Abstract
Advancing age is a major risk factor of Alzheimer’s disease (AD). The worldwide prevalence of AD is approximately 50 million people, and this number is projected to increase substantially. The molecular mechanisms underlying the aging-associated susceptibility to cognitive impairment in AD are largely unknown. As a hallmark of aging, cellular senescence is a significant contributor to aging and age-related diseases including AD. Senescent neurons and glial cells have been detected to accumulate in the brains of AD patients and mouse models. Importantly, selective elimination of senescent cells ameliorates amyloid beta and tau pathologies and improves cognition in AD mouse models, indicating a critical role of cellular senescence in AD pathogenesis. Nonetheless, the mechanisms underlying when and how cellular senescence contributes to AD pathogenesis remain unclear. This review provides an overview of cellular senescence and discusses recent advances in the understanding of the impact of cellular senescence on AD pathogenesis, with brief discussions of the possible role of cellular senescence in other neurodegenerative diseases including Down syndrome, Parkinson’s disease, multiple sclerosis, and amyotrophic lateral sclerosis.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abud EM, Ramirez RN, Martinez ES et al (2017) iPSC-derived human microglia-like cells to study neurological diseases. Neuron 94:278-293.e9. https://doi.org/10.1016/j.neuron.2017.03.042
Acklin S, Zhang M, Du W et al (2020) Depletion of senescent-like neuronal cells alleviates cisplatin-induced peripheral neuropathy in mice. Sci Rep 10:14170. https://doi.org/10.1038/s41598-020-71042-6
Acosta JC, O’Loghlen A, Banito A et al (2008) Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133:1006–1018. https://doi.org/10.1016/j.cell.2008.03.038
Acosta JC, Banito A, Wuestefeld T et al (2013) A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat Cell Biol 15:978–990. https://doi.org/10.1038/ncb2784
Adams PD (2007) Remodeling of chromatin structure in senescent cells and its potential impact on tumor suppression and aging. Gene 397:84–93. https://doi.org/10.1016/j.gene.2007.04.020
Alcorta DA, Xiong Y, Phelps D et al (1996) Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts. Proc Natl Acad Sci USA 93:13742–13747. https://doi.org/10.1073/pnas.93.24.13742
Arendt T, Rödel L, Gärtner U, Holzer M (1996) Expression of the cyclin-dependent kinase inhibitor p16 in Alzheimer’s disease. NeuroReport 7:3047–3049. https://doi.org/10.1097/00001756-199611250-00050
Arendt T, Holzer M, Gärtner U (1998) Neuronal expression of cycline dependent kinase inhibitors of the INK4 family in Alzheimer’s disease. J Neural Transm (vienna) 105:949–960. https://doi.org/10.1007/s007020050104
Atadja P, Wong H, Garkavtsev I et al (1995) Increased activity of p53 in senescing fibroblasts. Proc Natl Acad Sci USA 92:8348–8352. https://doi.org/10.1073/pnas.92.18.8348
Avelar RA, Ortega JG, Tacutu R et al (2020) A multidimensional systems biology analysis of cellular senescence in aging and disease. Genome Biol 21:91. https://doi.org/10.1186/s13059-020-01990-9
Baar MP, Brandt RMC, Putavet DA et al (2017) Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell 169:132-147.e16. https://doi.org/10.1016/j.cell.2017.02.031
Baker DJ, Petersen RC (2018) Cellular senescence in brain aging and neurodegenerative diseases: evidence and perspectives. J Clin Invest 128:1208–1216. https://doi.org/10.1172/JCI95145
Baker DJ, Perez-Terzic C, Jin F et al (2008) Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency. Nat Cell Biol 10:825–836. https://doi.org/10.1038/ncb1744
Baker DJ, Wijshake T, Tchkonia T et al (2011) Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479:232–236. https://doi.org/10.1038/nature10600
Baker DJ, Childs BG, Durik M et al (2016) Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature 530:184–189. https://doi.org/10.1038/nature16932
Bateman RJ, Xiong C, Benzinger TLS et al (2012) Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med 367:795–804. https://doi.org/10.1056/NEJMoa1202753
Bauer J, Strauss S, Schreiter-Gasser U et al (1991) Interleukin-6 and alpha-2-macroglobulin indicate an acute-phase state in Alzheimer’s disease cortices. FEBS Lett 285:111–114. https://doi.org/10.1016/0014-5793(91)80737-n
Beck CR, Garcia-Perez JL, Badge RM, Moran JV (2011) LINE-1 elements in structural variation and disease. Annu Rev Genom Hum Genet 12:187–215. https://doi.org/10.1146/annurev-genom-082509-141802
Bhat R, Crowe EP, Bitto A et al (2012) Astrocyte senescence as a component of Alzheimer’s disease. PLoS ONE 7:e45069–e45069. https://doi.org/10.1371/journal.pone.0045069
Birger A, Ben-Dor I, Ottolenghi M et al (2019) Human iPSC-derived astrocytes from ALS patients with mutated C9ORF72 show increased oxidative stress and neurotoxicity. EBioMedicine 50:274–289. https://doi.org/10.1016/j.ebiom.2019.11.026
Biron-Shental T, Liberman M, Sharvit M et al (2015) Amniocytes from aneuploidy embryos have enhanced random aneuploidy and signs of senescence—can these findings be related to medical problems? Gene 562:232–235. https://doi.org/10.1016/j.gene.2015.02.075
Bjerke M, Zetterberg H, Edman Å et al (2011) Cerebrospinal fluid matrix metalloproteinases and tissue inhibitor of metalloproteinases in combination with subcortical and cortical biomarkers in vascular dementia and Alzheimer’s disease. J Alzheimers Dis 27:665–676. https://doi.org/10.3233/JAD-2011-110566
Blasco MA, Lee HW, Hande MP et al (1997) Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91:25–34. https://doi.org/10.1016/s0092-8674(01)80006-4
Blum-Degen D, Müller T, Kuhn W et al (1995) Interleukin-1 beta and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer’s and de novo Parkinson’s disease patients. Neurosci Lett 202:17–20. https://doi.org/10.1016/0304-3940(95)12192-7
Bodnar AG, Ouellette M, Frolkis M et al (1998) Extension of life-span by introduction of telomerase into normal human cells. Science 279:349–352. https://doi.org/10.1126/science.279.5349.349
Bond JA, Wyllie FS, Wynford-Thomas D (1994) Escape from senescence in human diploid fibroblasts induced directly by mutant p53. Oncogene 9:1885–1889
Bond J, Haughton M, Blaydes J et al (1996) Evidence that transcriptional activation by p53 plays a direct role in the induction of cellular senescence. Oncogene 13:2097–2104
Boquoi A, Arora S, Chen T et al (2015) Reversible cell cycle inhibition and premature aging features imposed by conditional expression of p16Ink4a. Aging Cell 14:139–147. https://doi.org/10.1111/acel.12279
