Abstract
Senescence is an irreversible mitotic arrest of the cell that can result from replicative aging or stressors. It can be beneficial by conferring resistance to apoptosis, or detrimental by inducing pro-inflammatory signaling in the microenvironment. Senescent cells have been observed in both aged and diseased tissue, including the brain. The aging brain undergoes changes such as cortical atrophy and increases in inflammatory and oxidative factors, with decreases in synaptic plasticity and mitochondrial function. Significant neuronal loss is observed and thought to drive the atrophy in the corresponding areas of the brain in neurodegenerative diseases (ND). Despite being terminally differentiated, a senescence-like phenotype is observed in neurons upon stress in vitro and also in neurocognitive disorders like HIV-associated dementia and Alzheimer’s disease in vivo. Aging is also associated with lower regenerative capacity of neural stem and progenitor cells (NSPC). In vivo, their neurogenerative capacity is modulated by a variety of external factors, including growth factors, diet, and inflammation. NSPC have been observed to undergo stress-induced senescence in vitro. Deregulation of other CNS cell types, including oligodendrocytes and microglia occur in aging and ND. Microglia, which are not post-mitotic, senesce in culture in response to replicative or inflammatory stress. Astrocytes, which make up half of all cells in the CNS, maintain and protect neurons. In response to insult or injury however, astrocytes undergo phenotypic changes collectively termed reactive astrogliosis. This response can be both detrimental and beneficial to the neurons, and its downregulation improves disease parameters in a mouse model of AD. We have observed astrocyte senescence in vitro in response to replicative and oxidative stress and Aβ peptides, along with accumulation of senescent astrocytes in aged and AD brain. Given that astrocytes perform a myriad of complex functions in the CNS in order to maintain homeostasis, the loss of astrocyte function or the gain of neuroinflammatory function as a result of senescence could have profound implications for aging brain and neurodegenerative disorders.
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Abbott N, Rönnbäck L, Hansson E (2006) Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 7:41–53
Abramov AY, Canevari L, Duchen MR (2004) Beta-amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase. J Neurosci 24:565–575
Ajami B, Bennett J, Krieger C, Tetzlaff W, Rossi F (2007) Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat Neurosci 10:1538–1543
Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole G, Cooper N, Eikelenboom P, Emmerling M, Fiebich B, Finch C, Frautschy S, Griffin W, Hampel H, Hull M, Landreth G, Lue L, Mrak R, Mackenzie I, Mcgeer P, O’Banion M, Pachter J, Pasinetti G, Plata-Salaman C, Rogers J, Rydel R, Shen Y, Streit W, Strohmeyer R, Tooyoma I, van Muiswinkel F, Veerhuis R, Walker D, Webster S, Wegrzyniak B, Wenk G, Wyss-Coray T (2000) Inflammation and Alzheimer’s disease. Neurobiol Aging 21:383–421
Allaman I, Gavillet M, Belanger M, Laroche T, Viertl D, Lashuel HA, Magistretti PJ (2010) Amyloid-beta aggregates cause alterations of astrocytic metabolic phenotype: impact on neuronal viability. J Neurosci 30:3326–3338
Alliot F, Godin I, Pessac B (1999) Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain. Brain Res Dev Brain Res 117:145–152
Altmann-Schneider I, de Craen A, Veer I, van den Berg-Huysmans A, Slagboom P, Westendorp R, van Buchem M, van der Grond J, Leiden Longevity Study G (2013) Preserved white matter integrity is a marker of familial longevity. Ann Neurol 74:883–892
Alvarez-Buylla A, Lim D (2004) For the long run: maintaining germinal niches in the adult brain. Neuron 41:683–686
Anderson M, Aberg M, Nilsson M, Eriksson P (2002) Insulin-like growth factor-I and neurogenesis in the adult mammalian brain. Brain Res Dev Brain Res 134:115–122
Apostolova L, Green A, Babakchanian S, Hwang K, Chou Y-Y, Toga A, Thompson P (2012) Hippocampal atrophy and ventricular enlargement in normal aging, mild cognitive impairment (MCI), and Alzheimer disease. Alzheimer Dis Assoc Disord 26:17–27
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
Azevedo F, Carvalho L, Grinberg L, Farfel J, Ferretti R, Leite R, Jacob Filho W, Lent R, Herculano-Houzel S (2009) Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain. J Comp Neurol 513:532–541
Baker D, Wijshake T, Tchkonia T, Lebrasseur N, Childs B, van de Sluis B, Kirkland J, van Deursen J (2011) Clearance of p16(Ink4a)-positive senescent cells delays ageing-associated disorders. Nature 479(7372):232–236
