Epigenetic dysregulation in cardiovascular aging and disease

Abstract

Cardiovascular disease (CVD) is the leading cause of mortality and morbidity for all sexes, racial and ethnic groups. Age, and its associated physiological and pathological consequences, exacerbate CVD incidence and progression, while modulation of biological age with interventions track with cardiovascular health. Despite the strong link between aging and CVD, surprisingly few studies have directly investigated heart failure and vascular dysfunction in aged models and subjects. Nevertheless, strong correlations have been found between heart disease, atherosclerosis, hypertension, fibrosis, and regeneration efficiency with senescent cell burden and its proinflammatory sequelae. In agreement, senotherapeutics have had success in reducing the detrimental effects in experimental models of cardiovascular aging and disease. Aside from senotherapeutics, cellular reprogramming strategies targeting epigenetic enzymes remain an unexplored yet viable option for reversing or delaying CVD. Epigenetic alterations comprising local and global changes in DNA and histone modifications, transcription factor binding, disorganization of the nuclear lamina, and misfolding of the genome are hallmarks of aging. Limited studies in the aging cardiovascular system of murine models or human patient samples have identified strong correlations between the epigenome, age, and senescence. Here, we compile the findings in published studies linking epigenetic changes to CVD and identify clear themes of epigenetic deregulation during aging. Pending direct investigation of these general mechanisms in aged tissues, this review predicts that future work will establish epigenetic rejuvenation as a potent method to delay CVD.

Keywords

Epigenetics / chromatin / cardiovascular / senescence / aging

References

[1] Fleg JL,Frishman WH.Cardiovascular drug therapy in the elderly: benefits and challenges.Nat Rev Cardiol2011;8:13-28

[2] Heidenreich PA,Khavjou OA.American Heart Association Advocacy Coordinating CommitteeStroke CouncilCouncil on Cardiovascular Radiology and InterventionCouncil on Clinical CardiologyCouncil on Epidemiology and PreventionCouncil on ArteriosclerosisThrombosis and Vascular BiologyCouncil on CardiopulmonaryCritical CarePerioperative and ResuscitationCouncil on Cardiovascular NursingCouncil on the Kidney in Cardiovascular DiseaseCouncil on Cardiovascular Surgery and AnesthesiaInterdisciplinary Council on Quality of Care and Outcomes ResearchForecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association.Circulation2011;123:933-44

[3] Foreman KJ,Dolgert A.Forecasting life expectancy, years of life lost, and all-cause and cause-specific mortality for 250 causes of death: reference and alternative scenarios for 2016-40 for 195 countries and territories.Lancet2018;392:2052-90 PMCID:PMC6227505

[4] Savji N,Skolnick AH.Association between advanced age and vascular disease in different arterial territories: a population database of over 3.6 million subjects.J Am Coll Cardiol2013;61:1736-43

[5] Lakatta EG.Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part I: aging arteries: a "set up" for vascular disease.Circulation2003;107:139-46

[6] 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

[7] Barton M,Meyer MR.Accelerated vascular aging as a paradigm for hypertensive vascular disease: prevention and therapy.Can J Cardiol2016;32:680-6.e4

[8] Fadini GP,Pagnin E,Avogaro A.At the crossroads of longevity and metabolism: the metabolic syndrome and lifespan determinant pathways.Aging Cell2011;10:10-7

[9] Niccoli T.Ageing as a risk factor for disease.Curr Biol2012;22:R741-52

[10] Aviv A.Chronology versus biology: telomeres, essential hypertension, and vascular aging.Hypertension2002;40:229-32

[11] Shakeri H,Gevaert AB,Segers VFM.Cellular senescence links aging and diabetes in cardiovascular disease.Am J Physiol Heart Circ Physiol2018;315:H448-62

[12] Mccay CM,Sperling G.Retarded growth, life span, ultimate body size and age changes in the Albino rat after feeding diets restricted in calories.J Nutr1939;18:1-13

[13] Mattison JA,Beasley TM.Caloric restriction improves health and survival of rhesus monkeys.Nat Commun2017;8:14063 PMCID:PMC5247583

[14] Campisi J,Lithgow GJ,Newman JC.From discoveries in ageing research to therapeutics for healthy ageing.Nature2019;571:183-92 PMCID:PMC7205183