Brodacki B, Staszewski J, Toczyłowska B et al (2008) Serum interleukin (IL-2, IL-10, IL-6, IL-4), TNFalpha, and INFgamma concentrations are elevated in patients with atypical and idiopathic parkinsonism. Neurosci Lett 441:158–162. https://doi.org/10.1016/j.neulet.2008.06.040
Brouha B, Schustak J, Badge RM et al (2003) Hot L1s account for the bulk of retrotransposition in the human population. Proc Natl Acad Sci USA 100:5280. https://doi.org/10.1073/pnas.0831042100
Brown JP, Wei W, Sedivy JM (1997) Bypass of senescence after disruption of p21CIP1/WAF1 gene in normal diploid human fibroblasts. Science 277:831–834. https://doi.org/10.1126/science.277.5327.831
Burma S, Chen BP, Murphy M et al (2001) ATM phosphorylates histone H2AX in response to DNA double-strand breaks. J Biol Chem 276:42462–42467. https://doi.org/10.1074/jbc.C100466200
Buscemi G, Perego P, Carenini N et al (2004) Activation of ATM and Chk2 kinases in relation to the amount of DNA strand breaks. Oncogene 23:7691–7700. https://doi.org/10.1038/sj.onc.1207986
Bussian TJ, Aziz A, Meyer CF et al (2018) Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature 562:578–582. https://doi.org/10.1038/s41586-018-0543-y
Cacabelos R, Alvarez XA, Fernández-Novoa L et al (1994) Brain interleukin-1 beta in Alzheimer’s disease and vascular dementia. Methods Find Exp Clin Pharmacol 16:141–151
Camp JG, Badsha F, Florio M et al (2015) Human cerebral organoids recapitulate gene expression programs of fetal neocortex development. Proc Natl Acad Sci USA 112:15672–15677. https://doi.org/10.1073/pnas.1520760112
Campisi J (2013) Aging, cellular senescence, and cancer. Annu Rev Physiol 75:685–705. https://doi.org/10.1146/annurev-physiol-030212-183653
Casella G, Munk R, Kim KM et al (2019) Transcriptome signature of cellular senescence. Nucl Acids Res 47:7294–7305. https://doi.org/10.1093/nar/gkz555
Cataldo AM, Hamilton DJ, Nixon RA (1994) Lysosomal abnormalities in degenerating neurons link neuronal compromise to senile plaque development in Alzheimer disease. Brain Res 640:68–80. https://doi.org/10.1016/0006-8993(94)91858-9
Cesare AJ, Hayashi MT, Crabbe L, Karlseder J (2013) The telomere deprotection response is functionally distinct from the genomic DNA damage response. Mol Cell 51:141–155. https://doi.org/10.1016/j.molcel.2013.06.006
Chaib S, Tchkonia T, Kirkland JL (2022) Cellular senescence and senolytics: the path to the clinic. Nat Med 28:1556–1568. https://doi.org/10.1038/s41591-022-01923-y
Chang J, Wang Y, Shao L et al (2016) Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat Med 22:78–83. https://doi.org/10.1038/nm.4010
Chen Q, Fischer A, Reagan JD et al (1995) Oxidative DNA damage and senescence of human diploid fibroblast cells. Proc Natl Acad Sci USA 92:4337–4341. https://doi.org/10.1073/pnas.92.10.4337
Chen QM, Bartholomew JC, Campisi J et al (1998) Molecular analysis of H2O2-induced senescent-like growth arrest in normal human fibroblasts: p53 and Rb control G1 arrest but not cell replication. Biochem J 332(Pt 1):43–50. https://doi.org/10.1042/bj3320043
Childs BG, Baker DJ, Wijshake T et al (2016) Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science 354:472–477. https://doi.org/10.1126/science.aaf6659
Chin L, Artandi SE, Shen Q et al (1999) p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell 97:527–538. https://doi.org/10.1016/s0092-8674(00)80762-x
Chinta SJ, Woods G, Demaria M et al (2018) Cellular senescence is induced by the environmental neurotoxin paraquat and contributes to neuropathology linked to Parkinson’s disease. Cell Rep 22:930–940. https://doi.org/10.1016/j.celrep.2017.12.092
Coppé J-P, Patil CK, Rodier F et al (2008) Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 6:e301. https://doi.org/10.1371/journal.pbio.0060301
Coppé J-P, Desprez P-Y, Krtolica A, Campisi J (2010) The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol Mech Dis 5:99–118. https://doi.org/10.1146/annurev-pathol-121808-102144
Coppé J-P, Rodier F, Patil CK et al (2011) Tumor suppressor and aging biomarker p16(INK4a) induces cellular senescence without the associated inflammatory secretory phenotype. J Biol Chem 286:36396–36403. https://doi.org/10.1074/jbc.M111.257071
d’Adda di Fagagna F (2008) Living on a break: cellular senescence as a DNA-damage response. Nat Rev Cancer 8:512–522. https://doi.org/10.1038/nrc2440
d’Adda di Fagagna F, Reaper PM, Clay-Farrace L et al (2003) A DNA damage checkpoint response in telomere-initiated senescence. Nature 426:194–198. https://doi.org/10.1038/nature02118
D’Amico M, Wu K, Fu M et al (2004) The inhibitor of cyclin-dependent kinase 4a/alternative reading frame (INK4a/ARF) locus encoded proteins p16INK4a and p19ARF repress cyclin D1 transcription through distinct cis elements. Cancer Res 64:4122–4130. https://doi.org/10.1158/0008-5472.CAN-03-2519
Das MM, Svendsen CN (2015) Astrocytes show reduced support of motor neurons with aging that is accelerated in a rodent model of ALS. Neurobiol Aging 36:1130–1139. https://doi.org/10.1016/j.neurobiolaging.2014.09.020
De Cecco M, Criscione SW, Peckham EJ et al (2013) Genomes of replicatively senescent cells undergo global epigenetic changes leading to gene silencing and activation of transposable elements. Aging Cell 12:247–256. https://doi.org/10.1111/acel.12047
De Cecco M, Ito T, Petrashen AP et al (2019) L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature 566:73–78. https://doi.org/10.1038/s41586-018-0784-9
de la Monte SM, Sohn YK, Wands JR (1997) Correlates of p53- and Fas (CD95)-mediated apoptosis in Alzheimer’s disease. J Neurol Sci 152:73–83. https://doi.org/10.1016/s0022-510x(97)00131-7
de Oliveira Mann CC, Kranzusch PJ (2017) cGAS conducts micronuclei DNA surveillance. Trends Cell Biol 27:697–698. https://doi.org/10.1016/j.tcb.2017.08.007
Dehkordi SK, Walker J, Sah E et al (2021) Profiling senescent cells in human brains reveals neurons with CDKN2D/p19 and tau neuropathology. Nat Aging 1:1107–1116. https://doi.org/10.1038/s43587-021-00142-3
Dembny P, Newman AG, Singh M et al (2020) Human endogenous retrovirus HERV-K(HML-2) RNA causes neurodegeneration through toll-like receptors. JCI Insight 5:e131093. https://doi.org/10.1172/jci.insight.131093
Dementia Forecasting Collaborators (2022) 2022 Alzheimer’s disease facts and figures. Alzheimers Dement 18:700–789. https://doi.org/10.1002/alz.12638
Di Leonardo A, Linke SP, Clarkin K, Wahl GM (1994) DNA damage triggers a prolonged p53-dependent G1 arrest and long-term induction of Cip1 in normal human fibroblasts. Genes Dev 8:2540–2551. https://doi.org/10.1101/gad.8.21.2540
