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Aging, Senescence, and Dementia

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Abstract

The underlying processes occurring in aging are complex, involving numerous biological changes that result in chronic cellular stress and sterile inflammation. One of the main hallmarks of aging is senescence. While originally the term senescence was defined in the field of oncology further research has established that also microglia, astrocytes and neurons become senescent. Since age is the main risk factor for neurodegenerative diseases, it is reasonable to argue that cellular senescence might play a major role in Alzheimer’s disease. Specific cellular changes seen during Alzheimer’s disease are similar to those observed during senescence across all resident brain cell types. Furthermore, increased levels of senescence-associated secretory phenotype proteins such as IL-6, IGFBP, TGF-β and MMP-10 have been found in both CSF and plasma samples from Alzheimer’s disease patients. In addition, genome-wide association studies have identified that individuals with Alzheimer’s disease carry a high burden of genetic risk variants in genes known to be involved in senescence, including ADAMIO, ADAMTS4, and BIN1. Thus, cellular senescence is emerging as a potential underlying disease process operating in Alzheimer’s disease. This has also attracted more attention to exploiting cellular senescence as a therapeutic target. Several senolytic compounds with the capability to eliminate senescent cells have been examined in vivo and in vitro with notable results, suggesting they may provide a novel therapeutic avenue. Here, we reviewed the current knowledge of cellular senescence and discussed the evidence of senescence in various brain cell types and its putative role in inflammaging and neurodegenerative processes.

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References

  1. Kirkwood TBL. Why and how are we living longer? Exp Physiol. 2017;102(9):1067–1074. doi:https://doi.org/10.1113/EP086205

    Article  PubMed  Google Scholar 

  2. Guerville F, De Souto Barreto P, Ader I, et al. Revisiting the Hallmarks of Aging to Identify Markers of Biological Age. J Prev Alzheimer’s Dis. 2020;7(1):56–64. doi:https://doi.org/10.14283/jpad.2019.50

    CAS  Google Scholar 

  3. Boccardi V, Comanducci C, Baroni M, Mecocci P. Of energy and entropy: The ineluctable impact of aging in old age dementia. Int J Mol Sci. 2017;18(12):2672. doi:https://doi.org/10.3390/ijms18122672

    Article  PubMed Central  CAS  Google Scholar 

  4. Margolick JB, Ferrucci L. Accelerating aging research: How can we measure the rate of biologic aging?. Exp Gerontol. 2015;64:78–80. doi:https://doi.org/10.1016/j.exger.2015.02.009

    Article  PubMed  PubMed Central  Google Scholar 

  5. Partridge L, Deelen J, Slagboom PE. Facing up to the global challenges of ageing. Nature. 2018;561(7721):45–56. doi:https://doi.org/10.1038/s41586-018-0457-8

    Article  CAS  PubMed  Google Scholar 

  6. Seals DR, Justice JN, Larocca TJ. Physiological geroscience: Targeting function to increase healthspan and achieve optimal longevity. J Physiol. 2016;594(8):2001–2024. doi:https://doi.org/10.1113/jphysiol.2014.282665

    Article  CAS  PubMed  Google Scholar 

  7. Hedden T, Gabrieli JDE. Insights into the ageing mind: A view from cognitive neuroscience. Nat Rev Neurosa. 2004;5(2):87–96. doi:https://doi.org/10.1038/nrn1323

    Article  CAS  Google Scholar 

  8. Pierce AL, Bullain SS, Kawas CH. Late-Onset Alzheimer Disease. Neurol Clin. 2017;35(2):283–293. doi:https://doi.org/10.1016/j.ncl.2017.01.006

    Article  PubMed  Google Scholar 

  9. Corrada MM, Brookmeyer R, Paganini-Hill A, Berlau D, Kawas CH. Dementia incidence continues to increase with age in the oldest old the 90+ study. Ann Neurol. 2010;67(1):114–121. doi:https://doi.org/10.1002/ana.21915

    Article  PubMed  PubMed Central  Google Scholar 

  10. Muñoz-Espín D, Serrano M. Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol. 2014;15(7):482–496. doi:https://doi.org/10.1038/nrm3823

    Article  PubMed  CAS  Google Scholar 

  11. Howcroft TK, Campisi J, Louis GB, et al. The role of inflammation in age-related disease. Aging (Albany NY). 2013;5(1):84–93. doi:https://doi.org/10.18632/AGING.100531

