Pre- and post-conditioning hormesis in elderly mice, rats, and humans: its loss and restoration

Abete P, Ferrara N, Cioppa A, Ferrara P, Bianco S, Calabrese C, Cacciatore F, Longobardi G, Rengo F (1996) Preconditioning does not prevent postischemic dysfunction in aging heart. J Am Coll Cardiol 27(7):1777–1786 Abete P, Ferrara N, Cacciatore F, Madrid A, Bianco S, Calabrese C, Napoli C, Scognamiglio P, Bollella O, Cioppa A, Longobardi G, Rengo F (1997) Angina-induced protection against myocardial infarction in adult and elderly patients: a loss of preconditioning mechanism in the aging heart? J Am Coll Cardiol 30(4):947–954 Abete P, Calabrese C, Ferrara N, Cioppa A, Pisanelli P, Caciatore F, Longobardi G, Napoli C, Rengo F (2000) Exercise training restores ischemic preconditioning in the aging heart. J Am Coll Cardiol 36(2):643–650 Abete P, Ferrara N, Cacciatore F, Sagnelli E, Manzi M, Carnovale V, Calabrese C, de Santis D, Testa G, Longobardi G, Napoli C, Rengo F (2001) High level of physical activity preserves the cardioprotective effect of preinfarction angina in elderly patients. J Am Coll Cardiol 38(5):1357–1365 Abete P, Testa G, Ferrara N, De Santis D, Capaccio P, Viati L, Calabrese C, Cacciatore F, Longobardi G, Condorelli M, Napoli C, Rengo F (2002) Cardioprotective effect of ischemic preconditioning is preserved in food-restricted senescent rats. Am J Physiol Heart Circ Physiol 282:H1978–H1987. doi:10.1152/ajpheart.00929.2001 Abete P, Testa G, Galizia G, Mazzela F, Morte DD, de Santis D, Calabrese C, Caciatore F, Gargiulo G, Ferrara N, Rengo G, Sica V, Napoli C, Rengo F (2005) Tandem action of exercise training and food restriction completely preserves ischemic preconditioning in the aging heart. Exp Gerontol 40:43–50 Alkhulaifi AM, Yellon DM, Pugsley WB (1994) Preconditioning the human heart during aorto-coronary bypass surgery. Eur J Cardiothorac Surg 8:270–276 Ancel P, Lallemand S (1928) Sur la protection contre l’action des rayons X par une irradiation prealable (radiophylaxie). C R Soc Biol 99:1588–1596 Anzai T, Yoshikawa T, Asakura Y, Abe S, Meguro T, Akaishi M, Mitamura H, Handa S, Ogawa S (1994) Effect on short-term prognosis and left ventricular function of angina pectoris prior to first Q-wave anterior wall acute myocardial infarction. Am J Cardiol 74:755–759 Anzai T, Yoshikawa T, Asakura Y, Abe S, Akaishi M, Mitamura H, Handa S, Ogawa S (1995) Preinfarction angina as a major predictor of left ventricular function and long-term prognosis after a first Q-wave myocardial infarction. J Am Coll Cardiol 26:319–327 Azhar G, Gao W, Liu L, Wei JY (1999) Ischemia-reperfusion in the adult mouse heart influence of age. Exp Gerontol 34:699–714 Banerjee A, Lock-Winter C, Rogers KB, Mitchell MB (1993) Preconditioning against myocardial dysfunction after ischemia and reperfusion by an α1-adrenergic mechanism. Circ Res 73:656–670 Bartling B, Hilgefort C, Friedrich I, Silber RE, Simm A (2003a) Cardio-protective determinants are conserved in aged human myocardium after ischemic preconditioning. FEBS Lett 555:539–544 Bartling B, Friedrich I, Silber RE, Simm A (2003b) Ischemic preconditioning is not cardioprotective in senescent human myocardium. Ann Thorac Surg 76:105–111 Boengler K, Dodoni G, Ruiz-Meana M, Cabestrero A, Rodriguez-Sinovas A, Garcia-Dorado D, Gres P, Di Lisa F, Heusch G, Schulz R (2005) Connexin 43 in cardiomyocyte mitochondria and its increase by ischemic preconditioning. Cardiovasc Res 67:234–244 Boengler K, Heusch G, Schulz R (2006) Connexin 43 and ischemic preconditioning: