Skip to content
2000
  1. Home
  2. A-Z Publications
  3. Current Molecular Pharmacology
  4. Volume 17, Issue 1
  5. Article
Volume 17, Issue 1
  • ISSN: 1874-4672
  • E-ISSN: 1874-4702
file format text download EPUB
file format pdf download PDF
side by side viewer icon HTML

Abstract

Although Amyloid beta plaque and neurofibrillary tangles are considered the two main hallmarks of Alzheimer’s disease (AD), the mechanism by which they contribute is not clearly understood. Cellular senescence (CS) has been demonstrated to be a key characteristic of AD. Recent research suggests that persistent buildup of senescent cells over time results in protracted activation of inflammatory stress as an organism ages because of the accumulation of irreversible DNA damage and oxidative stress as well as the deterioration of immune system function. Studies on both humans and animals have shown evidence that CS is a crucial factor in AD. The brains of AD patients have been found to have senescent glial cells and neurons, and removal of these senescent cells results in a decrease in Amyloid beta plaque and Neurofibrillary tangles, along with improved cognitive functions. This review summarises recent results and the mechanism by which CS contributes to the development of AD, and how the elimination of senescent cells may be a therapeutic target in the management of AD.

© 2024 The Author(s). Published by Bentham Science Publisher.
This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Loading

Article metrics loading...

/content/journals/cmp/10.2174/1874467217666230601113430
2023-07-13
2024-11-24

  • From This Site

    /content/journals/cmp/10.2174/1874467217666230601113430
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

/deliver/fulltext/cmp/17/1/CMP-17-E010623217543.html?itemId=/content/journals/cmp/10.2174/1874467217666230601113430&mimeType=html&fmt=ahah

References

  1. PasseriE. ElkhouryK. MorsinkM. BroersenK. LinderM. TamayolA. MalaplateC. YenF.T. Arab-TehranyE. Alzheimer’s Disease: Treatment Strategies and Their Limitations.Int. J. Mol. Sci.202223221395410.3390/ijms23221395436430432
     [Google Scholar]
  2. World Health OrganizationDementia.Available from: https://www.who.int/news-room/fact-sheets/detail/dementia (Accessed on: Dec 4, 2022).
  3. SaundersA.M. BurnsD.K. GottschalkW.K. Reassessment of Pioglitazone for Alzheimer’s Disease.Front. Neurosci.20211566695810.3389/fnins.2021.66695834220427
     [Google Scholar]
  4. Alzheimer’s Association. Alzheimer’s stages-early, middle, late dementia symptoms.Available from: https://www.alz.org/alzheimers-dementia/stages#middle# (Accessed on: Apr 4, 2023).
  5. BraakH. BraakE. Neuropathological stageing of Alzheimer-related changes.Acta Neuropathol.199182423925910.1007/BF003088091759558
     [Google Scholar]
  6. ThalD.R. RübU. OrantesM. BraakH. Phases of Aβ-deposition in the human brain and its relevance for the development of AD.Neurology200258121791180010.1212/WNL.58.12.179112084879
     [Google Scholar]
  7. ScheltensP. De StrooperB. KivipeltoM. HolstegeH. ChételatG. TeunissenC.E. CummingsJ. van der FlierW.M. Alzheimer’s disease.Lancet2021397102841577159010.1016/S0140‑6736(20)32205‑433667416
     [Google Scholar]
  8. GuerreroA. De StrooperB. Arancibia-CárcamoI.L. Cellular senescence at the crossroads of inflammation and Alzheimer’s disease.Trends Neurosci.202144971472710.1016/j.tins.2021.06.00734366147
     [Google Scholar]
  9. López-OtínC. BlascoM.A. PartridgeL. SerranoM. KroemerG. The hallmarks of aging.Cell201315361194121710.1016/j.cell.2013.05.03923746838
     [Google Scholar]
  10. Hernandez-SeguraA. NehmeJ. DemariaM. Hallmarks of cellular senescence. Trends in Cell BiologyElsevier Ltd201843645310.1016/j.tcb.2018.02.001
     [Google Scholar]
  11. BeckJ. HorikawaI. HarrisC. Cellular senescence: Mechanisms, morphology, and mouse models.Vet. Pathol.202057674775710.1177/030098582094384132744147
     [Google Scholar]
  12. HerranzN. GilJ. Mechanisms and functions of cellular senescence.J. Clin. Invest.201812841238124610.1172/JCI9514829608137
