Cardiovascular aging: from cellular and molecular changes to therapeutic interventions

Angeliki Vakka , Junco S. Warren , Konstantinos Drosatos

The Journal of Cardiovascular Aging ›› 2023, Vol. 3 ›› Issue (3) : 23

PDF
The Journal of Cardiovascular Aging ›› 2023, Vol. 3 ›› Issue (3) :23 DOI: 10.20517/jca.2023.09
Review

Cardiovascular aging: from cellular and molecular changes to therapeutic interventions

Author information +
History +
PDF

Abstract

Progressive age-induced deterioration in the structure and function of the cardiovascular system involves cardiac hypertrophy, diastolic dysfunction, myocardial fibrosis, arterial stiffness, and endothelial dysfunction. These changes are driven by complex processes that are interconnected, such as oxidative stress, mitochondrial dysfunction, autophagy, inflammation, fibrosis, and telomere dysfunction. In recent years, the advances in research of cardiovascular aging, including the wide use of animal models of cardiovascular aging, elucidated an abundance of cell signaling pathways involved in these processes and brought into sight possible interventions, which span from pharmacological agents, such as metformin, sodium-glucose cotransporter 2-inhibitors, rapamycin, dasatinib and quercetin, to lifestyle changes.

Keywords

Cardiovascular aging / oxidative stress / mitochondrial dysfunction / autophagy / inflammaging / fibrosis

Cite this article

Download citation ▾
Angeliki Vakka, Junco S. Warren, Konstantinos Drosatos. Cardiovascular aging: from cellular and molecular changes to therapeutic interventions. The Journal of Cardiovascular Aging, 2023, 3(3): 23 DOI:10.20517/jca.2023.09

登录浏览全文

4963

注册一个新账户 忘记密码

References

[1]

American Heart Association. 2022 heart disease & stroke statistical update fact sheet global burden of disease. Available from: https://www.heart.org/-/media/PHD-Files-2/Science-News/2/2022-Heart-and-Stroke-Stat-Update/2022-Stat-Update-factsheet-GIobal-Burden-of-Disease.pdf [Last accessed on 20 Apr 2023]

[2]

Yazdanyar A.The burden of cardiovascular disease in the elderly: morbidity, mortality, and costs.Clin Geriatr Med2009;25:563-77, vii PMCID:PMC2797320

[3]

World population prospects 2022 summary of results. Available from: https://www.un.org/development/desa/pd/sites/www.un.org.development.desa.pd/files/wpp2022_summary_of_results.pdf [Last accessed on 20 Apr 2023]

[4]

Levy D,Savage DD,Christiansen JC.Echocardiographically detected left ventricular hypertrophy: prevalence and risk factors. The framingham heart study.Ann Intern Med1988;108:7-13

[5]

Schulman SP,Fleg JL,Becker LC.Age-related decline in left ventricular filling at rest and exercise.Am J Physiol1992;263:H1932-8

[6]

Debessa CR, Mesiano Maifrino LB, Rodrigues de Souza R. Age related changes of the collagen network of the human heart.Mech Ageing Dev2001;122:1049-58

[7]

Chen CH,Nevo E,Maughan WL.Coupled systolic-ventricular and vascular stiffening with age: implications for pressure regulation and cardiac reserve in the elderly.J Am Coll Cardiol1998;32:1221-7

[8]

Egashira K,Hirooka Y.Effects of age on endothelium-dependent vasodilation of resistance coronary artery by acetylcholine in humans.Circulation1993;88:77-81

[9]

Judge S,Smith A,Leeuwenburgh C.Age-associated increases in oxidative stress and antioxidant enzyme activities in cardiac interfibrillar mitochondria: implications for the mitochondrial theory of aging.FASEB J2005;19:419-21

[10]

Chang E.Telomere length and replicative aging in human vascular tissues.Proc Natl Acad Sci USA1995;92:11190-4 PMCID:PMC40597

[11]

Peng L,Liao L.Changes in cell autophagy and apoptosis during age-related left ventricular remodeling in mice and their potential mechanisms.Biochem Biophys Res Commun2013;430:822-6

[12]

Lakatta EG.Cardiovascular regulatory mechanisms in advanced age.Physiol Rev1993;73:413-67

[13]

Zieman SJ,Kass DA.Mechanisms, pathophysiology, and therapy of arterial stiffness.Arterioscler Thromb Vasc Biol2005;25:932-43

[14]

Donato AJ,Silver AE.Direct evidence of endothelial oxidative stress with aging in humans: relation to impaired endothelium-dependent dilation and upregulation of nuclear factor-kappaB.Circ Res2007;100:1659-66

[15]

O’Rourke MF.Mechanical factors in arterial aging: a clinical perspective.J Am Coll Cardiol2007;50:1-13

[16]

Messerli FH.The J-curve between blood pressure and coronary artery disease or essential hypertension: exactly how essential?.J Am Coll Cardiol2009;54:1827-34

[17]

Cheng S,Sullivan LM.Correlates of echocardiographic indices of cardiac remodeling over the adult life course: longitudinal observations from the Framingham Heart Study.Circulation2010;122:570-8 PMCID:PMC2942081

[18]

Lakatta EG.Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part II: the aging heart in health: links to heart disease.Circulation2003;107:346-54

[19]

Olivetti G,Capasso JM.Cardiomyopathy of the aging human heart. Myocyte loss and reactive cellular hypertrophy.Circ Res1991;68:1560-8

[20]

Anversa P,Ricci R,Olivetti G.Myocyte cell loss and myocyte hypertrophy in the aging rat heart.J Am Coll Cardiol1986;8:1441-8

[21]

Sanders D,Groban L.Diastolic dysfunction, cardiovascular aging, and the anesthesiologist.Anesthesiol Clin2009;27:497-517 PMCID:PMC2771111

[22]