[15] McHugh D.Senescence and aging: causes, consequences, and therapeutic avenues.J Cell Biol2018;217:65-77 PMCID:PMC5748990

[16] Hayflick L.The limited in vitro lifetime of human diploid cell strains.Exp Cell Res1965;37:614-36

[17] Coppé JP,Rodier F.Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor.PLoS Biol2008;6:2853-68 PMCID:PMC2592359

[18] Niedernhofer LJ.Senotherapeutics for healthy ageing.Nat Rev Drug Discov2018;17:377

[19] Childs BG,Baker DJ.Senescent cells: an emerging target for diseases of ageing.Nat Rev Drug Discov2017;16:718-35 PMCID:PMC5942225

[20] Zhu Y,Pirtskhalava T.The Achilles' heel of senescent cells: from transcriptome to senolytic drugs.Aging Cell2015;14:644-58 PMCID:PMC4531078

[21] Ellison-Hughes GM.First evidence that senolytics are effective at decreasing senescent cells in humans.EBioMedicine2020;56:102473 PMCID:PMC7248649

[22] Deursen JM. Senolytic therapies for healthy longevity.Science2019;364:636-7 PMCID:PMC6816502

[23] Kang C.Senolytics and Senostatics: A two-pronged approach to target cellular senescence for delaying aging and age-related diseases.Mol Cells2019;42:821-7 PMCID:PMC6939651

[24] Kirkland JL.Senolytic drugs: from discovery to translation. J Intern Med 2020;5:518-36. PMCID:PMC7405395

[25] Lujambio A.To clear, or not to clear (senescent cells)?.Bioessays2016;38 Suppl 1:S56-64

[26] Robbins PD,Khosla S.Senolytic drugs: reducing senescent cell viability to extend health span.Annu Rev Pharmacol Toxicol2021;61:779-803 PMCID:PMC7790861

[27] Demaria M,Youssef SA.An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA.Dev Cell2014;31:722-33 PMCID:PMC4349629

[28] Matthews C,Scott S.Vascular smooth muscle cells undergo telomere-based senescence in human atherosclerosis: effects of telomerase and oxidative stress.Circ Res2006;99:156-64

[29] Chen HZ,Gao P.Age-associated Sirtuin 1 reduction in vascular smooth muscle links vascular senescence and inflammation to abdominal aortic aneurysm.Circ Res2016;119:1076-88 PMCID:PMC6546422

[30] Sawaki D,Pini M.Visceral adipose tissue drives cardiac aging through modulation of fibroblast senescence by osteopontin production.Circulation2018;138:809-22

[31] Gevaert AB,Leloup AJ.Endothelial senescence contributes to heart failure with preserved ejection fraction in an aging mouse model.Circ Heart Fail2017;10:e003806

[32] Boe AE,Murphy SB.Plasminogen activator inhibitor-1 antagonist TM5441 attenuates Nω-nitro-L-arginine methyl ester-induced hypertension and vascular senescence.Circulation2013;128:2318-24 PMCID:PMC3933362

[33] Childs BG,Wijshake T,Campisi J.Senescent intimal foam cells are deleterious at all stages of atherosclerosis.Science2016;354:472-7 PMCID:PMC5112585

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

[35] Mosterd A.Clinical epidemiology of heart failure.Heart2007;93:1137-46 PMCID:PMC1955040

[36] Benjamin EJ,Alonso A.American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics SubcommitteeHeart disease and stroke statistics-2019 update: a report from the american heart association.Circulation2019;139:e56-e528

[37] Ock S,Ahn J.Deletion of IGF-1 receptors in cardiomyocytes attenuates cardiac aging in male mice.Endocrinology2016;157:336-45 PMCID:PMC4701888

[38] Tang X,Chen HZ.Cardiomyocyte senescence and cellular communications within myocardial microenvironments.Front Endocrinol (Lausanne)2020;11:280 PMCID:PMC7253644

[39] Torella D,Nurzynska D.Cardiac stem cell and myocyte aging, heart failure, and insulin-like growth factor-1 overexpression.Circ Res2004;94:514-24

[40] Spallarossa P,Aloi C.Doxorubicin induces senescence or apoptosis in rat neonatal cardiomyocytes by regulating the expression levels of the telomere binding factors 1 and 2.Am J Physiol Heart Circ Physiol2009;297:H2169-81