     [Google Scholar]
  13. CampisiJ. d’Adda di FagagnaF. Cellular senescence: When bad things happen to good cells.Nat. Rev. Mol. Cell Biol.20078972974010.1038/nrm223317667954
     [Google Scholar]
  14. Muñoz-EspínD. SerranoM. Cellular senescence: From physiology to pathology.Nat. Rev. Mol. Cell Biol.201415748249610.1038/nrm382324954210
     [Google Scholar]
  15. de LangeT. Telomere Capping-one strand fits all.Science (1979)200129255191075107610.1126/science.1061032
     [Google Scholar]
  16. Ben-PorathI. WeinbergR.A. The signals and pathways activating cellular senescence.Int. J. Biochem. Cell Biol.200537596197610.1016/j.biocel.2004.10.01315743671
     [Google Scholar]
  17. Ben-PorathI. WeinbergR.A. When cells get stressed: An integrative view of cellular senescence.J. Clin. Invest.2004113181310.1172/JCI20042066314702100
     [Google Scholar]
  18. HayflickL. MoorheadP.S. The serial cultivation of human diploid cell strains.Exp. Cell Res.196125358562110.1016/0014‑4827(61)90192‑613905658
     [Google Scholar]
  19. CalcinottoA. KohliJ. ZagatoE. PellegriniL. DemariaM. AlimontiA. Cellular Senescence: Aging, cancer, and injury.Physiol. Rev.20199921047107810.1152/physrev.00020.201830648461
     [Google Scholar]
  20. Saez-AtienzarS. MasliahE. Cellular senescence and Alzheimer disease: The egg and the chicken scenario.Nat. Rev. Neurosci.202021843344410.1038/s41583‑020‑0325‑z32601397
     [Google Scholar]
  21. OvadyaY. LandsbergerT. LeinsH. VadaiE. GalH. BiranA. YosefR. SagivA. AgrawalA. ShapiraA. WindheimJ. TsooryM. SchirmbeckR. AmitI. GeigerH. KrizhanovskyV. Impaired immune surveillance accelerates accumulation of senescent cells and aging.Nat. Commun.201891543510.1038/s41467‑018‑07825‑330575733
     [Google Scholar]
  22. Martínez-CuéC. RuedaN. Cellular senescence in neurodegenerative diseases.Front. Cell. Neurosci.2020141610.3389/fncel.2020.0001632116562
     [Google Scholar]
  23. van DeursenJ.M. The role of senescent cells in ageing.Nature2014509750143944610.1038/nature1319324848057
     [Google Scholar]
  24. KumariR. JatP. Mechanisms of cellular senescence: Cell cycle arrest and senescence associated secretory phenotype.Front. Cell Dev. Biol.2021964559310.3389/fcell.2021.64559333855023
     [Google Scholar]
  25. Debacq-ChainiauxF. Ben AmeurR. BauwensE. DumortierE. ToutfaireM. ToussaintO. Stress-Induced (Premature).Senescence201624326210.1007/978‑3‑319‑26239‑0_13
     [Google Scholar]
  26. McConnellB.B. StarborgM. BrookesS. PetersG. Inhibitors of cyclin-dependent kinases induce features of replicative senescence in early passage human diploid fibroblasts.Curr. Biol.19988635135410.1016/S0960‑9822(98)70137‑X9512419
     [Google Scholar]
  27. RovillainE. MansfieldL. LordC.J. AshworthA. JatP.S. An RNA interference screen for identifying downstream effectors of the p53 and pRB tumour suppressor pathways involved in senescence.BMC Genomics201112135510.1186/1471‑2164‑12‑35521740549
     [Google Scholar]
  28. ProvincialiM. CardelliM. MarchegianiF. PierpaoliE. Impact of cellular senescence in aging and cancer.Curr. Pharm. Des.20131991699170910.2174/138161281131909001723061727
     [Google Scholar]
  29. Di MiccoR. KrizhanovskyV. BakerD. d’Adda di FagagnaF. Cellular senescence in ageing: From mechanisms to therapeutic opportunities.Nat. Rev. Mol. Cell Biol.2021222759510.1038/s41580‑020‑00314‑w33328614
     [Google Scholar]
  30. ShayJ. Pereira-SmithO.M. WrightW.E. A role for both RB and p53 in the regulation of human cellular senescence*1.Exp. Cell Res.19911961333910.1016/0014‑4827(91)90453‑21652450
     [Google Scholar]
  31. BeauséjourC.M. KrtolicaA. GalimiF. NaritaM. LoweS.W. YaswenP. CampisiJ. Reversal of human cellular senescence: Roles of the p53 and p16 pathways.EMBO J.200322164212422210.1093/emboj/cdg41712912919
     [Google Scholar]
  32. ChildsB.G. DurikM. BakerD.J. van DeursenJ.M. Cellular senescence in aging and age-related disease: From mechanisms to therapy.Nat. Med.201521121424143510.1038/nm.400026646499
     [Google Scholar]