effects of age and disease. Exp Gerontol 41:485–488 Boengler K, Konietzka I, Buechert A, Heinen Y, Garcia-Dorado D, Heusch G, Schulz R (2007) Loss of ischemic preconditioning’s cardioprotection in aged mouse hearts is associated with reduced gap junctional and mitochondrial levels of connexin 43. Am J Physiol Heart Circ Physiol 292:H1764–H1769 Boengler K, Buechert A, Heinen Y, Roeskes C, Hilfiker-Kleiner D, Heusch G, Schulz R (2008) Cardioprotection by ischemic postconditioning is lost in aged and STAT3-deficient mice. Circ Res 102:131–135 Boucher F, Tanguy S, Besse S, Tresallet N, Favier A, de Leiris J (1998) Age-dependent changes in myocardial susceptibility to zero flow ischemia and reperfusion in isolated perfused rat hearts: relation to antioxidant status. Mech Ageing Dev 103:301–316 Calabrese EJ (2015) What is hormesis and its relevance to healthy aging and longevity? Biogerontology 16(6):693–707 Calabrese EJ (2016a) Preconditioning is hormesis. Part I. Documentation, dose-response features and mechanistic foundations. Pharmacol Res. doi:10.1016/j.phrs.2015.12.021 (in press) Calabrese EJ (2016b) Preconditioning is hormesis. Part II: how the conditioning dose mediates protection: dose optimization within temporal and mechanistic frameworks. Pharmacol Res. doi:10.1016/j.phrs.2015.12.020 (in press) Calabrese EJ, Blain RB (2005) The occurrence of hormetic dose responses in the toxicological literature, the hormesis database: an overview. Toxicol Appl Pharmacol 202(3):289–301 Calabrese EJ, Blain RB (2011) The hormesis database: the occurrence of hormetic dose responses in the toxicological literature. Reg Toxicol Pharmacol 61:73–81 Calabrese EJ, Bachmann KA, Bailer AJ, Bolger PM, Borak J, Cai L et al (2007) Biological stress response terminology: integrating the concepts of adaptive response and preconditioning stress within a hormetic dose-response framework. Toxicol Appl Pharmacol 222:122–128 Chang DJ, Chang CH, Kim JS, Hong YW, Lee WK, Shim YH (2012) Isoflurane-induced post-conditioning in senescent hearts is attenuated by failure to activate reperfusion injury salvage kinase pathway. Acta Anaesthesiol Scand 56:896–903 Chen M, Jones DL (2000) Age- and myopathy-dependent changes in connexins of normal and cardiomyopathic Syrian hamster ventricular myocardium. Can J Physiol Pharmacol 78:669–678 Chen H, Xing B, Wang L, Weng X, Chen Z, Liu X (2014) Aged kidneys are refractory to ischemic postconditioning in a rat model. Ren Fail 36(10):1575–1580 Coleman GL, Barthold SW, Osbaldiston GW, Foster SJ, Jonas AM (1977) Pathological changes during aging in barrier-reared Fischer 344 male rats. J Gerontol 32:258–278 Cremer J, Steinhoff G, Karck M, Ahnsell T, Brandt M, Teebken OE, Hollander D, Haverich A (1997) Ischaemic preconditioning prior to myocardial protection with cold blood cardioplegia in coronary surgery. Eur J Cardiothorac Surg 12:753–758 Dai W, Simkhovich BZ, Kloner RA (2009) Ischemic preconditioning maintains cardioprotection in aging normotensive and spontaneously hypertensive rats. Exp Gerontol 44:344–349 De Luca G, Parodi G, Sciagra R, Bellandi B, Comito V, Vergara R, Migliorini A, Valenti R, Antoniucci D (2013) Preinfarction angina does not affect infarct size in STEMI patients undergoing primary angioplasty. Atherosclerosis 226:153–156 Della-Morte D, Caciatore F, Slsano E, Pirozzi G, DelGenio MT, D’Antonio I, Gargiulo G, Palmirotta R, Guadagni F, Rundek T, Abete P (2013) Age-related reduction of cerebral ischemic preconditioning: myth or reality? Clin Interv Aging 8:1055–1061 Desai