Please wait a minute...
 Home  About the Journal Editorial Board Aims & Scope Peer Review Policy Subscription Contact us
 
Early Edition  //  Current Issue  //  Open Special Issues  //  Archives  //  Most Read  //  Most Downloaded  //  Most Cited
Aging and disease    2019, Vol. 10 Issue (1) : 116-133     DOI: 10.14336/AD.2018.0501
Review |
Snapshot: Implications for mTOR in Aging-related Ischemia/Reperfusion Injury
Dong Liu1, Liqun Xu1,2,3,4, Xiaoyan Zhang2,3, Changhong Shi4, Shubin Qiao1,*, Zhiqiang Ma1,2,*, Jiansong Yuan1,*
1State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China.
2Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, 1 Xinsi Road, Xi’an 710038, China.
3Cadet group 3, School of Basic Medical Sciences, The Fourth Military Medical University, Xi’an 710032, China.
4Laboratory Animal Center, The Fourth Military Medical University, Xi’an 710032, China
Download: PDF(980 KB)   HTML
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks    
Abstract  

Aging may aggravate the damage and dysfunction of different components of multiorgan and thus increasing multiorgan ischemia/reperfusion (IR) injury. IR injury occurs in many organs and tissues, which is a major cause of morbidity and mortality worldwide. The kinase mammalian target of rapamycin (mTOR), an atypical serine/threonine protein kinase, involves in the pathophysiological process of IR injury. In this review, we first briefly introduce the molecular features of mTOR, the association between mTOR and aging, and especially its role on autophagy. Special focus is placed on the roles of mTOR during ischemic and IR injury. We then clarify the association between mTOR and conditioning phenomena. Following this background, we expand our discussion to potential future directions of research in this area. Collectively, information reviewed herein will serve as a comprehensive reference for the actions of mTOR in IR injury and may be significant for the design of future research and increase the potential of mTOR as a therapeutic target.

Keywords Ischemia/reperfusion injury      Aging      mTOR      Autophagy     
Corresponding Authors: Qiao Shubin,Ma Zhiqiang,Yuan Jiansong   
About author:

These authors contributed equally to this work.

Issue Date: 23 December 2017
Service
E-mail this article
E-mail Alert
RSS
Articles by authors
Liu Dong
Xu Liqun
Zhang Xiaoyan
Shi Changhong
Qiao Shubin
Ma Zhiqiang
Yuan Jiansong
Cite this article:   
Liu Dong,Xu Liqun,Zhang Xiaoyan, et al. Snapshot: Implications for mTOR in Aging-related Ischemia/Reperfusion Injury[J]. Aging and disease, 2019, 10(1): 116-133.
URL:  
http://www.aginganddisease.org/EN/10.14336/AD.2018.0501     OR     http://www.aginganddisease.org/EN/Y2019/V10/I1/116
Figure 1.  Structural characteristics of mTOR and mTORC1/2. (A) part illustrates the structure of mTORC1 and mTORC2. The mTOR kinase nucleates two distinct protein complexes termed mTORC1 and mTORC2. mTORC1 contains six known protein components: mTOR, regulatory protein associated with mTOR (Raptor), mammalian lethal with Sec13 protein 8 (mLST8), proline-rich Akt substrate of 40 kDa (PRAS40), DEP domain containing mTOR interacting protein (DEPTOR) and the Tti1/Tel2 complex. mTORC2 containing seven protein components constitutes mTOR, DEPTOR, mLST8, Tti1/Tel2 complex, Protor1/2 mammalian stress-activated protein kinase-interacting protein 1 (mSin1) and rapamycin insensitive companion of mTOR (Rictor). (B) This diagram depicts the structure of mTOR. mTOR are characterized by five distinct protein domains: FAT-carboxy terminal domain (FAT domain), FRAP-ATM-TTRAP domain (FATC domain), FKBP12-rapamycin binding domain (FRB domain), Huntingtin-Elongation factor 3-regulatory subunit A of PP2A-TOR1 repeats (HEAT repeats).
Figure 2.  mTORC1 related autophagy signaling in ischemic and ischemia/reperfusion injury and mTORC1/2 signaling pathways involved in IR injury. (A) mTORC1 inhibition thus activating autophagy during ischemia protects against ischemia injury. However, the role of mTORC1 signaling and autophagy in reperfusion injury is complicated. Protective autophagy via suppression of mTORC1 can reduce reperfusion injury while excessive autophagy may increase the injurious effects of reperfusion. (B) The mTORC1/2 signaling pathways involved in IR injury. Abbreviations: 4E-BP1, eIF4E-binding protein-1; AMP, adenosine monophosphate; AMPK, adenosine monophosphate-activated protein kinase; Akt, protein kinase B; ATP, adenosine triphosphate; FKBP12, FK506-binding protein 12; GSK-3β, glycogen synthase kinase-3β; HIF-1α, transcription factor-1α; MAPK, mitogen-activated protein kinase; mPTP, mitochondrial permeability transition pore; mTORC, mammalian target of rapamycin complex; NF-κB, nuclear factor-κB; PGC-1α, peroxisome-proliferator-activated receptor coactivator-1α; PI3K, phosphoinositide 3 kinase; Rheb, Ras homolog enriched in brain; S6K, S6 kinase; STAT3, signal transducer and activator of transcription 3; TFEB, transcription factor EB; TSC, tuberous sclerosis protein; ULK, unc-51-like kinase.
Figure 3.  The protective roles of mTOR against multiorgan IR injury. The blue arrows with dark cross represent ischemia and the red arrows represent reperfusion.
Type of organExperiment modelsTreatmentsMechanismsRefs.