  33. SharplessN.E. SherrC.J. Forging a signature of in vivo senescence.Nat. Rev. Cancer201515739740810.1038/nrc396026105537
     [Google Scholar]
  34. FischerM. MüllerG.A. Cell cycle transcription control: DREAM/MuvB and RB-E2F complexes.Crit. Rev. Biochem. Mol. Biol.201752663866210.1080/10409238.2017.136083628799433
     [Google Scholar]
  35. GilJ. PetersG. Regulation of the INK4b–ARF–INK4a tumour suppressor locus: all for one or one for all.Nat. Rev. Mol. Cell Biol.20067966767710.1038/nrm198716921403
     [Google Scholar]
  36. BrackenA.P. Kleine-KohlbrecherD. DietrichN. PasiniD. GargiuloG. BeekmanC. Theilgaard-MönchK. MinucciS. PorseB.T. MarineJ.C. HansenK.H. HelinK. The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells.Genes Dev.200721552553010.1101/gad.41550717344414
     [Google Scholar]
  37. SalminenA. KauppinenA. KaarnirantaK. Emerging role of NF-κB signaling in the induction of senescence-associated secretory phenotype (SASP).Cell. Signal.201224483584510.1016/j.cellsig.2011.12.00622182507
     [Google Scholar]
  38. GaikwadS. PuangmalaiN. BittarA. MontalbanoM. GarciaS. McAllenS. BhattN. SonawaneM. SenguptaU. KayedR. Tau oligomer induced HMGB1 release contributes to cellular senescence and neuropathology linked to Alzheimer’s disease and frontotemporal dementia.Cell Rep.202136310941910.1016/j.celrep.2021.10941934289368
     [Google Scholar]
  39. McSheaA. HarrisP.L. WebsterK.R. WahlA.F. SmithM.A. Abnormal expression of the cell cycle regulators P16 and CDK4 in Alzheimer’s disease.Am. J. Pathol.19971506193319399176387
     [Google Scholar]
  40. ThadathilN. DelotterieD.F. XiaoJ. HoriR. McDonaldM.P. KhanM.M. DNA double-strand break accumulation in Alzheimer’s Disease: Evidence from experimental models and postmortem human brains.Mol. Neurobiol.202158111813110.1007/s12035‑020‑02109‑832895786
     [Google Scholar]
  41. LiuR.M. Aging, cellular senescence, and Alzheimer’s disease.Int. J. Mol. Sci.2022234198910.3390/ijms2304198935216123
     [Google Scholar]
  42. BhatR. CroweE.P. BittoA. MohM. KatsetosC.D. GarciaF.U. JohnsonF.B. TrojanowskiJ.Q. SellC. TorresC. Astrocyte senescence as a component of Alzheimer’s disease.PLoS One201279e4506910.1371/journal.pone.004506922984612
     [Google Scholar]
  43. CaldeiraC. CunhaC. VazA.R. FalcãoA.S. BarateiroA. SeixasE. FernandesA. BritesD. Key aging-associated alterations in primary microglia response to beta-amyloid stimulation.Front. Aging Neurosci.2017927710.3389/fnagi.2017.0027728912710
     [Google Scholar]
  44. MusiN. ValentineJ.M. SickoraK.R. BaeuerleE. ThompsonC.S. ShenQ. OrrM.E. Tau protein aggregation is associated with cellular senescence in the brain.Aging Cell2018176e1284010.1111/acel.1284030126037
     [Google Scholar]
  45. WangQ. DuanL. LiX. WangY. GuoW. GuanF. MaS. Glucose metabolism, neural cell senescence and Alzheimer’s Disease.Int. J. Mol. Sci.2022238435110.3390/ijms2308435135457168
     [Google Scholar]
  46. BussianT.J. AzizA. MeyerC.F. SwensonB.L. van DeursenJ.M. BakerD.J. Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline.Nature2018562772857858210.1038/s41586‑018‑0543‑y30232451
     [Google Scholar]
  47. AngelovaD.M. BrownD.R. Altered processing of β-Amyloid in SH-SY5Y cells induced by model senescent microglia.ACS Chem. Neurosci.20189123137315210.1021/acschemneuro.8b0033430052418
     [Google Scholar]
  48. MendelsohnA.R. LarrickJ.W. Cellular senescence as the key intermediate in Tau-Mediated neurodegeneration.Rejuvenation Res.201821657257910.1089/rej.2018.215530489222
     [Google Scholar]
  49. BakerD.J. PetersenR.C. Cellular senescence in brain aging and neurodegenerative diseases: Evidence and perspectives.J. Clin. Invest.201812841208121610.1172/JCI9514529457783
     [Google Scholar]
  50. MansourH. ChamberlainC.G. WeibleM.W.II HughesS. ChuY. Chan-LingT. Aging-related changes in astrocytes in the rat retina: Imbalance between cell proliferation and cell death reduces astrocyte availability.Aging Cell20087452654010.1111/j.1474‑9726.2008.00402.x18489730
     [Google Scholar]