Bartzokis G, Lu P, Mintz J (2004) Quantifying age-related myelin breakdown with MRI: novel therapeutic targets for preventing cognitive decline and Alzheimer’s disease. J Alzheimers Dis 6:9
Bartzokis G, Lu P, Geschwind D, Edwards N, Mintz J, Cummings J (2006) Apolipoprotein E genotype and age-related myelin breakdown in healthy individuals: implications for cognitive decline and dementia. Arch Gen Psychiatry 63:63–72
Berlet H, Volk B (1980) Studies of human myelin proteins during old age. Mech Ageing Dev 14:211–222
Besancenot R, Chaligne R, Tonetti C, Pasquier F, Marty C, Lecluse Y, Vainchenker W, Constantinescu SN, Giraudier S (2010) A senescence-like cell-cycle arrest occurs during megakaryocytic maturation: implications for physiological and pathological megakaryocytic proliferation. PLoS Biol 8(9). pii: e1000476. doi: 10.1371/journal.pbio.1000476. PMID:20838657
Bhaskar M, Rao K (1994) Altered conformation and increased strand breaks in neuronal and astroglial DNA of aging rat brain. Biochem Mol Biol Int 33:377–384
Bhat R, Crowe EP, Bitto A, Moh M, Katsetos CD, Garcia FU, Johnson FB, Trojanowski JQ, Sell C, Torres C (2012) Astrocyte senescence as a component of Alzheimer’s disease. PLoS One 7:e45069
Bi F, Huang C, Tong J, Qiu G, Huang B, Wu Q, Li F, Xu Z, Bowser R, Xia X-G, Zhou H (2013) Reactive astrocytes secrete lcn2 to promote neuron death. Proc Natl Acad Sci U S A 110:4069–4074
Biber K, Owens T, Boddeke E (2014) What is microglia neurotoxicity (Not)? Glia 62(6):841–854
Bitto A, Sell C, Crowe E, Lorenzini A, Malaguti M, Hrelia S, Torres C (2010) Stress-induced senescence in human and rodent astrocytes. Exp Cell Res 316:2961–2968
Blomquist E, Westermark B, Pontén J (1980) Ageing of human glial cells in culture: increase in the fraction of non-dividers as demonstrated by a minicloning technique. Mech Ageing Dev 12:173–182
Boje K, Arora P (1992) Microglial-produced nitric oxide and reactive nitrogen oxides mediate neuronal cell death. Brain Res 587:250–256
Bonni A, Sun Y, Nadal-Vicens M, Bhatt A, Frank D, Rozovsky I, Stahl N, Yancopoulos G, Greenberg M (1997) Regulation of gliogenesis in the central nervous system by the JAK-STAT signaling pathway. Science 278:477–483
Bossers K, Wirz K, Meerhoff G, Essing A, van Dongen J, Houba P, Kruse C, Verhaagen J, Swaab D (2010) Concerted changes in transcripts in the prefrontal cortex precede neuropathology in Alzheimer’s disease. Brain 133:3699–3723
Bradley M, Markesbery W, Lovell M (2010) Increased levels of 4-hydroxynonenal and acrolein in the brain in preclinical Alzheimer disease. Free Radic Biol Med 48:1570–1576
Bradley-Whitman M, Timmons M, Beckett T, Murphy M, Lynn B, Lovell M (2014) Nucleic acid oxidation: an early feature of Alzheimer’s disease. J Neurochem 128:294–304
Brambilla R, Bracchi-Ricard V, Hu W-H, Frydel B, Bramwell A, Karmally S, Green E, Bethea J (2005) Inhibition of astroglial nuclear factor kappaB reduces inflammation and improves functional recovery after spinal cord injury. J Exp Med 202:145–156
Burguillos M, Deierborg T, Kavanagh E, Persson A, Hajji N, Garcia-Quintanilla A, Cano J, Brundin P, Englund E, Venero J, Joseph B (2011) Caspase signalling controls microglia activation and neurotoxicity. Nature 472:319–324
Burke S, Barnes C (2006) Neural plasticity in the ageing brain. Nat Rev Neurosci 7:30–40
Bush T, Puvanachandra N, Horner C, Polito A, Ostenfeld T, Svendsen C, Mucke L, Johnson M, Sofroniew M (1999) Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice. Neuron 23:297–308
Campisi J, D’Adda Di Fagagna F (2007) Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 8:729–740
Campisi J, Andersen JK, Kapahi P, Melov S (2011) Cellular senescence: a link between cancer and age-related degenerative disease? Semin Cancer Biol 21:354–359
Cao L, Wang H, Wang F, Xu D, Liu F, Liu C (2013) Aβ-induced senescent retinal pigment epithelial cells create a proinflammatory microenvironment in AMD. Invest Ophthalmol Vis Sci 54:3738–3750
Chen Q, Ames BN (1994) Senescence-like growth arrest induced by hydrogen peroxide in human diploid fibroblast F65 cells. Proc Natl Acad Sci U S A 91:4130–4134
Chen Z, Zhong C (2014) Oxidative stress in Alzheimer’s disease. Neurosci Bull 30(2):271–281
Chen C-D, Sloane J, Li H, Aytan N, Giannaris E, Zeldich E, Hinman J, Dedeoglu A, Rosene D, Bansal R, Luebke J, Kuro-O M, Abraham C (2013) The antiaging protein Klotho enhances oligodendrocyte maturation and myelination of the CNS. J Neurosci 33:1927–1939
Clausen A, Doctrow S, Baudry M (2010) Prevention of cognitive deficits and brain oxidative stress with superoxide dismutase/catalase mimetics in aged mice. Neurobiol Aging 31:425–433
Clausen A, Xu X, Bi X, Baudry M (2012) Effects of the superoxide dismutase/catalase mimetic EUK-207 in a mouse model of Alzheimer’s disease: protection against and interruption of progression of amyloid and tau pathology and cognitive decline. J Alzheimers Dis 30:183–208