HeartIsolated perfused rat heartsIPCActivation of mTORC1 via stimulating Akt and inhibiting GSK-3β[156]
Prolonged ischemia model of Tg-DnGSK-3β or GSK-3β KO miceProlonged ischemia without reperfusionInhibiting GSK-3β and reactivating mTORC1[104]
IR model of Akt KO miceIPostCmTOR-dependent GSK-3β inhibition mechanisms[104]
IR model of Akt KO miceGSK-3 inhibitor SB415286 PCInhibition of GSK-3β through mTORC1 hyperactivation[104]
H/R model of ratsGhrelin PCActivation of PI3K/Akt/mTOR/S6K1 signaling pathway[117, 118]
Ischemia model of diabetic miceRapamycin PCInhibition of mTOR via activating the JAK2-STAT3 signaling[16, 160]
IR model of miceRapamycin PCp38 MAPK pathway signals through REDD1, Tsc2 to activate mTOR[132]
IR model of miceRapamycin or DMSO PostCSelective activation of mTORC2 and ERK with concurrent inhibition of mTORC1 and p38 MAPK
[6]
IR model of ratsPL PCAttenuating mTORC1 signaling and inhibiting Beclin-1-dependent pathway[5, 148]
IR model of miceCrocin PCActivation of AMPK during ischemia while activation of Akt during reperfusion[79]
IR model of ratsEpigallocatechin gallate PostCInhibiting apoptosis and restoring the autophagic flux via stimulating mTOR[157]
BrainIR model of miceIsoflurane PCHIF-1α upregulation through stimulating Akt/mTOR/S6K signaling pathway[115]
IR model of miceSMXZF PostCInhibition of autophagy provides protection against cerebral IR injury during reperfusion[83]
IR model of ratsN-Butylphthalide PostCStimulating PI3K/Akt/mTOR activity and suppressing apoptosis[114]
LiverIR model of ratsOctreotide or octreotide combined with 3-methyladenine PCEnhancement of autophagy regulated through Akt/mTOR/p70S6K pathway deactivation[18]
KidneyStimulated IR model of HUVECsRapamycin PCmTOR inhibits ICAM-1 expression[47, 143]
IR model of miceAloperine PCActivation of PI3K/Akt signaling thus activating mTOR and NFκB transcriptional activity[11]
Kidney transplantation model of ratsXenon PostCActivation of mTOR thus enhancing the activity of HIF-1α[85]
OthersIR model of ratsIPostCAttenuating autophagy via strengthening mTOR signaling[13]
IR model of ratsCAPE PCInhibition mTOR reduces the apoptosis on IR damage in rat testis[15]
Hindlimb ischemia model of murinesApelin PostCActivation of AMPK and inhibition of mTOR during hypoxia while activation of Akt and inhibition of Beclin1during reoxygenation[14]
Table 1  mTOR is involved in conditioning against IR injury.
[1] Favero G, Franceschetti L, Buffoli B, Moghadasian MH, Reiter RJ, Rodella LF, et al. (2017). Melatonin: Protection against age-related cardiac pathology. Ageing Res Rev, 35:336-349.
[2] Wojtovich AP, Nadtochiy SM, Brookes PS, Nehrke K (2012). Ischemic preconditioning: the role of mitochondria and aging. Exp Gerontol, 47:1-7.
[3] Ma Z, Xin Z, Di W, Yan X, Li X, Reiter RJ, et al. (2017). Melatonin and mitochondrial function during ischemia/reperfusion injury. Cell Mol Life Sci.
[4] Chouchani ET, Pell VR, James AM, Work LM, Saeb-Parsy K, Frezza C, et al. (2016). A Unifying Mechanism for Mitochondrial Superoxide Production during Ischemia-Reperfusion Injury. Cell Metab, 23:254-263.
[5] Su HH, Chu YC, Liao JM, Wang YH, Jan MS, Lin CW, et al. (2017). Phellinus linteus Mycelium Alleviates Myocardial Ischemia-Reperfusion Injury through Autophagic Regulation. Front Pharmacol, 8:175.
[6] Filippone S, Samidurai A, Roh S, Cain C, He J, Salloum F, et al. (2017). Reperfusion Therapy with Rapamycin Attenuates Myocardial Infarction through Activation of AKT and ERK. Oxid Med Cell Longev, 2017:4619720.
[7] Zheng Y, Bu J, Yu L, Chen J, Liu H (2017). Nobiletin improves propofol-induced neuroprotection via regulating Akt/mTOR and TLR 4/NF-kappaB signaling in ischemic brain injury in rats. Biomed Pharmacother, 91:494-503.
[8] Wu ZQ, Cui SY, Zhu L, Zou ZQ (2016). Study on the Mechanism of mTOR-Mediated Autophagy during Electroacupuncture Pretreatment against Cerebral Ischemic Injury. 2016:9121597.
[9] Yang H, Li L, Zhou K, Wang Y, Guan T, Chai C, et al. (2016). Shengmai injection attenuates the cerebral ischemia/reperfusion induced autophagy via modulation of the AMPK, mTOR and JNK pathways. Pharm Biol, 54:2288-2297.
[10] Zhu J, Lu T, Yue S, Shen X, Gao F, Busuttil RW, et al. (2015). Rapamycin protection of livers from ischemia and reperfusion injury is dependent on both autophagy induction and mammalian target of rapamycin complex 2-Akt activation. Transplantation, 99:48-55.
[11] Hu S, Zhang Y, Zhang M, Guo Y, Yang P, Zhang S, et al. (2015). Aloperine protects mice against ischemia reperfusion (IR)-induced renal injury by regulating PI3K/AKT/mTOR signaling and AP-1 activity. Mol Med.
[12] Pu T, Liao XH, Sun H, Guo H, Jiang X, Peng JB, et al. (2017). Augmenter of liver regeneration regulates autophagy in renal ischemia-reperfusion injury via the AMPK/mTOR pathway. Apoptosis, 22:955-969.
[13] Duan M, Fu Y, Lan J, Wu Y, Xu S, Bai Y (2014). Effects of postconditioning on autophagy of lung ischemic reperfusion injury in rats. Zhonghua Yi Xue Za Zhi, 94:1577-1580.
[14] Liang D, Han D, Fan W, Zhang R, Qiao H, Fan M, et al. (2016). Therapeutic efficacy of apelin on transplanted mesenchymal stem cells in hindlimb ischemic mice via regulation of autophagy. Sci Rep, 6:21914.
[15] Dilber Y, Inan S, Ercan GA, Sencan A (2016). The role of CAPE in PI3K/AKT/mTOR activation and oxidative stress on testis torsion. Acta Histochem, 118:31-37.
[16] Zhao D, Yang J (2017). Insights for Oxidative Stress and mTOR Signaling in Myocardial Ischemia/Reperfusion Injury under Diabetes. 2017:6437467.
[17] Wei H, Li Y, Han S, Liu S, Zhang N, Zhao L, et al. (2016). cPKCgamma-Modulated Autophagy in Neurons Alleviates Ischemic Injury in Brain of Mice with Ischemic Stroke Through Akt-mTOR Pathway. Transl Stroke Res, 7:497-511.
[18] Sun H, Zou S, Candiotti KA, Peng Y, Zhang Q, Xiao W, et al. (2017). Octreotide Attenuates Acute Kidney Injury after Hepatic Ischemia and Reperfusion by Enhancing Autophagy. Sci Rep, 7:42701.