Di Micco R, Fumagalli M, Cicalese A et al (2006) Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444:638–642. https://doi.org/10.1038/nature05327
Di Micco R, Krizhanovsky V, Baker D, d’Adda di Fagagna F (2021) Cellular senescence in ageing: from mechanisms to therapeutic opportunities. Nat Rev Mol Cell Biol 22:75–95. https://doi.org/10.1038/s41580-020-00314-w
Dimri GP, Lee X, Basile G et al (1995) A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 92:9363–9367. https://doi.org/10.1073/pnas.92.20.9363
Dou Z, Ghosh K, Vizioli MG et al (2017) Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature 550:402–406. https://doi.org/10.1038/nature24050
Dulić V, Drullinger LF, Lees E et al (1993) Altered regulation of G1 cyclins in senescent human diploid fibroblasts: accumulation of inactive cyclin E-Cdk2 and cyclin D1-Cdk2 complexes. Proc Natl Acad Sci USA 90:11034–11038. https://doi.org/10.1073/pnas.90.23.11034
Dursun E, Gezen-Ak D, Hanağası H et al (2015) The interleukin 1 alpha, interleukin 1 beta, interleukin 6 and alpha-2-macroglobulin serum levels in patients with early or late onset Alzheimer’s disease, mild cognitive impairment or Parkinson’s disease. J Neuroimmunol 283:50–57. https://doi.org/10.1016/j.jneuroim.2015.04.014
Esteras N, Bartolomé F, Alquézar C et al (2012) Altered cell cycle-related gene expression in brain and lymphocytes from a transgenic mouse model of Alzheimer’s disease [amyloid precursor protein/presenilin 1 (PS1)]. Eur J Neurosci 36:2609–2618. https://doi.org/10.1111/j.1460-9568.2012.08178.x
Farr JN, Xu M, Weivoda MM et al (2017) Targeting cellular senescence prevents age-related bone loss in mice. Nat Med 23:1072–1079. https://doi.org/10.1038/nm.4385
Fathi A, Mathivanan S, Kong L et al (2022) Chemically induced senescence in human stem cell-derived neurons promotes phenotypic presentation of neurodegeneration. Aging Cell 21:e13541. https://doi.org/10.1111/acel.13541
Fatt MP, Tran LM, Vetere G et al (2022) Restoration of hippocampal neural precursor function by ablation of senescent cells in the aging stem cell niche. Stem Cell Rep 17:259–275. https://doi.org/10.1016/j.stemcr.2021.12.010
Flanary BE, Sammons NW, Nguyen C et al (2007) Evidence that aging and amyloid promote microglial cell senescence. Rejuvenation Res 10:61–74. https://doi.org/10.1089/rej.2006.9096
Flasch DA, Macia Á, Sánchez L et al (2019) Genome-wide de novo L1 retrotransposition connects endonuclease activity with replication. Cell 177:837-851.e28. https://doi.org/10.1016/j.cell.2019.02.050
Forero DA, González-Giraldo Y, López-Quintero C et al (2016) Meta-analysis of telomere length in Alzheimer’s disease. J Gerontol A Biol Sci Med Sci 71:1069–1073. https://doi.org/10.1093/gerona/glw053
Franceschi C, Campisi J (2014) Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci 69(Suppl 1):S4-9. https://doi.org/10.1093/gerona/glu057
Franco S, Blasco MA, Siedlak SL et al (2006) Telomeres and telomerase in Alzheimer’s disease: epiphenomena or a new focus for therapeutic strategy? Alzheimers Dement 2:164–168. https://doi.org/10.1016/j.jalz.2006.03.001
Freund A, Laberge R-M, Demaria M, Campisi J (2012) Lamin B1 loss is a senescence-associated biomarker. Mol Biol Cell 23:2066–2075. https://doi.org/10.1091/mbc.E11-10-0884
Fridman AL, Tainsky MA (2008) Critical pathways in cellular senescence and immortalization revealed by gene expression profiling. Oncogene 27:5975–5987. https://doi.org/10.1038/onc.2008.213
Frobel J, Hemeda H, Lenz M et al (2014) Epigenetic rejuvenation of mesenchymal stromal cells derived from induced pluripotent stem cells. Stem Cell Rep 3:414–422. https://doi.org/10.1016/j.stemcr.2014.07.003
Frost B, Hemberg M, Lewis J, Feany MB (2014) Tau promotes neurodegeneration through global chromatin relaxation. Nat Neurosci 17:357–366. https://doi.org/10.1038/nn.3639
Frost B, Bardai FH, Feany MB (2016) Lamin dysfunction mediates neurodegeneration in tauopathies. Curr Biol 26:129–136. https://doi.org/10.1016/j.cub.2015.11.039
Gaikwad S, Puangmalai N, Bittar A et al (2021) Tau oligomer induced HMGB1 release contributes to cellular senescence and neuropathology linked to Alzheimer’s disease and frontotemporal dementia. Cell Rep 36:109419. https://doi.org/10.1016/j.celrep.2021.109419
Garcia-Montojo M, Doucet-O’Hare T, Henderson L, Nath A (2018) Human endogenous retrovirus-K (HML-2): a comprehensive review. Crit Rev Microbiol 44:715–738. https://doi.org/10.1080/1040841X.2018.1501345
GBD (2019) Dementia Forecasting Collaborators (2022) Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019. Lancet Public Health 7:e105–e125. https://doi.org/10.1016/S2468-2667(21)00249-8
Georgakopoulou EA, Tsimaratou K, Evangelou K et al (2013) Specific lipofuscin staining as a novel biomarker to detect replicative and stress-induced senescence. A method applicable in cryo-preserved and archival tissues. Aging (Albany) 5:37–50. https://doi.org/10.18632/aging.100527
Gezen-Ak D, Dursun E, Hanağası H et al (2013) BDNF, TNFα, HSP90, CFH, and IL-10 serum levels in patients with early or late onset Alzheimer’s disease or mild cognitive impairment. J Alzheimers Dis 37:185–195. https://doi.org/10.3233/JAD-130497
Going JJ, Stuart RC, Downie M et al (2002) “Senescence-associated” beta-galactosidase activity in the upper gastrointestinal tract. J Pathol 196:394–400. https://doi.org/10.1002/path.1059
Gonzalez C, Armijo E, Bravo-Alegria J et al (2018) Modeling amyloid beta and tau pathology in human cerebral organoids. Mol Psychiatry 23:2363–2374. https://doi.org/10.1038/s41380-018-0229-8
González-Suárez E, Geserick C, Flores JM, Blasco MA (2005) Antagonistic effects of telomerase on cancer and aging in K5-mTert transgenic mice. Oncogene 24:2256–2270. https://doi.org/10.1038/sj.onc.1208413
Guan JZ, Maeda T, Sugano M et al (2008) A percentage analysis of the telomere length in Parkinson’s disease patients. J Gerontol A Biol Sci Med Sci 63:467–473. https://doi.org/10.1093/gerona/63.5.467
Guo C, Jeong H-H, Hsieh Y-C et al (2018) Tau activates transposable elements in Alzheimer’s disease. Cell Rep 23:2874–2880. https://doi.org/10.1016/j.celrep.2018.05.004
Ha L, Ichikawa T, Anver M et al (2007) ARF functions as a melanoma tumor suppressor by inducing p53-independent senescence. Proc Natl Acad Sci USA 104:10968–10973. https://doi.org/10.1073/pnas.0611638104
Habib R, Ocklenburg S, Hoffjan S et al (2020) Association between shorter leukocyte telomeres and multiple sclerosis. J Neuroimmunol 341:577187. https://doi.org/10.1016/j.jneuroim.2020.577187