Colodner KJ, Montana RA, Anthony DC, Folkerth RD, de Girolami U, Feany MB (2005) Proliferative potential of human astrocytes. J Neuropathol Exp Neurol 64:163–169
Coppe JP, Patil CK, Rodier F, Sun Y, Munoz DP, Goldstein J, Nelson PS, Desprez PY, Campisi J (2008) Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 6:2853–2868
Cotman C, Berchtold N, Christie L-A (2007) Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci 30:464–472
Cristofalo V, Allen R, Pignolo R, Martin B, Beck J (1998) Relationship between donor age and the replicative lifespan of human cells in culture: a reevaluation. Proc Natl Acad Sci U S A 95:10614–10619
Damani M, Zhao L, Fontainhas A, Amaral J, Fariss R, Wong W (2011) Age-related alterations in the dynamic behavior of microglia. Aging Cell 10:263–276
Desai M, Sudol K, Janelsins M, Mastrangelo M, Frazer M, Bowers W (2009) Triple-transgenic Alzheimer’s disease mice exhibit region-specific abnormalities in brain myelination patterns prior to appearance of amyloid and tau pathology. Glia 57:54–65
Dimri G, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano E, Linskens M, Rubelj I, Pereira-Smith O (1995) A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A 92:9363–9367
Ding Q, Vaynman S, Akhavan M, Ying Z, Gomez-Pinilla F (2006) Insulin-like growth factor I interfaces with brain-derived neurotrophic factor-mediated synaptic plasticity to modulate aspects of exercise-induced cognitive function. Neuroscience 140:823–833
Dong CM, Wang sXL, Wang GM, Zhang WJ, Zhu L, Gao S, Yang DJ, Qin Y, Liang QJ, Chen YL, Deng HT, Ning K, Liang AB, Gao ZL, Xu J (2014) A stress-induced cellular aging model with postnatal neural stem cells. Cell Death Dis 5:e1116. doi: 10.1038/cddis.2014.82
Donnini S, Solito R, Cetti E, Corti F, Giachetti A, Carra S, Beltrame M, Cotelli F, Ziche M (2010) Abeta peptides accelerate the senescence of endothelial cells in vitro and in vivo, impairing angiogenesis. FASEB J 24:2385–2395
Driscoll I, Davatzikos C, An Y, Wu X, Shen D, Kraut M, Resnick S (2009) Longitudinal pattern of regional brain volume change differentiates normal aging from MCI. Neurology 72:1906–1913
Dumitriu D, Hao J, Hara Y, Kaufmann J, Janssen W, Lou W, Rapp P, Morrison J (2010) Selective changes in thin spine density and morphology in monkey prefrontal cortex correlate with aging-related cognitive impairment. J Neurosci 30:7507–7515
Dysken M, Sano M, Asthana S, Vertrees J, Pallaki M, Llorente M, Love S, Schellenberg G, McCarten J, Malphurs J, Prieto S, Chen P, Loreck D, Trapp G, Bakshi R, Mintzer J, Heidebrink J, Vidal-Cardona A, Arroyo L, Cruz A, Zachariah S, Kowall N, Chopra M, Craft S, Thielke S, Turvey C, Woodman C, Monnell K, Gordon K, Tomaska J, Segal Y, Peduzzi P, Guarino P (2014) Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial. JAMA 311:33–44
Dziedzic T (2006) Systemic inflammatory markers and risk of dementia. Am J Alzheimers Dis Other Demen 21:258–262
Ekdahl C, Claasen J-H, Bonde S, Kokaia Z, Lindvall O (2003) Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci U S A 100:13632–13637
Enciu A-M, Gherghiceanu M, Popescu B (2013) Triggers and effectors of oxidative stress at blood-brain barrier level: relevance for brain ageing and neurodegeneration. Oxid Med Cell Longev 2013:297512
Eriksson P, Perfilieva E, Björk-Eriksson T, Alborn A, Nordborg C, Peterson D, Gage F (1998) Neurogenesis in the adult human hippocampus. Nat Med 4:1313–1317
Evans R, Wyllie F, Wynford-Thomas D, Kipling D, Jones C (2003) A P53-dependent, telomere-independent proliferative life span barrier in human astrocytes consistent with the molecular genetics of glioma development. Cancer Res 63:4854–4861
Evans D, Morris M, Rajan K (2014) Vitamin E, memantine, and Alzheimer disease. JAMA 311:29–30
Flanary B, Streit W (2004) Progressive telomere shortening occurs in cultured rat microglia, but not astrocytes. Glia 45:75–88
Flanary B, Streit W (2005) Effects of axotomy on telomere length, telomerase activity, and protein in activated microglia. J Neurosci Res 82:160–171
Flanary B, Sammons N, Nguyen C, Walker D, Streit W (2007) Evidence that aging and amyloid promote microglial cell senescence. Rejuvenation Res 10:61–74
Franklin R, Ffrench-Constant C (2008) Remyelination in the CNS: from biology to therapy. Nat Rev Neurosci 9:839–855
Fünfschilling U, Supplie L, Mahad D, Boretius S, Saab A, Edgar J, Brinkmann B, Kassmann C, Tzvetanova I, Möbius W, Diaz F, Meijer D, Suter U, Hamprecht B, Sereda M, Moraes C, Frahm J, Goebbels S, Nave K-A (2012) Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Nature 485:517–521
