishman GI (2001) Conditional gene targeting of connexin43: exploring the consequences of gap junction remodeling in the heart. Cell Commun Adhes 8:345–348

    Article  CAS  PubMed  Google Scholar 

  • Harman D (1972) The biologic clock: the mitochondria? J Am Geriatr Soc 20:145–147

    Article  CAS  PubMed  Google Scholar 

  • Heidenreich PA, Trogdon JG, Khavjou OA, Butler J, Dracup K, Ezekowitz MD, Finkelstein EA, Hong Y, Johnston SC, Khera A, Lloyd-Jones DM, Nelson SA, Nichol G, Orenstein D, Wilson PW, Woo YJ, American Heart Association Advocacy Coordinating C, Stroke C, Council on Cardiovascular R, Intervention, Council on Clinical C, Council on E, Prevention, Council on A, Thrombosis, Vascular B, Council on C, Critical C, Perioperative, Resuscitation, Council on Cardiovascular N, Council on the Kidney in Cardiovascular D, Council on Cardiovascular S, Anesthesia, Interdisciplinary Council on Quality of C, Outcomes R (2011) Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association. Circulation 123:933–944

    Article  PubMed  Google Scholar 

  • Horn MA, Graham HK, Richards MA, Clarke JD, Greensmith DJ, Briston SJ, Hall MC, Dibb KM, Trafford AW (2012) Age-related divergent remodeling of the cardiac extracellular matrix in heart failure: collagen accumulation in the young and loss in the aged. J Mol Cell Cardiol 53:82–90

    Article  CAS  PubMed  Google Scholar 

  • Ide T, Tsutsui H, Kinugawa S, Utsumi H, Kang D, Hattori N, Uchida K, Arimura K, Egashira K, Takeshita A (1999) Mitochondrial electron transport complex I is a potential source of oxygen free radicals in the failing myocardium. Circ Res 85:357–363

    Article  CAS  PubMed  Google Scholar 

  • Ingwall JS (2009) Energy metabolism in heart failure and remodelling. Cardiovasc Res 81:412–419

    Article  CAS  PubMed  Google Scholar 

  • Jang YC, Perez VI, Song W, Lustgarten MS, Salmon AB, Mele J, Qi W, Liu Y, Liang H, Chaudhuri A, Ikeno Y, Epstein CJ, Van Remmen H, Richardson A (2009) Overexpression of Mn superoxide dismutase does not increase life span in mice. J Gerontol A Biol Sci Med Sci 64:1114–1125

    Article  PubMed  CAS  Google Scholar 

  • Jeppesen DK, Bohr VA, Stevnsner T (2011) DNA repair deficiency in neurodegeneration. Prog Neurobiol 94:166–200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Judge S, Leeuwenburgh C (2007) Cardiac mitochondrial bioenergetics, oxidative stress, and aging. Am J Physiol Cell Physiol 292:C1983–C1992

    Article  CAS  PubMed  Google Scholar 

  • Kalyani RR, Saudek CD, Brancati FL, Selvin E (2010) Association of diabetes, comorbidities, and A1C with functional disability in older adults: results from the National Health and Nutrition Examination Survey (NHANES), 1999-2006. Diabetes Care 33:1055–1060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kannel WB (2002) Coronary heart disease risk factors in the elderly. Am J Geriatr Cardiol 11:101–107

    Article  PubMed  Google Scholar 

  • Karavidas A, Lazaros G, Tsiachris D, Pyrgakis V (2010) Aging and the cardiovascular system. Hell J Cardiol 51:421–427

    Google Scholar 

  • Kavli B, Otterlei M, Slupphaug G, Krokan HE (2007) Uracil in DNA—general mutagen, but normal intermediate in acquired immunity. DNA Repair (Amst) 6:505–516

    Article  CAS  Google Scholar 

  • Kim JA, Wei YZ, Sowers JR (2008) Role of mitochondrial dysfunction in insulin resistance. Circ Res 102:401–414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kolwicz SC Jr, Purohit S, Tian R (2013) Cardiac metabolism and its interactions with contraction, growth, and survival of cardiomyocytes. Circ Res 113:603–616

