Cardiovascular aging: the mitochondrial influence

Abstract

Age-associated cardiovascular disease is becoming progressively prevalent due to the increased lifespan of the population. However, the fundamental mechanisms underlying the aging process and the corresponding decline in tissue functions are still poorly understood. The heart has a very high energy demand and the cellular energy needed to sustain contraction is primarily generated by mitochondrial oxidative phosphorylation. Mitochondria are also involved in supporting various metabolic processes, as well as activation of the innate immune response and cell death pathways. Given the central role of mitochondria in energy metabolism and cell survival, the heart is highly susceptible to the effects of mitochondrial dysfunction. These key organelles have been implicated as underlying drivers of cardiac aging. Here, we review the evidence demonstrating the mitochondrial contribution to the cardiac aging process and disease susceptibility. We also discuss the potential mechanisms responsible for the age-related decline in mitochondrial function.

Keywords

Aging / mitochondria / heart disease

References

[1] Quiles JM.Mitochondrial quality control and cellular proteostasis: two sides of the same coin.Front Physiol2020;11:515 PMCID:PMC7263099

[2] Lima T,Mottis A.Pleiotropic effects of mitochondria in aging.Nat Aging2022;2:199-213

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

[4] Owada T,Saitoh SI,Machii H.Resolution of mitochondrial oxidant stress improves aged-cardiovascular performance.Coron Artery Dis2017;28:33-43 PMCID:PMC5145249

[5] 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

[6] Gioscia-Ryan RA,Sindler AL,Murphy MP.Mitochondria-targeted antioxidant (MitoQ) ameliorates age-related arterial endothelial dysfunction in mice.J Physiol2014;592:2549-61 PMCID:PMC4080937

[7] Chiao YA,Sweetwyne M.Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice.Elife2020;9:e55513

[8] Pagan LU,Gatto M,Okoshi K.The role of oxidative stress in the aging heart.Antioxidants2022;11:336 PMCID:PMC8868312

[9] Kowalczyk P,Kleczkowska P.Mitochondrial oxidative stress-a causative factor and therapeutic target in many diseases.Int J Mol Sci2021;22:13384 PMCID:PMC8707347

[10] Rizvi F,Emelyanova L.Effects of aging on cardiac oxidative stress and transcriptional changes in pathways of reactive oxygen species generation and clearance.J Am Heart Assoc2021;10:e019948 PMCID:PMC8475058

[11] Schriner SE,Martin GM.Extension of murine life span by overexpression of catalase targeted to mitochondria.Science2005;308:1909-11

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

[13] Tranah GJ,Lauterjung K.Mitochondrial DNA m.3243A  >  G heteroplasmy affects multiple aging phenotypes and risk of mortality.Sci Rep2018;8:11887 PMCID:PMC6082898

[14] Zapico SC.mtDNA mutations and their role in aging, diseases and forensic sciences.Aging Dis2013;4:364-80 PMCID:PMC3843653

[15] Cortopassi GA.Detection of a specific mitochondrial DNA deletion in tissues of older humans.Nucleic Acids Res1990;18:6927-33 PMCID:PMC332752

[16] Corral-Debrinski M,Lott MT.Marked changes in mitochondrial DNA deletion levels in Alzheimer brains.Genomics1994;23:471-6

[17] Meissner C,Mohamed SA.The 4977 bp deletion of mitochondrial DNA in human skeletal muscle, heart and different areas of the brain: a useful biomarker or more?.Exp Gerontol2008;43:645-52

[18] Trifunovic A,Falkenberg M.Premature ageing in mice expressing defective mitochondrial DNA polymerase.Nature2004;429:417-23

[19] Kujoth GC,Pugh TD.Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging.Science2005;309:481-4

[20] Yu T,Liu W.Premature aging is associated with higher levels of 8-oxoguanine and increased DNA damage in the Polg mutator mouse.Aging Cell2022;21:e13669 PMCID:PMC9470903

[21] Ahlqvist KJ,Yatsuga S.Somatic progenitor cell vulnerability to mitochondrial DNA mutagenesis underlies progeroid phenotypes in Polg mutator mice.Cell Metab2012;15:100-9

[22] Kolesar JE,Abadi A.Defects in mitochondrial DNA replication and oxidative damage in muscle of mtDNA mutator mice.Free Radic Biol Med2014;75:241-51

[23] Shabalina IG,Gibanova N.Improved health-span and lifespan in mtDNA mutator mice treated with the mitochondrially targeted antioxidant SkQ1.Aging2017;9:315-39 PMCID:PMC5361666