KK, Dikdan GS, Shareef A, Koneru B (2008) Ischemic preconditioning of the liver: a few perspectives from the bench to bedside translation. Liver Transpl 14:1569–1577 Dow J, Bhandari A, Kloner RA (2008) Ischemic postconditioning’s benefit on reperfusion ventricular arrhythmias is maintained in the senescent heart. J Cardio Pharmacol Ther 13(2):144–148 Dowden J, Corbett D (1999) Ischemic preconditioning in 18- to 20-month-old gerbils. Long-term survival with functional outcome measures. Stroke 30:1240–1246 Ebrahim Z, Yellon DM, Baxter GF (2007) Ischemic preconditioning is lost in aging hypertensive rat heart: independent effects of aging and longstanding hypertension. Exp Gerontol 42:807–814 Fenton RA, Dickson EW, Meyer TE, Dobson JG Jr (2000) Aging reduces the cardioprotective effect of ischemic preconditioning in the rat heart. J Mol Cell Cardiol 32:1371–1375. doi:10.1006/jmcc.2000.1189 Folkow B, Svanborg A (1993) Physiology of cardiovascular aging. Physiol Rev 73(4):725–764 Goodman DG, Ward JM, Squire RA, Chu KC, Linhart MS (1979) Neoplastic and nonneoplastic lesions in aging F344 rats. Toxicol Appl Pharmacol 48:237–248 Gotto M, Liu Y, Yang XM, Ardell JL, Cohen MV, Downey JM (1995) Role of bradykinin in protection of ischemic preconditioning in rabbit hearts. Circ Res 77:611–621 Heinen A, Huhn R, Smeele KMA, Zuurbier CJ, Schlack W, Preckel B, Weber NC, Hollmann MW (2008) Helium-induced preconditioning in young and old rat heart. Anesthesiology 109:830–836 Heinzel FR, Luo Y, Li X, Boengler K, Buechert A, Garcia-Dorado D, Di LF, Schulz R, Heusch G (2005) Impairment of diazoxide-induced formation of reactive oxygen species and loss of cardioprotection in connexin 43 deficient mice. Circ Res 97:583–586 Honma Y, Tani M, Takayama M, Yamamura K, Hasegawa H (2002) Aging abolishes the cardioprotective effect of combination heat shock and hypoxic preconditioning in reperfused rat hearts. Basic Res Cardiol 97(6):489–495 Honma Y, Tani M, Yamamura K, Takayama M, Hasegawa H (2003) Preconditioning with heat shock further improved functional recovery in young adult but not in middle-aged rat hearts. Exp Gerontol 38:299–306 Huhn R, Heinen A, Weber NC, Kerindongo RP, Oei GTML, Hollmann MW, Schlack W, Preckel B (2009) Helium-induced early preconditioning and postconditioning are abolished in obese Zucker rats in vivo. J Pharmacol Exp Ther 329(2):600–607 Huhn R, Weber NC, Preckel B, Schlack W, Bauer I, Hollmann MW, Heinen A (2012) Age-related loss of cardiac preconditioning: impact of protein kinase A. Exp Gerontol 47:116–121 Illes RW, Swoyer KD (1998) Prospective, randomized clinical study of ischaemic preconditioning as an adjunct to intermittent cold blood cardioplegia. Ann Thorac Surg 65:748–753 Ishihara M, Sato H, Tateishi H, Kawagoe T, Shimatani Y, Kurisu S, Saki K, Ueda K (1997) Implications of prodromal angina pectoris in anterior wall acute myocardial infarction: acute angiographic findings and long-term prognosis. J Am Coll Cardiol 30:970–975 Ishihara M, Sato H, Tateishi H, Kawagoe T, Shimatani Y, Ueda K, Noma K, Yumoto A, Nishioka K (2000) Beneficial effect of prodromal angina pectoris is lost in elderly patients with acute myocardial infarction. Am Heart J 139:881–888 Jenkins DP, Pugsley WB, Alkhulaifi AM, Kemp M, Hooper J, Yellon DB (1997) Ischaemic preconditioning reduces troponin T release in patients undergoing coronary artery bypass surgery. Heart 77:314–318 Jiménez-Navarro M, Gómez-Doblas JJ, Alonso-Briales J, Garcia JMH, Gómez G, Alcántara AG, Rodriguez-Bailón I, Barrera A, Montiel A, Caliani