    Article  CAS  Google Scholar 

  12. Cormenier J, Martin N, Deslé J, et al. The ATF6α arm of the Unfolded Protein Response mediates replicative senescence in human fibroblasts through a COX2/prostaglandin E2 intracrine pathway. Mech Ageing Dev. 2018;170:82–91. doi:https://doi.org/10.1016/J.MAD.2017.08.003

    Article  CAS  PubMed  Google Scholar 

  13. Druelle C, Drullion C, Deslé J, et al. ATF6α regulates morphological changes associated with senescence in human fibroblasts. Oncotarget. 2016;7(42):67699–67715. doi:https://doi.org/10.18632/oncotarget.11505

    Article  PubMed  PubMed Central  Google Scholar 

  14. Ohno-Iwashita Y, Shimada Y, Hayashi M, Inomata M. Plasma membrane microdomains in aging and disease. Geriatr Gerontol Int. 2010;10:S41–S52. doi:https://doi.org/10.1111/j.1447-0594.2010.00600.X

    Article  PubMed  Google Scholar 

  15. Freund A, Laberge R-M, Demaria M, Campisi J. Lamin Bl loss is a senescence-associated biomarker. Magin TM, ed. Mol Biol Cell. 2012;23 (11):2066–2075. doi:https://doi.org/10.1091/mbc.e11-10-0884

  16. Bannister AJ, Zegerman P, Partridge JF, et al. Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature. 2001;410(6824):120–124. doi:https://doi.org/10.1038/35065138

    Article  CAS  PubMed  Google Scholar 

  17. Dou Z, Ghosh K, Vizioli MG, et al. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature. 2017;550(7676):402–406. doi:https://doi.org/10.1038/nature24050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Di Micco R, Sulli G, Dobreva M, et al. Interplay between oncogene-induced DNA damage response and heterochromatin in senescence and cancer. Nat Cell Biol. 2011;13(3):292–302. doi:https://doi.org/10.1038/ncb2170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Salama R, Sadaie M, Hoare M, Narita M. Cellular senescence and its effector programs. Genes Dev. 2014;28(2):99–114. doi:https://doi.org/10.1101/gad.235184.113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Pluquet O, Pourtier A, Abbadie C. The unfolded protein response and cellular senescence. A review in the theme: cellular mechanisms of endoplasmic reticulum stress signaling in health and disease. Am J Physiol Cell Physiol. 2015;308(6):C415–25. doi:https://doi.org/10.1152/ajpcell.00334.2014

    Article  CAS  PubMed  Google Scholar 

  21. Coppé J-P, Desprez P-Y, Krtolica A, Campisi J. The Senescence-Associated Secretory Phenotype: The Dark Side of Tumor Suppression. Annu Rev Pathol Mech Dis. 2010;5(1):99–118. doi:https://doi.org/10.1146/annurev-pathol-121808-102144

    Article  CAS  Google Scholar 

  22. BY L, JA H, JS I, et al. Senescence-associated beta-galactosidase is lysosomal beta-galactosidase. Aging Cell. 2006;5(2). doi:https://doi.org/10.1111/J.1474-9726.2006.00199.X

  23. Lee BY, Han JA, Im JS, et al. Senescence-associated β-galactosidase is lysosomal β-galactosidase. Aging Cell. 2006;5(2):187–195. doi:https://doi.org/10.1111/j.1474-9726.2006.00199.x

    Article  CAS  PubMed  Google Scholar 

  24. Weichhart T. mTOR as Regulator of Lifespan, Aging, and Cellular Senescence: A Mini-Review. Gerontology. 2018;64(2):127–134. doi:https://doi.org/10.1159/000484629

    Article  CAS  PubMed  Google Scholar 

  25. Höhn A, Grune T. Lipofuscin: formation, effects and role of macroautophagy. Redox Biol. 2013;1(1):140–144. doi:https://doi.org/10.1016/J.REDOX.2013.01.006

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Ashburner J. A fast diffeomorphic image registration algorithm. Neuroimage. 2007;38(1):95–113. doi:https://doi.org/10.1016/j.neuroimage.2007.07.007