  • Koren MJ, Devereux RB, Casale PN, Savage DD, Laragh JH (1991) Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern Med 114:345–352

    Article  CAS  PubMed  Google Scholar 

  • Krishnan KJ, Reeve AK, Samuels DC, Chinnery PF, Blackwood JK, Taylor RW, Wanrooij S, Spelbrink JN, Lightowlers RN, Turnbull DM (2008) What causes mitochondrial DNA deletions in human cells? Nat Genet 40:275–279

    Article  CAS  PubMed  Google Scholar 

  • Kujoth GC, Bradshaw PC, Haroon S, Prolla TA (2007) The role of mitochondrial DNA mutations in mammalian aging. PLoS Genet 3:e24

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kujoth GC, Hiona A, Pugh TD, Someya S, Panzer K, Wohlgemuth SE, Hofer T, Seo AY, Sullivan R, Jobling WA, Morrow JD, Van Remmen H, Sedivy JM, Yamasoba T, Tanokura M, Weindruch R, Leeuwenburgh C, Prolla TA (2005) Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309:481–484

    Article  CAS  PubMed  Google Scholar 

  • Kujoth GC, Leeuwenburgh C, Prolla TA (2006) Mitochondrial DNA mutations and apoptosis in mammalian aging. Cancer Res 66:7386–7389

    Article  CAS  PubMed  Google Scholar 

  • Kwak HB (2013) Aging, exercise, and extracellular matrix in the heart. Journal of exercise rehabilitation 9:338–347

    Article  PubMed  PubMed Central  Google Scholar 

  • L’Heveder R, Nolan T (2013) International diabetes federation. Diabetes Res Clin Pract 101:349–351

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • Lakatta EG, 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

    Article  PubMed  Google Scholar 

  • Leri A, Malhotra A, Liew CC, Kajstura J, Anversa P (2000) Telomerase activity in rat cardiac myocytes is age and gender dependent. J Mol Cell Cardiol 32:385–390

    Article  CAS  PubMed  Google Scholar 

  • Li QX, Xiong ZY, BP H, Tian ZJ, Zhang HF, Gou WY, Wang HC, Gao F, Zhang QJ (2009) Aging-associated insulin resistance predisposes to hypertension and its reversal by exercise: the role of vascular vasorelaxation to insulin. Basic Res Cardiol 104:269–284

    Article  CAS  PubMed  Google Scholar 

  • Liao RL, Nascimben L, Friedrich J, Gwathmey JK, Ingwall JS (1996) Decreased energy reserve in an animal model of dilated cardiomyopathy relationship to contractile performance. Circ Res 78:893–902

    Article  CAS  PubMed  Google Scholar 

  • Ling F, Hori A, Yoshitani A, Niu R, Yoshida M, Shibata T (2013) Din7 and Mhr1 expression levels regulate double-strand-break-induced replication and recombination of mtDNA at ori5 in yeast. Nucleic Acids Res 41:5799–5816

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu P, Demple B (2010) DNA repair in mammalian mitochondria: much more than we thought? Environ Mol Mutagen 51:417–426

    CAS  PubMed  Google Scholar 

  • Lopaschuk GD, Spafford M (1989) Response of isolated working hearts to fatty acids and carnitine palmitoyltransferase I inhibition during reduction of coronary flow in acutely and chronically diabetic rats. Circ Res 65:378–387

    Article  CAS  PubMed  Google Scholar 

  • Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153:1194–1217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mallikarjun V, Sriram A, Scialo F, Sanz A (2014) The interplay between mitochondrial protein and iron homeostasis and its possible role in ageing. Exp Gerontol 56:123–134

    Article  CAS  PubMed  Google Scholar 

  • Marin-Garcia J (2016) Mitochondrial DNA repair: a novel therapeutic target for heart failure. Heart Fail Rev.