  51. PertusaM. García-MatasS. Rodríguez-FarréE. SanfeliuC. CristòfolR. Astrocytes aged in vitro show a decreased neuroprotective capacity.J. Neurochem.2007101379480510.1111/j.1471‑4159.2006.04369.x17250685
     [Google Scholar]
  52. KritsilisM. V RizouS. KoutsoudakiP.N. EvangelouK. GorgoulisV.G. PapadopoulosD. Ageing, cellular senescence and neurodegenerative disease.Int. J. Mol. Sci.20181910293710.3390/ijms1910293730261683
     [Google Scholar]
  53. BittoA. SellC. CroweE. LorenziniA. MalagutiM. HreliaS. TorresC. Stress-induced senescence in human and rodent astrocytes.Exp. Cell Res.2010316172961296810.1016/j.yexcr.2010.06.02120620137
     [Google Scholar]
  54. EvansR.J. WyllieF.S. Wynford-ThomasD. KiplingD. JonesC.J.A. A P53-dependent, telomere-independent proliferative life span barrier in human astrocytes consistent with the molecular genetics of glioma development.Cancer Res.200363164854486112941806
     [Google Scholar]
  55. ShangD. HongY. XieW. TuZ. XuJ. Interleukin-1β drives cellular senescence of rat astrocytes induced by oligomerized amyloid β peptide and oxidative stress.Front. Neurol.20201192910.3389/fneur.2020.0092933013631
     [Google Scholar]
  56. ShangD. SunD. ShiC. XuJ. ShenM. HuX. LiuH. TuZ. Activation of epidermal growth factor receptor signaling mediates cellular senescence induced by certain pro-inflammatory cytokines.Aging Cell2020195e1314510.1111/acel.1314532323422
     [Google Scholar]
  57. HalleA. HornungV. PetzoldG.C. StewartC.R. MonksB.G. ReinheckelT. FitzgeraldK.A. LatzE. MooreK.J. GolenbockD.T. The NALP3 inflammasome is involved in the innate immune response to amyloid-β.Nat. Immunol.20089885786510.1038/ni.163618604209
     [Google Scholar]
  58. HanX. ZhangT. LiuH. MiY. GouX. Astrocyte senescence and Alzheimer’s Disease: A review.Front. Aging Neurosci.20201214810.3389/fnagi.2020.0014832581763
     [Google Scholar]
  59. LiuC.C. HuJ. ZhaoN. WangJ. WangN. CirritoJ.R. KanekiyoT. HoltzmanD.M. BuG. Astrocytic LRP1 mediates brain Aβ clearance and impacts amyloid deposition.J. Neurosci.201737154023403110.1523/JNEUROSCI.3442‑16.201728275161
     [Google Scholar]
  60. RiesM. SastreM. Mechanisms of Aβ clearance and degradation by glial cells.Front. Aging Neurosci.2016816010.3389/fnagi.2016.0016027458370
     [Google Scholar]
  61. FrostG.R. LiY.M. The role of astrocytes in amyloid production and Alzheimer’s disease.Open Biol.201771217022810.1098/rsob.17022829237809
     [Google Scholar]
  62. GarwoodC.J. RatcliffeL.E. SimpsonJ.E. HeathP.R. InceP.G. WhartonS.B. Review: Astrocytes in Alzheimer’s disease and other age-associated dementias: A supporting player with a central role.Neuropathol. Appl. Neurobiol.201743428129810.1111/nan.1233827442752
     [Google Scholar]
  63. AngelovaD.M. BrownD.R. Microglia and the aging brain: Are senescent microglia the key to neurodegeneration?J. Neurochem.2019151667668810.1111/jnc.1486031478208
     [Google Scholar]
  64. FlanaryB.E. SammonsN.W. NguyenC. WalkerD. StreitW.J. Evidence that aging and amyloid promote microglial cell senescence.Rejuvenation Res.2007101617410.1089/rej.2006.909617378753
     [Google Scholar]
  65. FlanaryB.E. StreitW.J. Progressive telomere shortening occurs in cultured rat microglia, but not astrocytes.Glia2004451758810.1002/glia.1030114648548
     [Google Scholar]
  66. TaylorJ.M. MooreZ. MinterM.R. CrackP.J. Type-I interferon pathway in neuroinflammation and neurodegeneration: focus on Alzheimer’s disease.J. Neural Transm.2018125579780710.1007/s00702‑017‑1745‑428676934
     [Google Scholar]
  67. SafaiyanS. KannaiyanN. SnaideroN. BrioschiS. BiberK. YonaS. EdingerA.L. JungS. RossnerM.J. SimonsM. Age-related myelin degradation burdens the clearance function of microglia during aging.Nat. Neurosci.201619899599810.1038/nn.432527294511
     [Google Scholar]
  68. BarkerR. AshbyE.L. WellingtonD. BarrowV.M. PalmerJ.C. KehoeP.G. EsiriM.M. LoveS. Pathophysiology of white matter perfusion in Alzheimer’s disease and vascular dementia.Brain201413751524153210.1093/brain/awu04024618270
     [Google Scholar]