    Article  PubMed  Google Scholar 

  27. Georgakopoulou EA, Tsimaratou K, Evangelou K, et al. Specific lipofusdn staining as a novel biomarker to detect replicative and stress-induced senescence. A method applicable in cryo-preserved and archival tissues. Aging (Albany NY). 2013;5(1):37–50. doi:https://doi.org/10.18632/aging.100527

    Article  CAS  Google Scholar 

  28. Nakamura AJ, Chiang YJ, Hathcock KS, et al. Both telomeric and nontelomeric DNA damage are determinants of mammalian cellular senescence. Epigenetics Chromatin. 2008;1(1):6. doi:https://doi.org/10.1186/1756-8935-1-6

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Lee S, Schmitt CA. The dynamic nature of senescence in cancer. Nat Cell Biol. 2019;21(1):94–101. doi:https://doi.org/10.1038/s41556-018-0249-2

    Article  CAS  PubMed  Google Scholar 

  30. Bezzerri V, Piacenza F, Caporelli N, Malavolta M, Provindali M, Cipolli M. Is cellular senescence involved in cystic fibrosis? Respir Res. 2019;20(1):32. doi:https://doi.org/10.1186/s12931-019-0993-2

    Article  PubMed  PubMed Central  Google Scholar 

  31. Nyunoya T, Monick MM, Klingelhutz A, Yarovinsky TO, Cagley JR, Hunninghake GW. Cigarette Smoke Induces Cellular Senescence. Am J Respir Cell Mol Biol. 2006;35(6):681–688. doi:https://doi.org/10.1165/rcmb.2006-0169OC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Coppé J-P, Patil CK, Rodier F, et al. Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor. Downward J, ed. PLoS Biol. 2008;6 (12):e301. doi:https://doi.org/10.1371/journal.pbio.0060301

  33. Freund A, Orjalo A V, Desprez P-Y, Campisi J. Inflammatory networks during cellular senescence: causes and consequences. Trends Mol Med. 2010;16(5):238–246. doi:https://doi.org/10.1016/j.molmed.2010.03.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hayakawa T, Iwai M, Aoki S, et al. SIRT1 suppresses the senescence-associated secretory phenotype through epigenetic gene regulation. PLoS One. 2015;10(1):e0116480. doi:https://doi.org/10.1371/journal.pone.0116480

    Article  PubMed  PubMed Central  Google Scholar 

  35. Horvath S. DNA methylation age of human tissues and cell types. Genome Biol. 2013;14(10):R115. doi:https://doi.org/10.1186/gb-2013-14-10-r115

    Article  PubMed  PubMed Central  Google Scholar 

  36. Hannum G, Guinney J, Zhao L, et al. Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell. 2013;49(2):359–367. doi:https://doi.org/10.1016/j.molcel.2012.10.016

    Article  CAS  PubMed  Google Scholar 

  37. Krizhanovsky V, Xue W, Zender L, Yon M, Hernando E, Lowe SW. Implications of Cellular Senescence in Tissue Damage Response, Tumor Suppression, and Stem Cell Biology. Cold Spring Harb Symp Quant Biol. 2008;73:513–522. doi:https://doi.org/10.1101/sqb.2008.73.048

    Article  CAS  PubMed  Google Scholar 

  38. Childs BG, Baker DJ, Wijshake T, Conover CA, Campisi J, van Deursen JM. Senescent intimai foam cells are deleterious at all stages of atherosclerosis. Science. 2016;354(6311):472–477. doi:https://doi.org/10.1126/science.aat6659

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Jeon OH, David N, Campisi J, Elisseeff JH. Senescent cells and osteoarthritis: a painful connection. J Clin Invest. 2018;128(4):1229–1237. doi:https://doi.org/10.1172/JCI95147

    Article  PubMed  PubMed Central  Google Scholar 

  40. Baker DJ, Childs BG, Durik M, et al. Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature. 2016;530(7589):184–189. doi:https://doi.org/10.1038/naturel6932

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Franceschi C, Bonafè M, Valensin S, et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci. 2000;908:244–254. doi:https://doi.org/10.1111/j.1749-6632.2000.tb06651.x

    Article  CAS  PubMed  Google Scholar 

  42. Nathan C, Ding A. Nonresolving inflammation. Cell. 2010;140(6):871–882. doi:https://doi.org/10.1016/j.cell.2010.02.029