Furman J, Sama D, Gant J, Beckett T, Murphy M, Bachstetter A, van Eldik L, Norris C (2012) Targeting astrocytes ameliorates neurologic changes in a mouse model of Alzheimer’s disease. J Neurosci 32:16129–16140
Gagyi E, Kormos B, Castellanos K, Valyi-Nagy K, Korneff D, Lopresti P, Woltjer R, Valyi-Nagy T (2012) Decreased oligodendrocyte nuclear diameter in Alzheimer’s disease and Lewy body dementia. Brain Pathol 22:803–810
Galasko D, Peskind E, Clark C, Quinn J, Ringman J, Jicha G, Cotman C, Cottrell B, Montine T, Thomas R, Aisen P, Alzheimer’s Disease Cooperative, S (2012) Antioxidants for Alzheimer disease: a randomized clinical trial with cerebrospinal fluid biomarker measures. Arch Neurol 69:836–841
Galimberti D, Schoonenboom N, Scheltens P, Fenoglio C, Bouwman F, Venturelli E, Guidi I, Blankenstein M, Bresolin N, Scarpini E (2006) Intrathecal chemokine synthesis in mild cognitive impairment and Alzheimer disease. Arch Neurol 63:538–543
Garwood C, Pooler A, Atherton J, Hanger D (2011) Noble W (2011) Astrocytes are important mediators of Aβ-induced neurotoxicity and tau phosphorylation in primary culture. Cell Death Dis 2:e167. doi:10.1038/cddis.2011.50.PMID:21633390
Gazzaley A, Thakker M, Hof P, Morrison J (1997) Preserved number of entorhinal cortex layer II neurons in aged macaque monkeys. Neurobiol Aging 18:549–553
Ge W-P, Miyawaki A, Gage F, Jan Y, Jan L (2012) Local generation of glia is a major astrocyte source in postnatal cortex. Nature 484:376–380
Geng Y-Q, Guan J-T, Xu X-H, Fu Y-C (2010) Senescence-associated beta-galactosidase activity expression in aging hippocampal neurons. Biochem Biophys Res Commun 396:866–869
Ghosh S, Wu M, Shaftel S, Kyrkanides S, Laferla F, Olschowka J, O’Banion M (2013) Sustained interleukin-1β overexpression exacerbates tau pathology despite reduced amyloid burden in an Alzheimer’s mouse model. J Neurosci 33:5053–5064
Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH (2010) Mechanisms underlying inflammation in neurodegeneration. Cell 140:918–934
Gong Z, Kennedy O, Sun H, Wu Y, Williams G, Klein L, Cardoso L, Matheny R, Hubbard G, Ikeno Y, Farrar R, Schaffler M, Adamo M, Muzumdar R, Yakar S (2014) Reductions in serum IGF-1 during aging impair health span. Aging Cell 69(3):408–418
Gottfried C, Tramontina F, Gonçalves D, Gonçalves C, Moriguchi E, Dias R, Wofchuk S, Souza D (2002) Glutamate uptake in cultured astrocytes depends on age: a study about the effect of guanosine and the sensitivity to oxidative stress induced by H(2)O(2). Mech Ageing Dev 123:1333–1340
Hamby ME, Sofroniew MV (2010) Reactive astrocytes as therapeutic targets for CNS disorders. Neurotherapeutics 7:494–506
Hamilton L, Joppé S, Cochard LM, Fernandes K (2013) Aging and neurogenesis in the adult forebrain: what we have learned and where we should go from here. Eur J Neurosci 37:1978–1986
Harms C, Albrecht K, Harms U, Seidel K, Hauck L, Baldinger T, Hübner D, Kronenberg G, An J, Ruscher K, Meisel A, Dirnagl U, Von Harsdorf R, Endres M, Hörtnagl H (2007) Phosphatidylinositol 3-Akt-kinase-dependent phosphorylation of p21(Waf1/Cip1) as a novel mechanism of neuroprotection by glucocorticoids. J Neurosci 27:4562–4571
Hayflick L (1965) The limited in vitro lifetime of human diploid strains. Exp Cell Res 37:614–636
Hayflick L, Moorhead P (1961) The serial cultivation of human diploid cell strains. Exp Cell Res 25:585–621
He N, Jin WL, Lok KH, Wang Y, Yin M, Wang ZJ (2013) Amyloid-β(1-42) oligomer accelerates senescence in adult hippocampal neural stem/progenitor cells via formylpeptide receptor 2. Cell Death Dis 4:e924. doi: 10.1038/cddis.2013.437. PMID: 24263098
Heringa S, van den Berg E, Reijmer Y, Nijpels G, Stehouwer C, Schalkwijk C, Teerlink T, Scheffer P, van den Hurk K, Kappelle L, Dekker J, Biessels G (2014) Markers of low-grade inflammation and endothelial dysfunction are related to reduced information processing speed and executive functioning in an older population – the Hoorn study. Psychoneuroendocrinology 40:108–118
Herrmann J, Imura T, Song B, Qi J, Ao Y, Nguyen T, Korsak R, Takeda K, Akira S, Sofroniew M (2008) STAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury. J Neurosci 28:7231–7243
Herrup K, Yang Y (2007) Cell cycle regulation in the postmitotic neuron: oxymoron or new biology? Nat Rev Neurosci 8:368–378
Hickman S, Kingery N, Ohsumi T, Borowsky M, Wang L-C, Means T, El Khoury J (2013) The microglial sensome revealed by direct RNA sequencing. Nat Neurosci 16:1896–1905
Ihara M, Polvikoski T, Hall R, Slade J, Perry R, Oakley A, Englund E, O’Brien J, Ince P, Kalaria R (2010) Quantification of myelin loss in frontal lobe white matter in vascular dementia, Alzheimer’s disease, and dementia with Lewy bodies. Acta Neuropathol 119:579–589