[19] Laplante M, Sabatini DM (2012). mTOR signaling in growth control and disease. Cell, 149:274-293.
[20] Saxton RA, Sabatini DM (2017). mTOR Signaling in Growth, Metabolism, and Disease. Cell, 169:361-371.
[21] Johnson SC, Rabinovitch PS, Kaeberlein M (2013). mTOR is a key modulator of ageing and age-related disease. Nature, 493:338-345.
[22] Chen-Scarabelli C, Agrawal PR, Saravolatz L, Abuniat C, Scarabelli G, Stephanou A, et al. (2014). The role and modulation of autophagy in experimental models of myocardial ischemia-reperfusion injury. J Geriatr Cardiol, 11:338-348.
[23] Benjamin D, Colombi M, Moroni C, Hall MN (2011). Rapamycin passes the torch: a new generation of mTOR inhibitors. Nat Rev Drug Discov, 10:868-880.
[24] Cafferkey R, Young PR, McLaughlin MM, Bergsma DJ, Koltin Y, Sathe GM, et al. (1993). Dominant missense mutations in a novel yeast protein related to mammalian phosphatidylinositol 3-kinase and VPS34 abrogate rapamycin cytotoxicity. Mol Cell Biol, 13:6012-6023.
[25] Kunz J, Henriquez R, Schneider U, Deuter-Reinhard M, Movva NR, Hall MN (1993). Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression. Cell, 73:585-596.
[26] Loewith R, Jacinto E, Wullschleger S, Lorberg A, Crespo JL, Bonenfant D, et al. (2002). Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell, 10:457-468.
[27] Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, et al. (2002). mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell, 110:163-175.
[28] Kim DH, Sarbassov DD, Ali SM, Latek RR, Guntur KV, Erdjument-Bromage H, et al. (2003). GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell, 11:895-904.
[29] Hara K, Maruki Y, Long X, Yoshino K, Oshiro N, Hidayat S, et al. (2002). Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell, 110:177-189.
[30] Sancak Y, Thoreen CC, Peterson TR, Lindquist RA, Kang SA, Spooner E, et al. (2007). PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell, 25:903-915.
[31] Vander Haar E, Lee SI, Bandhakavi S, Griffin TJ, Kim DH (2007). Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol, 9:316-323.
[32] Peterson TR, Laplante M, Thoreen CC, Sancak Y, Kang SA, Kuehl WM, et al. (2009). DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell, 137:873-886.
[33] Kaizuka T, Hara T, Oshiro N, Kikkawa U, Yonezawa K, Takehana K, et al. (2010). Tti1 and Tel2 are critical factors in mammalian target of rapamycin complex assembly. J Biol Chem, 285:20109-20116.
[34] Nojima H, Tokunaga C, Eguchi S, Oshiro N, Hidayat S, Yoshino K, et al. (2003). The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif. J Biol Chem, 278:15461-15464.
[35] Schalm SS, Fingar DC, Sabatini DM, Blenis J (2003). TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function. Curr Biol, 13:797-806.
[36] Sancak Y, Peterson TR, Shaul YD, Lindquist RA, Thoreen CC, Bar-Peled L, et al. (2008). The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science, 320:1496-1501.
[37] Yang H, Rudge DG, Koos JD, Vaidialingam B, Yang HJ, Pavletich NP (2013). mTOR kinase structure, mechanism and regulation. Nature, 497:217-223.
[38] Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY, Moffat J, et al. (2006). Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell, 11:859-871.
[39] Pearce LR, Huang X, Boudeau J, Pawlowski R, Wullschleger S, Deak M, et al. (2007). Identification of Protor as a novel Rictor-binding component of mTOR complex-2. Biochem J, 405:513-522.
[40] Thedieck K, Polak P, Kim ML, Molle KD, Cohen A, Jeno P, et al. (2007). PRAS40 and PRR5-like protein are new mTOR interactors that regulate apoptosis. PLoS One, 2:e1217.
[41] Woo SY, Kim DH, Jun CB, Kim YM, Haar EV, Lee SI, et al. (2007). PRR5, a novel component of mTOR complex 2, regulates platelet-derived growth factor receptor beta expression and signaling. J Biol Chem, 282:25604-25612.
[42] Frias MA, Thoreen CC, Jaffe JD, Schroder W, Sculley T, Carr SA, et al. (2006). mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr Biol, 16:1865-1870.
[43] Jacinto E, Facchinetti V, Liu D, Soto N, Wei S, Jung SY, et al. (2006). SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell, 127:125-137.
[44] Yang Q, Inoki K, Ikenoue T, Guan KL (2006). Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity. Genes Dev, 20:2820-2832.
[45] Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg MA, Hall A, et al. (2004). Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol, 6:1122-1128.
[46] Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, et al. (2004). Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol, 14:1296-1302.
[47] Saemann MD, Haidinger M, Hecking M, Horl WH, Weichhart T (2009). The multifunctional role of mTOR in innate immunity: implications for transplant immunity. Am J Transplant, 9:2655-2661.
[48] Lamming DW, Ye L, Katajisto P, Goncalves MD, Saitoh M, Stevens DM, et al. (2012). Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science, 335:1638-1643.
[49] Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, et al. (2006). Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell, 22:159-168.
[50] Cao W, Manicassamy S, Tang H, Kasturi SP, Pirani A, Murthy N, et al. (2008). Toll-like receptor-mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway. Nat Immunol, 9:1157-1164.
[51] Schmitz F, Heit A, Dreher S, Eisenacher K, Mages J, Haas T, et al. (2008). Mammalian target of rapamycin (mTOR) orchestrates the defense program of innate immune cells. Eur J Immunol, 38:2981-2992.
[52] Jacinto E, Lorberg A (2008). TOR regulation of AGC kinases in yeast and mammals. Biochem J, 410:19-37.
[53] Gingras AC, Raught B, Sonenberg N (2001). Regulation of translation initiation by FRAP/mTOR. Genes Dev, 15:807-826.
[54] Inoki K, Kim J, Guan KL (2012). AMPK and mTOR in cellular energy homeostasis and drug targets. Annu Rev Pharmacol Toxicol, 52:381-400.
[55] Hellsten Y, Richter EA, Kiens B, Bangsbo J (1999). AMP deamination and purine exchange in human skeletal muscle during and after intense exercise. J Physiol, 520 Pt 3:909-920.
[56] McBride A, Hardie DG (2009). AMP-activated protein kinase--a sensor of glycogen as well as AMP and ATP? Acta Physiol (Oxf), 196:99-113.