Hall BM, Balan V, Gleiberman AS et al (2016) Aging of mice is associated with p16(Ink4a)- and β-galactosidase-positive macrophage accumulation that can be induced in young mice by senescent cells. Aging (Albany) 8:1294–1315. https://doi.org/10.18632/aging.100991
Harley CB, Futcher AB, Greider CW (1990) Telomeres shorten during ageing of human fibroblasts. Nature 345:458–460. https://doi.org/10.1038/345458a0
Hayflick L, Moorehead PS (1961) The serial cultivation of human diploid cell strains. Exp Cell Res 25:585–621
He N, Jin W-L, Lok K-H et al (2013) Amyloid-β(1-42) oligomer accelerates senescence in adult hippocampal neural stem/progenitor cells via formylpeptide receptor 2. Cell Death Dis 4:e924. https://doi.org/10.1038/cddis.2013.437
Hebert LE, Weuve J, Scherr PA, Evans DA (2013) Alzheimer disease in the United States (2010–2050) estimated using the 2010 census. Neurology 80:1778–1783. https://doi.org/10.1212/WNL.0b013e31828726f5
Hemmer B, Kerschensteiner M, Korn T (2015) Role of the innate and adaptive immune responses in the course of multiple sclerosis. Lancet Neurol 14:406–419. https://doi.org/10.1016/S1474-4422(14)70305-9
Herbig U, Jobling WA, Chen BPC et al (2004) Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a). Mol Cell 14:501–513. https://doi.org/10.1016/s1097-2765(04)00256-4
Herbig U, Ferreira M, Condel L et al (2006) Cellular senescence in aging primates. Science 311:1257. https://doi.org/10.1126/science.1122446
Herdy JR, Traxler L, Agarwal RK et al (2022) Increased post-mitotic senescence in aged human neurons is a pathological feature of Alzheimer’s disease. Cell Stem Cell 29:1637-1652.e6. https://doi.org/10.1016/j.stem.2022.11.010
Hernandez-Segura A, de Jong TV, Melov S et al (2017) Unmasking transcriptional heterogeneity in senescent cells. Curr Biol 27:2652-2660.e4. https://doi.org/10.1016/j.cub.2017.07.033
Hernandez-Segura A, Nehme J, Demaria M (2018) Hallmarks of cellular senescence. Trends Cell Biol 28:436–453. https://doi.org/10.1016/j.tcb.2018.02.001
Herranz N, Gallage S, Mellone M et al (2015) mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype. Nat Cell Biol 17:1205–1217. https://doi.org/10.1038/ncb3225
Hewitt G, Jurk D, Marques FDM et al (2012) Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence. Nat Commun 3:708. https://doi.org/10.1038/ncomms1708
Holdt LM, Sass K, Gäbel G et al (2011) Expression of Chr9p21 genes CDKN2B (p15(INK4b)), CDKN2A (p16(INK4a), p14(ARF)) and MTAP in human atherosclerotic plaque. Atherosclerosis 214:264–270. https://doi.org/10.1016/j.atherosclerosis.2010.06.029
Horstmann S, Budig L, Gardner H et al (2010) Matrix metalloproteinases in peripheral blood and cerebrospinal fluid in patients with Alzheimer’s disease. Int Psychogeriatr 22:966–972. https://doi.org/10.1017/S1041610210000827
Hu Y, Fryatt GL, Ghorbani M et al (2021) Replicative senescence dictates the emergence of disease-associated microglia and contributes to Aβ pathology. Cell Rep. https://doi.org/10.1016/j.celrep.2021.109228
Hudgins AD, Tazearslan C, Tare A et al (2018) Age- and tissue-specific expression of senescence biomarkers in mice. Front Genet 9:59. https://doi.org/10.3389/fgene.2018.00059
Huell M, Strauss S, Volk B et al (1995) Interleukin-6 is present in early stages of plaque formation and is restricted to the brains of Alzheimer’s disease patients. Acta Neuropathol 89:544–551. https://doi.org/10.1007/BF00571510
Ide T, Tsuji Y, Ishibashi S, Mitsui Y (1983) Reinitiation of host DNA synthesis in senescent human diploid cells by infection with Simian virus 40. Exp Cell Res 143:343–349. https://doi.org/10.1016/0014-4827(83)90060-5
Imamura K, Hishikawa N, Sawada M et al (2003) Distribution of major histocompatibility complex class II-positive microglia and cytokine profile of Parkinson’s disease brains. Acta Neuropathol 106:518–526. https://doi.org/10.1007/s00401-003-0766-2
Ishikawa S, Ishikawa F (2020) Proteostasis failure and cellular senescence in long-term cultured postmitotic rat neurons. Aging Cell 19:e13071. https://doi.org/10.1111/acel.13071
Islam MI, Nagakannan P, Shcholok T et al (2022) Regulatory role of cathepsin L in induction of nuclear laminopathy in Alzheimer’s disease. Aging Cell 21:e13531. https://doi.org/10.1111/acel.13531
Israel MA, Yuan SH, Bardy C et al (2012) Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells. Nature 482:216–220. https://doi.org/10.1038/nature10821
Ivanov A, Pawlikowski J, Manoharan I et al (2013) Lysosome-mediated processing of chromatin in senescence. J Cell Biol 202:129–143. https://doi.org/10.1083/jcb.201212110
Janzen V, Forkert R, Fleming HE et al (2006) Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature 443:421–426. https://doi.org/10.1038/nature05159
Jeck WR, Siebold AP, Sharpless NE (2012) Review: a meta-analysis of GWAS and age-associated diseases. Aging Cell 11:727–731. https://doi.org/10.1111/j.1474-9726.2012.00871.x
Jenkins EC, Ye L, Gu H et al (2008) Increased “absence” of telomeres may indicate Alzheimer’s disease/dementia status in older individuals with Down syndrome. Neurosci Lett 440:340–343. https://doi.org/10.1016/j.neulet.2008.05.098
Jenkins EC, Ye L, Gu H et al (2010) Shorter telomeres may indicate dementia status in older individuals with Down syndrome. Neurobiol Aging 31:765–771. https://doi.org/10.1016/j.neurobiolaging.2008.06.001
Jeon OH, Kim C, Laberge R-M et al (2017) Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat Med 23:775–781. https://doi.org/10.1038/nm.4324
Jochems F, Thijssen B, De Conti G et al (2021) The cancer SENESCopedia: a delineation of cancer cell senescence. Cell Rep 36:109441. https://doi.org/10.1016/j.celrep.2021.109441
Johnson WE (2019) Origins and evolutionary consequences of ancient endogenous retroviruses. Nat Rev Microbiol 17:355–370. https://doi.org/10.1038/s41579-019-0189-2
Jönsson ME, Garza R, Johansson PA, Jakobsson J (2020) Transposable elements: a common feature of neurodevelopmental and neurodegenerative disorders. Trends Genet 36:610–623. https://doi.org/10.1016/j.tig.2020.05.004
Jun J-I, Lau LF (2010) The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing. Nat Cell Biol 12:676–685. https://doi.org/10.1038/ncb2070
Jurk D, Wang C, Miwa S et al (2012) Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response. Aging Cell 11:996–1004. https://doi.org/10.1111/j.1474-9726.2012.00870.x
Kang C, Xu Q, Martin TD et al (2015) The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4. Science 349:aaa5612. https://doi.org/10.1126/science.aaa5612
Kazazian HH, Moran JV (2017) Mobile DNA in health and disease. N Engl J Med 377:361–370. https://doi.org/10.1056/NEJMra1510092