[24] Logan A,Prime TA.In vivo levels of mitochondrial hydrogen peroxide increase with age in mtDNA mutator mice.Aging Cell2014;13:765-8 PMCID:PMC4326952

[25] Lei Y,Torres-Odio S.Elevated type I interferon responses potentiate metabolic dysfunction, inflammation, and accelerated aging in mtDNA mutator mice.Sci Adv2021;7:eabe7548 PMCID:PMC8153723

[26] Marchi S,Tait SWG,Galluzzi L.Mitochondrial control of inflammation.Nat Rev Immunol2023;23:159-73 PMCID:PMC9310369

[27] Zheng Y,Dong N.NLRP3 inflammasome: the rising star in cardiovascular diseases.Front Cardiovasc Med2022;9:927061 PMCID:PMC9530053

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

[29] McBride MJ,D'Souza DM.The NLRP3 inflammasome contributes to sarcopenia and lower muscle glycolytic potential in old mice.Am J Physiol Endocrinol Metab2017;313:E222-32 PMCID:PMC5582883

[30] Marín-Aguilar F,Alcocer-Gómez E.NLRP3 inflammasome suppression improves longevity and prevents cardiac aging in male mice.Aging Cell2020;19:e13050 PMCID:PMC6974709

[31] Sun L,Du F,Chen ZJ.Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway.Science2013;339:786-91 PMCID:PMC3863629

[32] Ishikawa H,Barber GN.STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity.Nature2009;461:788-92 PMCID:PMC4664154

[33] Paul BD,Bohr VA.Signaling by cGAS-STING in Neurodegeneration, Neuroinflammation, and Aging.Trends Neurosci2021;44:83-96 PMCID:PMC8662531

[34] Sladitschek-Martens HL,Brumana G.YAP/TAZ activity in stromal cells prevents ageing by controlling cGAS-STING.Nature2022;607:790-8 PMCID:PMC7613988

[35] He F,Wen T.NRF2, a transcription factor for stress response and beyond.Int J Mol Sci2020;21:4777 PMCID:PMC7369905

[36] Zhao Q,Levichkin IV,Ryan MT.A mitochondrial specific stress response in mammalian cells.EMBO J2002;21:4411-9 PMCID:PMC126185

[37] Fiorese CJ,Lin YF,Pellegrino MW.The transcription factor ATF5 mediates a mammalian mitochondrial UPR.Curr Biol2016;26:2037-43 PMCID:PMC4980197

[38] Benedetti C,Yang Y,Ron D.Ubiquitin-like protein 5 positively regulates chaperone gene expression in the mitochondrial unfolded protein response.Genetics2006;174:229-39 PMCID:PMC1569816

[39] Haynes CM,Benedetti C,Ron D.ClpP mediates activation of a mitochondrial unfolded protein response in C. elegans.Dev Cell2007;13:467-80

[40] Münch C.Mitochondrial unfolded protein response controls matrix pre-RNA processing and translation.Nature2016;534:710-3 PMCID:PMC4939261

[41] Sheng Y,Markovich Z,Xiao R.Distinct temporal actions of different types of unfolded protein responses during aging.J Cell Physiol2021;236:5069-79 PMCID:PMC8026671

[42] Zhang Q,Zhang W.The memory of neuronal mitochondrial stress is inherited transgenerationally via elevated mitochondrial DNA levels.Nat Cell Biol2021;23:870-80

[43] Ozkurede U.Improved mitochondrial stress response in long-lived Snell dwarf mice.Aging Cell2019;18:e13030 PMCID:PMC6826134

[44] Neill G.A stay of execution: ATF4 regulation and potential outcomes for the integrated stress response.Front Mol Neurosci2023;16:1112253 PMCID:PMC9941348

[45] Santos-Ribeiro D,Pilette C.The integrated stress response system in cardiovascular disease.Drug Discov Today2018;23:920-9

[46] Statzer C,Venz R.ATF-4 and hydrogen sulfide signalling mediate longevity in response to inhibition of translation or mTORC1.Nat Commun2022;13:967

[47] Li W,Miller RA.ATF4 activity: a common feature shared by many kinds of slow-aging mice.Aging Cell2014;13:1012-8 PMCID:PMC4326926

[48] Wang X,Dasgupta S.ATF4 Protects the Heart From Failure by Antagonizing Oxidative Stress.Circ Res2022;131:91-105 PMCID:PMC9351829

[49] Sun Y,Liu B.Loss of ATF4 leads to functional aging-like attrition of adult hematopoietic stem cells.Sci Adv2021;7:eabj6877 PMCID:PMC8694622

[50] Guo X,Liu Y.Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway.Nature2020;579:427-32 PMCID:PMC7147832