[57] Dibble CC, Asara JM, Manning BD (2009). Characterization of Rictor phosphorylation sites reveals direct regulation of mTOR complex 2 by S6K1. Mol Cell Biol, 29:5657-5670.
[58] Oakhill JS, Scott JW, Kemp BE (2009). Structure and function of AMP-activated protein kinase. Acta Physiol (Oxf), 196:3-14.
[59] Xiao B, Sanders MJ, Underwood E, Heath R, Mayer FV, Carmena D, et al. (2011). Structure of mammalian AMPK and its regulation by ADP. Nature, 472:230-233.
[60] Das S, Aiba T, Rosenberg M, Hessler K, Xiao C, Quintero PA, et al. (2012). Pathological role of serum- and glucocorticoid-regulated kinase 1 in adverse ventricular remodeling. Circulation, 126:2208-2219.
[61] Xiao B, Heath R, Saiu P, Leiper FC, Leone P, Jing C, et al. (2007). Structural basis for AMP binding to mammalian AMP-activated protein kinase. Nature, 449:496-500.
[62] Kennedy BK, Kaeberlein M (2009). Hot topics in aging research: protein translation, 2009. Aging Cell, 8:617-623.
[63] Wieser D, Papatheodorou I, Ziehm M, Thornton JM (2011). Computational biology for ageing. Philos Trans R Soc Lond B Biol Sci, 366:51-63.
[64] AbouRjaili G, Shtaynberg N, Wetz R, Costantino T, Abela GS (2010). Current concepts in triglyceride metabolism, pathophysiology, and treatment. Metabolism, 59:1210-1220.
[65] Kennedy BK, Pennypacker JK (2016). Mammalian Target of Rapamycin: A Target for (Lung) Diseases and Aging. Ann Am Thorac Soc, 13:S398-s401.
[66] Newgard CB, Sharpless NE (2013). Coming of age: molecular drivers of aging and therapeutic opportunities. J Clin Invest, 123:946-950.
[67] Avruch J, Hara K, Lin Y, Liu M, Long X, Ortiz-Vega S, et al. (2006). Insulin and amino-acid regulation of mTOR signaling and kinase activity through the Rheb GTPase. Oncogene, 25:6361-6372.
[68] Kennedy BK, Lamming DW (2016). The Mechanistic Target of Rapamycin: The Grand ConducTOR of Metabolism and Aging. Cell Metab, 23:990-1003.
[69] Wilkinson JE, Burmeister L, Brooks SV, Chan CC, Friedline S, Harrison DE, et al. (2012). Rapamycin slows aging in mice. Aging Cell, 11:675-682.
[70] Sokollik C, Ang M, Jones N (2011). Autophagy: a primer for the gastroenterologist/hepatologist. Can J Gastroenterol, 25:667-674.
[71] Cuervo AM (2008). Autophagy and aging: keeping that old broom working. Trends Genet, 24:604-612.
[72] Sciarretta S, Volpe M, Sadoshima J (2014). Mammalian target of rapamycin signaling in cardiac physiology and disease. Circ Res, 114:549-564.
[73] Rosenbluth J, Mays D, Pino M, Tang L, Pietenpol J (2008). A gene signature-based approach identifies mTOR as a regulator of p73. Mol. Cell. Biol., 28:5951-5964.
[74] Martina J, Chen Y, Gucek M, Puertollano R (2012). MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB. Autophagy, 8:903-914.
[75] Settembre C, Di Malta C, Polito V, Garcia Arencibia M, Vetrini F, Erdin S, et al. (2011). TFEB links autophagy to lysosomal biogenesis. Science, 332:1429-1433.
[76] Egan DF, Shackelford DB, Mihaylova MM, Gelino S, Kohnz RA, Mair W, et al. (2011). Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science, 331:456-461.
[77] Levine B, Kroemer G (2008). Autophagy in the pathogenesis of disease. Cell, 132:27-42.
[78] Mizushima N, Levine B, Cuervo AM, Klionsky DJ (2008). Autophagy fights disease through cellular self-digestion. Nature, 451:1069-1075.
[79] Zeng C, Li H, Fan Z, Zhong L, Guo Z, Guo Y, et al. (2016). Crocin-Elicited Autophagy Rescues Myocardial Ischemia/Reperfusion Injury via Paradoxical Mechanisms. Am J Chin Med, 44:515-530.
[80] Yitzhaki S, Huang C, Liu W, Lee Y, Gustafsson AB, Mentzer RM Jr., et al. (2009). Autophagy is required for preconditioning by the adenosine A1 receptor-selective agonist CCPA. Basic Res Cardiol, 104:157-167.
[81] Wei C, Li H, Han L, Zhang L, Yang X (2013). Activation of autophagy in ischemic postconditioning contributes to cardioprotective effects against ischemia/reperfusion injury in rat hearts. J Cardiovasc Pharmacol, 61:416-422.
[82] Valentim L, Laurence KM, Townsend PA, Carroll CJ, Soond S, Scarabelli TM, et al. (2006). Urocortin inhibits Beclin1-mediated autophagic cell death in cardiac myocytes exposed to ischaemia/reperfusion injury. J Mol Cell Cardiol, 40:846-852.
[83] Guo Z, Cao G, Yang H, Zhou H, Li L, Cao Z, et al. (2014). A combination of four active compounds alleviates cerebral ischemia-reperfusion injury in correlation with inhibition of autophagy and modulation of AMPK/mTOR and JNK pathways. J Neurosci Res, 92:1295-1306.
[84] Yao H, Han X, Han X (2014). The cardioprotection of the insulin-mediated PI3K/Akt/mTOR signaling pathway. Am J Cardiovasc Drugs, 14:433-442.
[85] Fan W, Han D, Sun Z, Ma S, Gao L, Chen J, et al. (2017). Endothelial deletion of mTORC1 protects against hindlimb ischemia in diabetic mice via activation of autophagy, attenuation of oxidative stress and alleviation of inflammation. Free Radic Biol Med, 108:725-740.
[86] Matsui Y, Takagi H, Qu X, Abdellatif M, Sakoda H, Asano T, et al. (2007). Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ. Res., 100:914-922.
[87] Das A, Salloum F, Durrant D, Ockaili R, Kukreja R (2012). Rapamycin protects against myocardial ischemia-reperfusion injury through JAK2-STAT3 signaling pathway. J Mol Cell Cardiol, 53:858-869.
[88] Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J (2005). Rheb binds and regulates the mTOR kinase. Curr Biol, 15:702-713.
