Skip to main content

Advertisement

SpringerLink
Log in

Astroglial asthenia and loss of function, rather than reactivity, contribute to the ageing of the brain

  • Invited Review
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Astroglia represent a class of heterogeneous, in form and function, cells known as astrocytes, which provide for homoeostasis and defence of the central nervous system (CNS). Ageing is associated with morphological and functional remodelling of astrocytes with a prevalence of morphological atrophy and loss of function. In particular, ageing is associated with (i) decrease in astroglial synaptic coverage, (ii) deficits in glutamate and potassium clearance, (iii) reduced astroglial synthesis of synaptogenic factors such as cholesterol, (iv) decrease in aquaporin 4 channels in astroglial endfeet with subsequent decline in the glymphatic clearance, (v) decrease in astroglial metabolic support through the lactate shuttle, (vi) dwindling adult neurogenesis resulting from diminished proliferative capacity of radial stem astrocytes, (vii) decline in the astroglial-vascular coupling and deficient blood-brain barrier and (viii) decrease in astroglial ability to mount reactive astrogliosis. Decrease in reactive capabilities of astroglia are associated with rise of age-dependent neurodegenerative diseases. Astroglial morphology and function can be influenced and improved by lifestyle interventions such as intellectual engagement, social interactions, physical exercise, caloric restriction and healthy diet. These modifications of lifestyle are paramount for cognitive longevity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Notes

  1. George Murray Humphry, 1889, The Old Age. The results of information received respecting nearly nine hundred persons who had attained the age of 80 years, including seventy-four centenarians. MacMillan & Bowes, Cambridge, p. 48

  2. George Murray Humphry, 1889, The Old Age. The results of information received respecting nearly nine hundred persons who had attained the age of 80 years, including seventy-four centenarians. MacMillan & Bowes, Cambridge, p. 24

References

  1. Adermark L, Lovinger DM (2008) Electrophysiological properties and gap junction coupling of striatal astrocytes. Neurochem Int 52:1365–1372. https://doi.org/10.1016/j.neuint.2008.02.006

    Article  CAS  PubMed  Google Scholar 

  2. Al-Dalahmah O, Sosunov AA, Shaik A, Ofori K, Liu Y, Vonsattel JP, Adorjan I, Menon V, Goldman JE (2020) Single-nucleus RNA-seq identifies Huntington disease astrocyte states. Acta Neuropathol Commun 8:19. https://doi.org/10.1186/s40478-020-0880-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Amenta F, Bronzetti E, Sabbatini M, Vega JA (1998) Astrocyte changes in aging cerebral cortex and hippocampus: a quantitative immunohistochemical study. Microsc Res Tech 43:29–33. https://doi.org/10.1002/(SICI)1097-0029(19981001)43

    Article  CAS  PubMed  Google Scholar 

  4. Amin-Hanjani S, Du X, Pandey DK, Thulborn KR, Charbel FT (2015) Effect of age and vascular anatomy on blood flow in major cerebral vessels. J Cereb Blood Flow Metab 35:312–318. https://doi.org/10.1038/jcbfm.2014.203

    Article  PubMed  Google Scholar 

  5. Arani A, Murphy MC, Glaser KJ, Manduca A, Lake DS, Kruse SA, Jack CR Jr, Ehman RL, Huston J 3rd (2015) Measuring the effects of aging and sex on regional brain stiffness with MR elastography in healthy older adults. Neuroimage 111:59–64. https://doi.org/10.1016/j.neuroimage.2015.02.016

    Article  PubMed  PubMed Central  Google Scholar 

  6. Augusto-Oliveira M, Arrifano GP, Takeda PY, Lopes-Araújo A, Santos-Sacramento L, Anthony DC, Verkhratsky A, Crespo-Lopez ME (2020) Astroglia-specific contributions to the regulation of synapses, cognition and behaviour. Neurosci Biobehav Rev 118:331–357. https://doi.org/10.1016/j.neubiorev.2020.07.039

    Article  CAS  PubMed  Google Scholar 

  7. Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, Kirkland JL, van Deursen JM (2011) Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479:232–236. https://doi.org/10.1038/nature10600

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bartzokis G (2011) Alzheimer’s disease as homeostatic responses to age-related myelin breakdown. Neurobiol Aging 32:1341–1371. https://doi.org/10.1016/j.neurobiolaging.2009.08.007

    Article  CAS  PubMed  Google Scholar 

  9. Bartzokis G, Beckson M, Lu PH, Nuechterlein KH, Edwards N, Mintz J (2001) Age-related changes in frontal and temporal lobe volumes in men: a magnetic resonance imaging study. Arch Gen Psychiatry 58:461–465

    Article  CAS  Google Scholar 

  10. Beauquis J, Pavia P, Pomilio C, Vinuesa A, Podlutskaya N, Galvan V, Saravia F (2013) Environmental enrichment prevents astroglial pathological changes in the hippocampus of APP transgenic mice, model of Alzheimer’s disease. Exp Neurol 239:28–37. https://doi.org/10.1016/j.expneurol.2012.09.009