[51] Fessler E,Schmitt S.A pathway coordinated by DELE1 relays mitochondrial stress to the cytosol.Nature2020;579:433-7 PMCID:PMC7116715

[52] Ahola S,Hermans S.OMA1-mediated integrated stress response protects against ferroptosis in mitochondrial cardiomyopathy.Cell Metab2022;34:1875-1891.e7

[53] Huynh H,Lee S.DELE1 is protective for mitochondrial cardiomyopathy.J Mol Cell Cardiol2023;175:44-8

[54] Gustafsson ÅB.Evolving and expanding the roles of mitophagy as a homeostatic and pathogenic process.Physiol Rev2019;99:853-92 PMCID:PMC6442924

[55] Wirth M,Tooze SA.Autophagosome formation--the role of ULK1 and Beclin1-PI3KC3 complexes in setting the stage.Semin Cancer Biol2013;23:301-9

[56] Quiles JM,Gonzalez E.Deciphering functional roles and interplay between Beclin1 and Beclin2 in autophagosome formation and mitophagy.Sci Signal2023;16:eabo4457 PMCID:PMC10019900

[57] Tóth ML,Borsos E.Longevity pathways converge on autophagy genes to regulate life span in Caenorhabditis elegans.Autophagy2008;4:330-8

[58] Liang W,Lampert MA,Najor RH.Aging is associated with a decline in Atg9b-mediated autophagosome formation and appearance of enlarged mitochondria in the heart.Aging Cell2020;19:e13187 PMCID:PMC7431832

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

[60] Wang F,Gao Z.Atg5 knockdown induces age-dependent cardiomyopathy which can be rescued by repeated remote ischemic conditioning.Basic Res Cardiol2021;116:47 PMCID:PMC8316897

[61] Pyo JO,Ahn HH.Overexpression of Atg5 in mice activates autophagy and extends lifespan.Nat Commun2013;4:2300 PMCID:PMC3753544

[62] Woodall BP.Autophagy-a key pathway for cardiac health and longevity.Acta Physiol2018;223:e13074 PMCID:PMC6527442

[63] Morselli E,Markaki M.Caloric restriction and resveratrol promote longevity through the Sirtuin-1-dependent induction of autophagy.Cell Death Dis2010;1:e10 PMCID:PMC3032517

[64] Madeo F,Maiuri MC.Essential role for autophagy in life span extension.J Clin Invest2015;125:85-93 PMCID:PMC4382258

[65] Juricic P,Leech T.Long-lasting geroprotection from brief rapamycin treatment in early adulthood by persistently increased intestinal autophagy.Nat Aging2022;2:824-36 PMCID:PMC10154223

[66] Eisenberg T,Schauer A.Induction of autophagy by spermidine promotes longevity.Nat Cell Biol2009;11:1305-14

[67] 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

[68] Bjedov I,Kerr F.Mechanisms of life span extension by rapamycin in the fruit fly drosophila melanogaster.Cell Metab2010;11:35-46 PMCID:PMC2824086

[69] Alvers AL,Wood MS.Autophagy and amino acid homeostasis are required for chronological longevity in Saccharomyces cerevisiae.Aging Cell2009;8:353-69 PMCID:PMC2802268

[70] Pattingre S,Qu X.Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy.Cell2005;122:927-39

[71] Fernández ÁF,Wei Y.Disruption of the beclin 1-BCL2 autophagy regulatory complex promotes longevity in mice.Nature2018;558:136-40 PMCID:PMC5992097

[72] Jin SM,Wang C,Narendra DP.Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL.J Cell Biol2010;191:933-42 PMCID:PMC2995166

[73] Greene AW,Aguileta MA.Mitochondrial processing peptidase regulates PINK1 processing, import and Parkin recruitment.EMBO Rep2012;13:378-85 PMCID:PMC3321149

[74] Matsuda N,Shiba K.PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy.J Cell Biol2010;189:211-21 PMCID:PMC2856912

[75] Lazarou M,Kane LA.The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy.Nature2015;524:309-14 PMCID:PMC5018156

[76] Narendra D,Hauser DN,Youle RJ.p62/SQSTM1 is required for Parkin-induced mitochondrial clustering but not mitophagy; VDAC1 is dispensable for both.Autophagy2010;6:1090-106 PMCID:PMC3359490

[77] Pankiv S,Lamark T.p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy.J Biol Chem2007;282:24131-45

[78] Sun N,Liu J.Measuring in vivo mitophagy.Mol Cell2015;60:685-96 PMCID:PMC4656081

[79] Gautier CA,Shen J.Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress.Proc Natl Acad Sci USA2008;105:11364-9 PMCID:PMC2516271