JSE, de Teresa E (2001) Does angina the week before protect against first myocardial infarction in elderly patients? Am J Cardiol 87:11–15 Kaukoranta PK, Lepojarvi MP, Ylitalo KV, Kiviluoma KT, Kauhkurinen KJ (1997) Normothermic retrograde blood cardioplegia with or without preceding ischaemic preconditioning. Ann Thorac Surg 63:1268–1274 Kloner RA, Shook T, Przyklenk K, Davis VG, Junio L, Matthews RV, Burstein S, Gibson CM, Poole WK, Cannon CP, McCabe CH, Braunwald E (1995a) Previous angina alters in-hospital outcome in TIMI4: a clinical correlate to preconditioning? Circulation 91:37–45 Kloner RA, Muller J, Davis V (1995b) Effects of previous angina pectoris in patients with first acute myocardial infarction not receiving thrombolytics. Am J Cardiol 75:615–617 Kloner RA, Shook T, Antman EM, Cannon CP, Przyklenk K, McCabe CH, Braunwald E (1996) TIMI 9 investigators. A prospective analysis on the potential preconditioning effect of preinfarct angina in TIMI 9. Circulation 94(Suppl. I):I611 Kloner RA, Przyklenk K, Shook T, Cannon CP (1998a) Protection conferred by preinfarct angina is manifest in the aged heart: evidence from the TIMI 4 trial. J Thromb Thrombolysis 6:89–92 Kloner RA, Shook T, Antman EM, Cannon CP, Przyklenk K, Yoo K, McCabe CH, Braunwald E, TIMI-9B Investigators (1998b) Prospective temporal analysis of the onset of preinfarction angina versus outcome. An ancillary study in TIMI-9B. Circulation 97:1042–1045 Kluz K, Parenica J, Kubkova L, Littnerova S, Tomandi J, Poloczek M, Toman O, Tesak M, Cermakova Z, Gottwaldova J, Manousek J, Goldbergova MP, Spinar J, Jarkovsky J (2015) Unstable angina pectoris prior to ST elevation myocardial infarction in patients treated with primary percutaneous coronary intervention has no influence on prognosis. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 159(2):251–258 Kosuge M, Kimura K, Kojima S, Sakamoto T, Ishihara M, Asada Y, Tei C, Miyazaki S, Sonoda M, Tsuchihashi K, Yamagishi M, Ikeda Y, Shirai M, Hiraoka H, Inoue T, Saito F, Ogawa H (2005) Beneficial effect of preinfarction angina on in-hospital outcome is preserved in elderly patients undergoing coronary intervention for anterior acute myocardial infarction. Circ J 69:630–635 Lee TM, Su SF, Chou TF, Lee YT, Tsai CH (2002) Loss of preconditioning by attenuated activation of myocardial ATP-sensitive potassium channels in elderly patients undergoing coronary angioplasty. Circulation 105:334–340 Lerner DL, Yamada KA, Schuessler RB, Saffitz JE (2000) Accelerated onset and increased incidence of ventricular arrhythmias induced by ischemia in Cx43-deficient mice. Circulation 101:547–552 Lesnefsky EJ, Gallo DS, Ye J, Whittingham TS, Lust WD (1994) Aging increases ischemia-reperfusion injury in the isolated, buffer-perfused heart. J Lab Clin Med 124:843–851 Leung CH, Caldarone CA, Wang F, Venkateswaran S, Ailenberg M, Vadasz B, Wen SY, Rotstein OD (2015) Remote ischemic conditioning prevents lung and liver injury after hemorrhagic shock/resuscitation: potential role of a humoral plasma factor. Ann Surg 261(6):1215–1225 Li G, Chen S, Lu E, Li Y (1999) Ischaemic preconditioning improves preservation with cold blood cardioplegia in valve replacement patients. Eur J Cardiothorac Surg 15:653–657 Li X, Heinzel FR, Boengler K, Schulz R, Heusch G (2004) Role of connexin 43 in ischemic preconditioning does not involve intercellular communications through gap junctions. J Mol Cell Cardiol 36:161–163 Li H, Zhou C, Chen D, Fang N, Yao Y, Li L (2013) Failure to protect against myocardial ischemia-reperfusion