    Article  CAS  PubMed  Google Scholar 

  43. Chen Y, Swanson RA. Astrocytes and Brain Injury. J Cereb Blood Flow Metab. 2003;23(2):137–149. doi:https://doi.org/10.1097/01.WCB.0000044631.80210.3C

    Article  PubMed  Google Scholar 

  44. Bitto A, Sell C, Crowe E, et al. Stress-induced senescence in human and rodent astrocytes. Exp Cell Res. 2010;316(17):2961–2968. doi:https://doi.org/10.1016/j.yexcr.2010.06.021

    Article  CAS  PubMed  Google Scholar 

  45. Evans RJ, Wyllie FS, Wynford-Thomas D, Kipling D, Jones CJ. A P53-dependent, telomere-independent proliferative life span barrier in human astrocytes consistent with the molecular genetics of glioma development. Cancer Res. 2003;63(16):4854–4861. http://www.ncbi.nlm.nih.gov/pubmed/12941806

    CAS  PubMed  Google Scholar 

  46. Zou Y, Zhang N, Ellerby LM, et al. Responses of human embryonic stem cells and their differentiated progeny to ionizing radiation. Biochem Biophys Res Commun. 2012;426(1):100–105. doi:https://doi.org/10.1016/j.bbrc.2012.08.043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Limbad C, Oron TR, Alimirah F, et al. Astrocyte senescence promotes glutamate toxicity in cortical neurons. PLoS One. 2020;15(1):e0227887. doi:https://doi.org/10.1371/journal.pone.0227887

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Matias I, Diniz LP, Damico IV, et al. Loss of lamin-B1 and defective nuclear morphology are hallmarks of astrocyte senescence in vitro and in the aging human hippocampus. Aging Cell. 2022;21(1). doi:https://doi.org/10.1111/acel.13521

  49. Ransohoff RM, Brown MA. Innate immunity in the central nervous system. J Clin Invest. 2012;122(4):1164–1171. doi:https://doi.org/10.1172/JCI58644

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science. 2005;308(5726):1314–1318. doi:https://doi.org/10.1126/science.1110647

    Article  CAS  PubMed  Google Scholar 

  51. Mosher KI, Wyss-Coray T. Microglial dysfunction in brain aging and Alzheimer’s disease. Biochem Pharmacol. 2014;88(4):594–604. doi:https://doi.org/10.1016/j.bcp.2014.01.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Streit WJ, Sammons NW, Kuhns AJ, Sparks DL. Dystrophic microglia in the aging human brain. Glia. 2004;45(2):208–212. doi:https://doi.org/10.1002/glia.10319

    Article  PubMed  Google Scholar 

  53. Schuitemaker A, van der Doef TF, Boellaard R, et al. Microglial activation in healthy aging. Neurobiol Aging. 2012;33(6):1067–1072. doi:https://doi.org/10.1016/j.neurobiolaging.2010.09.016

    Article  CAS  PubMed  Google Scholar 

  54. Tan FCC, Hutchison ER, Eitan E, Mattson MP. Are there roles for brain cell senescence in aging and neurodegenerative disorders?. Biogerontology. 2014;15(6):643–660. doi:https://doi.org/10.1007/s10522-014-9532-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kang C, Xu Q, Martin TD, et al. The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4. Science. 2015;349(6255):aaa5612. doi:https://doi.org/10.1126/science.aaa5612

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Dehkordi SK, Walker J, Sah E, et al. Profiling senescent cells in human brains reveals neurons with CDKN2D/p19 and tau neuropathology. Nat Aging. 2021;1(12):1107–1116. doi:https://doi.org/10.1038/s43587-021-00142-3

    Article  PubMed  PubMed Central  Google Scholar 

  57. Minamino T, Miyauchi H, Yoshida T, Ishida Y, Yoshida H, Komuro I. Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction. Circulation. 2002;105(13):1541–1544. doi:https://doi.org/10.1161/01.cir.0000013836.85741.17

    Article  CAS  PubMed  Google Scholar 

  58. Yamazaki Y, Baker DJ, Tachibana M, et al. Vascular Cell Senescence Contributes to Blood-Brain Barrier Breakdown. Stroke. 2016;47(4):1068–1077. doi:https://doi.org/10.1161/STROKEAHA.115.010835