Lam CS,Tay WT.Atrial fibrillation in heart failure with preserved ejection fraction: association with exercise capacity, left ventricular filling pressures, natriuretic peptides, and left atrial volume.JACC Heart Fail2017;5:92-8

[23]

Nkomo VT,Skelton TN,Scott CG.Burden of valvular heart diseases: a population-based study.Lancet2006;368:1005-11

[24]

Pomerance A. Ageing changes in human heart valves; 1967. Available from: http://heart.bmj.com [Last accessed on 20 Apr 2023]

[25]

Oomen PJA,van Geemen D.Age-dependent changes of stress and strain in the human heart valve and their relation with collagen remodeling.Acta Biomater2016;29:161-9

[26]

Kim KM,Mergner WJ,Pendergrass RF.Aging changes in the human aortic valve in relation to dystrophic calcification.Hum Pathol1976;7:47-60

[27]

Rahman TT, Elabad AA, Elmenyawy KA, Mortagy AK. Risk factors of degenerative calcification of cardiac valves in the elderly.J Taibah Univ Med Sci2006;1:42-7.Available from: https://core.ac.uk/download/pdf/82023734.pdf

[28]

Wang Y,He C,Song M.Mitochondrial regulation of cardiac aging.Biochim Biophys Acta Mol Basis Dis2019;1865:1853-64

[29]

HARMAN D.Aging: a theory based on free radical and radiation chemistry.J Gerontol1956;11:298-300

[30]

McMurray J,Abdullah I,Dargie HJ.Evidence of oxidative stress in chronic heart failure in humans.Eur Heart J1993;14:1493-8

[31]

Runge MS.The role of oxidative stress in atherosclerosis: the hope and the hype.Trans Am Clin Climatol Assoc1999;110:119-29

[32]

Touyz RM.Oxidative stress and vascular damage in hypertension.Curr Hypertens Rep2000;2:98-105

[33]

Samman Tahhan A,Hayek SS.Association between oxidative stress and atrial fibrillation.Heart Rhythm2017;14:1849-55 PMCID:PMC5817893

[34]

Balaban RS,Finkel T.Mitochondria, oxidants, and aging.Cell2005;120:483-95

[35]

Quan Y,Tian G,Liu X.Mitochondrial ROS-Modulated mtDNA: a potential target for cardiac aging.Oxid Med Cell Longev2020;2020:9423593 PMCID:PMC7139858

[36]

Harman D.The biologic clock: the mitochondria?.J Am Geriatr Soc1972;20:145-7

[37]

Chistiakov DA,Revin VV,Bobryshev YV.Mitochondrial aging and age-related dysfunction of mitochondria.Biomed Res Int2014;2014:238463 PMCID:PMC4003832

[38]

Dai DF,Vermulst M.Overexpression of catalase targeted to mitochondria attenuates murine cardiac aging.Circulation2009;119:2789-97 PMCID:PMC2858759

[39]

Dai DF,Wanagat J.Age-dependent cardiomyopathy in mitochondrial mutator mice is attenuated by overexpression of catalase targeted to mitochondria.Aging Cell2010;9:536-44 PMCID:PMC3265170

[40]

Chiao YA,Sweetwyne M.Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice.Elife2020;9:1-26

[41]

Ago T,Kuroda J,Kitazono T.The NADPH oxidase Nox4 and aging in the heart.Aging2010;2:1012-6 PMCID:PMC3034169

[42]

Vendrov AE,Smith A.NOX4 NADPH oxidase-dependent mitochondrial oxidative stress in aging-associated cardiovascular disease.Antioxid Redox Signal2015;23:1389-409 PMCID:PMC4692134

[43]

Canugovi C,Vendrov AE.Increased mitochondrial NADPH oxidase 4 (NOX4) expression in aging is a causative factor in aortic stiffening.Redox Biol2019;26:101288 PMCID:PMC6831838

[44]

Luo X,Liu Z.Ageing increases cardiac electrical remodelling in rats and mice via NOX4/ROS/CaMKII-Mediated calcium signalling.Oxid Med Cell Longev2022;2022:8538296 PMCID:PMC8979732

[45]

Nemoto S,French S.The mammalian longevity-associated gene product p66shc regulates mitochondrial metabolism.J Biol Chem2006;281:10555-60

[46]

Giorgio M,Orsini F.Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis.Cell2005;122:221-33

[47]

Ljubicic V,Hood DA.Mitochondrial dysfunction is associated with a pro-apoptotic cellular environment in senescent cardiac muscle.Mech Ageing Dev2010;131:79-88

[48]

Francia P,Bachschmid M.Deletion of p66shc gene protects against age-related endothelial dysfunction.Circulation2004;110:2889-95

[49]

Mengozzi A,Paneni F.Targeting SIRT1 rescues age- and obesity-induced microvascular dysfunction in ex vivo human vessels.Circ Res2022;131:476-91 PMCID:PMC9426744

[50]

Chen HZ,Liu DP.Cross-talk between SIRT1 and p66Shc in vascular diseases.Trends Cardiovasc Med2013;23:237-41

[51]

Gano LB,Pasha HM,Sindler AL.The SIRT1 activator SRT1720 reverses vascular endothelial dysfunction, excessive superoxide production, and inflammation with aging in mice.Am J Physiol Heart Circ Physiol2014;307:H1754-63 PMCID:PMC4269699

[52]

Xiong Y,Montani JP,Ming XF.Arginase-II induces vascular smooth muscle cell senescence and apoptosis through p66Shc and p53 independently of its l-arginine ureahydrolase activity: implications for atherosclerotic plaque vulnerability.J Am Heart Assoc2013;2:e000096 PMCID:PMC3828809

[53]

Yepuri G,Xiong Y.Positive crosstalk between arginase-II and S6K1 in vascular endothelial inflammation and aging.Aging Cell2012;11:1005-16

[54]

Xiong Y,Montani JP,Yang Z.Arginase-II deficiency extends lifespan in mice.Front Physiol2017;8:682 PMCID:PMC5596098

[55]