    Article  CAS  PubMed  Google Scholar 

  11. Becquet D, Girardet C, Guillaumond F, Francois-Bellan AM, Bosler O (2008) Ultrastructural plasticity in the rat suprachiasmatic nucleus. Possible involvement in clock entrainment. Glia 56:294–305. https://doi.org/10.1002/glia.20613

    Article  PubMed  Google Scholar 

  12. Ben Abdallah NM, Slomianka L, Vyssotski AL, Lipp HP (2010) Early age-related changes in adult hippocampal neurogenesis in C57 mice. Neurobiol Aging 31:151–161. https://doi.org/10.1016/j.neurobiolaging.2008.03.002

    Article  PubMed  Google Scholar 

  13. 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. https://doi.org/10.1016/j.yexcr.2010.06.021

    Article  CAS  PubMed  Google Scholar 

  14. Bjorklund H, Eriksdotter-Nilsson M, Dahl D, Rose G, Hoffer B, Olson L (1985) Image analysis of GFA-positive astrocytes from adolescence to senescence. Exp Brain Res 58:163–170. https://doi.org/10.1007/BF00238964

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  16. Boisvert MM, Erikson GA, Shokhirev MN, Allen NJ (2018) The aging astrocyte transcriptome from multiple regions of the mouse brain. Cell Rep 22:269–285. https://doi.org/10.1016/j.celrep.2017.12.039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bors L, Toth K, Toth EZ, Bajza A, Csorba A, Szigeti K, Mathe D, Perlaki G, Orsi G, Toth GK, Erdo F (2018) Age-dependent changes at the blood-brain barrier. A comparative structural and functional study in young adult and middle aged rats. Brain Res Bull 139:269–277. https://doi.org/10.1016/j.brainresbull.2018.03.001

    Article  CAS  PubMed  Google Scholar 

  18. Bouab M, Paliouras GN, Aumont A, Forest-Berard K, Fernandes KJ (2011) Aging of the subventricular zone neural stem cell niche: evidence for quiescence-associated changes between early and mid-adulthood. Neuroscience 173:135–149. https://doi.org/10.1016/j.neuroscience.2010.11.032

    Article  CAS  PubMed  Google Scholar 

  19. Brawek B, Chesters R, Klement D, Muller J, Lerdkrai C, Hermes M, Garaschuk O (2018) A bell-shaped dependence between amyloidosis and GABA accumulation in astrocytes in a mouse model of Alzheimer’s disease. Neurobiol Aging 61:187–197. https://doi.org/10.1016/j.neurobiolaging.2017.09.028

    Article  CAS  PubMed  Google Scholar 

  20. Bredesen DE (2014) Reversal of cognitive decline: a novel therapeutic program. Aging (Albany NY) 6:707–717. https://doi.org/10.18632/aging.100690

    Article  Google Scholar 

  21. Breslin K, Wade JJ, Wong-Lin K, Harkin J, Flanagan B, Van Zalinge H, Hall S, Walker M, Verkhratsky A, McDaid L (2018) Potassium and sodium microdomains in thin astroglial processes: a computational model study. PLoS Comput Biol 14:e1006151. https://doi.org/10.1371/journal.pcbi.1006151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bridges RJ, Natale NR, Patel SA (2012) System xc− cystine/glutamate antiporter: an update on molecular pharmacology and roles within the CNS. Br J Pharmacol 165:20–34. https://doi.org/10.1111/j.1476-5381.2011.01480.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Brothers HM, Bardou I, Hopp SC, Kaercher RM, Corona AW, Fenn AM, Godbout JP, Wenk GL (2013) Riluzole partially rescues age-associated, but not LPS-induced, loss of glutamate transporters and spatial memory. J NeuroImmune Pharmacol 8:1098–1105. https://doi.org/10.1007/s11481-013-9476-2

    Article  PubMed  Google Scholar 

  24. Burnett M (1974) Intrinsic mutagenesis. Medical and Technical Publishing Co, Lancaster

    Book  Google Scholar 

  25. Bushong EA, Martone ME, Jones YZ, Ellisman MH (2002) Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains. J Neurosci 22:183–192

    Article  CAS  Google Scholar 

  26. Butt AM, Papanikolaou M, Rivera A (2019) Physiology of oligodendroglia. Adv Exp Med Biol 1175:117–128. https://doi.org/10.1007/978-981-13-9913-8_5

    Article  CAS  PubMed  Google Scholar 

  27. Carter SF, Scholl M, Almkvist O, Wall A, Engler H, Langstrom B, Nordberg A (2012) Evidence for astrocytosis in prodromal Alzheimer disease provided by 11C-deuterium-L-deprenyl: a multitracer PET paradigm combining 11C-Pittsburgh compound B and 18F-FDG. J Nucl Med 53:37–46. https://doi.org/10.2967/jnumed.110.087031

    Article  CAS  PubMed  Google Scholar 

  28. Castiglioni Jr. AJ, Legare ME, D.L., B., and Tiffany-Castiglioni E (1991). Morphological changes in astrocytes of aging mice fed normal or caloric restricted diets. Age 14; 102–106.