[89] Sciarretta S, Zhai P, Shao D, Maejima Y, Robbins J, Volpe M, et al. (2012). Rheb is a critical regulator of autophagy during myocardial ischemia: pathophysiological implications in obesity and metabolic syndrome. Circulation, 125:1134-1146.
[90] Wu X, Cao Y, Nie J, Liu H, Lu S, Hu X, et al. (2013). Genetic and pharmacological inhibition of Rheb1-mTORC1 signaling exerts cardioprotection against adverse cardiac remodeling in mice. Am J Pathol, 182:2005-2014.
[91] Zong H, Li X, Lin H, Hou C, Ma F (2017). Lipoxin A4 pretreatment mitigates skeletal muscle ischemia-reperfusion injury in rats. Am J Transl Res, 9:1139-1150.
[92] Hardie DG (2011). AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Genes Dev, 25:1895-1908.
[93] Kim TW, Kim YJ, Kim HT, Park SR, Lee MY, Park YD, et al. (2016). NQO1 Deficiency Leads Enhanced Autophagy in Cisplatin-Induced Acute Kidney Injury Through the AMPK/TSC2/mTOR Signaling Pathway. Antioxid Redox Signal, 24:867-883.
[94] Duan P, Hu C, Quan C, Yu T, Zhou W, Yuan M, et al. (2016). 4-Nonylphenol induces apoptosis, autophagy and necrosis in Sertoli cells: Involvement of ROS-mediated AMPK/AKT-mTOR and JNK pathways. Toxicology, 341-343:28-40.
[95] Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, et al. (2008). AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell, 30:214-226.
[96] Shaw RJ, Bardeesy N, Manning BD, Lopez L, Kosmatka M, DePinho RA, et al. (2004). The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell, 6:91-99.
[97] Dibble CC, Elis W, Menon S, Qin W, Klekota J, Asara JM, et al. (2012). TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1. Mol Cell, 47:535-546.
[98] Inoki K, Li Y, Xu T, Guan KL (2003). Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev, 17:1829-1834.
[99] Tee AR, Manning BD, Roux PP, Cantley LC, Blenis J (2003). Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr Biol, 13:1259-1268.
[100] Dai SH, Chen T, Li X, Yue KY, Luo P, Yang LK, et al. (2017). Sirt3 confers protection against neuronal ischemia by inducing autophagy: Involvement of the AMPK-mTOR pathway. Free Radic Biol Med, 108:345-353.
[101] Buss SJ, Muenz S, Riffel JH, Malekar P, Hagenmueller M, Weiss CS, et al. (2009). Beneficial effects of Mammalian target of rapamycin inhibition on left ventricular remodeling after myocardial infarction. J Am Coll Cardiol, 54:2435-2446.
[102] Volkers M, Konstandin MH, Doroudgar S, Toko H, Quijada P, Din S, et al. (2013). Mechanistic target of rapamycin complex 2 protects the heart from ischemic damage. Circulation, 128:2132-2144.
[103] Buss S, Muenz S, Riffel J, Malekar P, Hagenmueller M, Weiss C, et al. (2009). Beneficial effects of Mammalian target of rapamycin inhibition on left ventricular remodeling after myocardial infarction. J Am Coll Cardiol, 54:2435-2446.
[104] Zhai P, Sciarretta S, Galeotti J, Volpe M, Sadoshima J (2011). Differential roles of GSK-3beta during myocardial ischemia and ischemia/reperfusion. Circ Res, 109:502-511.
[105] Völkers M, Konstandin M, Doroudgar S, Toko H, Quijada P, Din S, et al. (2013). Mechanistic target of rapamycin complex 2 protects the heart from ischemic damage. Circulation, 128:2132-2144.
[106] Heusch G (2004). Postconditioning: old wine in a new bottle? J Am Coll Cardiol, 44:1111-1112.
[107] Bainey KR, Armstrong PW (2014). Clinical perspectives on reperfusion injury in acute myocardial infarction. Am Heart J, 167:637-645.
[108] Bulluck H, Hausenloy DJ (2015). Ischaemic conditioning: are we there yet? Heart, 101:1067-1077.
[109] Cai W, Zhang K, Li P, Zhu L, Xu J, Yang B, et al. (2017). Dysfunction of the neurovascular unit in ischemic stroke and neurodegenerative diseases: An aging effect. Ageing Res Rev, 34:77-87.
[110] Christoffersen M, Tybjaerg-Hansen A (2016). Visible aging signs as risk markers for ischemic heart disease: Epidemiology, pathogenesis and clinical implications. Ageing Res Rev, 25:24-41.
[111] Nagata K, Yamazaki T, Takano D, Maeda T, Fujimaki Y, Nakase T, et al. (2016). Cerebral circulation in aging. Ageing Res Rev, 30:49-60.
[112] Lesnefsky EJ, He D, Moghaddas S, Hoppel CL (2006). Reversal of mitochondrial defects before ischemia protects the aged heart. Faseb j, 20:1543-1545.
[113] Lesnefsky EJ, Moghaddas S, Tandler B, Kerner J, Hoppel CL (2001). Mitochondrial dysfunction in cardiac disease: ischemia--reperfusion, aging, and heart failure. J Mol Cell Cardiol, 33:1065-1089.
[114] Zhang P, Guo ZF, Xu YM, Li YS, Song JG (2016). N-Butylphthalide (NBP) ameliorated cerebral ischemia reperfusion-induced brain injury via HGF-regulated TLR4/NF-kappaB signaling pathway. Biomed Pharmacother, 83:658-666.
[115] Yan W, Chen Z, Chen J, Chen H (2016). Isoflurane preconditioning protects rat brain from ischemia reperfusion injury via up-regulating the HIF-1alpha expression through Akt/mTOR/s6K activation. Cell Mol Biol (Noisy-le-grand), 62:38-44.
[116] Iliadis F, Kadoglou N, Didangelos T (2011). Insulin and the heart. Diabetes Res Clin Pract, 93 Suppl 1:S86-91.
[117] Wang L, Lu Y, Liu X, Wang X (2017). Ghrelin protected neonatal rat cardiomyocyte against hypoxia/reoxygenation injury by inhibiting apoptosis through Akt-mTOR signal. Mol Biol Rep, 44:219-226.
[118] Park BM, Cha SA, Lee SH, Kim SH (2016). Angiotensin IV protects cardiac reperfusion injury by inhibiting apoptosis and inflammation via AT4R in rats. Peptides, 79:66-74.