Ungvari Z,Gautam T.Age-associated vascular oxidative stress, Nrf2 dysfunction, and NF-{kappa}B activation in the nonhuman primate Macaca mulatta.J Gerontol A Biol Sci Med Sci2011;66:866-75

[56]

Yang X,Ding L,Qu C.The Role of Nrf2 in D-galactose-induced cardiac aging in mice: involvement of oxidative stress.Gerontology2021;67:91-100

[57]

Chen K,Sun QW,Ullah M.Klotho deficiency causes heart aging via impairing the Nrf2-GR pathway.Circ Res2021;128:492-507 PMCID:PMC8782577

[58]

Pedersen L,Brasen CL.Soluble serum Klotho levels in healthy subjects. Comparison of two different immunoassays.Clin Biochem2013;46:1079-83

[59]

Nakano M,Katoh H.Age-related accumulation of lipofuscin in myocardium of Japanese monkey (Macaca fuscata).Mech Ageing Dev1989;49:41-8

[60]

Taneike M,Nakai A.Inhibition of autophagy in the heart induces age-related cardiomyopathy.Autophagy2010;6:600-6

[61]

Weichhart T.mTOR as regulator of lifespan, aging, and cellular senescence: a mini-review.Gerontology2018;64:127-34 PMCID:PMC6089343

[62]

Loewith R,Wullschleger S.Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control.Mol Cell2002;10:457-68

[63]

Hua Y,Ceylan-Isik AF,Nunn JM.Chronic akt activation accentuates aging-induced cardiac hypertrophy and myocardial contractile dysfunction: role of autophagy.Basic Res Cardiol2011;106:1173-91

[64]

Lesniewski LA,Walker AE.Dietary rapamycin supplementation reverses age-related vascular dysfunction and oxidative stress, while modulating nutrient-sensing, cell cycle, and senescence pathways.Aging Cell2017;16:17-26 PMCID:PMC5242306

[65]

Zhou J,Ahmad F.GSK-3α is a central regulator of age-related pathologies in mice.J Clin Invest2013;123:1821-32 PMCID:PMC3613907

[66]

Shi J,Yang Y.Disruption of both ROCK1 and ROCK2 genes in cardiomyocytes promotes autophagy and reduces cardiac fibrosis during aging.FASEB J2019;33:7348-62 PMCID:PMC6529334

[67]

Li Y,Sladojevic N,Liao JK.Vascular stiffening mediated by Rho-associated coiled-coil containing kinase isoforms.J Am Heart Assoc2021;10:e022568 PMCID:PMC8751888

[68]

Balgi AD,Donohue E.Screen for chemical modulators of autophagy reveals novel therapeutic inhibitors of mTORC1 signaling.PLoS One2009;4:e7124 PMCID:PMC2742736

[69]

Chang K,Liu Y.TGFB-INHB/activin signaling regulates age-dependent autophagy and cardiac health through inhibition of MTORC2.Autophagy2020;16:1807-22 PMCID:PMC8386626

[70]

Matsui Y,Qu X.Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy.Circ Res2007;100:914-22

[71]

Li Y,Yao F.AMPK inhibits cardiac hypertrophy by promoting autophagy via mTORC1.Arch Biochem Biophys2014;558:79-86

[72]

Turdi S,Li J.AMP-activated protein kinase deficiency exacerbates aging-induced myocardial contractile dysfunction.Aging Cell2010;9:592-606 PMCID:PMC2910211

[73]

Lesniewski LA,Durrant JR,Seals DR.Sustained activation of AMPK ameliorates age-associated vascular endothelial dysfunction via a nitric oxide-independent mechanism.Mech Ageing Dev2012;133:368-71 PMCID:PMC3359767

[74]

Wang L,Sun W.Cardiomyocyte-specific deletion of Sirt1 gene sensitizes myocardium to ischaemia and reperfusion injury.Cardiovasc Res2018;114:805-21 PMCID:PMC5909650

[75]

Wang S,Ren J.Double knockout of Akt2 and AMPK predisposes cardiac aging without affecting lifespan: role of autophagy and mitophagy.Biochim Biophys Acta Mol Basis Dis2019;1865:1865-75 PMCID:PMC6530587

[76]

Wu NN,Ren J.Mitophagy, mitochondrial dynamics, and homeostasis in cardiovascular aging.Oxid Med Cell Longev2019;2019:9825061 PMCID:PMC6875274

[77]

Gao B,Lv P,Sun S.Parkin overexpression alleviates cardiac aging through facilitating K63-polyubiquitination of TBK1 to facilitate mitophagy.Biochim Biophys Acta Mol Basis Dis2021;1867:165997

[78]

Hoshino A,Okawa Y.Cytosolic p53 inhibits Parkin-mediated mitophagy and promotes mitochondrial dysfunction in the mouse heart.Nat Commun2013;4:2308

[79]

Rowe JW,Pallotta JA.Characterization of the insulin resistance of aging.J Clin Invest1983;71:1581-7 PMCID:PMC370364

[80]

Fink RI,Griffin J.Mechanisms of insulin resistance in aging.J Clin Invest1983;71:1523-35 PMCID:PMC370358

[81]

Wang L,Markovich R,Wang PH.Regulation of cardiomyocyte apoptotic signaling by insulin-like growth factor I.Circ Res1998;83:516-22

[82]

Ren J,Sowers JR.Insulin-like growth factor I as a cardiac hormone: physiological and pathophysiological implications in heart disease.J Mol Cell Cardiol1999;31:2049-61

[83]

Abdellatif M,Heberle AM.Fine-tuning cardiac insulin-like growth factor 1 receptor signaling to promote health and longevity.Circulation2022;145:1853-66 PMCID:PMC9203038

[84]

Moellendorf S,Peiseler L.IGF-IR signaling attenuates the age-related decline of diastolic cardiac function.Am J Physiol Endocrinol Metab2012;303:E213-22

[85]