    Article  PubMed  PubMed Central  Google Scholar 

  59. Hanisch UK, Kettenmann H. Microglia: Active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosa. Published online 2007. doi:https://doi.org/10.1038/nn1997

  60. Shen X-N, Niu L-D, Wang Y-J, et al. Inflammatory markers in Alzheimer’s disease and mild cognitive impairment: a meta-analysis and systematic review of 170 studies. J Neurol Neurosurg Psychiatry. 2019;90(5):590–598. doi:https://doi.org/10.1136/jnnp-2018-319148

    Article  PubMed  Google Scholar 

  61. Farrall AJ, Wardlaw JM. Blood-brain barrier: Ageing and microvascular disease — systematic review and meta-analysis. Neurobiol Aging. 2009;30(3):337–352. doi:https://doi.org/10.1016/J.NEUROBIOLAGING.2007.07.015

    Article  CAS  PubMed  Google Scholar 

  62. Montagne A, Barnes SR, Sweeney MD, et al. Blood-brain barrier breakdown in the aging human hippocampus. Neuron. 2015;85(2):296–302. doi:https://doi.org/10.1016/j.neuron.2014.12.032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Togo T, Akiyama H, Iseki E, et al. Occurrence of T cells in the brain of Alzheimer’s disease and other neurological diseases. J Neuroimmunol. 2002;124(1–2):83–92. doi:https://doi.org/10.1016/s0165-5728(01)00496-9

    Article  CAS  PubMed  Google Scholar 

  64. Stichel CC, Luebbert H. Inflammatory processes in the aging mouse brain: Participation of dendritic cells and T-cells. Neurobiol Aging. 2007;28(10):1507–1521.doi:https://doi.org/10.1016/J.NEUROBIOLAGING.2006.07.022

    Article  CAS  PubMed  Google Scholar 

  65. McShea A, Harris PL, Webster KR, Wahl AF, Smith MA. Abnormal expression of the cell cycle regulators P16 and CDK4 in Alzheimer’s disease. Am J Pathol. 1997;150(6):1933–1939.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Musi N, Valentine JM, Sickora KR, et al. Tau protein aggregation is associated with cellular senescence in the brain. Aging Cell. 2018;17(6):e12840.doi:https://doi.org/10.1111/acel.12840

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Blasko I, Stampfer-Kountchev M, Robatscher P, Veerhuis R, Eikelenboom P, Grubeck-Loebenstein B. How chronic inflammation can affect the brain and support the development of Alzheimer’s disease in old age: the role of microglia and astrocytes. Aging Cell. 2004;3(4):169–176. doi:https://doi.org/10.1111/J.1474-9728.2004.00101.X

    Article  CAS  PubMed  Google Scholar 

  68. Bhat R, Crowe EP, Bitto A, et al. Astrocyte Senescence as a Component of Alzheimer’s Disease. Zheng JC, ed. PLoS One. 2012;7 (9):e45069. doi:https://doi.org/10.1371/journal.pone.0045069

  69. Campuzano O, Castillo-Ruiz MM, Acarin L, Castellano B, Gonzalez B. Increased levels of proinflammatory cytokines in the aged rat brain attenuate injury-induced cytokine response after excitotoxic damage. J Neurosci Res. 2009;87(11):2484–2497. doi:https://doi.org/10.1002/JNR.22074

    Article  CAS  PubMed  Google Scholar 

  70. Enokido Y, Yoshitake A, Ito H, Okazawa H. Age-dependent change of HMGB1 and DNA double-strand break accumulation in mouse brain. Biochem Biophys Res Commun. 2008;376(1):128–133. doi:https://doi.org/10.1016/J.BBRC.2008.08.108

    Article  CAS  PubMed  Google Scholar 

  71. Salminen A, Ojala J, Kaarniranta K, Haapasalo A, Hiltunen M, Soininen H. Astrocytes in the aging brain express characteristics of senescence-associated secretory phenotype. Eur J Neurosci. 2011;34(1):3–11. doi:https://doi.org/10.1111/j.1460-9568.2011.07738.x

    Article  PubMed  Google Scholar 

  72. Yoon KB, Park KR, Kim SY, Han SY. Induction of Nuclear Enlargement and Senescence by Sirtuin Inhibitors in Glioblastoma Cells. Immune Netw. 2016;16(3):183–188. doi:https://doi.org/10.4110/IN.2016.16.3.183