[41] Sharifi-Sanjani M,Tichy ED.Cardiomyocyte-specific telomere shortening is a distinct signature of heart failure in humans.J Am Heart Assoc2017;6:e005086 PMCID:PMC5634248

[42] Anderson R,Maggiorani D.Length-independent telomere damage drives post-mitotic cardiomyocyte senescence.EMBO J2019;38:e100492 PMCID:PMC6396144

[43] Cui S,Yang F.Postinfarction hearts are protected by premature senescent cardiomyocytes via GATA 4-dependent CCN 1 secretion.J Am Heart Assoc2018;7:e009111 PMCID:PMC6222958

[44] Xie F,Huang SF.The endoplasmic reticulum stress-autophagy pathway is involved in apelin-13-induced cardiomyocyte hypertrophy in vitro.Acta Pharmacol Sin2017;38:1589-600 PMCID:PMC5719161

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

[46] Walaszczyk A,Redgrave R.Pharmacological clearance of senescent cells improves survival and recovery in aged mice following acute myocardial infarction.Aging Cell2019;18:e12945 PMCID:PMC6516151

[47] Chimenti C,Torella D.Senescence and death of primitive cells and myocytes lead to premature cardiac aging and heart failure.Circ Res2003;93:604-13

[48] Maejima Y,Ito H,Isobe M.Induction of premature senescence in cardiomyocytes by doxorubicin as a novel mechanism of myocardial damage.Aging Cell2008;7:125-36

[49] Mitry MA,Keith BL.Accelerated cardiomyocyte senescence contributes to late-onset doxorubicin-induced cardiotoxicity.Am J Physiol Cell Physiol2020;318:C380-91 PMCID:PMC7052608

[50] Civitarese RA,McCulloch CA.Role of integrins in mediating cardiac fibroblast-cardiomyocyte cross talk: a dynamic relationship in cardiac biology and pathophysiology.Basic Res Cardiol2017;112:6

[51] Saucerman JJ,Buchholz KS,Omens JH.Mechanical regulation of gene expression in cardiac myocytes and fibroblasts.Nat Rev Cardiol2019;16:361-78 PMCID:PMC6525041

[52] Yoshida Y,Katsuumi G.p53-Induced inflammation exacerbates cardiac dysfunction during pressure overload.J Mol Cell Cardiol2015;85:183-98

[53] Biernacka A,Aging and cardiac fibrosis.Aging Dis 2011;2:158-73. PMCID:PMC3153299

[54] Russo I.Diabetes-associated cardiac fibrosis: Cellular effectors, molecular mechanisms and therapeutic opportunities.J Mol Cell Cardiol2016;90:84-93 PMCID:PMC4718740

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

[56] Porrello ER,Simpson E.Transient regenerative potential of the neonatal mouse heart.Science2011;331:1078-80 PMCID:PMC3099478

[57] Senyo SE,Pizzimenti CL.Mammalian heart renewal by pre-existing cardiomyocytes.Nature2013;493:433-6 PMCID:PMC3548046

[58] Bergmann O,Bernard S.Evidence for cardiomyocyte renewal in humans.Science2009;324:98-102 PMCID:PMC2991140

[59] Bergmann O,Felker A.Dynamics of cell generation and turnover in the human heart.Cell2015;161:1566-75

[60] Wencker D,Nguyen K.A mechanistic role for cardiac myocyte apoptosis in heart failure.J Clin Invest2003;111:1497-504 PMCID:PMC155051

[61] Eschenhagen T,Braun T.Cardiomyocyte regeneration: a consensus statement.Circulation2017;136:680-6 PMCID:PMC5557671

[62] Ali SR,Saadat LV,Weissman IL.Existing cardiomyocytes generate cardiomyocytes at a low rate after birth in mice.Proc Natl Acad Sci U S A2014;111:8850-5 PMCID:PMC4066522

[63] Hsieh PC,Davis ME.Evidence from a genetic fate-mapping study that stem cells refresh adult mammalian cardiomyocytes after injury.Nat Med2007;13:970-4 PMCID:PMC2754571

[64] Safar ME.Systolic hypertension in the elderly: arterial wall mechanical properties and the renin-angiotensin-aldosterone system.J Hypertens2005;23:673-81