Inuzuka Y,Kawashima T.Suppression of phosphoinositide 3-kinase prevents cardiac aging in mice.Circulation2009;120:1695-703

[86]

Steenman M.Cardiac aging and heart disease in humans.Biophys Rev2017;9:131-7 PMCID:PMC5418492

[87]

Babušíková E,Dobrota D,Kaplán P.Age-associated changes in Ca2+-ATPase and oxidative damage in sarcoplasmic reticulum of rat heart.Physiol Res2012;61:453-60

[88]

Qin F,Lancel S.Hydrogen peroxide-mediated SERCA cysteine 674 oxidation contributes to impaired cardiac myocyte relaxation in senescent mouse heart.J Am Heart Assoc2013;2:e000184

[89]

Upadhya B,Cheng CP.Heart failure with preserved ejection fraction in the elderly: scope of the problem.J Mol Cell Cardiol2015;83:73-87 PMCID:PMC5300019

[90]

Yeh CH,Kao CH.Mitochondria and calcium homeostasis: Cisd2 as a big player in cardiac ageing.Int J Mol Sci2020;21:9238 PMCID:PMC7731030

[91]

Yeh CH,Hsiung SY.Cisd2 is essential to delaying cardiac aging and to maintaining heart functions.PLoS Biol2019;17:e3000508 PMCID:PMC6799937

[92]

Hunter WG,McGarrah RW 3rd,Shah SH.Metabolic dysfunction in heart failure: diagnostic, prognostic, and pathophysiologic insights from metabolomic profiling.Curr Heart Fail Rep2016;13:119-31 PMCID:PMC5504685

[93]

Schmidt DR,Kirsch DG,Vander Heiden MG.Metabolomics in cancer research and emerging applications in clinical oncology.CA Cancer J Clin2021;71:333-58 PMCID:PMC8298088

[94]

Wilkins JM.Application of metabolomics in alzheimer’s disease.Front Neurol2017;8:719 PMCID:PMC5770363

[95]

de Lucia C,Wang L.Effects of myocardial ischemia/reperfusion injury on plasma metabolomic profile during aging.Aging Cell2021;20:e13284 PMCID:PMC7811846

[96]

Seo C,Kim Y.Metabolomic study of aging in mouse plasma by gas chromatography-mass spectrometry.J Chromatogr B Analyt Technol Biomed Life Sci2016;1025:1-6

[97]

Johnson LC,Aguirre BF.The plasma metabolome as a predictor of biological aging in humans.Geroscience2019;41:895-906 PMCID:PMC6925078

[98]

De Favari Signini É,Rehder-Santos P.Integrative perspective of the healthy aging process considering the metabolome, cardiac autonomic modulation and cardiorespiratory fitness evaluated in age groups.Sci Rep2022;12:21314 PMCID:PMC9734749

[99]

Pallister T,Martin TC.Hippurate as a metabolomic marker of gut microbiome diversity: Modulation by diet and relationship to metabolic syndrome.Sci Rep2017;7:13670 PMCID:PMC5651863

[100]

Ho KJ,Kulkarni R.Plasma gut microbe-derived metabolites associated with peripheral artery disease and major adverse cardiac events.Microorganisms2022;10:2065 PMCID:PMC9609963

[101]

Franceschi C,Valensin S.Inflamm-aging. an evolutionary perspective on immunosenescence.Ann N Y Acad Sci2000;908:244-54

[102]

Liberale L,Tardif JC,Camici GG.Inflamm-ageing: the role of inflammation in age-dependent cardiovascular disease.Eur Heart J2020;41:2974-82 PMCID:PMC7453832

[103]

Puspitasari YM,Schwarz L,Liberale L.Modern concepts in cardiovascular disease: inflamm-aging.Front Cell Dev Biol2022;10:882211 PMCID:PMC9158480

[104]

Tong Y,Cai L,Liu J.NLRP3 inflammasome and its central role in the cardiovascular diseases.Oxid Med Cell Longev2020;2020:4293206 PMCID:PMC7180412

[105]

Youm YH,McCabe LR.Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging.Cell Metab2013;18:519-32 PMCID:PMC4017327

[106]

Swanson KV,Ting JP.The NLRP3 inflammasome: molecular activation and regulation to therapeutics.Nat Rev Immunol2019;19:477-89 PMCID:PMC7807242

[107]

Liao LZ,Wang SS,Zhao CL.NLRP3 inflammasome activation contributes to the pathogenesis of cardiocytes aging.Aging2021;13:20534-51 PMCID:PMC8436929

[108]

Yin Y,Liu W,Sun G.Vascular endothelial cells senescence is associated with NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation via reactive oxygen species (ROS)/thioredoxin-interacting protein (TXNIP) pathway.Int J Biochem Cell Biol2017;84:22-34

[109]

Liu H,Wu Z.Loss of toll-like receptor 4 ameliorates cardiovascular dysfunction in aged mice.Immun Ageing2021;18:42 PMCID:PMC8569991

[110]

Wang Y,Bao Y.The serum soluble Klotho alleviates cardiac aging and regulates M2a/M2c macrophage polarization via inhibiting TLR4/Myd88/NF-κB pathway.Tissue Cell2022;76:101812

[111]

Csiszar A,Labinskyy N,Rivera A.Resveratrol attenuates TNF-alpha-induced activation of coronary arterial endothelial cells: role of NF-kappaB inhibition.Am J Physiol Heart Circ Physiol2006;291:H1694-9

[112]

Csiszar A,Lakatta EG.Inflammation and endothelial dysfunction during aging: role of NF-kappaB.J Appl Physiol2008;105:1333-41 PMCID:PMC2576023

[113]

Cong W,Lv L.Metallothionein prevents age-associated cardiomyopathy via inhibiting NF-κB pathway activation and associated nitrative damage to 2-OGD.Antioxid Redox Signal2016;25:936-52

[114]