Iseki K, Hagino S, Nikaido T, Zhang Y, Mori T, Yokoya S, Hozumi Y, Goto K, Wanaka A, Tase C (2012) Gliosis-specific transcription factor OASIS coincides with proteoglycan core protein genes in the glial scar and inhibits neurite outgrowth. Biomed Res 33:345–353
Jayadev S, Yun B, Nguyen H, Yokoo H, Morrison R, Garden G (2007) The glial response to CNS HIV infection includes p53 activation and increased expression of p53 target genes. J Neuroimmune Pharm 2:359–370
Jensen C, Massie A, de Keyser J (2013) Immune players in the CNS: the astrocyte. J Neuroimmune Pharm 8:824–839
Jeyapalan JC, Sedivy JM (2008) Cellular senescence and organismal aging. Mech Ageing Dev 129:467–474
Jeyapalan J, Ferreira M, Sedivy J, Herbig U (2006) Accumulation of senescent cells in mitotic tissue of aging primates. Mech Ageing Dev 128:36–80
Jurk D, Wang C, Miwa S, Maddick M, Korolchuk V, Tsolou A, Gonos E, Thrasivoulou C, Saffrey M, Cameron K, von Zglinicki T (2012) Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response. Aging Cell 11:996–1004
Kamat CD, Gadal S, Mhatre M, Williamson KS, Pye QN, Hensley K (2008) Antioxidants in central nervous system diseases: preclinical promise and translational challenges. J Alzheimers Dis 15:473–493
Kang S, Fukaya M, Yang J, Rothstein J, Bergles D (2010) NG2+ CNS glial progenitors remain committed to the oligodendrocyte lineage in postnatal life and following neurodegeneration. Neuron 68:668–681
Kasai H, Matsuzaki M, Noguchi J, Yasumatsu N, Nakahara H (2003) Structure-stability-function relationships of dendritic spines. Trends Neurosci 26:360–368
Kawano H, Katsurabayashi S, Kakazu Y, Yamashita Y, Kubo N, Kubo M, Okuda H, Takasaki K, Kubota K, Mishima K, Fujiwara M,Harata N, Iwasaki K (2012) Long-term culture of astrocytes attenuates the readily releasable pool of synaptic vesicles. PLoS One 7(10):e48034. doi:10.1371/journal.pone.0048034. Epub 2012 Oct 26 (Erratum in: PLoS One 7(11). doi:10.1371/annotation/9dd1f25a-55e9-4968-9f70-929d1b8d5064. PMID:23110166)
Kreiling J, Tamamori-Adachi M, Sexton A, Jeyapalan J, Munoz-Najar U, Peterson A, Manivannan J, Rogers E, Pchelintsev N, Adams P, Sedivy J (2011) Age-associated increase in heterochromatic marks in murine and primate tissues. Aging Cell 10:292–304
Kuhlmann T, Miron V, Cui Q, Cuo Q, Wegner C, Antel J, Brück W (2008) Differentiation block of oligodendroglial progenitor cells as a cause for remyelination failure in chronic multiple sclerosis. Brain 131:1749–1758
Kulijewicz-Nawrot M, Verkhratsky A, Chvátal A, Syková E, Rodríguez J (2012) Astrocytic cytoskeletal atrophy in the medial prefrontal cortex of a triple transgenic mouse model of Alzheimer’s disease. J Anat 221:252–262
Lee C, Weindruch R, Prolla T (2000) Gene-expression profile of the ageing brain in mice. Nat Genet 25:294–297
Lee J, Duan W, Mattson M (2002) Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice. J Neurochem 82:1367–1375
Lee J, Song S, Hong J, Sunwoo M-K, Park H-J, Sohn Y, Lee P (2013) Changes in the blood-brain barrier status closely correlate with the rate of disease progression in patients with multiple system atrophy: a longitudinal study. Parkinsonism Relat Disord 19:450–452
Lu T, Pan Y, Kao S-Y, Li C, Kohane I, Chan J, Yankner B (2004) Gene regulation and DNA damage in the ageing human brain. Nature 429:883–891
Magnotta V, Andreasen N, Schultz S, Harris G, Cizadlo T, Heckel D, Nopoulos P, Flaum M (1999) Quantitative in vivo measurement of gyrification in the human brain: changes associated with aging. Cereb Cortex 9:151–160
Mattson M, Magnus T (2006) Ageing and neuronal vulnerability. Nat Rev Neurosci 7:278–294
Mattson M, Gleichmann M, Cheng A (2008) Mitochondria in neuroplasticity and neurological disorders. Neuron 60:748–766
Mcshea A, Harris P, Webster K, Wahl A, Smith M (1997) Abnormal expression of the cell cycle regulators P16 and CDK4 in Alzheimer’s disease. Am J Pathol 150:1933–1939
Miranda C, Braun L, Jiang Y, Hester M, Zhang L, Riolo M, Wang H, Rao M, Altura R, Kaspar B (2012) Aging brain microenvironment decreases hippocampal neurogenesis through Wnt-mediated survivin signaling. Aging Cell 11:542–552
Molofsky A, Slutsky S, Joseph N, He S, Pardal R, Krishnamurthy J, Sharpless N, Morrison S (2006) Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature 443:448–452
Monson N, Ireland S, Ligocki A, Chen D, Rounds W, Li M, Huebinger R, Munro Cullum C, Greenberg B, Stowe A, Zhang R (2014) Elevated CNS inflammation in patients with preclinical Alzheimer’s disease. J Cereb Blood Flow Metab 34:30–33
Montuschi P, Barnes PJ, Roberts LJ 2nd (2004 Dec) Isoprostanes: markers and mediators of oxidative stress. FASEB J 18(15):1791–800
Morrison J, Baxter M (2012) The ageing cortical synapse: hallmarks and implications for cognitive decline. Nat Rev Neurosci 13:240–250