injury with sevoflurane post-conditioning in old rats in vivo. Acta Anaesthesiol Scand 57:1024–1031 Li H, Chen D, Fang N, Yao Y, Li L (2015a) Age-associated differences in response to sevoflurane postconditioning in rats. Scand Cardiovasc J 14:1–9 Li H, Meng F, Li N, Zhang L, Wang J, Wang H, Li D, Zhang X, Dong P, Chen Y (2015b) Exercise training prevents the attenuation of anesthetic pre-conditioning-mediated cardioprotection in diet-induced obese rats. Acta Anaesthesiol Scand 59:85–97 Liu L, Zhu J, Brink PR, Glass PSA, Rebecchi MJ (2011) Age-associated differences in the inhibition of mitochondrial permeability transition pore opening by cyclosporine A. Acta Anaesthesiol Scand 55:622–630 Loubani M, Ghosh S, Galinanes M (2003) The aging human myocardium: tolerance to ischemia and responsiveness to ischemic preconditioning. J Thorac Cardiovasc Surg 126:143–147 Lu EX, Chen SX, Yuan MD, Hu TH, Zhou HC, Luo WJ, Li GH, Xu LM (1997) Preconditioning improves myocardial preservation in patients undergoing open heart operation. Ann Thorac Surg 64:1320–1324 Lu R, Hu C-P, Deng H-W, Li Y-J (2001) Calcitonin gene-related peptide-mediated ischemic preconditioning in the rat heart: influence of age. Regul Pept 99:183–189 Lund J, Hafstad AD, Boardman NT, Rossvoil L, Rolim NP, Ahmed MS, Florholmen G, Altramadal H, Wisloff U, Larsen TS, Aasum E (2015) Exercise training promotes cardioprotection through oxygen-sparing action in high fat-fed mice. Am J Physiol Heart Circ Physiol 308:H823–H829 Mariani J, Ou RC, Bailey M, Rowland M, Nagley P, Rosenfeldt F, Pepe S (2000) Tolerance to ischemia and hypoxia is reduced in aged human myocardium. J Thorac Cardiovasc Surg 120(4):660–667 Matsubara M, Ranji M, Leshnower BG, Noma M, Ratcliffe SJ, Chance B, Gorman RC, Gorman JH III (2010) In vivo fluorometric assessment of cyclosporine on mitochondrial function during myocardial ischemia and reperfusion. Ann Thorac Surg 89:1532–1537 Moro L, Pedone C, Mondi A, Nunziata E, Incalzi RA (2011) Effect of local and remote ischemic preconditioning on endothelial function in young people and healthy or hypertensive elderly people. Atherosclerosis 219:750–752 Murphy E (2004) Primary and secondary signaling pathways in early preconditioning that converge on the mitochondria to produce cardioprotection. Circ Res 94:7–16 Murry CE, Jennings RB, Reimer KA (1986) Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74:1124–1136 Nakagawa Y, Ito H, Kitakaze M, Kusuoka H, Hori M, Kuzuya T, Higashino Y, Fujii K, Minamino T (1995) Effect of angina pectoris on myocardial protection in patients with reperfused anterior wall myocardial infarction: retrospective clinical evidence of “preconditioning”. J Am Coll 25:1076–1083 Nguyen LT, Rebecchi MJ, Moore LC, Glass PSA, Brink PR, Liu L (2008) Attenuation of isoflurane-induced preconditioning and reactive oxygen species production in the senescent rat heart. Anesth Analg 107:776–782 Niemann B, Chen Y, Issa H, Silber RE, Rohrbach S (2010) Caloric restriction delays cardiac ageing in rats: role of mitochondria. Cardio Res 88:267–276 O’Rourke B (2004) Evidence for mitochondrial K+ channels and their role in cardioprotection. Circ Res 94:420–432 Okaya T, Blanchard J, Schuster R, Kuboki S, Husted T, Caldwell CC, Zingarelli B, Wong H, Solomkin JS, Lentsch AB (2005) Age-dependent responses to hepatic ischemia/reperfusion injury. Shock 24(5):421–427 Orenstein TL, Parker TG, Butany JW, Goodman JM, Dawood F, Wen WH, Wee L, Martino T, McLaughlin PR, Liu PP (1995) Favorable left ventricular remodeling