Wang X,Ong H.MG53 suppresses NF-κB activation to mitigate age-related heart failure.JCI Insight2021;6:e148375 PMCID:PMC8492351

[115]

Chiao YA,Zhang J.Multi-analyte profiling reveals matrix metalloproteinase-9 and monocyte chemotactic protein-1 as plasma biomarkers of cardiac aging.Circ Cardiovasc Genet2011;4:455-62 PMCID:PMC3158732

[116]

Ma Y,Clark R.Deriving a cardiac ageing signature to reveal MMP-9-dependent inflammatory signalling in senescence.Cardiovasc Res2015;106:421-31 PMCID:PMC4498140

[117]

Horn MA.Aging and the cardiac collagen matrix: novel mediators of fibrotic remodelling.J Mol Cell Cardiol2016;93:175-85 PMCID:PMC4945757

[118]

Kajstura J,Sarangarajan R.Necrotic and apoptotic myocyte cell death in the aging heart of Fischer 344 rats.Am J Physiol1996;271:H1215-28

[119]

Porter KE.Cardiac fibroblasts: at the heart of myocardial remodeling.Pharmacol Ther2009;123:255-78

[120]

Camelliti P,Kohl P.Structural and functional characterisation of cardiac fibroblasts.Cardiovasc Res2005;65:40-51

[121]

Meyer K,Ramanujam D,Sarikas A.Essential role for premature senescence of myofibroblasts in myocardial fibrosis.J Am Coll Cardiol2016;67:2018-28

[122]

Brooks WW.Myocardial fibrosis in transforming growth factor β1 heterozygous mice.J Mol Cell Cardiol2000;32:187-95

[123]

Derangeon M,Cerpa CO.Transforming growth factor β receptor inhibition prevents ventricular fibrosis in a mouse model of progressive cardiac conduction disease.Cardiovasc Res2017;113:464-74

[124]

Cieslik KA,Crawford JR,Entman ML.Adverse fibrosis in the aging heart depends on signaling between myeloid and mesenchymal cells; role of inflammatory fibroblasts.J Mol Cell Cardiol2014;70:56-63 PMCID:PMC3995828

[125]

Frangogiannis NG.Transforming growth factor-β in myocardial disease.Nat Rev Cardiol2022;19:435-55

[126]

Wang M,Walker SJ,Lakatta EG.Involvement of NADPH oxidase in age-associated cardiac remodeling.J Mol Cell Cardiol2010;48:765-72 PMCID:PMC2877878

[127]

Yoon HE,Kim MY.Age-Associated changes in the vascular renin-angiotensin system in mice.Oxid Med Cell Longev2016;2016:6731093

[128]

Kim SK,DuPont JJ.Smooth muscle cell-mineralocorticoid receptor as a mediator of cardiovascular stiffness with aging.Hypertension2018;71:609-21

[129]

Friebel J,Witkowski M.Protease-activated receptor 2 deficiency mediates cardiac fibrosis and diastolic dysfunction.Eur Heart J2019;40:3318-32

[130]

Maruyama K,McGuire JJ.Age-related changes to vascular protease-activated receptor 2 in metabolic syndrome: a relationship between oxidative stress, receptor expression, and endothelium-dependent vasodilation.Can J Physiol Pharmacol2017;95:356-64

[131]

Zakian VA.Telomeres: beginning to understand the end.Science1995;270:1601-7

[132]

d’Adda di Fagagna F,Clay-Farrace L.A DNA damage checkpoint response in telomere-initiated senescence.Nature2003;426:194-8

[133]

Rossiello F,Passos JF.Telomere dysfunction in ageing and age-related diseases.Nat Cell Biol2022;24:135-47 PMCID:PMC8985209

[134]

Zhan Y.Telomere length and cardiovascular disease risk.Curr Opin Cardiol2019;34:270-4

[135]

Sahin E,Liesa M.Telomere dysfunction induces metabolic and mitochondrial compromise.Nature2011;470:359-65 PMCID:PMC3741661

[136]

Moslehi J,Sahin E.Telomeres and mitochondria in the aging heart.Circ Res2012;110:1226-37 PMCID:PMC3718635

[137]

Leri A,Zacheo A.Ablation of telomerase and telomere loss leads to cardiac dilatation and heart failure associated with p53 upregulation.EMBO J2003;22:131-9 PMCID:PMC140062

[138]

Bhayadia R,Melk A.Senescence-Induced oxidative stress causes endothelial dysfunction.J Gerontol A Biol Sci Med Sci2016;71:161-9

[139]

Cai Y,Song E.Deficiency of telomere-associated repressor activator protein 1 precipitates cardiac aging in mice via p53/PPARα signaling.Theranostics2021;11:4710-27 PMCID:PMC7978321

[140]

Shay JW.Senescence and immortalization: role of telomeres and telomerase.Carcinogenesis2005;26:867-74

[141]

Calado RT.Telomere dynamics in mice and humans.Semin Hematol2013;50:165-74 PMCID:PMC3742037

[142]

Yan M,Xu K.Cardiac aging: from basic research to therapeutics.Oxid Med Cell Longev2021;2021:9570325 PMCID:PMC7969106

[143]

Anderson R,Maggiorani D.Length-independent telomere damage drives post-mitotic cardiomyocyte senescence.EMBO J2019;38

[144]

Cieslik KA,Carlson S,Trial J.Immune-inflammatory dysregulation modulates the incidence of progressive fibrosis and diastolic stiffness in the aging heart.J Mol Cell Cardiol2011;50:248-56 PMCID:PMC3019252

[145]

Zhang TY,Wang T.Effect of aging and sex on cardiovascular structure and function in wildtype mice assessed with echocardiography.Sci Rep2021;11:22800 PMCID:PMC8611093

[146]

Roth GS,Ottinger MA,Lane MA.Aging in rhesus monkeys: relevance to human health interventions.Science2004;305:1423-6.