  • Martin-Fernandez B, Miana M, De las Heras N, Ruiz-Hurtado G, Fernandez-Velasco M, Bas M, Ballesteros S, Lahera V, Cachofeiro V, Delgado C (2009) Cardiac L-type calcium current is increased in a model of hyperaldosteronism in the rat. Exp Physiol 94:675–683

    Article  CAS  PubMed  Google Scholar 

  • Maruyama Y (2012) Aging and arterial-cardiac interactions in the elderly. Int J Cardiol 155:14–19

    Article  PubMed  Google Scholar 

  • McMurray JJV, Pfeffer MA (2005) Heart failure. Lancet 365:1877–1889

    Article  PubMed  Google Scholar 

  • McQueen AP, Zhang D, Hu P, Swenson L, Yang Y, Zaha VG, Hoffman JL, Yun UJ, Chakrabarti G, Wang Z, Albertine KH, Abel ED, Litwin SE (2005) Contractile dysfunction in hypertrophied hearts with deficient insulin receptor signaling: possible role of reduced capillary density. J Mol Cell Cardiol 39:882–892

    Article  CAS  PubMed  Google Scholar 

  • Mendes AB, Ferro M, Rodrigues B, Souza MR, Araujo RC, Souza RR (2012) Quantification of left ventricular myocardial collagen system in children, young adults, and the elderly. Medicina 72:216–220

    CAS  PubMed  Google Scholar 

  • Minamino T, Komuro I (2008) Vascular aging: insights from studies on cellular senescence, stem cell aging, and progeroid syndromes. Nat Clin Pract Cardiovasc Med 5:637–648

    Article  CAS  PubMed  Google Scholar 

  • Miquel J, Economos AC, Fleming J, JE J Jr (1980) Mitochondrial role in cell aging. Exp Gerontol 15:575–591

    Article  CAS  PubMed  Google Scholar 

  • Modrego J, de las Heras N, Zamorano-Leon JJ, Mateos-Caceres PJ, Martin-Fernandez B, Valero-Munoz M, Lahera V, Lopez-Farre AJ (2013) Changes in cardiac energy metabolic pathways in overweighed rats fed a high-fat diet. Eur J Nutr 52:847–856

    Article  CAS  PubMed  Google Scholar 

  • Nassimiha D, Aronow WS, Ahn C, Goldman ME (2001) Association of coronary risk factors with progression of valvular aortic stenosis in older persons. Am J Cardiol 87:1313–1314

    Article  CAS  PubMed  Google Scholar 

  • Neubauer S (2007) Mechanisms of disease—the failing heart—an engine out of fuel. New Engl J Med 356:1140–1151

    Article  PubMed  Google Scholar 

  • Opie LH, Knuuti J (2009) The adrenergic-fatty acid load in heart failure. J Am Coll Cardiol 54:1637–1646

    Article  CAS  PubMed  Google Scholar 

  • Pangonyte D, Stalioraityte E, Ziuraitiene R, Kazlauskaite D, Palubinskiene J, Balnyte I (2008) Cardiomyocyte remodeling in ischemic heart disease. Med Lith 44:848–854

    Google Scholar 

  • Piquereau J, Caffin F, Novotova M, Lemaire C, Veksler V, Garnier A, Ventura-Clapier R, Joubert F (2013) Mitochondrial dynamics in the adult cardiomyocytes: which roles for a highly specialized cell? Front Physiol 4:102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rajawat YS, Hilioti Z, Bossis I (2009) Aging: central role for autophagy and the lysosomal degradative system. Ageing Res Rev 8:199–213

    Article  CAS  PubMed  Google Scholar 

  • Ren J, Bode AM (2000) Altered cardiac excitation-contraction coupling in ventricular myocytes from spontaneously diabetic BB rats. Am J Physiol-Heart C 279:H238–H244

    CAS  Google Scholar 

  • Ren J, Pulakat L, Whaley-Connell A, Sowers JR (2010) Mitochondrial biogenesis in the metabolic syndrome and cardiovascular disease. J Mol Med 88:993–1001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ristow M, Zarse K (2010) How increased oxidative stress promotes longevity and metabolic health: the concept of mitochondrial hormesis (mitohormesis). Exp Gerontol 45:410–418

    Article  CAS  PubMed  Google Scholar 

  • Rugarli E, Trifunovic A (2015) Is mitochondrial free radical theory of aging getting old? Biochim Biophys Acta 1847:1345–1346

    Article  CAS  PubMed  Google Scholar 

  • Safdar A, Bourgeois JM, Ogborn DI, Little JP, Hettinga BP, Akhtar M, Thompson JE, Melov S, Mocellin NJ, Kujoth GC, Prolla TA, Tarnopolsky MA (2011) Endurance exercise rescues progeroid aging and induces systemic mitochondrial rejuvenation in mtDNA mutator mice. Proc Natl Acad Sci U S A 108:4135–4140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sanz A (2016) Mitochondrial reactive oxygen species: do they extend or shorten animal lifespan? Biochim Biophys Acta.