Müller KC, Welker L, Paasch K, Feindt B, Erpenbeck V, Hohlfeld J, Krug N, Nakashima M, Branscheid D, Magnussen H, Jörres R, Holz O (2006) Lung fibroblasts from patients with emphysema show markers of senescence in vitro. Respir Res 7:32
Namihira M, Nakashima K (2013) Mechanisms of astrocytogenesis in the mammalian brain. Curr Opin Neurobiol 23:921–927
Namihira M, Nakashima K, Taga T (2004) Developmental stage dependent regulation of DNA methylation and chromatin modification in a immature astrocyte specific gene promoter. FEBS Lett 572:184–188
Naylor RM, Baker DJ, van Deursen JM (2013) Senescent cells: a novel therapeutic target for aging and age-related diseases. Clin Pharmacol Ther 93:105–116
Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–1318
Njie E, Boelen E, Stassen F, Steinbusch H, Borchelt D, Streit W (2012) Ex vivo cultures of microglia from young and aged rodent brain reveal age-related changes in microglial function. Neurobiol Aging 33:1950–1912
Noureddine H, Gary-Bobo G, Alifano M, Marcos E, Saker M, Vienney N, Amsellem V, Maitre B, Chaouat A, Chouaid C, Dubois-Rande J-L, Damotte D, Adnot S (2011) Pulmonary artery smooth muscle cell senescence is a pathogenic mechanism for pulmonary hypertension in chronic lung disease. Circ Res 109:543–553
Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, Jones PK, Ghanbari H, Wataya T, Shimohama S, Chiba S, Atwood CS, Petersen RB, Smith MA (2001) Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol 60:759–767
Oberheim N, Wang X, Goldman S, Nedergaard M (2006) Astrocytic complexity distinguishes the human brain. Trends Neurosci 29:547–553
Oberheim N, Takano T, Han X, He W, Lin J, Wang F, Xu Q, Wyatt J, Pilcher W, Ojemann J, Ransom B, Goldman S, Nedergaard M (2009) Uniquely hominid features of adult human astrocytes. J Neurosci 29:3276–3287
Olabarria M, Noristani H, Verkhratsky A, Rodríguez J (2010) Concomitant astroglial atrophy and astrogliosis in a triple transgenic animal model of Alzheimer’s disease. Glia 58:831–838
Paolo M, Peter JB, Jackson LR (2004) Isoprostanes: markers and mediators of oxidative stress. FASEB J 18(15):1791–1800
Park H, Park M, Choi J, Park K-Y, Chung H, Lee J (2010) A high-fat diet impairs neurogenesis: involvement of lipid peroxidation and brain-derived neurotrophic factor. Neurosci Lett 482:235–239
Pechnick R, Zonis S, Wawrowsky K, Pourmorady J, Chesnokova V (2008) p21Cip1 restricts neuronal proliferation in the subgranular zone of the dentate gyrus of the hippocampus. Proc Natl Acad Sci U S A 105:1358–1363
Perea G, Navarrete M, Araque A (2009) Tripartite synapses: astrocytes process and control synaptic information. Trends Neurosci 32:421–431
Pertusa M, Garcia-Matas S, Rodriguez-Farre E, Sanfeliu C, Cristofol R (2007) Astrocytes aged in vitro show a decreased neuroprotective capacity. J Neurochem 101:794–805
Peters A (2002) The effects of normal aging on myelin and nerve fibers: a review. J Neurocytol 31:581–593
Pontén J, Macintyre E (1968) Long term culture of normal and neoplastic human glia. Acta Pathol Microbiol Scand 74:465–486
Price J, Waters J, Darrah C, Pennington C, Edwards D, Donell S, Clark I (2002) The role of chondrocyte senescence in osteoarthritis. Aging Cell 1:57–65
Raabe E, Lim K, Kim J, Meeker A, Mao X-G, Nikkhah G, Maciaczyk J, Kahlert U, Jain D, Bar E, Cohen K, Eberhart C (2011) BRAF activation induces transformation and then senescence in human neural stem cells: a pilocytic astrocytoma model. Clin Cancer Res 17:3590–3599
Rapp P, Gallagher M (1996) Preserved neuron number in the hippocampus of aged rats with spatial learning deficits. Proc Natl Acad Sci U S A 93:9926–9930
Ressler S, Bartkova J, Niederegger H, Bartek J, Scharffetter-Kochanek K, Jansen-Dürr P, Wlaschek M (2006) p16INK4A is a robust in vivo biomarker of cellular aging in human skin. Aging Cell 5:379–468
Rhein V, Baysang G, Rao S, Meier F, Bonert A, Muller-Spahn F, Eckert A (2009) Amyloid-beta leads to impaired cellular respiration, energy production and mitochondrial electron chain complex activities in human neuroblastoma cells. Cell Mol Neurobiol 29:1063–1071
Robertson K, Jones P (1999) Tissue-specific alternative splicing in the human INK4a/ARF cell cycle regulatory locus. Oncogene 18:3810–3820
Rodríguez J, Yeh C-Y, Terzieva S, Olabarria M, Kulijewicz-Nawrot M, Verkhratsky A (2014) Complex and region-specific changes in astroglial markers in the aging brain. Neurobiol Aging 35:15–23
Roy Choudhury G, Ryou M-G, Poteet E, Wen Y, He R, Sun F, Yuan F, Jin K, Yang S-H (2014) Involvement of p38 MAPK in reactive astrogliosis induced by ischemic stroke. Brain Res 1551:45–58
Ruckh J, Zhao J-W, Shadrach J, van Wijngaarden P, Rao T, Wagers A, Franklin R (2012) Rejuvenation of regeneration in the aging central nervous system. Cell Stem Cell 10:96–103