[147]

Takeda T,Higuchi K,Akiguchi I.A novel murine model of aging, Senescence-Accelerated Mouse (SAM).Arch Gerontol Geriatr1994;19:185-92

[148]

Reed AL,Sorescu D.Diastolic dysfunction is associated with cardiac fibrosis in the senescence-accelerated mouse.Am J Physiol Heart Circ Physiol2011;301:H824-31 PMCID:PMC3191096

[149]

Matsumoto C,Emathinger J.Short telomeres induce p53 and autophagy and modulate age-associated changes in cardiac progenitor cell fate.Stem Cells2018;36:868-80 PMCID:PMC5992026

[150]

Wang SS,Ke ZZ.D-galactose-induced cardiac ageing: A review of model establishment and potential interventions.J Cell Mol Med2022;26:5335-59 PMCID:PMC9639053

[151]

Bo-Htay C,Higgins L.Aging induced by D-galactose aggravates cardiac dysfunction via exacerbating mitochondrial dysfunction in obese insulin-resistant rats.Geroscience2020;42:233-49 PMCID:PMC7031455

[152]

Bo-Htay C,Jaiwongkam T.Hyperbaric oxygen therapy effectively alleviates D-galactose-induced-age-related cardiac dysfunction via attenuating mitochondrial dysfunction in pre-diabetic rats.Aging2021;13:10955-72 PMCID:PMC8109141

[153]

Yang L,Wang X.Curcumin alleviates D-galactose-induced cardiomyocyte senescence by promoting autophagy via the SIRT1/AMPK/mTOR pathway.Evid Based Complement Alternat Med2022;2022:2990843 PMCID:PMC9308546

[154]

Lin HJ,Chang YM.D-galactose-induced toxicity associated senescence mitigated by alpinate oxyphyllae fructus fortified adipose-derived mesenchymal stem cells.Environ Toxicol2020:86-94

[155]

Brayson D.Current insights into LMNA cardiomyopathies: existing models and missing LINCs.Nucleus2017;8:17-33 PMCID:PMC5287098

[156]

Zaghini A,Barboni C.Long term breeding of the Lmna G609G progeric mouse: characterization of homozygous and heterozygous models.Exp Gerontol2020;130:110784

[157]

Fanjul V,Camafeita E.Identification of common cardiometabolic alterations and deregulated pathways in mouse and pig models of aging.Aging Cell2020;19:e13203 PMCID:PMC7511870

[158]

Woodall BP,Najor RH.Parkin does not prevent accelerated cardiac aging in mitochondrial DNA mutator mice.JCI Insight2019;5:127713 PMCID:PMC6542612

[159]

Li H,Rhee J,Roh JD.Targeting age-related pathways in heart failure.Circ Res2020;126:533-51 PMCID:PMC7041880

[160]

Koczor CA,Fields E.Mitochondrial polymerase gamma dysfunction and aging cause cardiac nuclear DNA methylation changes.Physiol Genomics2016;48:274-80 PMCID:PMC4824151

[161]

Golob MJ,Wang Z.Mitochondria DNA mutations cause sex-dependent development of hypertension and alterations in cardiovascular function.J Biomech2015;48:405-12 PMCID:PMC4306604

[162]

Levy WC,Abrass IB,Stratton JR.Endurance exercise training augments diastolic filling at rest and during exercise in healthy young and older men.Circulation1993;88:116-26

[163]

Seals DR,Spina RJ,Schechtman KB.Enhanced left ventricular performance in endurance trained older men.Circulation1994;89:198-205

[164]

Schilke JM.Slowing the aging process with physical activity.J Gerontol Nurs1991;17:4-8

[165]

Clayton ZS,Darvish S.Promoting healthy cardiovascular aging: emerging topics.J Cardiovasc Aging2022;2:43 PMCID:PMC9632540

[166]

Fujimoto N,Hastings JL.Cardiovascular effects of 1 year of progressive and vigorous exercise training in previously sedentary individuals older than 65 years of age.Circulation2010;122:1797-805 PMCID:PMC3730488

[167]

Roh JD,Yu A.Exercise training reverses cardiac aging phenotypes associated with heart failure with preserved ejection fraction in male mice.Aging Cell2020;19:e13159 PMCID:PMC7294786

[168]

Lerchenmüller C,Mittag S.Restoration of cardiomyogenesis in aged mouse hearts by voluntary exercise.Circulation2022;146:412-26 PMCID:PMC9357140

[169]

Elhelaly W.Exercise induces cardiomyogenesis in the aged heart.J Cardiovasc Aging2023;3:18

[170]

Safdar A,Ogborn DI.Endurance exercise rescues progeroid aging and induces systemic mitochondrial rejuvenation in mtDNA mutator mice.Proc Natl Acad Sci USA2011;108:4135-40 PMCID:PMC3053975

[171]

Yeo HS.Effects of different types of exercise training on angiogenic responses in the left ventricular muscle of aged rats.Exp Gerontol2022;158:111650

[172]

Wu T,Wu B.Hydrogen sulfide reduces recruitment of CD11b+Gr-1+ cells in mice with myocardial infarction.Cell Transplant2017;26:753-64 PMCID:PMC5657722

[173]

Snijder PM,de Boer RA.Exogenous administration of thiosulfate, a donor of hydrogen sulfide, attenuates angiotensin II-induced hypertensive heart disease in rats.Br J Pharmacol2015;172:1494-504 PMCID:PMC4369259

[174]

Meng G,Xiao Y.Hydrogen sulfide donor GYY4137 protects against myocardial fibrosis.Oxid Med Cell Longev2015;2015:691070 PMCID:PMC4442292

[175]

Ma N,Xia T,Wang XZ.Chronic aerobic exercise training alleviates myocardial fibrosis in aged rats through restoring bioavailability of hydrogen sulfide.Can J Physiol Pharmacol2018;96:902-8

[176]

Speakman JR.Caloric restriction.Mol Aspects Med2011;32:159-221

[177]