[65] Strait JB.Aging-associated cardiovascular changes and their relationship to heart failure.Heart Fail Clin2012;8:143-64 PMCID:PMC3223374

[66] Spina M,Hinnie J,Serafini-Fracassini A.Age-related changes in composition and mechanical properties of the tunica media of the upper thoracic human aorta.Arteriosclerosis1983;3:64-76

[67] Harvey A,Touyz RM.Vascular biology of ageing-Implications in hypertension.J Mol Cell Cardiol2015;83:112-21 PMCID:PMC4534766

[68] Morgan RG,Lesniewski LA.Age-related telomere uncapping is associated with cellular senescence and inflammation independent of telomere shortening in human arteries.Am J Physiol Heart Circ Physiol2013;305:H251-8 PMCID:PMC3726958

[69] Marchand A,Gaaya A.The Wnt/beta-catenin pathway is activated during advanced arterial aging in humans.Aging Cell2011;10:220-32

[70] Minamino T,Yoshida T,Yoshida H.Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction.Circulation2002;105:1541-4

[71] O'Brien ER,Stewart DK.Proliferation in primary and restenotic coronary atherectomy tissue. Implications for antiproliferative therapy.Circ Res1993;73:223-31

[72] Bennett MR,Schwartz SM.Apoptosis of human vascular smooth muscle cells derived from normal vessels and coronary atherosclerotic plaques.J Clin Invest1995;95:2266-74 PMCID:PMC295839

[73] O'Sullivan M,McCarthy N.Differential cyclin E expression in human in-stent stenosis smooth muscle cells identifies targets for selective anti-restenosis therapy.Cardiovasc Res2003;60:673-83

[74] Bennett MR,Chan SW,Weissberg PL.Cooperative interactions between RB and p53 regulate cell proliferation, cell senescence, and apoptosis in human vascular smooth muscle cells from atherosclerotic plaques.Circ Res1998;82:704-12

[75] Miao SB,Yin YJ.Accumulation of smooth muscle 22α protein accelerates senescence of vascular smooth muscle cells via stabilization of p53 in vitro and in vivo.Arterioscler Thromb Vasc Biol2017;37:1849-59

[76] Gardner SE,Bennett MR.Senescent vascular smooth muscle cells drive inflammation through an interleukin-1α-dependent senescence-associated secretory phenotype.Arterioscler Thromb Vasc Biol2015;35:1963-74 PMCID:PMC4548545

[77] Uryga AK,Garrido AM.Telomere damage promotes vascular smooth muscle cell senescence and immune cell recruitment after vessel injury.Commun Biol2021;4:611 PMCID:PMC8140103

[78] Warboys CM,Amini N.Disturbed flow promotes endothelial senescence via a p53-dependent pathway.Arterioscler Thromb Vasc Biol2014;34:985-95

[79] Ungvari Z,de Cabo R,Csiszar A.Mechanisms of vascular aging: new perspectives.J Gerontol A Biol Sci Med Sci2010;65:1028-41 PMCID:PMC2950814

[80] Chilton W,Charchar F.Telomeres, aging and exercise: guilty by association?.Int J Mol Sci2017;18:2573 PMCID:PMC5751176

[81] Cawthon RM,O'brien E,Kerber RA.Association between telomere length in blood and mortality in people aged 60 years or older.Lancet2003;361:393-5

[82] Benetos A,Gautier S.Short leukocyte telomere length precedes clinical expression of atherosclerosis: the blood-and-muscle model.Circ Res2018;122:616-23 PMCID:PMC5821479

[83] Haycock PC,Kaptoge S,Thompson A.Leucocyte telomere length and risk of cardiovascular disease: systematic review and meta-analysis.BMJ2014;349:g4227 PMCID:PMC4086028

[84] Nakajima T,Warrington KJ.T-cell-mediated lysis of endothelial cells in acute coronary syndromes.Circulation2002;105:570-5

[85] Calvert PA,Gorenne I.Leukocyte telomere length is associated with high-risk plaques on virtual histology intravascular ultrasound and increased proinflammatory activity.Arterioscler Thromb Vasc Biol2011;31:2157-64