Salminen A, Ojala J, Kaarniranta K, Haapasalo A, Hiltunen M, Soininen H (2011) Astrocytes in the aging brain express characteristics of senescence-associated secretory phenotype. Eur J Neurosci 34:3–11
Salthouse T (2010) Selective review of cognitive aging. J Int Neuropsychol Soc 16:754–760
Samson R, Barnes C (2013) Impact of aging brain circuits on cognition. Eur J Neurosci 37:1903–1915
Sano M, Ernesto C, Thomas R, Klauber M, Schafer K, Grundman M, Woodbury P, Growdon J, Cotman C, Pfeiffer E, Schneider L, Thal L (1997) A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. Alzheimers Dis Coop Study N Engl J Med 336:1216–1222
Scheff S, Price D, Schmitt F, Mufson E (2006) Hippocampal synaptic loss in early Alzheimer’s disease and mild cognitive impairment. Neurobiol Aging 27:1372–1384
Schneider L, Pellegatta S, Favaro R, Pisati F, Roncaglia P, Testa G, Nicolis S, Finocchiaro G, D’Adda Di Fagagna F (2013) DNA damage in mammalian neural stem cells leads to astrocytic differentiation mediated by BMP2 signaling through JAK-STAT. Stem Cell Rep 1:123–138
Schousboe A, Bak L, Waagepetersen H (2013) Astrocytic control of biosynthesis and turnover of the neurotransmitters glutamate and GABA. Front Endocrinol 4:102
Serrano M, Lin A, Mccurrach M, Beach D, Lowe S (1997) Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88:593–602
Shelton D, Chang E, Whittier P, Choi D, Funk W (1999) Microarray analysis of replicative senescence. Curr Biol 9:939–945
Shields S, Gilson J, Blakemore W, Franklin R (1999) Remyelination occurs as extensively but more slowly in old rats compared to young rats following gliotoxin-induced CNS demyelination. Glia 28:77–83
Sim F, Zhao C, Penderis J, Franklin R (2002) The age-related decrease in CNS remyelination efficiency is attributable to an impairment of both oligodendrocyte progenitor recruitment and differentiation. J Neurosci 22:2451–2459
Simard M, Nedergaard M (2004) The neurobiology of glia in the context of water and ion homeostasis. Neuroscience 129:877–896
Smart I, Leblond CP (1961) Evidence for division and transformations of neuroglia cells in the mouse brain, as derived from radioautography after injection of thymidine-H3. J Comp Neurol 116:349–367
Smith T, Adams M, Gallagher M, Morrison J, Rapp P (2000) Circuit-specific alterations in hippocampal synaptophysin immunoreactivity predict spatial learning impairment in aged rats. J Neurosci 20:6587–6593
Sofroniew M (2009) Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci 32:638–647
Sofroniew M, Vinters H (2010) Astrocytes: biology and pathology. Acta Neuropathol 119:7–35
Souza D, Bellaver B, Souza D, Quincozes-Santos A (2013) Characterization of adult rat astrocyte cultures. PLoS One 8:e60282
Stanley A, Osler T (2001) Senescence and the healing rates of venous ulcers. J Vasc Surg 33:1206–1211
Stewart S, Ben-Porath I, Carey V, O’Connor B, Hahn W, Weinberg R (2003) Erosion of the telomeric single-strand overhang at replicative senescence. Nat Genet 33:492–496
Streit W, Sammons N, Kuhns A, Sparks D (2004) Dystrophic microglia in the aging human brain. Glia 45:208–212
Streit W, Braak H, Xue Q-S, Bechmann I (2009) Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer’s disease. Acta Neuropathol 118:475–485
Suberbielle E, Sanchez P, Kravitz A, Wang X, Ho K, Eilertson K, Devidze N, Kreitzer A, Mucke L (2013) Physiologic brain activity causes DNA double-strand breaks in neurons, with exacerbation by amyloid-β. Nat Neurosci 16:613–621
Takizawa T, Nakashima K, Namihira M, Ochiai W, Uemura A, Yanagisawa M, Fujita N, Nakao M, Taga T (2001) DNA methylation is a critical cell-intrinsic determinant of astrocyte differentiation in the fetal brain. Dev Cell 1:749–758
Tang D, Tokumoto Y, Apperly J, Lloyd A, Raff M (2001) Lack of replicative senescence in cultured rat oligodendrocyte precursor cells. Science 291:868–871
Torres C, Lewis L, Cristofalo VJ (2006) Proteasome inhibitors shorten replicative life span and induce a senescent-like phenotype of human fibroblasts. J Cell Physiol 207:845–853
Trejo J, Carro E, Torres-Aleman I (2001) Circulating insulin-like growth factor I mediates exercise-induced increases in the number of new neurons in the adult hippocampus. J Neurosci 21:1628–1634
van Praag H, Shubert T, Zhao C, Gage F (2005) Exercise enhances learning and hippocampal neurogenesis in aged mice. J Neurosci 25:8680–8685
Vasile E, Tomita Y, Brown L, Kocher O, Dvorak H (2001) Differential expression of thymosin beta-10 by early passage and senescent vascular endothelium is modulated by VPF/VEGF: evidence for senescent endothelial cells in vivo at sites of atherosclerosis. FASEB J 15:458–466
Verkhratsky A, Sofroniew MV, Messing A, Delanerolle NC, Rempe D, Rodriguez Arellano JJ, Nedergaard M (2012) Neurological diseases as primary gliopathies: a reassessment of neurocentrism. ASN Neuro 4(3):399–412