following large myocardial infarction by exercise training. Effect on ventricular morphology and gene expression. J Clin Invest 96:858–866 Ottani F, Galvani M, Ferrini D, Sorbello F, Limonetti P, Pantoli D, Rusticali F (1995a) Prodromal angina limits infarct size. A role for ischemic preconditioning. Circulation 91:291–297 Ottani F, Galvani M, Ferrini D, Rusticali F (1995b) Prodromal angina limits infarct size. A role for ischemic preconditioning—response. Circulation 92(4):1062 Ottani F, Galvani M, Ferrini D, Rusticali F (1995c) Prodromal angina limits infarct size. A role for ischemic preconditioning—reply. Circulation 92(6):1668 Papadopoulos CE, Karvounis HI, Gourasas IT, Parharidis GE, Louridas GE (2003) Evidence of ischemic preconditioning in patients experiencing first non-ST-segment elevation myocardial infarction (NSTEMI). Int J Cardiol 92:209–217 Peart JN, Gross GJ (2004) Chronic exposure to morphine produces a marked cardioprotective phenotype in aged mouse hearts. Exp Gerontol 39:1021–1026. doi:10.1016/j.exger.2004.03.038 Peart JN, Pepe S, Reichelt ME, Beckett N, Hoe LS, Ozberk V, Niesman IR, Patel HH, Headrick JP (2014) Dysfunctional survival-signaling and stress-intolerance in aged murine and human myocardium. Exp Gerontol 50:72–81. doi:10.1016/jexger.2013.11.015 Perrault LP, Menasche P, Bel A, de Chaumaray T, Peynet J, Mondry A, Olivero P, EmanoilRavier R, Moalic JM (1996) Ischaemic preconditioning in cardiac surgery: a word of caution. J Thorac Cardiovasc Surg 112:1378–1386 Peters J, Nieuwenhuijs VB, Morphett A, Porte RJ, Padbury RTA, Barritt GJ (2010) Increasing cycles of intermittent ischemia can effectively maintain liver function during the acute phase of ischemia reperfusion injury by promotion of bile flow and reduction in bile salt toxicity. Dig Surg 26:455–464 Pons S, Martin V, Portal L, Zini R, Morin D, Berdeaux A, Ghaleh B (2013) Regular treadmill exercise restores cardioprotective signaling pathways in obese mice independently from improvement in associated co-morbidities. J Mol Cell Cardiol 54:82–89 Przyklenk K, Li G, Simkhovich BZ, Kloner RA (2003) Mechanisms of myocardial ischemic preconditioning are age related: PKC-epsilon does not play a requisite role in old rabbits. J Appl Physiol 95:2563–2569 Przyklenk K, Maynard M, Darling CE, Whittaker P (2008) Aging mouse hearts are refractory to infarct size reduction with post-conditioning. J Am Coll Cardiol 51(14):1393–1398. doi:10.1016/j.jacc.2007.11.070 Rengo G, Parisi V, Femminella GD, Pagano G, de Lucia C, Cannavo A, Liccardo D, Giallauria F, Scala O, Zincarelli C, Filardi PP, Ferrara N, Leosco D (2013) Molecular aspects of the cardioprotective effect of exercise in the elderly. Aging Clin Exp Res 25:487–497 Riess ML, Camara AKS, Thodes S, McCormick J, Jiang MT, Stowe DF (2005) Increasing heart size and age attenuate anesthetic preconditioning in guinea pig isolated hearts. Cardiothorac Anesth 101:1572–1576 Rodriguez-Sinovas A, Boengler K, Cabestrero A, GressP Morente M, Ruiz-Meana M, Konietzka I, Miro E, Totzeck A, Heusch G, Schulz R, Garcia-Dorado D (2006) Translocation of connexin 43 to the inner mitochondrial membrane of cardiomyocytes through the heat shock protein 90-dependent TOM pathway and its importance for cardioprotection. Circ Res 99:93–101 Romero-Farina G, Candell-Riera J, Aguade-Bruix S, de Leon G, Castell-Conesa J (2008) Influence of chronic angina prior to infarction in the diagnosis of viability and left ventricular remodeling in myocardial perfusion gated-SPECT. Rev Esp Med Nucl 27(4):245–252 Schneider