Kim NW, Piatyszek MA, Prowse KR et al (1994) Specific association of human telomerase activity with immortal cells and cancer. Science 266:2011–2015. https://doi.org/10.1126/science.7605428
Kitamura Y, Shimohama S, Kamoshima W et al (1997) Changes of p53 in the brains of patients with Alzheimer’s disease. Biochem Biophys Res Commun 232:418–421. https://doi.org/10.1006/bbrc.1997.6301
Kiyono T, Foster SA, Koop JI et al (1998) Both Rb/p16INK4a inactivation and telomerase activity are required to immortalize human epithelial cells. Nature 396:84–88. https://doi.org/10.1038/23962
Krimpenfort P, Quon KC, Mooi WJ et al (2001) Loss of p16Ink4a confers susceptibility to metastatic melanoma in mice. Nature 413:83–86. https://doi.org/10.1038/35092584
Krishnamurthy J, Torrice C, Ramsey MR et al (2004) Ink4a/Arf expression is a biomarker of aging. J Clin Invest 114:1299–1307. https://doi.org/10.1172/JCI22475
Krishnamurthy J, Ramsey MR, Ligon KL et al (2006) p16INK4a induces an age-dependent decline in islet regenerative potential. Nature 443:453–457. https://doi.org/10.1038/nature05092
Kritsilis M, Rizou VS, Koutsoudaki PN et al (2018) Ageing, cellular senescence and neurodegenerative disease. Int J Mol Sci 19:2937. https://doi.org/10.3390/ijms19102937
Kuilman T, Peeper DS (2009) Senescence-messaging secretome: SMS-ing cellular stress. Nat Rev Cancer 9:81–94. https://doi.org/10.1038/nrc2560
Kuilman T, Michaloglou C, Vredeveld LCW et al (2008) Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133:1019–1031. https://doi.org/10.1016/j.cell.2008.03.039
Kuilman T, Michaloglou C, Mooi WJ, Peeper DS (2010) The essence of senescence. Genes Dev 24:2463–2479. https://doi.org/10.1101/gad.1971610
Kun A, González-Camacho F, Hernández S et al (2018) Characterization of amyloid-β plaques and autofluorescent lipofuscin aggregates in Alzheimer’s disease brain: a confocal microscopy approach. Methods Mol Biol 1779:497–512. https://doi.org/10.1007/978-1-4939-7816-8_31
Laberge R-M, Sun Y, Orjalo AV et al (2015) MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nat Cell Biol 17:1049–1061. https://doi.org/10.1038/ncb3195
Lai KSP, Liu CS, Rau A et al (2017) Peripheral inflammatory markers in Alzheimer’s disease: a systematic review and meta-analysis of 175 studies. J Neurol Neurosurg Psychiatry 88:876–882. https://doi.org/10.1136/jnnp-2017-316201
Lander ES, Linton LM, Birren B et al (2001) Initial sequencing and analysis of the human genome. Nature 409:860–921. https://doi.org/10.1038/35057062
Lapasset L, Milhavet O, Prieur A et al (2011) Rejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state. Genes Dev 25:2248–2253. https://doi.org/10.1101/gad.173922.111
Larson CM, Pillsworth EG, Haselton MG (2012) Ovulatory shifts in women’s attractions to primary partners and other men: further evidence of the importance of primary partner sexual attractiveness. PLoS ONE 7:e44456. https://doi.org/10.1371/journal.pone.0044456
Le ONL, Rodier F, Fontaine F et al (2010) Ionizing radiation-induced long-term expression of senescence markers in mice is independent of p53 and immune status. Aging Cell 9:398–409. https://doi.org/10.1111/j.1474-9726.2010.00567.x
Leake A, Morris CM, Whateley J (2000) Brain matrix metalloproteinase 1 levels are elevated in Alzheimer’s disease. Neurosci Lett 291:201–203. https://doi.org/10.1016/s0304-3940(00)01418-x
Lee HW, Blasco MA, Gottlieb GJ et al (1998) Essential role of mouse telomerase in highly proliferative organs. Nature 392:569–574. https://doi.org/10.1038/33345
Li Y, Nichols MA, Shay JW, Xiong Y (1994) Transcriptional repression of the D-type cyclin-dependent kinase inhibitor p16 by the retinoblastoma susceptibility gene product pRb. Cancer Res 54:6078–6082
Li W, Lee M-H, Henderson L et al (2015) Human endogenous retrovirus-K contributes to motor neuron disease. Sci Transl Med. https://doi.org/10.1126/scitranslmed.aac8201
Liton PB, Challa P, Stinnett S et al (2005) Cellular senescence in the glaucomatous outflow pathway. Exp Gerontol 40:745–748. https://doi.org/10.1016/j.exger.2005.06.005
Liu Y, Johnson SM, Fedoriw Y et al (2011) Expression of p16(INK4a) prevents cancer and promotes aging in lymphocytes. Blood 117:3257–3267. https://doi.org/10.1182/blood-2010-09-304402
Liu X, Liu Z, Wu Z et al (2023) Resurrection of endogenous retroviruses during aging reinforces senescence. Cell. https://doi.org/10.1016/j.cell.2022.12.017
Lois AF, Cooper LT, Geng Y et al (1995) Expression of the p16 and p15 cyclin-dependent kinase inhibitors in lymphocyte activation and neuronal differentiation. Cancer Res 55:4010–4013
López-Otín C, Blasco MA, Partridge L et al (2013) The hallmarks of aging. Cell 153:1194–1217. https://doi.org/10.1016/j.cell.2013.05.039
Luterman JD, Haroutunian V, Yemul S et al (2000) Cytokine gene expression as a function of the clinical progression of Alzheimer disease dementia. Arch Neurol 57:1153–1160. https://doi.org/10.1001/archneur.57.8.1153
Lüth HJ, Holzer M, Gertz HJ, Arendt T (2000) Aberrant expression of nNOS in pyramidal neurons in Alzheimer’s disease is highly co-localized with p21ras and p16INK4a. Brain Res 852:45–55. https://doi.org/10.1016/s0006-8993(99)02178-2
Mahmoudi S, Brunet A (2012) Aging and reprogramming: a two-way street. Curr Opin Cell Biol 24:744–756. https://doi.org/10.1016/j.ceb.2012.10.004
Maier B, Gluba W, Bernier B et al (2004) Modulation of mammalian life span by the short isoform of p53. Genes Dev 18:306–319. https://doi.org/10.1101/gad.1162404
Marchi E, Kanapin A, Magiorkinis G, Belshaw R (2014) Unfixed endogenous retroviral insertions in the human population. J Virol 88:9529–9537. https://doi.org/10.1128/JVI.00919-14
Marcovecchio GE, Ferrua F, Fontana E et al (2021) Premature senescence and increased oxidative stress in the thymus of down syndrome patients. Front Immunol 12:669893. https://doi.org/10.3389/fimmu.2021.669893
Marion RM, Strati K, Li H et al (2009) Telomeres acquire embryonic stem cell characteristics in induced pluripotent stem cells. Cell Stem Cell 4:141–154. https://doi.org/10.1016/j.stem.2008.12.010
Martin JA, Brown TD, Heiner AD, Buckwalter JA (2004) Chondrocyte senescence, joint loading and osteoarthritis. Clin Orthop Relat Res. https://doi.org/10.1097/01.blo.0000143818.74887.b1
Martínez-Cué C, Rueda N (2020) Cellular senescence in neurodegenerative diseases. Front Cell Neurosci 14:1
Maurer K, Volk S, Gerbaldo H (1997) Auguste D and Alzheimer’s disease. Lancet 349:1546–1549. https://doi.org/10.1016/S0140-6736(96)10203-8
McConnell BB, Starborg M, Brookes S, Peters G (1998) Inhibitors of cyclin-dependent kinases induce features of replicative senescence in early passage human diploid fibroblasts. Curr Biol 8:351–354. https://doi.org/10.1016/s0960-9822(98)70137-x