  • Scialo F, Sriram A, Fernandez-Ayala D, Gubina N, Lohmus M, Nelson G, Logan A, Cooper HM, Navas P, Enriquez JA, Murphy MP, Sanz A (2016) Mitochondrial ROS produced via reverse electron transport extend animal lifespan. Cell Metab 23:725–734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schulz TJ, Zarse K, Voigt A, Urban N, Birringer M, Ristow M (2007) Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell Metab 6:280–293

    Article  CAS  PubMed  Google Scholar 

  • Seddon M, Looi YH, Shah AM (2007) Oxidative stress and redox signalling in cardiac hypertrophy and heart failure. Heart 93:903–907

    Article  CAS  PubMed  Google Scholar 

  • Seeberg E, Eide L, Bjoras M (1995) The base excision repair pathway. Trends Biochem Sci 20:391–397

    Article  CAS  PubMed  Google Scholar 

  • Sen D, Patel G, Patel SS (2016) Homologous DNA strand exchange activity of the human mitochondrial DNA helicase TWINKLE. Nucleic Acids Res.

  • Sena S, Hu P, Zhang D, Wang X, Wayment B, Olsen C, Avelar E, Abel ED, Litwin SE (2009) Impaired insulin signaling accelerates cardiac mitochondrial dysfunction after myocardial infarction. J Mol Cell Cardiol 46:910–918

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shadel GS, Horvath TL (2015) Mitochondrial ROS signaling in organismal homeostasis. Cell 163:560–569

    Article  CAS  PubMed  Google Scholar 

  • Speakman JR, Blount JD, Bronikowski AM, Buffenstein R, Isaksson C, Kirkwood TB, Monaghan P, Ozanne SE, Beaulieu M, Briga M, Carr SK, Christensen LL, Cocheme HM, Cram DL, Dantzer B, Harper JM, Jurk D, King A, Noguera JC, Salin K, Sild E, Simons MJ, Smith S, Stier A, Tobler M, Vitikainen E, Peaker M, Selman C (2015) Oxidative stress and life histories: unresolved issues and current needs. Ecol Evol 5:5745–5757

    Article  PubMed  PubMed Central  Google Scholar 

  • St-Pierre J, Buckingham JA, Roebuck SJ, Brand MD (2002) Topology of superoxide production from different sites in the mitochondrial electron transport chain. J Biol Chem 277:44784–44790

    Article  CAS  PubMed  Google Scholar 

  • Stanley WC, Recchia FA, Lopaschuk GD (2005) Myocardial substrate metabolism in the normal and failing heart. Physiol Rev 85:1093–1129

    Article  CAS  PubMed  Google Scholar 

  • Swynghedauw B (1999) Molecular mechanisms of myocardial remodeling. Physiol Rev 79:215–262

    CAS  PubMed  Google Scholar 

  • Terman A, Kurz T, Navratil M, Arriaga EA, Brunk UT (2010) Mitochondrial turnover and aging of long-lived postmitotic cells: the mitochondrial-lysosomal axis theory of aging. Antioxid Redox Signal 12:503–535

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thomas DP, Cotter TA, Li X, McCormick RJ, Gosselin LE (2001) Exercise training attenuates aging-associated increases in collagen and collagen crosslinking of the left but not the right ventricle in the rat. Eur J Appl Physiol 85:164–169

    Article  CAS  PubMed  Google Scholar 

  • Tian R, Nascimben L, Ingwall JS, Lorell BH (1997) Failure to maintain a low ADP concentration impairs diastolic function in hypertrophied rat hearts. Circulation 96:1313–1319

    Article  CAS  PubMed  Google Scholar 

  • Tocchi A, Quarles EK, Basisty N, Gitari L, Rabinovitch PS (2015) Mitochondrial dysfunction in cardiac aging. Biochim Biophys Acta 1847:1424–1433

    Article  CAS  PubMed  Google Scholar 

  • Tower J (2015) Programmed cell death in aging. Ageing research reviews.