[86] Cudejko C,Fuentes L.p16INK4a deficiency promotes IL-4-induced polarization and inhibits proinflammatory signaling in macrophages.Blood2011;118:2556-66 PMCID:PMC3677739

[87] Sen P,Nativio R.Epigenetic mechanisms of longevity and aging.Cell2016;166:822-39 PMCID:PMC5821249

[88] Yang N.The senescent cell epigenome.Aging (Albany NY)2018;10:3590-609 PMCID:PMC6286853

[89] Ellulu MS,Khaza'ai H,Abed Y.Obesity and inflammation: the linking mechanism and the complications.Arch Med Sci2017;13:851-63 PMCID:PMC5507106

[90] Cruzen C.Effects of caloric restriction on cardiovascular aging in non-human primates and humans.Clin Geriatr Med2009;25:733-43, ix PMCID:PMC2786902

[91] Colman RJ,Johnson SC.Caloric restriction delays disease onset and mortality in rhesus monkeys.Science2009;325:201-4 PMCID:PMC2812811

[92] Walford RL,Gunion MW.The calorically restricted low-fat nutrient-dense diet in Biosphere 2 significantly lowers blood glucose, total leukocyte count, cholesterol, and blood pressure in humans.Proc Natl Acad Sci U S A1992;89:11533-7 PMCID:PMC50586

[93] Heckman GA.Cardiovascular aging and exercise in healthy older adults.Clin J Sport Med2008;18:479-85

[94] Pimentel AE,Tanaka H,Gates PE.Greater rate of decline in maximal aerobic capacity with age in endurance-trained than in sedentary men.J Appl Physiol (1985)2003;94:2406-13

[95] Goldspink DF.Ageing and activity: their effects on the functional reserve capacities of the heart and vascular smooth and skeletal muscles.Ergonomics2005;48:1334-51

[96] Schulman SP,Goldberg AP.Continuum of cardiovascular performance across a broad range of fitness levels in healthy older men.Circulation1996;94:359-67

[97] Ding N,Chen J.Cigarette smoking, smoking cessation, and long-term risk of 3 major atherosclerotic diseases.J Am Coll Cardiol2019;74:498-507 PMCID:PMC6662625

[98] Zeilinger S,Klopp N.Tobacco smoking leads to extensive genome-wide changes in DNA methylation.PLoS One2013;8:e63812 PMCID:PMC3656907

[99] Lu AT,Wilson JG.DNA methylation GrimAge strongly predicts lifespan and healthspan.Aging (Albany NY)2019;11:303-27 PMCID:PMC6366976

[100] Pope CA 3rd,Thurston GD.Cardiovascular mortality and long-term exposure to particulate air pollution: epidemiological evidence of general pathophysiological pathways of disease.Circulation2004;109:71-7

[101] Brook RD,Cascio W.Expert Panel on Population and Prevention Science of the American Heart AssociationAir pollution and cardiovascular disease: a statement for healthcare professionals from the Expert Panel on Population and Prevention Science of the American Heart Association.Circulation2004;109:2655-71

[102] Levine ME,Quach A.An epigenetic biomarker of aging for lifespan and healthspan.Aging (Albany NY)2018;10:573-91 PMCID:PMC5940111

[103] Ammous F,Ratliff SM.Epigenetic age acceleration is associated with cardiometabolic risk factors and clinical cardiovascular disease risk scores in African Americans.Clin Epigenetics2021;13:55 PMCID:PMC7962278

[104] Horvath S.DNA methylation age of human tissues and cell types.Genome Biol2013;14:R115 PMCID:PMC4015143

[105] Gilsbach R,Grüning BA.Dynamic DNA methylation orchestrates cardiomyocyte development, maturation and disease.Nat Commun2014;5:5288 PMCID:PMC4220495

[106] Westerman K,Jacques P,DeMeo D.DNA methylation modules associate with incident cardiovascular disease and cumulative risk factor exposure.Clin Epigenetics2019;11:142 PMCID:PMC6792327

[107] Greco CM,Rubino M.DNA hydroxymethylation controls cardiomyocyte gene expression in development and hypertrophy.Nat Commun2016;7:12418 PMCID:PMC4976219

[108] Zaina S,Carmona FJ.DNA methylation map of human atherosclerosis.Circ Cardiovasc Genet2014;7:692-700