[80] Billia F,Konecny F,Shen J.PTEN-inducible kinase 1 (PINK1)/Park6 is indispensable for normal heart function.Proc Natl Acad Sci USA2011;108:9572-7 PMCID:PMC3111326

[81] Kubli DA,Gustafsson AB.Parkin deficiency results in accumulation of abnormal mitochondria in aging myocytes.Commun Integr Biol2013;6:e24511 PMCID:PMC3737749

[82] Kubli DA,Lee Y.Parkin protein deficiency exacerbates cardiac injury and reduces survival following myocardial infarction.J Biol Chem2013;288:915-26 PMCID:PMC3543040

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

[84] Liu L,Chen G.Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells.Nat Cell Biol2012;14:177-85

[85] Hanna RA,Orogo AM,Rikka S.Microtubule-associated protein 1 light chain 3 (LC3) interacts with Bnip3 protein to selectively remove endoplasmic reticulum and mitochondria via autophagy.J Biol Chem2012;287:19094-104 PMCID:PMC3365942

[86] Schwarten M,Ma P.Nix directly binds to GABARAP: a possible crosstalk between apoptosis and autophagy.Autophagy2009;5:690-8

[87] Novak I,McEwan DG.Nix is a selective autophagy receptor for mitochondrial clearance.EMBO Rep2010;11:45-51 PMCID:PMC2816619

[88] Chu CT,Dagda RK.Cardiolipin externalization to the outer mitochondrial membrane acts as an elimination signal for mitophagy in neuronal cells.Nat Cell Biol2013;15:1197-205

[89] Ma L,Wei W.Exercise protects aged mice against coronary endothelial senescence via FUNDC1-dependent mitophagy.Redox Biol2023;62:102693 PMCID:PMC10113862

[90] Wu S,Wang Q.Binding of FUN14 domain containing 1 with inositol 1,4,5-trisphosphate receptor in mitochondria-associated endoplasmic reticulum membranes maintains mitochondrial dynamics and function in hearts in vivo.Circulation2017;136:2248-66 PMCID:PMC5716911

[91] Schmid ET,Walker DW.Neuronal induction of BNIP3-mediated mitophagy slows systemic aging in drosophila.Nat Aging2022;2:494-507 PMCID:PMC9540997

[92] Irazoki A,Aparicio P.Coordination of mitochondrial and lysosomal homeostasis mitigates inflammation and muscle atrophy during aging.Aging Cell2022;21:e13583 PMCID:PMC9009131

[93] Dorn GW 2nd.Mitochondrial pruning by Nix and BNip3: an essential function for cardiac-expressed death factors.J Cardiovasc Transl Res2010;3:374-83 PMCID:PMC2900478

[94] Niemann B,Issa H,Rohrbach S.Caloric restriction delays cardiac ageing in rats: role of mitochondria.Cardiovasc Res2010;88:267-76

[95] No MH,Yoo SZ.Effects of aging and exercise training on mitochondrial function and apoptosis in the rat heart.Pflugers Arch2020;472:179-93

[96] Campos JC,Krum B.Exercise preserves physical fitness during aging through AMPK and mitochondrial dynamics.Proc Natl Acad Sci USA2023;120:e2204750120 PMCID:PMC9926278

[97] Tong D,Jiang N.NAD(+) repletion reverses heart failure with preserved ejection fraction.Circ Res2021;128:1629-41 PMCID:PMC8159891

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

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

[100] Srivastava V,Shukla V.Distinct designer diamines promote mitophagy, and thereby enhance healthspan in C. elegans and protect human cells against oxidative damage.Autophagy2023;19:474-504 PMCID:PMC9851263

[101] Song M,Gong G,Rabinovitch PS.Super-suppression of mitochondrial reactive oxygen species signaling impairs compensatory autophagy in primary mitophagic cardiomyopathy.Circ Res2014;115:348-53 PMCID:PMC4106429

[102] Hammerling BC,Cortez MQ.A Rab5 endosomal pathway mediates Parkin-dependent mitochondrial clearance.Nat Commun2017;8:14050 PMCID:PMC5290275

[103] Hammerling BC,Leon LJ,Gustafsson ÅB.Isolation of Rab5-positive endosomes reveals a new mitochondrial degradation pathway utilized by BNIP3 and Parkin.Small GTPases2020;11:69-76 PMCID:PMC6959301

[104] Saito T,Oka SI.An alternative mitophagy pathway mediated by Rab9 protects the heart against ischemia.J Clin Invest2019;129:802-19 PMCID:PMC6355232

[105] Tong M,Zhai P.Alternative mitophagy protects the heart against obesity-associated cardiomyopathy.Circ Res2021;129:1105-21