  69. ChildsB.G. GluscevicM. BakerD.J. LabergeR.M. MarquessD. DananbergJ. van DeursenJ.M. Senescent cells: An emerging target for diseases of ageing.Nat. Rev. Drug Discov.2017161071873510.1038/nrd.2017.11628729727
     [Google Scholar]
  70. LagoumtziS.M. ChondrogianniN. Senolytics and senomorphics: Natural and synthetic therapeutics in the treatment of aging and chronic diseases.Free Radic. Biol. Med.202117116919010.1016/j.freeradbiomed.2021.05.00333989756
     [Google Scholar]
  71. AlshadidiR. Anti-Senescence Therapy. Mechanisms and Management of Senescence HeshmatiH.M. IntechOpen202210.5772/intechopen.101585
     [Google Scholar]
  72. SongS. TchkoniaT. JiangJ. KirklandJ.L. SunY. Targeting senescent cells for a healthier aging: Challenges and opportunities.Adv. Sci.2020723200261110.1002/advs.20200261133304768
     [Google Scholar]
  73. BakerD.J. WijshakeT. TchkoniaT. LeBrasseurN.K. ChildsB.G. van de SluisB. KirklandJ.L. van DeursenJ.M. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders.Nature2011479737223223610.1038/nature1060022048312
     [Google Scholar]
  74. GasekN.S. KuchelG.A. KirklandJ.L. XuM. Strategies for targeting senescent cells in human disease.Nature Aging202111087087910.1038/s43587‑021‑00121‑834841261
     [Google Scholar]
  75. OvadyaY. KrizhanovskyV. Strategies targeting cellular senescence.J. Clin. Invest.201812841247125410.1172/JCI9514929608140
     [Google Scholar]
  76. SasakiM. KumazakiT. TakanoH. NishiyamaM. MitsuiY. Senescent cells are resistant to death despite low Bcl-2 level.Mech. Ageing Dev.2001122151695170610.1016/S0047‑6374(01)00281‑011557274
     [Google Scholar]
  77. YosefR. PilpelN. Tokarsky-AmielR. BiranA. OvadyaY. CohenS. VadaiE. DassaL. ShaharE. CondiottiR. Ben-PorathI. KrizhanovskyV. Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL.Nat. Commun.2016711119010.1038/ncomms1119027048913
     [Google Scholar]
  78. ZhuY. TchkoniaT. PirtskhalavaT. GowerA.C. DingH. GiorgadzeN. PalmerA.K. IkenoY. HubbardG.B. LenburgM. O’HaraS.P. LaRussoN.F. MillerJ.D. RoosC.M. VerzosaG.C. LeBrasseurN.K. WrenJ.D. FarrJ.N. KhoslaS. StoutM.B. McGowanS.J. Fuhrmann-StroissniggH. GurkarA.U. ZhaoJ. ColangeloD. DorronsoroA. LingY.Y. BarghouthyA.S. NavarroD.C. SanoT. RobbinsP.D. NiedernhoferL.J. KirklandJ.L. The Achilles’ heel of senescent cells: From transcriptome to senolytic drugs.Aging Cell201514464465810.1111/acel.1234425754370
     [Google Scholar]
  79. ZhangP. KishimotoY. GrammatikakisI. GottimukkalaK. CutlerR.G. ZhangS. AbdelmohsenK. BohrV.A. Misra SenJ. GorospeM. MattsonM.P. Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model.Nat. Neurosci.201922571972810.1038/s41593‑019‑0372‑930936558
     [Google Scholar]
  80. DhawanG. CombsC.K. Inhibition of Src kinase activity attenuates amyloid associated microgliosis in a murine model of Alzheimer’s disease.J. Neuroinflammation20129156310.1186/1742‑2094‑9‑11722673542
     [Google Scholar]
  81. DhawanG. FlodenA.M. CombsC.K. Amyloid-β oligomers stimulate microglia through a tyrosine kinase dependent mechanism.Neurobiol. Aging201233102247226110.1016/j.neurobiolaging.2011.10.02722133278
     [Google Scholar]
  82. LagasJ.S. van WaterschootR.A.B. van TilburgV.A.C.J. HillebrandM.J. LankheetN. RosingH. BeijnenJ.H. SchinkelA.H. Brain accumulation of dasatinib is restricted by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) and can be enhanced by elacridar treatment.Clin. Cancer Res.20091572344235110.1158/1078‑0432.CCR‑08‑225319276246
     [Google Scholar]
  83. GonzalesM.M. GarbarinoV.R. Marques ZilliE. PetersenR.C. KirklandJ.L. TchkoniaT. MusiN. SeshadriS. CraftS. OrrM.E. Senolytic therapy to modulate the progression of Alzheimer’s Disease (SToMP-AD): A pilot clinical trial.J. Prev. Alzheimers Dis.20211810.14283/jpad.2021.6235098970
     [Google Scholar]
  84. GonzalesM.M. KrishnamurthyS. GarbarinoV. DaeihaghA.S. GillispieG.J. DeepG. CraftS. OrrM.E. A geroscience motivated approach to treat Alzheimer’s disease: Senolytics move to clinical trials.Mech. Ageing Dev.202120011158910.1016/j.mad.2021.11158934687726