[119] Jope RS, Yuskaitis CJ, Beurel E (2007). Glycogen synthase kinase-3 (GSK3): inflammation, diseases, and therapeutics. Neurochem Res, 32:577-595.
[120] Jope RS, Johnson GV (2004). The glamour and gloom of glycogen synthase kinase-3. Trends Biochem Sci, 29:95-102.
[121] Juhaszova M, Zorov DB, Yaniv Y, Nuss HB, Wang S, Sollott SJ (2009). Role of glycogen synthase kinase-3beta in cardioprotection. Circ Res, 104:1240-1252.
[122] Juhaszova M, Zorov DB, Kim SH, Pepe S, Fu Q, Fishbein KW, et al. (2004). Glycogen synthase kinase-3beta mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore. J Clin Invest, 113:1535-1549.
[123] Govender J, Loos B, Marais E, Engelbrecht AM (2014). Mitochondrial catastrophe during doxorubicin-induced cardiotoxicity: a review of the protective role of melatonin. J Pineal Res, 57:367-380.
[124] Zhang YW, Shi J, Li YJ, Wei L (2009). Cardiomyocyte death in doxorubicin-induced cardiotoxicity. Arch Immunol Ther Exp (Warsz), 57:435-445.
[125] Lecour S (2009). Activation of the protective Survivor Activating Factor Enhancement (SAFE) pathway against reperfusion injury: Does it go beyond the RISK pathway? J Mol Cell Cardiol, 47:32-40.
[126] Zhuo C, Wang Y, Wang X, Wang Y, Chen Y (2011). Cardioprotection by ischemic postconditioning is abolished in depressed rats: role of Akt and signal transducer and activator of transcription-3. Mol Cell Biochem, 346:39-47.
[127] Downey J, Krieg T, Cohen M (2008). Mapping preconditioning’s signaling pathways: an engineering approach. Ann. N. Y. Acad. Sci., 1123:187-196.
[128] Sugden PH, Clerk A (1998). "Stress-responsive" mitogen-activated protein kinases (c-Jun N-terminal kinases and p38 mitogen-activated protein kinases) in the myocardium. Circ Res, 83:345-352.
[129] Ping P, Murphy E (2000). Role of p38 mitogen-activated protein kinases in preconditioning: a detrimental factor or a protective kinase? Circ Res, 86:921-922.
[130] Luss H, Neumann J, Schmitz W, Schulz R, Heusch G (2000). The stress-responsive MAP kinase p38 is activated by low-flow ischemia in the in situ porcine heart. J Mol Cell Cardiol, 32:1787-1794.
[131] Steenbergen C (2002). The role of p38 mitogen-activated protein kinase in myocardial ischemia/reperfusion injury; relationship to ischemic preconditioning. Basic Res Cardiol, 97:276-285.
[132] Hernández G, Lal H, Fidalgo M, Guerrero A, Zalvide J, Force T, et al. (2011). A novel cardioprotective p38-MAPK/mTOR pathway. Exp. Cell Res., 317:2938-2949.
[133] Birbrair A, Zhang T, Wang ZM, Messi ML, Olson JD, Mintz A, et al. (2014). Type-2 pericytes participate in normal and tumoral angiogenesis. Am J Physiol Cell Physiol, 307:C25-38.
[134] Lemaitre V, Dabo AJ, D’Armiento J (2011). Cigarette smoke components induce matrix metalloproteinase-1 in aortic endothelial cells through inhibition of mTOR signaling. Toxicol Sci, 123:542-549.
[135] Xiao Y, Peng H, Hong C, Chen Z, Deng X, Wang A, et al. (2017). PDGF Promotes the Warburg Effect in Pulmonary Arterial Smooth Muscle Cells via Activation of the PI3K/AKT/mTOR/HIF-1alpha Signaling Pathway. Cell Physiol Biochem, 42:1603-1613.
[136] Liu NN, Zhao N, Cai N (2015). Suppression of the proliferation of hypoxia-Induced retinal pigment epithelial cell by rapamycin through the /mTOR/HIF-1alpha/VEGF/ signaling. IUBMB Life, 67:446-452.
[137] Maugeri G, D’Amico AG, Saccone S, Federico C, Cavallaro S, D’Agata V (2017). PACAP and VIP Inhibit HIF-1alpha-Mediated VEGF Expression in a Model of Diabetic Macular Edema. J Cell Physiol, 232:1209-1215.
[138] Ding Y, Shan L, Nai W, Lin X, Zhou L, Dong X, et al. (2018). DEPTOR Deficiency-Mediated mTORc1 Hyperactivation in Vascular Endothelial Cells Promotes Angiogenesis. Cell Physiol Biochem, 46:520-531.
[139] Pallet N, Thervet E, Timsit MO (2014). Angiogenic response following renal ischemia reperfusion injury: new players. Prog Urol, 24 Suppl 1:S20-25.
[140] Zhao H, Huang H, Ologunde R, Lloyd DG, Watts H, Vizcaychipi MP, et al. (2015). Xenon Treatment Protects against Remote Lung Injury after Kidney Transplantation in Rats. Anesthesiology, 122:1312-1326.
[141] Miller JA, Kirkley KA, Padmanabhan R, Liang LP, Raol YH, Patel M, et al. (2014). Repeated exposure to low doses of kainic acid activates nuclear factor kappa B (NF-kappaB) prior to seizure in transgenic NF-kappaB/EGFP reporter mice. Neurotoxicology, 44:39-47.
[142] Zhu F, Yue W, Wang Y (2014). The nuclear factor kappa B (NF-kappaB) activation is required for phagocytosis of staphylococcus aureus by RAW 264.7 cells. Exp Cell Res, 327:256-263.
[143] Minhajuddin M, Fazal F, Bijli KM, Amin MR, Rahman A (2005). Inhibition of mammalian target of rapamycin potentiates thrombin-induced intercellular adhesion molecule-1 expression by accelerating and stabilizing NF-kappa B activation in endothelial cells. J Immunol, 174:5823-5829.
[144] Huang WQ, Wen JL, Lin RQ, Wei P, Huang F (2017). Effects of mTOR/NF-kappaB signaling pathway and high thoracic epidural anesthesia on myocardial ischemia-reperfusion injury via autophagy in rats.
[145] Goncalves GM, Cenedeze MA, Feitoza CQ, Wang PM, Bertocchi AP, Damiao MJ, et al. (2006). The role of heme oxygenase 1 in rapamycin-induced renal dysfunction after ischemia and reperfusion injury. Kidney Int, 70:1742-1749.