McShea A, Harris PL, Webster KR et al (1997) Abnormal expression of the cell cycle regulators P16 and CDK4 in Alzheimer’s disease. Am J Pathol 150:1933–1939
Medema RH, Herrera RE, Lam F, Weinberg RA (1995) Growth suppression by p16ink4 requires functional retinoblastoma protein. Proc Natl Acad Sci USA 92:6289–6293. https://doi.org/10.1073/pnas.92.14.6289
Meharena HS, Marco A, Dileep V et al (2022) Down-syndrome-induced senescence disrupts the nuclear architecture of neural progenitors. Cell Stem Cell 29:116-130.e7. https://doi.org/10.1016/j.stem.2021.12.002
Melk A, Schmidt BMW, Takeuchi O et al (2004) Expression of p16INK4a and other cell cycle regulator and senescence associated genes in aging human kidney. Kidney Int 65:510–520. https://doi.org/10.1111/j.1523-1755.2004.00438.x
Miller JD, Ganat YM, Kishinevsky S et al (2013) Human iPSC-based modeling of late-onset disease via progerin-induced aging. Cell Stem Cell 13:691–705. https://doi.org/10.1016/j.stem.2013.11.006
Mogi M, Harada M, Kondo T et al (1994) Interleukin-1 beta, interleukin-6, epidermal growth factor and transforming growth factor-alpha are elevated in the brain from parkinsonian patients. Neurosci Lett 180:147–150. https://doi.org/10.1016/0304-3940(94)90508-8
Molofsky AV, Slutsky SG, Joseph NM et al (2006) Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature 443:448–452. https://doi.org/10.1038/nature05091
Moreno-Blas D, Gorostieta-Salas E, Pommer-Alba A et al (2019) Cortical neurons develop a senescence-like phenotype promoted by dysfunctional autophagy. Aging (Albany) 11:6175–6198. https://doi.org/10.18632/aging.102181
Moreno-García A, Kun A, Calero O et al (2018) An overview of the role of lipofuscin in age-related neurodegeneration. Front Neurosci 12:464. https://doi.org/10.3389/fnins.2018.00464
Mungenast AE, Siegert S, Tsai L-H (2016) Modeling Alzheimer’s disease with human induced pluripotent stem (iPS) cells. Mol Cell Neurosci 73:13–31. https://doi.org/10.1016/j.mcn.2015.11.010
Muñoz-Espín D, Cañamero M, Maraver A et al (2013) Programmed cell senescence during mammalian embryonic development. Cell 155:1104–1118. https://doi.org/10.1016/j.cell.2013.10.019
Musi N, Valentine JM, Sickora KR et al (2018) Tau protein aggregation is associated with cellular senescence in the brain. Aging Cell 17:e12840–e12840. https://doi.org/10.1111/acel.12840
Myung N-H, Zhu X, Kruman II et al (2008) Evidence of DNA damage in Alzheimer disease: phosphorylation of histone H2AX in astrocytes. Age (dordr) 30:209–215. https://doi.org/10.1007/s11357-008-9050-7
Narita M, Nũnez S, Heard E et al (2003) Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 113:703–716. https://doi.org/10.1016/s0092-8674(03)00401-x
Neurohr GE, Terry RL, Lengefeld J et al (2019) Excessive cell growth causes cytoplasm dilution and contributes to senescence. Cell 176:1083-1097.e18. https://doi.org/10.1016/j.cell.2019.01.018
Nicaise AM, Wagstaff LJ, Willis CM et al (2019) Cellular senescence in progenitor cells contributes to diminished remyelination potential in progressive multiple sclerosis. Proc Natl Acad Sci USA 116:9030–9039. https://doi.org/10.1073/pnas.1818348116
Nielsen GP, Stemmer-Rachamimov AO, Shaw J et al (1999) Immunohistochemical survey of p16INK4A expression in normal human adult and infant tissues. Lab Invest 79:1137–1143
Noda A, Ning Y, Venable SF et al (1994) Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen. Exp Cell Res 211:90–98. https://doi.org/10.1006/excr.1994.1063
Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG (2000) Multiple sclerosis. N Engl J Med 343:938–952. https://doi.org/10.1056/NEJM200009283431307
Ochoa Thomas E, Zuniga G, Sun W, Frost B (2020) Awakening the dark side: retrotransposon activation in neurodegenerative disorders. Curr Opin Neurobiol 61:65–72. https://doi.org/10.1016/j.conb.2020.01.012
Ogrodnik M, Miwa S, Tchkonia T et al (2017) Cellular senescence drives age-dependent hepatic steatosis. Nat Commun 8:15691. https://doi.org/10.1038/ncomms15691
Ogrodnik M, Zhu Y, Langhi LGP et al (2019) Obesity-induced cellular senescence drives anxiety and impairs neurogenesis. Cell Metab 29:1061-1077.e8. https://doi.org/10.1016/j.cmet.2018.12.008
Ogrodnik M, Evans SA, Fielder E et al (2021) Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice. Aging Cell 20:e13296. https://doi.org/10.1111/acel.13296
Ogryzko VV, Hirai TH, Russanova VR et al (1996) Human fibroblast commitment to a senescence-like state in response to histone deacetylase inhibitors is cell cycle dependent. Mol Cell Biol 16:5210–5218. https://doi.org/10.1128/MCB.16.9.5210
Ohashi M, Korsakova E, Allen D et al (2018) Loss of MECP2 leads to activation of P53 and neuronal senescence. Stem Cell Rep 10:1453–1463. https://doi.org/10.1016/j.stemcr.2018.04.001
Ohyagi Y, Asahara H, Chui D-H et al (2005) Intracellular Abeta42 activates p53 promoter: a pathway to neurodegeneration in Alzheimer’s disease. FASEB J 19:255–257. https://doi.org/10.1096/fj.04-2637fje
Oubaha M, Miloudi K, Dejda A et al (2016) Senescence-associated secretory phenotype contributes to pathological angiogenesis in retinopathy. Sci Transl Med 8:362ra144. https://doi.org/10.1126/scitranslmed.aaf9440
Palmer A, Epton S, Crawley E et al (2021) Expression of p16 within myenteric neurons of the aged colon: a potential marker of declining function. Front Neurosci 15:747067. https://doi.org/10.3389/fnins.2021.747067
Panossian LA, Porter VR, Valenzuela HF et al (2003) Telomere shortening in T cells correlates with Alzheimer’s disease status. Neurobiol Aging 24:77–84. https://doi.org/10.1016/s0197-4580(02)00043-x
Paradis V, Youssef N, Dargère D et al (2001) Replicative senescence in normal liver, chronic hepatitis C, and hepatocellular carcinomas. Hum Pathol 32:327–332. https://doi.org/10.1053/hupa.2001.22747
Park J, Wetzel I, Marriott I et al (2018) A 3D human triculture system modeling neurodegeneration and neuroinflammation in Alzheimer’s disease. Nat Neurosci 21:941–951. https://doi.org/10.1038/s41593-018-0175-4
Parrinello S, Samper E, Krtolica A et al (2003) Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts. Nat Cell Biol 5:741–747. https://doi.org/10.1038/ncb1024
Payer LM, Burns KH (2019) Transposable elements in human genetic disease. Nat Rev Genet 20:760–772. https://doi.org/10.1038/s41576-019-0165-8
Pazolli E, Alspach E, Milczarek A et al (2012) Chromatin remodeling underlies the senescence-associated secretory phenotype of tumor stromal fibroblasts that supports cancer progression. Cancer Res 72:2251–2261. https://doi.org/10.1158/0008-5472.CAN-11-3386