     [Google Scholar]
  85. YousefzadehM.J. ZhuY. McGowanS.J. AngeliniL. Fuhrmann-StroissniggH. XuM. LingY.Y. MelosK.I. PirtskhalavaT. InmanC.L. McGuckianC. WadeE.A. KatoJ.I. GrassiD. WentworthM. BurdC.E. ArriagaE.A. LadigesW.L. TchkoniaT. KirklandJ.L. RobbinsP.D. NiedernhoferL.J. Fisetin is a senotherapeutic that extends health and lifespan.EBioMedicine201836182810.1016/j.ebiom.2018.09.01530279143
     [Google Scholar]
  86. CurraisA. FarrokhiC. DarguschR. ArmandoA. QuehenbergerO. SchubertD. MaherP. Fisetin reduces the impact of aging on behavior and physiology in the rapidly aging SAMP8 mouse.J. Gerontol. A Biol. Sci. Med. Sci.201873329930710.1093/gerona/glx10428575152
     [Google Scholar]
  87. The University of Texas Health Science Center at San AntonioSenolytic Therapy to Modulate Progression of Alzheimer’s DiseaseAvailable from: https://clinicaltrials.gov/ct2/show/study/NCT04063124
  88. Wake Forest University Health Sciences. Senolytic therapy to modulate the progression of Alzheimer’s Disease (SToMP-AD) study.Available from: https://clinicaltrials.gov/ct2/show/study/NCT04685590
  89. JamesL.K ALSENLITE: Senolytics for Alzheimer’s Disease.Available from: https://clinicaltrials.gov/ct2/show/study/NCT04785300
  90. ChangJ. WangY. ShaoL. LabergeR.M. DemariaM. CampisiJ. JanakiramanK. SharplessN.E. DingS. FengW. LuoY. WangX. Aykin-BurnsN. KragerK. PonnappanU. Hauer-JensenM. MengA. ZhouD. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice.Nat. Med.2016221788310.1038/nm.401026657143
     [Google Scholar]
  91. ZhuY. TchkoniaT. Fuhrmann-StroissniggH. DaiH.M. LingY.Y. StoutM.B. PirtskhalavaT. GiorgadzeN. JohnsonK.O. GilesC.B. WrenJ.D. NiedernhoferL.J. RobbinsP.D. KirklandJ.L. Identification of a novel senolytic agent, navitoclax, targeting the Bcl‐2 family of anti‐apoptotic factors.Aging Cell201615342843510.1111/acel.1244526711051
     [Google Scholar]
  92. TseC. ShoemakerA.R. AdickesJ. AndersonM.G. ChenJ. JinS. JohnsonE.F. MarshK.C. MittenM.J. NimmerP. RobertsL. TahirS.K. XiaoY. YangX. ZhangH. FesikS. RosenbergS.H. ElmoreS.W. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor.Cancer Res.20086893421342810.1158/0008‑5472.CAN‑07‑583618451170
     [Google Scholar]
  93. PanJ. LiD. XuY. ZhangJ. WangY. ChenM. LinS. HuangL. ChungE. J. CitrinD. E. WangY. Hauer-JensenM. ZhouD. MengA. Inhibition of Bcl-2/Xl With ABT-263 selectively kills senescent Type II pneumocytes and reverses persistent pulmonary fibrosis induced by ionizing radiation in mice.Int. J. Radiat. Oncol. Biol. Phys.201799235336110.1016/j.ijrobp.2017.02.216
     [Google Scholar]
  94. HanL. SchuringaJ.J. MulderA. VellengaE. Dasatinib impairs long-term expansion of leukemic progenitors in a subset of acute myeloid leukemia cases.Ann. Hematol.201089986187110.1007/s00277‑010‑0948‑720387067
     [Google Scholar]
  95. LiJ. RixU. FangB. BaiY. EdwardsA. ColingeJ. BennettK.L. GaoJ. SongL. EschrichS. Superti-FurgaG. KoomenJ. HauraE.B. A chemical and phosphoproteomic characterization of dasatinib action in lung cancer.Nat. Chem. Biol.20106429129910.1038/nchembio.33220190765
     [Google Scholar]
  96. Del Gaizo MooreV. BrownJ.R. CertoM. LoveT.M. NovinaC.D. LetaiA. Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737.J. Clin. Invest.2007117111212110.1172/JCI2828117200714
     [Google Scholar]
  97. van DelftM.F. WeiA.H. MasonK.D. VandenbergC.J. ChenL. CzabotarP.E. WillisS.N. ScottC.L. DayC.L. CoryS. AdamsJ.M. RobertsA.W. HuangD.C.S. The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized.Cancer Cell200610538939910.1016/j.ccr.2006.08.02717097561
     [Google Scholar]
  98. KonoplevaM. ContractorR. TsaoT. SamudioI. RuvoloP.P. KitadaS. DengX. ZhaiD. ShiY.X. SneedT. VerhaegenM. SoengasM. RuvoloV.R. McQueenT. SchoberW.D. WattJ.C. JiffarT. LingX. MariniF.C. HarrisD. DietrichM. EstrovZ. McCubreyJ. MayW.S. ReedJ.C. AndreeffM. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia.Cancer Cell200610537538810.1016/j.ccr.2006.10.00617097560
     [Google Scholar]