[146] Filho DW, Torres MA, Bordin AL, Crezcynski-Pasa TB, Boveris A (2004). Spermatic cord torsion, reactive oxygen and nitrogen species and ischemia-reperfusion injury. Mol Aspects Med, 25:199-210.
[147] Okur MH, Arslan S, Aydogdu B, Zeytun H, Basuguy E, Arslan MS, et al. (2017). Protective Effect of Cordycepin on Experimental Testicular Ischemia/Reperfusion Injury in Rats. J Invest Surg:1-8.
[148] Hao M, Zhu S, Hu L, Zhu H, Wu X, Li Q (2017). Myocardial Ischemic Postconditioning Promotes Autophagy against Ischemia Reperfusion Injury via the Activation of the nNOS/AMPK/mTOR Pathway. Int J Mol Sci, 18.
[149] Pantazi E, Zaouali MA, Bejaoui M, Folch-Puy E, Ben Abdennebi H, Varela AT, et al. (2015). Sirtuin 1 in rat orthotopic liver transplantation: an IGL-1 preservation solution approach. World J Gastroenterol, 21:1765-1774.
[150] Wang PR, Wang JS, Zhang C, Song XF, Tian N, Kong LY (2013). Huang-Lian-Jie-Du-Decotion induced protective autophagy against the injury of cerebral ischemia/reperfusion via MAPK-mTOR signaling pathway. J Ethnopharmacol, 149:270-280.
[151] Boengler K, Buechert A, Heinen Y, Roeskes C, Hilfiker-Kleiner D, Heusch G, et al. (2008). Cardioprotection by ischemic postconditioning is lost in aged and STAT3-deficient mice. Circ Res, 102:131-135.
[152] 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:H1630-1636.
[153] Boengler K, Schulz R, Heusch G (2009). Loss of cardioprotection with ageing. Cardiovasc Res, 83:247-261.
[154] Murry CE, Jennings RB, Reimer KA (1986). Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation, 74:1124-1136.
[155] Hausenloy DJ, Yellon DM (2011). The therapeutic potential of ischemic conditioning: an update. Nat Rev Cardiol, 8:619-629.
[156] Hausenloy DJ, Mocanu MM, Yellon DM (2004). Cross-talk between the survival kinases during early reperfusion: its contribution to ischemic preconditioning. Cardiovasc Res, 63:305-312.
[157] Xuan F, Jian J (2016). Epigallocatechin gallate exerts protective effects against myocardial ischemia/reperfusion injury through the PI3K/Akt pathway-mediated inhibition of apoptosis and the restoration of the autophagic flux. Int J Mol Med, 38:328-336.
[158] Aoyagi T, Kusakari Y, Xiao CY, Inouye BT, Takahashi M, Scherrer-Crosbie M, et al. (2012). Cardiac mTOR protects the heart against ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol, 303:H75-85.
[159] Chahine N, Makhlouf H, Duca L, Martiny L, Chahine R (2014). Cardioprotective effect of saffron extracts against acute doxorubicin toxicity in isolated rabbit hearts submitted to ischemia-reperfusion injury. Z Naturforsch C, 69:459-470.
[160] Thoreen CC, Sabatini DM (2009). Rapamycin inhibits mTORC1, but not completely. Autophagy, 5:725-726.
[161] Yu L, McPhee CK, Zheng L, Mardones GA, Rong Y, Peng J, et al. (2010). Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature, 465:942-946.
[162] Zhang D, Contu R, Latronico MV, Zhang J, Rizzi R, Catalucci D, et al. (2010). MTORC1 regulates cardiac function and myocyte survival through 4E-BP1 inhibition in mice. J Clin Invest, 120:2805-2816.
[163] Murakami M, Ichisaka T, Maeda M, Oshiro N, Hara K, Edenhofer F, et al. (2004). mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells. Mol Cell Biol, 24:6710-6718.
[164] Hamacher-Brady A, Brady NR, Gottlieb RA (2006). Enhancing macroautophagy protects against ischemia/reperfusion injury in cardiac myocytes. J Biol Chem, 281:29776-29787.
[165] Paradies G, Paradies V, Ruggiero FM, Petrosillo G (2015). Protective role of melatonin in mitochondrial dysfunction and related disorders. Arch Toxicol, 89:923-939.
[166] Heusch G (2015). Molecular basis of cardioprotection: signal transduction in ischemic pre-, post-, and remote conditioning. Circ Res, 116:674-699.
[167] Shih PH, Yen GC (2007). Differential expressions of antioxidant status in aging rats: the role of transcriptional factor Nrf2 and MAPK signaling pathway. Biogerontology, 8:71-80.
[168] Heusch G, Boengler K, Schulz R (2010). Inhibition of mitochondrial permeability transition pore opening: the Holy Grail of cardioprotection. Basic Res Cardiol, 105:151-154.
[169] Bernardi P, Di Lisa F (2015). The mitochondrial permeability transition pore: molecular nature and role as a target in cardioprotection. J Mol Cell Cardiol, 78:100-106.
[170] Petronilli V, Miotto G, Canton M, Brini M, Colonna R, Bernardi P, et al. (1999). Transient and long-lasting openings of the mitochondrial permeability transition pore can be monitored directly in intact cells by changes in mitochondrial calcein fluorescence. Biophys J, 76:725-734.
[171] Zorov DB, Juhaszova M, Sollott SJ (2014). Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol Rev, 94:909-950.
[172] Bernardi P, Petronilli V (1996). The permeability transition pore as a mitochondrial calcium release channel: a critical appraisal. J Bioenerg Biomembr, 28:131-138.
[173] Hausenloy D, Wynne A, Duchen M, Yellon D (2004). Transient mitochondrial permeability transition pore opening mediates preconditioning-induced protection. Circulation, 109:1714-1717.
[174] Anzell AR, Maizy R, Przyklenk K, Sanderson TH (2017). Mitochondrial Quality Control and Disease: Insights into Ischemia-Reperfusion Injury. Mol Neurobiol.
[175] Nan J, Zhu W, Rahman MS, Liu M, Li D, Su S, et al. (2017). Molecular regulation of mitochondrial dynamics in cardiac disease. Biochim Biophys Acta, 1864:1260-1273.
[176] Oakes SA, Papa FR (2015). The role of endoplasmic reticulum stress in human pathology. Annu Rev Pathol, 10:173-194.
[177] Bronner DN, Abuaita BH, Chen X, Fitzgerald KA, Nunez G, He Y, et al. (2015). Endoplasmic Reticulum Stress Activates the Inflammasome via NLRP3- and Caspase-2-Driven Mitochondrial Damage. Immunity, 43:451-462.