[109] Jiang YZ,Stoeckert CJ Jr.Arterial endothelial methylome: differential DNA methylation in athero-susceptible disturbed flow regions in vivo.BMC Genomics2015;16:506 PMCID:PMC4492093

[110] Yuan T,de Jong S,Beck S.An integrative multi-scale analysis of the dynamic DNA methylation landscape in aging.PLoS Genet2015;11:e1004996 PMCID:PMC4334892

[111] Ehrlich M.DNA methylation in cancer: too much, but also too little.Oncogene2002;21:5400-13

[112] De Cecco M,Petrashen AP.L1 drives IFN in senescent cells and promotes age-associated inflammation.Nature2019;566:73-8 PMCID:PMC6519963

[113] Booth MJ,Beraldi D.Oxidative bisulfite sequencing of 5-methylcytosine and 5-hydroxymethylcytosine.Nat Protoc2013;8:1841-51 PMCID:PMC3919000

[114] Fyodorov DV,Skoultchi AI.Emerging roles of linker histones in regulating chromatin structure and function.Nat Rev Mol Cell Biol2018;19:192-206 PMCID:PMC5897046

[115] Bannister AJ.Regulation of chromatin by histone modifications.Cell Res2011;21:381-95 PMCID:PMC3193420

[116] Papait R,Kunderfranco P.Genome-wide analysis of histone marks identifying an epigenetic signature of promoters and enhancers underlying cardiac hypertrophy.Proc Natl Acad Sci U S A2013;110:20164-9 PMCID:PMC3864351

[117] Benayoun BA,Ucar D.H3K4me3 breadth is linked to cell identity and transcriptional consistency.Cell2014;158:673-88 PMCID:PMC4137894

[118] Thienpont B,Robinson EL.The H3K9 dimethyltransferases EHMT1/2 protect against pathological cardiac hypertrophy.J Clin Invest2017;127:335-48 PMCID:PMC5199699

[119] Zhang QJ,Wang L,Hill JA.The histone trimethyllysine demethylase JMJD2A promotes cardiac hypertrophy in response to hypertrophic stimuli in mice.J Clin Invest2011;121:2447-56 PMCID:PMC3104772

[120] Haberland M,Olson EN.The many roles of histone deacetylases in development and physiology: implications for disease and therapy.Nat Rev Genet2009;10:32-42 PMCID:PMC3215088

[121] Montgomery RL,Potthoff MJ.Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractility.Genes Dev2007;21:1790-802 PMCID:PMC1920173

[122] Montgomery RL,Haberland M.Maintenance of cardiac energy metabolism by histone deacetylase 3 in mice.J Clin Invest2008;118:3588-97 PMCID:PMC2556240

[123] Imai S.NAD+ and sirtuins in aging and disease.Trends Cell Biol2014;24:464-71 PMCID:PMC4112140

[124] Potente M,Baldessari D.SIRT1 controls endothelial angiogenic functions during vascular growth.Genes Dev2007;21:2644-58 PMCID:PMC2000327

[125] Vassallo PF,Ligi I.Accelerated senescence of cord blood endothelial progenitor cells in premature neonates is driven by SIRT1 decreased expression.Blood2014;123:2116-26

[126] Zheng Z,Li J.Sirtuin 1-mediated cellular metabolic memory of high glucose via the LKB1/AMPK/ROS pathway and therapeutic effects of metformin.Diabetes2012;61:217-28 PMCID:PMC3237662

[127] Sleiman M, Jha P, Houtkooper R, Williams RW, Wang X, Auwerx J. The gene-regulatory footprint of aging highlights conserved central regulators.Cell Rep2020;32:108203 PMCID:PMC7527782

[128] Bahar R,Rodriguez KA.Increased cell-to-cell variation in gene expression in ageing mouse heart.Nature2006;441:1011-4

[129] Muris Consortium. A single-cell transcriptomic atlas characterizes ageing tissues in the mouse.Nature2020;583:590-5

[130] Eddy SR.Non-coding RNA genes and the modern RNA world.Nat Rev Genet2001;2:919-29

[131] Rossi M.Noncoding RNAs controlling telomere homeostasis in senescence and aging.Trends Mol Med2020;26:422-33 PMCID:PMC7152597