Sheng Y,Huang M.Opposing effects on cardiac function by calorie restriction in different-aged mice.Aging Cell2017;16:1155-67 PMCID:PMC5595678

[178]

Shinmura K,Sano M.Impact of long-term caloric restriction on cardiac senescence: caloric restriction ameliorates cardiac diastolic dysfunction associated with aging.J Mol Cell Cardiol2011;50:117-27

[179]

Granado M,Martín-Carro B.Caloric restriction attenuates aging-induced cardiac insulin resistance in male Wistar rats through activation of PI3K/Akt pathway.Nutr Metab Cardiovasc Dis2019;29:97-105

[180]

Donato AJ,Magerko KA.Life-long caloric restriction reduces oxidative stress and preserves nitric oxide bioavailability and function in arteries of old mice.Aging Cell2013;12:772-83 PMCID:PMC3772986

[181]

Madeo F,Hofer SJ.Caloric restriction mimetics against age-associated disease: targets, mechanisms, and therapeutic potential.Cell Metab2019;29:592-610

[182]

Pang L,Lian X.Caloric restriction-mimetics for the reduction of heart failure risk in aging heart: with consideration of gender-related differences.Mil Med Res2022;9:33 PMCID:PMC9252041

[183]

Börzsei D,Szabó R.Resveratrol as a promising polyphenol in age-associated cardiac alterations.Oxid Med Cell Longev2022;2022:7911222 PMCID:PMC9233576

[184]

Torregrosa-Muñumer R,Fernández-Tresguerres .Resveratrol supplementation at old age reverts changes associated with aging in inflammatory, oxidative and apoptotic markers in rat heart.Eur J Nutr2021;60:2683-93

[185]

Sin TK,Yung BY.Resveratrol protects against doxorubicin-induced cardiotoxicity in aged hearts through the SIRT1-USP7 axis.J Physiol2015;593:1887-99 PMCID:PMC4405749

[186]

Zhang L,Yan L,Xie H.Resveratrol ameliorates cardiac remodeling in a murine model of heart failure with preserved ejection fraction.Front Pharmacol2021;12:646240 PMCID:PMC8225267

[187]

Fleenor BS,Marvi NK.Curcumin ameliorates arterial dysfunction and oxidative stress with aging.Exp Gerontol2013;48:269-76 PMCID:PMC3557759

[188]

Santos-Parker JR,Bassett CJ,Chonchol MB.Curcumin supplementation improves vascular endothelial function in healthy middle-aged and older adults by increasing nitric oxide bioavailability and reducing oxidative stress.Aging2017;9:187-208 PMCID:PMC5310664

[189]

LaRocca TJ,Hearon CM Jr.The autophagy enhancer spermidine reverses arterial aging.Mech Ageing Dev2013;134:314-20 PMCID:PMC3700669

[190]

Eisenberg T,Schroeder S.Cardioprotection and lifespan extension by the natural polyamine spermidine.Nat Med2016;22:1428-38 PMCID:PMC5806691

[191]

Zhang H,Li L.Spermine and spermidine reversed age-related cardiac deterioration in rats.Oncotarget2017;8:64793-808 PMCID:PMC5630292

[192]

Wang J,Wang J.Spermidine alleviates cardiac aging by improving mitochondrial biogenesis and function.Aging2020;12:650-71 PMCID:PMC6977682

[193]

Bose C,Singh P.Sulforaphane prevents age-associated cardiac and muscular dysfunction through Nrf2 signaling.Aging Cell2020;19:e13261 PMCID:PMC7681049

[194]

Mehdizadeh M,Thorin E,Nattel S.The role of cellular senescence in cardiac disease: basic biology and clinical relevance.Nat Rev Cardiol2022;19:250-64

[195]

Salerno N,Scalise M.Pharmacological clearance of senescent cells improves cardiac remodeling and function after myocardial infarction in female aged mice.Mech Ageing Dev2022;208:111740

[196]

Roos CM,Palmer AK.Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice.Aging Cell2016;15:973-7 PMCID:PMC5013022

[197]

Zhu Y,Pirtskhalava T.The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs.Aging Cell2015;14:644-58

[198]

Flynn JM,Zambataro CA.Late-life rapamycin treatment reverses age-related heart dysfunction.Aging Cell2013;12:851-62 PMCID:PMC4098908

[199]

Urfer SR,Mailheau S.A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs.Geroscience2017;39:117-27 PMCID:PMC5411365

[200]

Quarles E,Chiao YA.Rapamycin persistently improves cardiac function in aged, male and female mice, even following cessation of treatment.Aging Cell2020;19:e13086 PMCID:PMC6996961

[201]

Ramos FJ,Garelick MG.Rapamycin reverses elevated mTORC1 signaling in lamin A/C-deficient mice, rescues cardiac and skeletal muscle function, and extends survival.Sci Transl Med2012;4:144ra103 PMCID:PMC3613228

[202]

Zhang ZD,Lin JR.Genetics of extreme human longevity to guide drug discovery for healthy ageing.Nat Metab2020;2:663-72 PMCID:PMC7912776

[203]

Justice JN,Robbins PD.Development of clinical trials to extend healthy lifespan.Cardiovasc Endocrinol Metab2018;7:80-3 PMCID:PMC6428447

[204]

Kulkarni AS,Anghel V.Metformin regulates metabolic and nonmetabolic pathways in skeletal muscle and subcutaneous adipose tissues of older adults.Aging Cell2018;17:e12723 PMCID:PMC5847877

[205]

Tai S,Zhou Y.Metformin suppresses vascular smooth muscle cell senescence by promoting autophagic flux.J Adv Res2022;41:205-18 PMCID:PMC9637479

[206]

Chen Q,Hu Y.Chronic metformin treatment decreases cardiac injury during ischemia-reperfusion by attenuating endoplasmic reticulum stress with improved mitochondrial function.Aging2021;13:7828-45 PMCID:PMC8034968

[207]