A, Ad N, Izhar U, Khaliulin I, Borman JB, Schwalb H (2003) Protection of myocardium cyclosporine A and insulin: in vitro simulated ischemia study in human myocardium. Ann Thorac Surg 76:1240–1245 Schulman D, Latchman DS, Yellon DM (2001) Effect of aging on the ability of preconditioning to protect rat hearts from ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 281:H1630–H1636 Schulz R, Gres P, Skyschally A, Duschin A, Belosjorow S, Konietzka I, Heusch G (2003) Ischemic preconditioning preserves connexin 43 phosphorylation during sustained ischemia in pig hearts in vivo. FASEB J 17:1355–1357 Schwanke U, Konietzka I, Duschin A, Li X, Schulz R, Heusch G (2002) No ischemic preconditioning in heterozygous connexin 43-deficient mice. Am J Physiol Heart Circ Physiol 283:H1740–H1742 Shian CW, de Lima SG, Filho BM (2007) Preinfarction angina and in-hospital outcome of elderly patients with acute myocardial infarctions. Arq Bras Cardiol 89(6):334–340 Shinmura K, Nagai M, Tamaki K, Bolli R (2004) Gender and aging do not impair opioid-induced late preconditioning in rats. Basic Res Cardiol 99:46–55. doi:10.1007/s00395-003-0436-5 Shinmura K, Tamaki K, Bolli R (2005) Short-term caloric restriction improves ischemic tolerance independent of opening of ATP-sensitive K+ channels in both young and aged hearts. J Mol Cell Cardiol 39:285–296 Sniecinski R, Liu H (2004) Reduced efficacy of volatile anesthetic preconditioning with advanced age in isolated rat myocardium. Anesthesiology 100:589–597 Solomon SD, Anavekar NS, Greaves S, Rouleau JL, Hennekens C, Pfeffer MA (2004) Angina pectoris prior to myocardial infarction protects against subsequent left ventricular remodeling. J Am Coll Cardiol 43(9):1151–1514 Song T, Lv LY, Xu J, Tian ZY, Gui WY, Wang QS, Qu G, Shi XM (2011) Diet-induced obesity suppresses sevoflurane preconditioning against myocardial ischemia-reperfusion injury: role of AMP-activated protein kinase pathway. Exp Biol Med 236:1427–1436 Szemagala P, Orawski W, Krejca M, Gburek T, Bochenek A (1998) Evaluation of perioperative myocardial tissue damage in ischemically preconditioned human heart during aortic coronary bypass surgery. J Cardiovasc Surg (Torino) 39:791–795 Tani M, Suganuma Y, Hasegawa H, Shinmura K, Hayashi Y, Guo X, Nakamura Y (1997a) Changes in ischemic tolerance and effects of ischemic preconditioning in middle-aged rat hearts. Circulation 95:2559–2566. doi:10.1161/01.CIR.95.11.2559 Tani M, Suganuma Y, Hasegawa H, Shinmura K, Ebihara Y, Hayashi Y, Guo X, Takayama M (1997b) 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 Tani M, Honma Y, Takayama M, Hasegawa H, Shinmura K, Ebihara Y, Tamaki K (1999) Loss of protection by hypoxic preconditioning in aging Fischer 344 rat hearts related to myocardial glycogen content and Na+ imbalance. Cardiovasc Res 41:594–602 Tani M, Honma Y, Hasegawa H, Tamaki K (2001) Direct activation of mitochondrial KATP channels mimics preconditioning but protein kinase C activation is less effective in middle-aged rat hearts. Cardiovasc Res 49:56–68 Taniguchi T, Shiomi H, Toyota T, Morimoto T, Akao M, Nakatsuma K, Ono K, Makiyama T, Shizuta S, Furukawa Y, Nakagawa Y, Ando K, Kadota K, Hori M, Kimura T (2014) Effect of preinfarction angina pectoris on long-term survival in patients with ST-segment elevation myocardial infarction who underwent primary percutaneous coronary intervention. Am J Cardiol 114:1179–1186 Taubes G (1995) Epidemiology faces its limits. Science 269(5221:164-169 Toombs CF, Al Wiltse, Shebuski RJ (1993) Ischemic preconditioning