[132] Grillari J.Novel modulators of senescence, aging, and longevity: small non-coding RNAs enter the stage.Exp Gerontol2010;45:302-11

[133] Thum T,Fiedler J.MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts.Nature2008;456:980-4

[134] Jazbutyte V,Kneitz S.MicroRNA-22 increases senescence and activates cardiac fibroblasts in the aging heart.Age (Dordr)2013;35:747-62 PMCID:PMC3636396

[135] Boon RA,Lechner S.MicroRNA-34a regulates cardiac ageing and function.Nature2013;495:107-10

[136] Ito T,Yamakuchi M.MicroRNA-34a regulation of endothelial senescence.Biochem Biophys Res Commun2010;398:735-40

[137] Badi I,Ruggeri C.MicroRNA-34a Induces Vascular Smooth Muscle Cells Senescence by SIRT1 Downregulation and Promotes the Expression of Age-Associated Pro-inflammatory Secretory Factors.J Gerontol A Biol Sci Med Sci2015;70:1304-11

[138] Menghini R,Cardellini M.MicroRNA 217 modulates endothelial cell senescence via silent information regulator 1.Circulation2009;120:1524-32

[139] Boon RA,Heydt S.MicroRNA-29 in aortic dilation: implications for aneurysm formation.Circ Res2011;109:1115-9

[140] de Lucia C,Borghetti G.microRNA in cardiovascular aging and age-related cardiovascular diseases.Front Med (Lausanne)2017;4:74 PMCID:PMC5466994

[141] Verduci L,Strano S,Blandino G.CircRNAs: role in human diseases and potential use as biomarkers.Cell Death Dis2021;12:468 PMCID:PMC8113373

[142] Altesha MA,Khan A,Zheng X.Circular RNA in cardiovascular disease.J Cell Physiol2019;234:5588-600

[143] Du WW,Chen Y.Foxo3 circular RNA promotes cardiac senescence by modulating multiple factors associated with stress and senescence responses.Eur Heart J2017;38:1402-12

[144] Holdt LM,Sass K.Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans.Nat Commun2016;7:12429 PMCID:PMC4992165

[145] Burd CE,Liu Y,Wang Z.Expression of linear and novel circular forms of an INK4/ARF-associated non-coding RNA correlates with atherosclerosis risk.PLoS Genet2010;6:e1001233 PMCID:PMC2996334

[146] Lozano-Vidal N,Boon RA.Long noncoding RNA in cardiac aging and disease.J Mol Cell Biol2019;11:860-7 PMCID:PMC6884711

[147] Han P,Lin CH.A long noncoding RNA protects the heart from pathological hypertrophy.Nature2014;514:102-6 PMCID:PMC4184960

[148] Wang Z,Ji YX.The long noncoding RNA Chaer defines an epigenetic checkpoint in cardiac hypertrophy.Nat Med2016;10:1131-9 PMCID:PMC5053883

[149] Boon RA,Michalik KM.Long noncoding RNA Meg3 controls endothelial cell aging and function: implications for regenerative angiogenesis.J Am Coll Cardiol2016;68:2589-91

[150] Chen J,Lv D.Comprehensive transcriptional landscape of porcine cardiac and skeletal muscles reveals differences of aging.Oncotarget2018;9:1524-41 PMCID:PMC5788579

[151] Hang CT,Han P.Chromatin regulation by Brg1 underlies heart muscle development and disease.Nature2010;466:62-7 PMCID:PMC2898892

[152] Han P,Yang J.Epigenetic response to environmental stress: assembly of BRG1-G9a/GLP-DNMT3 repressive chromatin complex on Myh6 promoter in pathologically stressed hearts.Biochim Biophys Acta2016;1863:1772-81 PMCID:PMC7397641

[153] Pierre R, Kadoch C. Mammalian SWI/SNF complexes in cancer: emerging therapeutic opportunities.Curr Opin Genet Dev2017;42:56-67 PMCID:PMC5777332

[154] Centore RC,Soares LMM,Chan HM.Mammalian SWI/SNF chromatin remodeling complexes: emerging mechanisms and therapeutic strategies.Trends Genet2020;36:936-50

[155] Olive M,Mitchell R.Cardiovascular pathology in Hutchinson-Gilford progeria: correlation with the vascular pathology of aging.Arterioscler Thromb Vasc Biol2010;30:2301-9 PMCID:PMC2965471