Villeda S, Luo J, Mosher K, Zou B, Britschgi M, Bieri G, Stan T, Fainberg N, Ding Z, Eggel A, Lucin K, Czirr E, Park J-S, Couillard-Després S, Aigner L, Li G, Peskind E, Kaye J, Quinn J, Galasko D, Xie X, Rando T, Wyss-Coray T (2011) The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477:90–94
Wake H, Moorhouse A, Jinno S, Kohsaka S, Nabekura J (2009) Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci 29:3974–3980
Walhovd K, Westlye L, Amlien I, Espeseth T, Reinvang I, Raz N, Agartz I, Salat D, Greve D, Fischl B, Dale A, Fjell A (2011) Consistent neuroanatomical age-related volume differences across multiple samples. Neurobiol Aging 32:916–932
Wan C, Liu J, Nie X, Zhao J, Zhou S, Duan Z, Tang C, Liang L, Xu G (2014) 2, 3, 7, 8-Tetrachlorodibenzo-P-dioxin (TCDD) induces premature senescence in human and rodent neuronal cells via ROS-dependent mechanisms. PLoS One 9(2):e89811. doi: 10.1371/journal.pone.0089811. eCollection 2014. PMID:24587053
Wang E (1995) Senescent human fibroblasts resist programmed cell death, and failure to suppress bcl2 is involved. Cancer Res 55:2284–2292
Wang X, Michaelis E (2010) Selective neuronal vulnerability to oxidative stress in the brain. Front Aging Neurosci 2:12
Wanner I, Anderson M, Song B, Levine J, Fernandez A, Gray-Thompson Z, Ao Y, Sofroniew M (2013) Glial scar borders are formed by newly proliferated, elongated astrocytes that interact to corral inflammatory and fibrotic cells via STAT3-dependent mechanisms after spinal cord injury. J Neurosci 33:12870–12886
Weaver JD, Huang MH, Albert M, Harris T, Rowe JW, Seeman TE (2002) Interleukin-6 and risk of cognitive decline: MacArthur studies of successful aging. Neurology 59:371–378
West M, Coleman P, Flood D, Troncoso J (1994) Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer’s disease. Lancet 344:769–772
Westhoff J, Hilgers K, Steinbach M, Hartner A, Klanke B, Amann K, Melk A (2008) Hypertension induces somatic cellular senescence in rats and humans by induction of cell cycle inhibitor p16INK4a. Hypertension 52:123–129
Wright C, Sacco R, Rundek TR, Delman JB, Rabbani LE, Elkind MSV (2006) Interleukin-6 is associated with cognitive function: the northern Manhattan study. J Stroke Cerebrovasc Dis 15:34–38
Wynne A, Henry C, Huang Y, Cleland A, Godbout J (2010) Protracted downregulation of CX3CR1 on microglia of aged mice after lipopolysaccharide challenge. Brain Behav Immun 24:1190–1201
Yaffe K, Lindquist K, Penninx BW, Simonsick EM, Pahor M, Kritchevsky S, Launer L, Kuller L, Rubin S, Harris T (2003) Inflammatory markers and cognition in well-functioning African-American and white elders. Neurology 61:76–80
Yankner B, Lu T, Loerch P (2008) The aging brain. Annu Rev Pathol 3:41–66
Yeh C-Y, Vadhwana B, Verkhratsky A, Rodríguez J (2011) Early astrocytic atrophy in the entorhinal cortex of a triple transgenic animal model of Alzheimer’s disease. ASN Neuro 3:271–279
Yeoman M, Scutt G, Faragher R (2012) Insights into CNS ageing from animal models of senescence. Nat Rev Neurosci 13:435–445
Young K, Psachoulia K, Tripathi R, Dunn S-J, Cossell L, Attwell D, Tohyama K, Richardson W (2013) Oligodendrocyte dynamics in the healthy adult CNS: evidence for myelin remodeling. Neuron 77:873–885
Yu H-M, Zhao Y-M, Luo X-G, Feng Y, Ren Y, Shang H, He Z-Y, Luo X-M, Chen S-D, Wang X-Y (2012) Repeated lipopolysaccharide stimulation induces cellular senescence in BV2 cells. Neuroimmunomodulation 19:131–136
Zamanian J, Xu L, Foo L, Nouri N, Zhou L, Giffard R, Barres B (2012) Genomic analysis of reactive astrogliosis. J Neurosci 32:6391–6410
Zuliani G, Ranzini M, Guerra G, Rossi L, Munari M, Zurlo A, Volpato S, Atti A, Blè A, Fellin R (2007) Plasma cytokines profile in older subjects with late onset Alzheimer’s disease or vascular dementia. J Psychiatr Res 41:686–693
Acknowledgements
This work was supported by grants 1RO1NS078283 (CT), R21AG046943 (CT), the Commonwealth of Pennsylvania Universal Research Enhancement Grant (CT), the Drexel University College of Medicine Research Program Planning Grant (CT); and the Drexel Aging Initiative. Research reported in this publication is also supported by the National Institute on Aging of the National Institutes of Health under Award Number F30AG043307 (EPC). The content of this chapter is solely the responsibility of the authors.
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Crowe, E.P. et al. (2016). Implications of Cellular Senescence on Aging and Disease in the Brain. In: Rattan, S., Hayflick, L. (eds) Cellular Ageing and Replicative Senescence. Healthy Ageing and Longevity. Springer, Cham. https://doi.org/10.1007/978-3-319-26239-0_14
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