    Article  PubMed  PubMed Central  Google Scholar 

  73. Yu Z, Yi M, Wei T, Gao X, Chen H. KCa3.1 Inhibition Switches the Astrocyte Phenotype during Astrogliosis Associated with Ischemic Stroke Via Endoplasmic Reticulum Stress and MAPK Signaling Pathways. Front Cell Neurosci. 2017;11. doi:https://doi.org/10.3389/FNCEL.2017.00319

  74. Hou J, Cui C, Kim S, Sung C, Choi C. Ginsenoside Fl suppresses astrocytic senescence-associated secretory phenotype. Chem Biol Interact. 2018;283:75–83. doi:https://doi.org/10.1016/J.CBI.2018.02.002

    Article  CAS  PubMed  Google Scholar 

  75. Keren-Shaul H, Spinrad A, Weiner A, et al. A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease. Cell. 2017;169(7):1276–1290.e17. doi:https://doi.org/10.1016/j.cell.2017.05.018

    Article  CAS  PubMed  Google Scholar 

  76. Bhat R, Crowe EP, Bitto A, et al. Astrocyte senescence as a component of Alzheimer’s disease. PLoS One. 2012;7(9):e45069. doi:https://doi.org/10.1371/journal.pone.0045069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Ray S, Britschgi M, Herbert C, et al. Classification and prediction of clinical Alzheimer’s diagnosis based on plasma signaling proteins. Nat Med. 2007;13(11):1359–1362. doi:https://doi.org/10.1038/nm1653

    Article  CAS  PubMed  Google Scholar 

  78. Motta C, Finardi A, Toniolo S, et al. Protective Role of Cerebrospinal Fluid Inflammatory Cytokines in Patients with Amnestic Mild Cognitive Impairment and Early Alzheimer’s Disease Carrying Apolipoprotein E4 Genotype. J Alzheimers Dis. 2020;76(2):681–689. doi:https://doi.org/10.3233/JAD-191250

    Article  CAS  PubMed  Google Scholar 

  79. Tham A, Nordberg A, Grissom FE, Carlsson-Skwirut C, Viitanen M, Sara VR. Insulin-like growth factors and insulin-like growth factor binding proteins in cerebrospinal fluid and serum of patients with dementia of the Alzheimer type. J Neural Transm Park Dis Dement Sect. 1993;5(3):165–176. doi:https://doi.org/10.1007/BF02257671

    Article  CAS  PubMed  Google Scholar 

  80. Chao CC, Ala TA, Hu S, et al. Serum cytokine levels in patients with Alzheimer’s disease. Clin Diagn Lab Immunol. 1994;1(4):433–436. doi:10.1128/cd1i.1.4.433–436.1994

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Chao CC, Hu S, Frey WH, Ala TA, Tourtellotte WW, Peterson PK. Transforming growth factor beta in Alzheimer’s disease. Clin Diagn Lab Immunol. 1994;1(1):109–110. doi:https://doi.org/10.1128/cdli.1.1.109-110.1994

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Whelan CD, Mattsson N, Nagle MW, et al. Multiplex proteomics identifies novel CSF and plasma biomarkers of early Alzheimer’s disease. Acta Neuropathol Commun. Published online 2019. doi:https://doi.org/10.1186/s40478-019-0795-2

  83. Duits FH, Hernandez-Guillamon M, Montaner J, et al. Matrix Metalloproteinases in Alzheimer’s Disease and Concurrent Cerebral Microbleeds. J Alzheimer’s Dis. 2015;48(3):711–720. doi:https://doi.org/10.3233/JAD-143186

    Article  CAS  Google Scholar 

  84. Jansen IE, Savage JE, Watanabe K, et al. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk. Nat Genet. 2019;51(3):404–413. doi:https://doi.org/10.1038/s41588-018-0311-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Zingoni A, Cecere F, Vulpis E, et al. Genotoxic Stress Induces Senescence-Associated ADAMIO-Dependent Release of NKG2D MIC Ligands in Multiple Myeloma Cells. J Immunol. 2015;195(2):736–748. doi:https://doi.org/10.4049/jimmunol.1402643