Penney J, Ralvenius WT, Tsai L-H (2020) Modeling Alzheimer’s disease with iPSC-derived brain cells. Mol Psychiatry 25:148–167. https://doi.org/10.1038/s41380-019-0468-3
Poewe W, Seppi K, Tanner CM et al (2017) Parkinson disease. Nat Rev Dis Primers 3:17013. https://doi.org/10.1038/nrdp.2017.13
Raffaele M, Kovacovicova K, Bonomini F et al (2020) Senescence-like phenotype in post-mitotic cells of mice entering middle age. Aging (Albany) 12:13979–13990. https://doi.org/10.18632/aging.103637
Reichel W (1968) Lipofuscin pigment accumulation and distribution in five rat organs as a function of age. J Gerontol 23:145–153. https://doi.org/10.1093/geronj/23.2.145
Ressler S, Bartkova J, Niederegger H et al (2006) p16INK4A is a robust in vivo biomarker of cellular aging in human skin. Aging Cell 5:379–389. https://doi.org/10.1111/j.1474-9726.2006.00231.x
Riessland M, Kolisnyk B, Kim TW et al (2019) Loss of SATB1 induces p21-dependent cellular senescence in post-mitotic dopaminergic neurons. Cell Stem Cell 25:514-530.e8. https://doi.org/10.1016/j.stem.2019.08.013
Rodier F, Coppé J-P, Patil CK et al (2009) Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol 11:973–979. https://doi.org/10.1038/ncb1909
Roos CM, Zhang B, Palmer AK et al (2016) Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell 15:973–977. https://doi.org/10.1111/acel.12458
Rowland LP, Shneider NA (2001) Amyotrophic lateral sclerosis. N Engl J Med 344:1688–1700. https://doi.org/10.1056/NEJM200105313442207
Rueda N, Vidal V, García-Cerro S et al (2018) Anti-IL17 treatment ameliorates Down syndrome phenotypes in mice. Brain Behav Immun 73:235–251. https://doi.org/10.1016/j.bbi.2018.05.008
Sapieha P, Mallette FA (2018) Cellular senescence in postmitotic cells: beyond growth arrest. Trends Cell Biol 28:595–607. https://doi.org/10.1016/j.tcb.2018.03.003
Sato S, Kawamata Y, Takahashi A et al (2015) Ablation of the p16(INK4a) tumour suppressor reverses ageing phenotypes of klotho mice. Nat Commun 6:7035. https://doi.org/10.1038/ncomms8035
Satyanarayana A, Wiemann SU, Buer J et al (2003) Telomere shortening impairs organ regeneration by inhibiting cell cycle re-entry of a subpopulation of cells. EMBO J 22:4003–4013. https://doi.org/10.1093/emboj/cdg367
Saul D, Kosinsky RL, Atkinson EJ et al (2022) A new gene set identifies senescent cells and predicts senescence-associated pathways across tissues. Nat Commun 13:4827. https://doi.org/10.1038/s41467-022-32552-1
Schafer MJ, White TA, Iijima K et al (2017) Cellular senescence mediates fibrotic pulmonary disease. Nat Commun 8:14532. https://doi.org/10.1038/ncomms14532
Sebastian T, Malik R, Thomas S et al (2005) C/EBPbeta cooperates with RB:E2F to implement Ras(V12)-induced cellular senescence. EMBO J 24:3301–3312. https://doi.org/10.1038/sj.emboj.7600789
Serrano M, Hannon GJ, Beach D (1993) A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 366:704–707. https://doi.org/10.1038/366704a0
Serrano M, Lin AW, McCurrach ME et al (1997) Oncogenic RAS provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88:593–602. https://doi.org/10.1016/s0092-8674(00)81902-9
Shah PP, Donahue G, Otte GL et al (2013) Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape. Genes Dev 27:1787–1799. https://doi.org/10.1101/gad.223834.113
Sharpless NE, Sherr CJ (2015) Forging a signature of in vivo senescence. Nat Rev Cancer 15:397–408. https://doi.org/10.1038/nrc3960
Sharpless NE, Bardeesy N, Lee KH et al (2001) Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis. Nature 413:86–91. https://doi.org/10.1038/35092592
Shay JW, Pereira-Smith OM, Wright WE (1991) A role for both RB and p53 in the regulation of human cellular senescence. Exp Cell Res 196:33–39. https://doi.org/10.1016/0014-4827(91)90453-2
Sherr CJ, DePinho RA (2000) Cellular senescence: mitotic clock or culture shock? Cell 102:407–410. https://doi.org/10.1016/s0092-8674(00)00046-5
Simon M, Van Meter M, Ablaeva J et al (2019) LINE1 derepression in aged wild-type and SIRT6-deficient mice drives inflammation. Cell Metab 29:871-885.e5. https://doi.org/10.1016/j.cmet.2019.02.014
Storer M, Mas A, Robert-Moreno A et al (2013) Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell 155:1119–1130. https://doi.org/10.1016/j.cell.2013.10.041
Sturmlechner I, Zhang C, Sine CC et al (2021) p21 produces a bioactive secretome that places stressed cells under immunosurveillance. Science 374:eabb3420. https://doi.org/10.1126/science.abb3420
Subramanian RP, Wildschutte JH, Russo C, Coffin JM (2011) Identification, characterization, and comparative genomic distribution of the HERV-K (HML-2) group of human endogenous retroviruses. Retrovirology 8:90. https://doi.org/10.1186/1742-4690-8-90
Sultana T, van Essen D, Siol O et al (2019) The landscape of L1 retrotransposons in the human genome is shaped by pre-insertion sequence biases and post-insertion selection. Mol Cell 74:555-570.e7. https://doi.org/10.1016/j.molcel.2019.02.036
Sumrejkanchanakij P, Eto K, Ikeda M-A (2006) Cytoplasmic sequestration of cyclin D1 associated with cell cycle withdrawal of neuroblastoma cells. Biochem Biophys Res Commun 340:302–308. https://doi.org/10.1016/j.bbrc.2005.11.181
Sun W, Samimi H, Gamez M et al (2018) Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies. Nat Neurosci 21:1038–1048. https://doi.org/10.1038/s41593-018-0194-1
Swanson EC, Manning B, Zhang H, Lawrence JB (2013) Higher-order unfolding of satellite heterochromatin is a consistent and early event in cell senescence. J Cell Biol 203:929–942. https://doi.org/10.1083/jcb.201306073
Swardfager W, Lanctôt K, Rothenburg L et al (2010) A meta-analysis of cytokines in Alzheimer’s disease. Biol Psychiatry 68:930–941. https://doi.org/10.1016/j.biopsych.2010.06.012
Takai H, Smogorzewska A, de Lange T (2003) DNA damage foci at dysfunctional telomeres. Curr Biol 13:1549–1556. https://doi.org/10.1016/s0960-9822(03)00542-6
Talma N, Gerrits E, Wang B et al (2021) Identification of distinct and age-dependent p16High microglia subtypes. Aging Cell 20:e13450. https://doi.org/10.1111/acel.13450
Tarkowski E, Liljeroth AM, Minthon L et al (2003) Cerebral pattern of pro- and anti-inflammatory cytokines in dementias. Brain Res Bull 61:255–260. https://doi.org/10.1016/s0361-9230(03)00088-1
Tcw J, Wang M, Pimenova AA et al (2017) An efficient platform for astrocyte differentiation from human induced pluripotent stem cells. Stem Cell Rep 9:600–614. https://doi.org/10.1016/j.stemcr.2017.06.018