fails to limit infarct size in reserpinized rabbit myocardium: implication of norepinephrine release in the preconditioning effect. Circulation 88:2351–2358 Van den Akker EK, Hesselink DA, Manintveld OC, Larranca JA, de Bruin RWF, Weimar W, Ijzermans JNM, Dor FJMF (2013) Ischemic postconditioning in human DCD kidney transplantation is feasible and appears safe. Trans Intern 27:226–234 Van den Munckhoff I, Riksen N, Seeger JPH, Schreuder TH, Borm GF, Eijsvogels TMH, Hopman MTE, Rongen GA, Thijssen DHJ (2013) Aging attenuates the protective effect of ischemic preconditioning against endothelial ischemia-reperfusion injury in humans. Am J Physiol Heart Circ Physiol 304:H1727–H1732 Wang Y, Huang C, Zhou Y, Cheng J, Wang H, Wu W, Liao W, Wen J, Ke Y, Zheng J (2011) ADAMTS-1 expression in rat myocardium after ischemic preconditioning: age-associated differences. Chin Med J 124(1):95–99 Wang W, Zhang H, Xue G, Zhang L, Zhang W, Wang L, Lu F, Li H, Bai S, Lin Y, Lou Y, Xu C, Zhao Y (2014) Exercise training preserves ischemic preconditioning in aged rat hearts by restoring the myocardial polyamine pool. Oxid Med Cell Long Article ID 457429, 14 pp. http://dx.doi.org/10.1155/2014/457429/ Wu ZK, Pehkonen E, Laurikka J, Kaukinen L, Honkonen EL, Kaukinen S, Laippala P, Tarkka MR (2001) The protective effects of preconditioning decline in aged patients undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg 122:972–978 Xaymardan M, Zheng J, Duignan I, Chin A, Holm JM, Ballard VLT, Edelberg JM (2004) Senescent impairment in synergistic cytokine pathways that provide rapid cardioprotection in the rat liver. J Exp Med 199(6):797–804. http://www.jem.org/cgi/doi/10.1084/jem.20031639 Xie JR, Yu LN (2007) Cardioprotective effects of cyclosporine A in an in vivo model of myocardial ischemia and reperfusion. Acta Anaesthesiol Scand 51:909–913 Xu X, Zhou Y, Luo S, Zhang W, Zhao Y, Yu M, Gao F, Shen H, Zhang J (2013) Effect of remote ischemic preconditioning in the elderly patients with coronary artery disease with diabetes mellitus undergoing elective drug-eluting stent implantation. Angiology 65(8):660–666 Yellon DM, Downey JM (2003) Preconditioning the myocardium: from cellular physiology to clinical cardiology. Physiol Rev 83(4):1113–1151 Yellon DM, Alkhulaifi AM, Pugsley WB (1993) Preconditioning the human myocardium. Lancet 342:276–277 Yin Z, Gao H, Wang H, Li L, Di C, Luan R, Tao L (2009) Ischaemic post-conditioning protects both adult and aged Sprague-Dawley rat heart from ischaemia-reperfusion injury through the phosphatidylinositol 3-kinase-AKT and glycogen synthase kinase-3β pathways. Clin Exp Pharmacol Physiol 36:756–763. doi:10.1111/j.1440-1681.2009.05148.x Zhao ZQ, Corvera JS, Halkos ME, Kerendi F, Wang NP, Guyton RA, Vinten-Johansen J (2003) Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol 185:H579–H588 Zheng J, Chin A, Duignan I, Won KH, Hong MK, Edelberg JM (2006) Growth factor-mediated reversal of senescent dysfunction of ischemia-induced cardioprotection. Am J Physiol Heart Circ Physiol 290:H525–H530. doi:10.1152/ajpheart.00470.2005 Zhu J, Rebecchi MJ, Tan M, Glass PSA, Brink PR, Liu L (2010) Age-associated differences in activation of Akt/GSK-3β signaling pathways and inhibition of mitochondrial permeability transition pore opening in the rat heart. J Gerontol A Biol Sci Med Sci 65(6):611–619 Zhu J, Rebecchi MJ, Wang Q, Glass PSA, Brink PR, Liu L (2013) Chronic tempol treatment restores pharmacological preconditioning in the senescent rat heart. Am J Physiol Heart Circ Physiol 304:H649–H659