  99. ZhuY. DoornebalE.J. PirtskhalavaT. GiorgadzeN. WentworthM. Fuhrmann-StroissniggH. NiedernhoferL.J. RobbinsP.D. TchkoniaT. KirklandJ.L. New agents that target senescent cells: The flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463.Aging20179395596310.18632/aging.10120228273655
     [Google Scholar]
  100. WangY. ChangJ. LiuX. ZhangX. ZhangS. ZhangX. ZhouD. ZhengG. Discovery of piperlongumine as a potential novel lead for the development of senolytic agents.Aging (Albany NY)20168112915292610.18632/aging.10110027913811
     [Google Scholar]
  101. ZhengJ. SonD.J. GuS.M. WooJ.R. HamY.W. LeeH.P. KimW.J. JungJ.K. HongJ.T. Piperlongumine inhibits lung tumor growth via inhibition of nuclear factor kappa B signaling pathway.Sci. Rep.2016612635710.1038/srep2635727198178
     [Google Scholar]
  102. RoeS.M. ProdromouC. O’BrienR. LadburyJ.E. PiperP.W. PearlL.H. Structural basis for inhibition of the Hsp90 molecular chaperone by the antitumor antibiotics radicicol and geldanamycin.J. Med. Chem.199942226026610.1021/jm980403y9925731
     [Google Scholar]
  103. Fuhrmann-StroissniggH. LingY.Y. ZhaoJ. McGowanS.J. ZhuY. BrooksR.W. GrassiD. GreggS.Q. StripayJ.L. DorronsoroA. CorboL. TangP. BukataC. RingN. GiaccaM. LiX. TchkoniaT. KirklandJ.L. NiedernhoferL.J. RobbinsP.D. Identification of HSP90 inhibitors as a novel class of senolytics.Nat. Commun.20178142210.1038/s41467‑017‑00314‑z28871086
     [Google Scholar]
  104. SamaraweeraL. AdomakoA. Rodriguez-GabinA. McDaidH.M. A novel indication for panobinostat as a senolytic drug in NSCLC and HNSCC.Sci. Rep.201771190010.1038/s41598‑017‑01964‑128507307
     [Google Scholar]
  105. Triana-MartínezF. Picallos-RabinaP. Da Silva-ÁlvarezS. PietrocolaF. LlanosS. RodillaV. SopranoE. PedrosaP. FerreirósA. BarradasM. Hernández-GonzálezF. LalindeM. PratsN. BernadóC. GonzálezP. GómezM. IkonomopoulouM.P. Fernández-MarcosP.J. García-CaballeroT. del PinoP. ArribasJ. VidalA. González-BarciaM. SerranoM. LozaM.I. DomínguezE. ColladoM. Identification and characterization of cardiac glycosides as senolytic compounds.Nat. Commun.2019101473110.1038/s41467‑019‑12888‑x31636264
     [Google Scholar]
  106. BaarM.P. BrandtR.M.C. PutavetD.A. KleinJ.D.D. DerksK.W.J. BourgeoisB.R.M. StryeckS. RijksenY. van WilligenburgH. FeijtelD.A. van der PluijmI. EssersJ. van CappellenW.A. van IJckenW.F. HoutsmullerA.B. PothofJ. de BruinR.W.F. MadlT. HoeijmakersJ.H.J. CampisiJ. de KeizerP.L.J. Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging.Cell20171691132147.e1610.1016/j.cell.2017.02.03128340339
     [Google Scholar]
  107. LiW. HeY. ZhangR. ZhengG. ZhouD. The curcumin analog EF24 is a novel senolytic agent.Aging (Albany NY)201911277178210.18632/aging.10178730694217
     [Google Scholar]
  108. GuerreroA. HerranzN. SunB. WagnerV. GallageS. GuihoR. WolterK. PomboJ. IrvineE.E. InnesA.J. BirchJ. GlegolaJ. ManshaeiS. HeideD. DharmalingamG. HarbigJ. OlonaA. BehmoarasJ. DauchD. UrenA.G. ZenderL. VerniaS. Martínez-BarberaJ.P. HeikenwalderM. WithersD.J. GilJ. Cardiac glycosides are broad-spectrum senolytics.Nat. Metab.20191111074108810.1038/s42255‑019‑0122‑z31799499
     [Google Scholar]
  109. HubackovaS. DavidovaE. RohlenovaK. StursaJ. WernerL. AnderaL. DongL. TerpM.G. HodnyZ. DitzelH.J. RohlenaJ. NeuzilJ. Selective elimination of senescent cells by mitochondrial targeting is regulated by ANT2.Cell Death Differ.201926227629010.1038/s41418‑018‑0118‑329786070
     [Google Scholar]
  110. JeonO.H. KimC. LabergeR.M. DemariaM. RathodS. VasserotA.P. ChungJ.W. KimD.H. PoonY. DavidN. BakerD.J. van DeursenJ.M. CampisiJ. ElisseeffJ.H. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment.Nat. Med.201723677578110.1038/nm.432428436958
     [Google Scholar]
  111. LimH. ParkH. KimH.P. Effects of flavonoids on senescence-associated secretory phenotype formation from bleomycin-induced senescence in BJ fibroblasts.Biochem. Pharmacol.201596433734810.1016/j.bcp.2015.06.01326093063
     [Google Scholar]
  112. MoiseevaO. Deschênes-SimardX. St-GermainE. IgelmannS. HuotG. CadarA.E. BourdeauV. PollakM.N. FerbeyreG. Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF -κ B activation.Aging Cell201312348949810.1111/acel.1207523521863