    Article  CAS  PubMed  Google Scholar 

  86. Vinatier C, Domínguez E, Guicheux J, Caramés B. Role of the Inflammation-Autophagy-Senescence Integrative Network in Osteoarthritis. Front Physiol. 2018;9:706. doi:https://doi.org/10.3389/fphys.2018.00706

    Article  PubMed  PubMed Central  Google Scholar 

  87. Folk WP, Kumari A, Iwasaki T, et al. Loss of the tumor suppressor BIN1 enables ATM Ser/Thr kinase activation by the nuclear protein E2F1 and renders cancer cells resistant to cisplatin. J Biol Chem. 2019;294(14):5700–5719. doi:https://doi.org/10.1074/jbc.RA118.005699

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Zhu Y, Tchkonia T, Pirtskhalava T, et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015;14(4):644–658. doi:https://doi.org/10.1111/acel.12344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Justice JN, Nambiar AM, Tchkonia T, et al. Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study. EBioMedicine. 2019;40:554–563. doi:https://doi.org/10.1016/j.ebiom.2018.12.052

    Article  PubMed  PubMed Central  Google Scholar 

  90. Hickson LJ, Langhi Prata LGP, Bobart SA, et al. Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine. 2019;47:446–456. doi:https://doi.org/10.1016/j.ebiom.2019.08.069

    Article  PubMed  PubMed Central  Google Scholar 

  91. Ishisaka A, Ichikawa S, Sakakibara H, et al. Accumulation of orally administered quercetin in brain tissue and its antioxidative effects in rats. Free Radic Biol Med. 2011;51(7):1329–1336. doi:https://doi.org/10.1016/j.freeradbiomed.2011.06.017

    Article  CAS  PubMed  Google Scholar 

  92. Porkka K, Koskenvesa P, Lundán T, et al. Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia. Blood. 2008;112(4):1005–1012. doi:https://doi.org/10.1182/blood-2008-02-140665

    Article  CAS  PubMed  Google Scholar 

  93. TJ B, A A, CF M, BL S, JM van D, DJ B. Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature. 2018;562(7728). doi:https://doi.org/10.1038/S41586-018-0543-Y

  94. Gonzales MM, Garbarino VR, Marques Zilli E, et al. Senolytic Therapy to Modulate the Progression of Alzheimer’s Disease (SToMP-AD): A Pilot Clinical Trial. J Prev Alzheimer’s Dis. 2022;9(1):22–29. doi:https://doi.org/10.14283/jpad.2021.62

    CAS  Google Scholar 

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Funding

Funding: This review has been funded by JPco-fuND-2 “Multinational research projects on Personalised Medicine for Neurodegenerative Diseases” PREADAPT project (BMBF grant: 01ED2007A). PVMA was supported by a Georg Foster Humboldt Fellowship. The sponsors had no role in the design, preparation, or review of the manuscript.

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Authors and Affiliations

  1. Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Kerpener Str. 62, 50937, Cologne, Germany

    Q. Behfar, A. Ramirez Zuniga & Pamela V. Martino-Adami

  2. Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Medical Faculty, Bonn, Germany

    A. Ramirez Zuniga

  3. German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany

    A. Ramirez Zuniga

  4. Department of Psychiatry and Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, San Antonio, Texas, USA

    A. Ramirez Zuniga

  5. Cluster of Excellence Cellular Stress Responses in Aging-associated Diseases (CECAD), University of Cologne, Cologne, Germany

    A. Ramirez Zuniga

Authors
  1. Q. Behfar
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  2. A. Ramirez Zuniga
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  3. Pamela V. Martino-Adami
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Corresponding author

Correspondence to Pamela V. Martino-Adami.

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Conflict of interest: The authors report no conflicts of interest.

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How to cite this article: Q. Behfar, A. Ramirez Zuniga, P.V. Martino-Adami. Aging, Senescence, and Dementia. J Prev Alz Dis 2022;3(9):523-531; https://doi.org/10.14283/jpad.2022.42

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Behfar, Q., Ramirez Zuniga, A. & Martino-Adami, P.V. Aging, Senescence, and Dementia. J Prev Alzheimers Dis 9, 523–531 (2022). https://doi.org/10.14283/jpad.2022.42

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  • DOI: https://doi.org/10.14283/jpad.2022.42

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