Zhu X,Liu Z.Effect of metformin on cardiac metabolism and longevity in aged female mice.Front Cell Dev Biol2020;8:626011 PMCID:PMC7877555

[208]

La Grotta R,Olivieri F.Anti-inflammatory effect of SGLT-2 inhibitors via uric acid and insulin.Cell Mol Life Sci2022;79:273 PMCID:PMC9064844

[209]

Evans M,Davies S,Strain WD.The role of sodium-glucose co-transporter-2 inhibitors in frail older adults with or without type 2 diabetes mellitus.Age Ageing2022;51:1-8

[210]

Soares RN,Cabral-Amador FJ.SGLT2 inhibition attenuates arterial dysfunction and decreases vascular F-actin content and expression of proteins associated with oxidative stress in aged mice.Geroscience2022;44:1657-75 PMCID:PMC9213629

[211]

Madonna R,Minnucci I,Pierdomenico DS.Empagliflozin reduces the senescence of cardiac stromal cells and improves cardiac function in a murine model of diabetes.J Cell Mol Med2020;24:12331-40 PMCID:PMC7687009

[212]

Shiraki A,Shimizu T,Yokota T.Empagliflozin improves cardiac mitochondrial function and survival through energy regulation in a murine model of heart failure.Eur J Pharmacol2022;931:175194

[213]

Withaar C,Markousis-Mavrogenis G.The effects of liraglutide and dapagliflozin on cardiac function and structure in a multi-hit mouse model of heart failure with preserved ejection fraction.Cardiovasc Res2021;117:2108-24 PMCID:PMC8318109

[214]

Olgar Y,Degirmenci S.Ageing-associated increase in SGLT2 disrupts mitochondrial/sarcoplasmic reticulum Ca2+ homeostasis and promotes cardiac dysfunction.J Cell Mol Med2020;24:8567-78 PMCID:PMC7412693

[215]

Anker SD,Filippatos G.EMPEROR-Preserved trial investigatorsempagliflozin in heart failure with a preserved ejection fraction.N Engl J Med2021;385:1451-61

[216]

Solomon SD,Claggett B.DELIVER trial committees and investigatorsdapagliflozin in heart failure with mildly reduced or preserved ejection fraction.N Engl J Med2022;387:1089-98

[217]

Kane AE,Heinze-Milne S,Grandy SA.Maladaptive Changes associated with cardiac aging are sex-specific and graded by frailty and inflammation in C57BL/6 mice.J Gerontol A Biol Sci Med Sci2021;76:233-43 PMCID:PMC7812442

[218]

De Moudt S,Neutel C.Progressive aortic stiffness in aging C57Bl/6 mice displays altered contractile behaviour and extracellular matrix changes.Commun Biol2022;5:605 PMCID:PMC9203497

[219]

Forman DE,Azhar G,Wei JY.Cardiac morphology and function in senescent rats: gender-related differences.J Am Coll Cardiol1997;30:1872-7

[220]

Chou C.Modeling heart failure with preserved ejection fraction in rodents: where do we stand?.Front Drug Discov2022;2:948407

[221]

Walker EM,Mangiarua EI.Age-associated changes in hearts of male Fischer 344/Brown Norway F1 rats.Ann Clin Lab Sci2006;36:427-38.

[222]

Karuppagounder V,Babu SS.The senescence accelerated mouse prone 8 (SAMP8): a novel murine model for cardiac aging.Ageing Res Rev2017;35:291-6

[223]

Mounkes LC,Rottman JN.Expression of an LMNA-N195K variant of A-type lamins results in cardiac conduction defects and death in mice.Hum Mol Genet2005;14:2167-80

[224]

Arimura T,Massart C.Mouse model carrying H222P-Lmna mutation develops muscular dystrophy and dilated cardiomyopathy similar to human striated muscle laminopathies.Hum Mol Genet2005;14:155-69

[225]

Baker DJ,Tchkonia T.Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders.Nature2011;479:232-6 PMCID:PMC3468323

[226]

Matsumoto T,d’Uscio LV,Katusic ZS.Aging-associated vascular phenotype in mutant mice with low levels of BubR1.Stroke2007;38:1050-6

[227]

Lewis W,Kohler JJ.Decreased mtDNA, oxidative stress, cardiomyopathy, and death from transgenic cardiac targeted human mutant polymerase gamma.Lab Invest2007;87:326-35

[228]

Gorr MW,Marcho LM.Molecular signature of cardiac remodeling associated with Polymerase Gamma mutation.Life Sci2022;298:120469 PMCID:PMC9158136

[229]

Acehan D,Houtkooper RH.Cardiac and skeletal muscle defects in a mouse model of human Barth syndrome.J Biol Chem2011;286:899-908 PMCID:PMC3020775

[230]

Nojiri H,Funakoshi M.Oxidative stress causes heart failure with impaired mitochondrial respiration.J Biol Chem2006;281:33789-801

[231]

Blasco MA,Hande MP.Telomere shortening and tumor formation by mouse cells lacking telomerase RNA.Cell1997;91:25-34

[232]

Wong LS,de Boer RA,van Veldhuisen DJ.Telomere biology in cardiovascular disease: the TERC-/- mouse as a model for heart failure and ageing.Cardiovasc Res2009;81:244-52

[233]

Din S,Johnson B.Metabolic dysfunction consistent with premature aging results from deletion of Pim kinases.Circ Res2014;115:376-87 PMCID:PMC4254755

[234]

Sikka G,Steppan J.Interleukin 10 knockout frail mice develop cardiac and vascular dysfunction with increased age.Exp Gerontol2013;48:128-35 PMCID:PMC3744178

[235]

Kamihara TK,Nishimura KN,Murohara TM.P6548Werner syndrome gene mutation is responsible for cardiac aging with transition from diastolic to systolic LV dysfunction.Eur Heart J2018;39:6548

AI Summary AI Mindmap
PDF

76

Accesses

0

Citation

Detail

Sections
Recommended

AI思维导图

/