Thomas P, O’Callaghan NJ, Fenech M (2008) Telomere length in white blood cells, buccal cells and brain tissue and its variation with ageing and Alzheimer’s disease. Mech Ageing Dev 129:183–190. https://doi.org/10.1016/j.mad.2007.12.004
Trias E, Beilby PR, Kovacs M et al (2019) Emergence of microglia bearing senescence markers during paralysis progression in a rat model of inherited ALS. Front Aging Neurosci 11:42. https://doi.org/10.3389/fnagi.2019.00042
Turnquist C, Horikawa I, Foran E et al (2016) p53 isoforms regulate astrocyte-mediated neuroprotection and neurodegeneration. Cell Death Differ 23:1515–1528. https://doi.org/10.1038/cdd.2016.37
van Deursen JM (2014) The role of senescent cells in ageing. Nature 509:439–446. https://doi.org/10.1038/nature13193
Vargiu L, Rodriguez-Tomé P, Sperber GO et al (2016) Classification and characterization of human endogenous retroviruses; mosaic forms are common. Retrovirology 13:7. https://doi.org/10.1186/s12977-015-0232-y
Vaziri H, Benchimol S (1998) Reconstitution of telomerase activity in normal human cells leads to elongation of telomeres and extended replicative life span. Curr Biol 8:279–282. https://doi.org/10.1016/s0960-9822(98)70109-5
Vaziri H, Schächter F, Uchida I et al (1993) Loss of telomeric DNA during aging of normal and trisomy 21 human lymphocytes. Am J Hum Genet 52:661–667
Vazquez-Villaseñor I, Garwood CJ, Heath PR et al (2020) Expression of p16 and p21 in the frontal association cortex of ALS/MND brains suggests neuronal cell cycle dysregulation and astrocyte senescence in early stages of the disease. Neuropathol Appl Neurobiol 46:171–185. https://doi.org/10.1111/nan.12559
Vera E, Studer L (2015) When rejuvenation is a problem: challenges of modeling late-onset neurodegenerative disease. Development 142:3085–3089. https://doi.org/10.1242/dev.120667
Voisin J, Farina F, Naphade S et al (2020) FOXO3 targets are reprogrammed as Huntington’s disease neural cells and striatal neurons face senescence with p16INK4a increase. Aging Cell 19:e13226. https://doi.org/10.1111/acel.13226
von Zglinicki T, Saretzki G, Döcke W, Lotze C (1995) Mild hyperoxia shortens telomeres and inhibits proliferation of fibroblasts: a model for senescence? Exp Cell Res 220:186–193. https://doi.org/10.1006/excr.1995.1305
Wang Y, Chang J, Shao L et al (2016) Hematopoietic stem cells from Ts65Dn mice are deficient in the repair of DNA double-strand breaks. Radiat Res 185:630–637. https://doi.org/10.1667/RR14407.1
Wei Z, Chen X-C, Song Y et al (2016) Amyloid β protein aggravates neuronal senescence and cognitive deficits in 5XFAD mouse model of Alzheimer’s disease. Chin Med J (engl) 129:1835–1844. https://doi.org/10.4103/0366-6999.186646
Weirich-Schwaiger H, Weirich HG, Gruber B et al (1994) Correlation between senescence and DNA repair in cells from young and old individuals and in premature aging syndromes. Mutat Res 316:37–48. https://doi.org/10.1016/0921-8734(94)90006-x
Welch GM, Boix CA, Schmauch E et al (2022) Neurons burdened by DNA double-strand breaks incite microglia activation through antiviral-like signaling in neurodegeneration. Sci Adv 8:eabo4662. https://doi.org/10.1126/sciadv.abo4662
Wilcock DM, Griffin WST (2013) Down’s syndrome, neuroinflammation, and Alzheimer neuropathogenesis. J Neuroinflammation 10:84. https://doi.org/10.1186/1742-2094-10-84
Wiley CD, Flynn JM, Morrissey C et al (2017) Analysis of individual cells identifies cell-to-cell variability following induction of cellular senescence. Aging Cell 16:1043–1050. https://doi.org/10.1111/acel.12632
Wiseman FK, Al-Janabi T, Hardy J et al (2015) A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome. Nat Rev Neurosci 16:564–574. https://doi.org/10.1038/nrn3983
Wong H, Riabowol K (1996) Differential CDK-inhibitor gene expression in aging human diploid fibroblasts. Exp Gerontol 31:311–325. https://doi.org/10.1016/0531-5565(95)00025-9
Xu M, Palmer AK, Ding H et al (2015) Targeting senescent cells enhances adipogenesis and metabolic function in old age. Elife 4:e12997. https://doi.org/10.7554/eLife.12997
Xu M, Pirtskhalava T, Farr JN et al (2018) Senolytics improve physical function and increase lifespan in old age. Nat Med 24:1246–1256. https://doi.org/10.1038/s41591-018-0092-9
Yeager T, Stadler W, Belair C et al (1995) Increased p16 levels correlate with pRb alterations in human urothelial cells. Cancer Res 55:493–497
Yousefzadeh MJ, Zhu Y, McGowan SJ et al (2018) Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine 36:18–28. https://doi.org/10.1016/j.ebiom.2018.09.015
Zhang H, Pan K-H, Cohen SN (2003) Senescence-specific gene expression fingerprints reveal cell-type-dependent physical clustering of up-regulated chromosomal loci. Proc Natl Acad Sci USA 100:3251–3256. https://doi.org/10.1073/pnas.2627983100
Zhang R, Chen W, Adams PD (2007) Molecular dissection of formation of senescence-associated heterochromatin foci. Mol Cell Biol 27:2343–2358. https://doi.org/10.1128/MCB.02019-06
Zhang P, Kishimoto Y, Grammatikakis I et al (2019) Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nat Neurosci 22:719–728
Zhang Y, Shao C, Li H et al (2021) The distinct function of p21Waf1/Cip1 with p16Ink4a in modulating aging phenotypes of werner syndrome by affecting tissue homeostasis. Front Genet 12:597566. https://doi.org/10.3389/fgene.2021.597566
Zhang X, Pearsall VM, Carver CM et al (2022) Rejuvenation of the aged brain immune cell landscape in mice through p16-positive senescent cell clearance. Nat Commun 13:5671. https://doi.org/10.1038/s41467-022-33226-8
Zhao M, Chen L, Qu H (2016) CSGene: a literature-based database for cell senescence genes and its application to identify critical cell aging pathways and associated diseases. Cell Death Dis 7:e2053. https://doi.org/10.1038/cddis.2015.414
Zhu Y, Tchkonia T, Pirtskhalava T et al (2015) The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14:644–658. https://doi.org/10.1111/acel.12344
Zhu Y, Tchkonia T, Fuhrmann-Stroissnigg H et al (2016) Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell 15:428–435. https://doi.org/10.1111/acel.12445
Zindy F, Quelle DE, Roussel MF, Sherr CJ (1997) Expression of the p16INK4a tumor suppressor versus other INK4 family members during mouse development and aging. Oncogene 15:203–211. https://doi.org/10.1038/sj.onc.1201178
Funding
This work is supported by NIH grants RF1AG056302 and RF1AG068281 to H.Z.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Holloway, K., Neherin, K., Dam, K.U. et al. Cellular senescence and neurodegeneration. Hum. Genet. 142, 1247–1262 (2023). https://doi.org/10.1007/s00439-023-02565-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00439-023-02565-x