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

    Article  CAS  PubMed  Google Scholar 

  • Tyler D (1991) The mitochondrion in health and disease. Wiley-VCH, Weinheim

  • Tyurina YY, Tungekar MA, Jung MY, Tyurin VA, Greenberger JS, Stoyanovsky DA, Kagan VE (2012) Mitochondria targeting of non-peroxidizable triphenylphosphonium conjugated oleic acid protects mouse embryonic cells against apoptosis: role of cardiolipin remodeling. FEBS Lett 586:235–241

    Article  CAS  PubMed  Google Scholar 

  • Upadhya B, Taffet GE, Cheng CP, Kitzman DW (2015) Heart failure with preserved ejection fraction in the elderly: scope of the problem. J Mol Cell Cardiol 83:73–87

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Walsh S, Ponten A, Fleischmann BK, Jovinge S (2010) Cardiomyocyte cell cycle control and growth estimation in vivo—an analysis based on cardiomyocyte nuclei. Cardiovasc Res 86:365–373

    Article  CAS  PubMed  Google Scholar 

  • Wang J, Silva JP, Gustafsson CM, Rustin P, Larsson NG (2001) Increased in vivo apoptosis in cells lacking mitochondrial DNA gene expression. Proc Natl Acad Sci U S A 98:4038–4043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang J, Wilhelmsson H, Graff C, Li H, Oldfors A, Rustin P, Bruning JC, Kahn CR, Clayton DA, Barsh GS, Thoren P, Larsson NG (1999) Dilated cardiomyopathy and atrioventricular conduction blocks induced by heart-specific inactivation of mitochondrial DNA gene expression. Nat Genet 21:133–137

    Article  CAS  PubMed  Google Scholar 

  • Weber KT, Sun Y, Katwa LC, Cleutjens JPM, Zhou GP (1995) Connective-tissue and repair in the heart—potential regulatory mechanisms. Ann N Y Acad Sci 752:286–299

    Article  CAS  PubMed  Google Scholar 

  • Westermeier F, Navarro-Marquez M, Lopez-Crisosto C, Bravo-Sagua R, Quiroga C, Bustamante M, Verdejo HE, Zalaquett R, Ibacache M, Parra V, Castro PF, Rothermel BA, Hill JA, Lavandero S (2015) Defective insulin signaling and mitochondrial dynamics in diabetic cardiomyopathy. Biochim Biophys Acta 1853:1113–1118

  • Wilson PW, Kannel WB (2002) Obesity, diabetes, and risk of cardiovascular disease in the elderly. Am J Geriatr Cardiol 11:119–123 125

    Article  PubMed  Google Scholar 

  • World Health Statistics (2014) Global Health Observatory data. World Health Organization (WHO). http://www.who.int/gho/publications/world_health_statistics/2014/en/ Accessed 10 Dec 2015.

  • Xu J, Marzetti E, Seo AY, Kim JS, Prolla TA, Leeuwenburgh C (2010) The emerging role of iron dyshomeostasis in the mitochondrial decay of aging. Mech Ageing Dev 131:487–493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Y, Ikeno Y, Qi W, Chaudhuri A, Li Y, Bokov A, Thorpe SR, Baynes JW, Epstein C, Richardson A, Van Remmen H (2009) Mice deficient in both Mn superoxide dismutase and glutathione peroxidase-1 have increased oxidative damage and a greater incidence of pathology but no reduction in longevity. J Gerontol A Biol Sci Med Sci 64:1212–1220

    Article  PubMed  CAS  Google Scholar 

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Both authors contributed equally to this paper.

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Correspondence to Beatriz Martín-Fernández or Ricardo Gredilla.

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Grant from the Complutense University/Community of Madrid to RG (CCG10-UCM/SAL 4798).

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Martín-Fernández, B., Gredilla, R. Mitochondria and oxidative stress in heart aging. AGE 38, 225–238 (2016). https://doi.org/10.1007/s11357-016-9933-y

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