     [Google Scholar]
  113. HerranzN. GallageS. MelloneM. WuestefeldT. KlotzS. HanleyC.J. RaguzS. AcostaJ.C. InnesA.J. BanitoA. GeorgilisA. MontoyaA. WolterK. DharmalingamG. FaullP. CarrollT. Martínez-BarberaJ.P. CutillasP. ReisingerF. HeikenwalderM. MillerR.A. WithersD. ZenderL. ThomasG.J. GilJ. mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype.Nat. Cell Biol.20151791205121710.1038/ncb322526280535
     [Google Scholar]
  114. LabergeR.M. SunY. OrjaloA.V. PatilC.K. FreundA. ZhouL. CurranS.C. DavalosA.R. Wilson-EdellK.A. LiuS. LimbadC. DemariaM. LiP. HubbardG.B. IkenoY. JavorsM. DesprezP.Y. BenzC.C. KapahiP. NelsonP.S. CampisiJ. MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation.Nat. Cell Biol.20151781049106110.1038/ncb319526147250
     [Google Scholar]
  115. XuM. TchkoniaT. DingH. OgrodnikM. LubbersE.R. PirtskhalavaT. WhiteT.A. JohnsonK.O. StoutM.B. MezeraV. GiorgadzeN. JensenM.D. LeBrasseurN.K. KirklandJ.L. JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age.Proc. Natl. Acad. Sci. USA201511246E6301E631010.1073/pnas.151538611226578790
     [Google Scholar]
  116. PitozziV. MocaliA. LaurenzanaA. GiannoniE. CifolaI. BattagliaC. ChiarugiP. DolaraP. GiovannelliL. Chronic resveratrol treatment ameliorates cell adhesion and mitigates the inflammatory phenotype in senescent human fibroblasts.J. Gerontol. A Biol. Sci. Med. Sci.201368437138110.1093/gerona/gls18322933405
     [Google Scholar]
  117. KumarR. SharmaA. KumariA. GulatiA. PadwadY. SharmaR. Epigallocatechin gallate suppresses premature senescence of preadipocytes by inhibition of PI3K/Akt/mTOR pathway and induces senescent cell death by regulation of Bax/Bcl-2 pathway.Biogerontology201920217118910.1007/s10522‑018‑9785‑130456590
     [Google Scholar]
  118. LabergeR.M. ZhouL. SarantosM.R. RodierF. FreundA. de KeizerP.L.J. LiuS. DemariaM. CongY.S. KapahiP. DesprezP.Y. HughesR.E. CampisiJ. Glucocorticoids suppress selected components of the senescence-associated secretory phenotype.Aging Cell201211456957810.1111/j.1474‑9726.2012.00818.x22404905
     [Google Scholar]
  119. KangH.T. ParkJ.T. ChoiK. KimY. ChoiH.J.C. JungC.W. LeeY.S. ParkS.C. Chemical screening identifies ATM as a target for alleviating senescence.Nat. Chem. Biol.201713661662310.1038/nchembio.234228346404
     [Google Scholar]
  120. TilstraJ.S. RobinsonA.R. WangJ. GreggS.Q. ClausonC.L. ReayD.P. NastoL.A. St CroixC.M. UsasA. VoN. HuardJ. ClemensP.R. StolzD.B. GuttridgeD.C. WatkinsS.C. GarinisG.A. WangY. NiedernhoferL.J. RobbinsP.D. NF-κB inhibition delays DNA damage–induced senescence and aging in mice.J. Clin. Invest.201212272601261210.1172/JCI4578522706308
     [Google Scholar]
  121. WileyC.D. SchaumN. AlimirahF. Lopez-DominguezJ.A. OrjaloA.V. ScottG. DesprezP.Y. BenzC. DavalosA.R. CampisiJ. Small-molecule MDM2 antagonists attenuate the senescence-associated secretory phenotype.Sci. Rep.201881241010.1038/s41598‑018‑20000‑429402901
     [Google Scholar]
  122. BaeY.U. SonY. KimC.H. KimK.S. HyunS.H. WooH.G. JeeB.A. ChoiJ.H. SungH.K. ChoiH.C. ParkS.Y. BaeJ.H. DohK.O. KimJ.R. Embryonic stem cell–derived mmu-miR-291a-3p inhibits cellular senescence in human dermal fibroblasts through the TGF-β receptor 2 pathway.J. Gerontol. A Biol. Sci. Med. Sci.20197491359136710.1093/gerona/gly20830239625
     [Google Scholar]
/content/journals/cmp/10.2174/1874467217666230601113430
Loading
Targeting Cellular Senescence: A Potential Therapeutic approach for Alzheimer’s Disease
Curr Mol Pharmacol 17, E010623217543 (2024); https://doi.org/10.2174/1874467217666230601113430
/content/journals/cmp/10.2174/1874467217666230601113430
/content/journals/cmp/10.2174/1874467217666230601113430
Loading

Data & Media loading...


  • Article Type:     Review Article
Keyword(s): Alzheimer’s disease; Cellular senescence; Cognitive functions; Neurofibrillary tangles; Senescent cells; Therapeutic target

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test