[156] Scaffidi P.Reversal of the cellular phenotype in the premature aging disease Hutchinson-Gilford progeria syndrome.Nat Med2005;11:440-5 PMCID:PMC1351119

[157] Shumaker DK,Kohlmaier A.Mutant nuclear lamin A leads to progressive alterations of epigenetic control in premature aging.Proc Natl Acad Sci U S A2006;103:8703-8 PMCID:PMC1472659

[158] Baker DJ,Durik M.Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan.Nature2016;530:184-9 PMCID:PMC4845101

[159] Kirkland JL,Zhu Y,Robbins PD.The Clinical Potential of Senolytic Drugs.J Am Geriatr Soc2017;65:2297-301 PMCID:PMC5641223

[160] Tchkonia T.Aging, cell senescence, and chronic disease: emerging therapeutic strategies.JAMA2018;320:1319-20

[161] Laberge RM,Sarantos MR.Glucocorticoids suppress selected components of the senescence-associated secretory phenotype.Aging Cell2012;11:569-78 PMCID:PMC3387333

[162] Wang R,Sunchu B.Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism.Aging Cell2017;16:564-74 PMCID:PMC5418203

[163] Moiseeva O,St-Germain E.Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-κB activation.Aging Cell2013;12:489-98

[164] Chen W,Wei G.Single-cell transcriptome analysis reveals six subpopulations reflecting distinct cellular fates in senescent mouse embryonic fibroblasts.Front Genet2020;11:867 PMCID:PMC7431633

[165] Shi C,Sen P.The eroding chromatin landscape of aging stem cells.Transl Med Aging2020;4:121-31 PMCID:PMC7534803

[166] Capell BC,Zhu J.MLL1 is essential for the senescence-associated secretory phenotype.Genes Dev2016;30:321-36 PMCID:PMC4743061

[167] Tasdemir N,Roe JS.BRD4 Connects Enhancer Remodeling to Senescence Immune Surveillance.Cancer Discov2016;6:612-29 PMCID:PMC4893996

[168] Phillips MI,Lee RJ,Burns AB.Antisense therapy for cardiovascular diseases.Curr Pharm Des2015;21:4417-26

[169] Yun MH.Changes in regenerative capacity through lifespan.Int J Mol Sci2015;16:25392-432 PMCID:PMC4632807

[170] Li Y,Huang X.Genetic lineage tracing of nonmyocyte population by dual recombinases.Circulation2018;138:793-805

[171] Ocampo A,Martinez-Redondo P.In vivo amelioration of age-associated hallmarks by partial reprogramming.Cell2016;167:1719-33.e12 PMCID:PMC5679279

[172] Aghajanian H,Rurik JG.Targeting cardiac fibrosis with engineered T cells.Nature2019;573:430-3 PMCID:PMC6752964

[173] North BJ.The intersection between aging and cardiovascular disease.Circ Res2012;110:1097-108 PMCID:PMC3366686

[174] Wang Z,Rosenfeld JA.Combinatorial patterns of histone acetylations and methylations in the human genome.Nat Genet2008;40:897-903 PMCID:PMC2769248

[175] Bonn S,Girardot C.Tissue-specific analysis of chromatin state identifies temporal signatures of enhancer activity during embryonic development.Nat Genet2012;44:148-56

[176] Schübeler D,Scalzo D.The histone modification pattern of active genes revealed through genome-wide chromatin analysis of a higher eukaryote.Genes Dev2004;18:1263-71 PMCID:PMC420352

[177] Poleshko A,Gupta M.Genome-nuclear lamina interactions regulate cardiac stem cell lineage restriction.Cell2017;171:573-87.e14 PMCID:PMC5683101

[178] Hahn MA,Li AX,Pfeifer GP.Relationship between gene body DNA methylation and intragenic H3K9me3 and H3K36me3 chromatin marks.PLoS One2011;6:e18844 PMCID:PMC3079728

[179] Wiles ET.H3K27 methylation: a promiscuous repressive chromatin mark.Curr Opin Genet Dev2017;43:31-7 PMCID:PMC5447479

[180] Dambacher S,Schotta G.The compact view on heterochromatin.Cell Cycle2013;12:2925-6 PMCID:PMC3875662