[178] Watorek E, Szymczak M, Boratynska M, Patrzalek D, Klinger M (2011). Cardiovascular risk in kidney transplant recipients receiving mammalian target of rapamycin inhibitors. Transplant Proc, 43:2967-2969.
[1] Fuellen Georg, Jansen Ludger, Cohen Alan A, Luyten Walter, Gogol Manfred, Simm Andreas, Saul Nadine, Cirulli Francesca, Berry Alessandra, Antal Peter, Köhling Rüdiger, Wouters Brecht, Möller Steffen. Health and Aging: Unifying Concepts, Scores, Biomarkers and Pathways[J]. Aging and disease, 2019, 10(4): 883-900.
[2] Xu Dingqiao, Liao Shanting, Li Pei, Zhang Qian, Lv Yan, Fu Xiaowei, Yang Minghua, Wang Junsong, Kong Lingyi. Metabolomics Coupled with Transcriptomics Approach Deciphering Age Relevance in Sepsis[J]. Aging and disease, 2019, 10(4): 854-870.
[3] Wang Min-jun, Chen Jiajia, Chen Fei, Liu Qinggui, Sun Yu, Yan Chen, Yang Tao, Bao Yiwen, Hu Yi-Ping. Rejuvenating Strategies of Tissue-specific Stem Cells for Healthy Aging[J]. Aging and disease, 2019, 10(4): 871-882.
[4] Cho Kyoungjoo. Emerging Roles of Complement Protein C1q in Neurodegeneration[J]. Aging and disease, 2019, 10(3): 652-663.
[5] Gourmelon Robin, Donadio-Andréi Sandrine, Chikh Karim, Rabilloud Muriel, Kuczewski Elisabetta, Gauchez Anne-Sophie, Charrié Anne, Brard Pierre-Yves, Andréani Raphaëlle, Bourre Jean-Cyril, Waterlot Christine, Guédel Domitille, Mayer Anne, Disse Emmanuel, Thivolet Charles, Boullay Hélène Du, Falandry Claire, Gilbert Thomas, François-Joubert Anne, Vignoles Antoine, Ronin Catherine, Bonnefoy Marc. Subclinical Hypothyroidism: is it Really Subclinical with Aging?[J]. Aging and disease, 2019, 10(3): 520-529.
[6] Jin Kunlin. A Microcirculatory Theory of Aging[J]. Aging and disease, 2019, 10(3): 676-683.
[7] Chung Hae Young, Kim Dae Hyun, Lee Eun Kyeong, Chung Ki Wung, Chung Sangwoon, Lee Bonggi, Seo Arnold Y., Chung Jae Heun, Jung Young Suk, Im Eunok, Lee Jaewon, Kim Nam Deuk, Choi Yeon Ja, Im Dong Soon, Yu Byung Pal. Redefining Chronic Inflammation in Aging and Age-Related Diseases: Proposal of the Senoinflammation Concept[J]. Aging and disease, 2019, 10(2): 367-382.
[8] Sarkar Saumyendra N., Russell Ashley E., Engler-Chiurazzi Elizabeth B., Porter Keyana N., Simpkins James W.. MicroRNAs and the Genetic Nexus of Brain Aging, Neuroinflammation, Neurodegeneration, and Brain Trauma[J]. Aging and disease, 2019, 10(2): 329-352.
[9] Cyprien Fabienne, Courtet Philippe, Maller Jerome, Meslin Chantal, Ritchie Karen, Ancelin Marie-Laure, Artero Sylvaine. Increased Serum C-reactive Protein and Corpus Callosum Alterations in Older Adults[J]. Aging and disease, 2019, 10(2): 463-469.
[10] Lana Alberto, Struijk Ellen A., Arias-Fernandez Lucía, Graciani Auxiliadora, Mesas Arthur E., Rodriguez-Artalejo Fernando, Lopez-Garcia Esther. Habitual Meat Consumption and Changes in Sleep Duration and Quality in Older Adults[J]. Aging and disease, 2019, 10(2): 267-277.
[11] Murtha Lucy A., Morten Matthew, Schuliga Michael J., Mabotuwana Nishani S., Hardy Sean A., Waters David W., Burgess Janette K., Ngo Doan TM., Sverdlov Aaron L., Knight Darryl A., Boyle Andrew J.. The Role of Pathological Aging in Cardiac and Pulmonary Fibrosis[J]. Aging and disease, 2019, 10(2): 419-428.
[12] Shetty Ashok K., Upadhya Raghavendra, Madhu Leelavathi N., Kodali Maheedhar. Novel Insights on Systemic and Brain Aging, Stroke, Amyotrophic Lateral Sclerosis, and Alzheimer’s Disease[J]. Aging and disease, 2019, 10(2): 470-482.
[13] Tingting Sui,Di Liu,Tingjun Liu,Jichao Deng,Mao Chen,Yuanyuan Xu,Yuning Song,Hongsheng Ouyang,Liangxue Lai,Zhanjun Li. LMNA-mutated Rabbits: A Model of Premature Aging Syndrome with Muscular Dystrophy and Dilated Cardiomyopathy[J]. Aging and disease, 2019, 10(1): 102-115.
[14] Jianji Xu,Yunjin Zang,Dongjie Liu,Tongwang Yang,Jieling Wang,Yanjun Wang,Xiaoni Liu,Dexi Chen. DRAM is Involved in Hypoxia/Ischemia-Induced Autophagic Apoptosis in Hepatocytes[J]. Aging and disease, 2019, 10(1): 82-93.
[15] Wanying Duan, Yuehua Pu, Haiyan Liu, Jing Jing, Yuesong Pan, Xinying Zou, Yilong Wang, Xingquan Zhao, Chunxue Wang, Yongjun Wang, Ka Sing Lawrence Wong, Ling Wei, Liping Liu, . Association between Leukoaraiosis and Symptomatic Intracranial Large Artery Stenoses and Occlusions: the Chinese Intracranial Atherosclerosis (CICAS) Study[J]. Aging and disease, 2018, 9(6): 1074-1083.
Viewed
Full text


Abstract

Cited

  Shared   
Copyright © 2014 Aging and Disease, All Rights Reserved.
Address: Aging and Disease Editorial Office 3400 Camp Bowie Boulevard Fort Worth, TX76106 USA
Fax: (817) 735-0408 E-mail: editorial@aginganddisease.org
Powered by Beijing Magtech Co. Ltd