  29. Cerbai F, Lana D, Nosi D, Petkova-Kirova P, Zecchi S, Brothers HM, Wenk GL, Giovannini MG (2012) The neuron-astrocyte-microglia triad in normal brain ageing and in a model of neuroinflammation in the rat hippocampus. PLoS One, e45250 7. https://doi.org/10.1371/journal.pone.0045250

  30. Chen Y, Swanson RA (2003) The glutamate transporters EAAT2 and EAAT3 mediate cysteine uptake in cortical neuron cultures. J Neurochem 84:1332–1339

    Article  CAS  Google Scholar 

  31. Cohen J, Torres C (2019) Astrocyte senescence: Evidence and significance. Aging Cell 18:e12937. https://doi.org/10.1111/acel.12937

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Colombo JA, Quinn B, Puissant V (2002) Disruption of astroglial interlaminar processes in Alzheimer’s disease. Brain Res Bull 58:235–242. https://doi.org/10.1016/s0361-9230(02)00785-2

    Article  CAS  PubMed  Google Scholar 

  33. Coppe JP, Desprez PY, Krtolica A, Campisi J (2010) The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol 5:99–118. https://doi.org/10.1146/annurev-pathol-121808-102144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Dalton MM, Hommes OR, Leblond CP (1968) Correlation of glial proliferation with age in the mouse brain. J Comp Neurol 134:397–400. https://doi.org/10.1002/cne.901340403

    Article  CAS  PubMed  Google Scholar 

  35. Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65:1–105. https://doi.org/10.1016/s0301-0082(00)00067-8

    Article  CAS  PubMed  Google Scholar 

  36. Dause TJ, Kirby ED (2019) Aging gracefully: social engagement joins exercise and enrichment as a key lifestyle factor in resistance to age-related cognitive decline. Neural Regen Res 14:39–42. https://doi.org/10.4103/1673-5374.243698

    Article  PubMed  PubMed Central  Google Scholar 

  37. David JP, Ghozali F, Fallet-Bianco C, Wattez A, Delaine S, Boniface B, Di Menza C, Delacourte A (1997) Glial reaction in the hippocampal formation is highly correlated with aging in human brain. Neurosci Lett 235:53–56. https://doi.org/10.1016/s0304-3940(97)00708-8

    Article  CAS  PubMed  Google Scholar 

  38. Davies DS, Ma J, Jegathees T, Goldsbury C (2017) Microglia show altered morphology and reduced arborization in human brain during aging and Alzheimer’s disease. Brain Pathol 27:795–808. https://doi.org/10.1111/bpa.12456

    Article  CAS  PubMed  Google Scholar 

  39. Davis CH, Kim KY, Bushong EA, Mills EA, Boassa D, Shih T, Kinebuchi M, Phan S, Zhou Y, Bihlmeyer NA, Nguyen JV, Jin Y, Ellisman MH, Marsh-Armstrong N (2014) Transcellular degradation of axonal mitochondria. Proc Natl Acad Sci U S A 111:9633–9638. https://doi.org/10.1073/pnas.1404651111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. del Río-Hortega P, Penfield WG (1927) Cerebral cicatrix: the reaction of neuroglia and microglia to brain wounds. Bull Johns Hopkins Hosp 41:278–303

    Google Scholar 

  41. Desagher S, Glowinski J, Premont J (1996) Astrocytes protect neurons from hydrogen peroxide toxicity. J Neurosci 16:2553–2562

    Article  CAS  Google Scholar 

  42. Dietschy JM, Turley SD (2001) Cholesterol metabolism in the brain. Curr Opin Lipidol 12:105–112. https://doi.org/10.1097/00041433-200104000-00003

    Article  CAS  PubMed  Google Scholar 

  43. Diniz DG, de Oliveira MA, de Lima CM, Foro CA, Sosthenes MC, Bento-Torres J, da Costa Vasconcelos PF, Anthony DC, Diniz CW (2016) Age, environment, object recognition and morphological diversity of GFAP-immunolabeled astrocytes. Behav Brain Funct 12:28. https://doi.org/10.1186/s12993-016-0111-2

    Article  PubMed  PubMed Central  Google Scholar 

  44. Diniz DG, Foro CA, Rego CM, Gloria DA, de Oliveira FR, Paes JM, de Sousa AA, Tokuhashi TP, Trindade LS, Turiel MC, Vasconcelos EG, Torres JB, Cunnigham C, Perry VH, Vasconcelos PF, Diniz CW (2010) Environmental impoverishment and aging alter object recognition, spatial learning, and dentate gyrus astrocytes. Eur J Neurosci 32:509–519. https://doi.org/10.1111/j.1460-9568.2010.07296.x

    Article  PubMed  Google Scholar 

  45. Duarte JM, Do KQ, Gruetter R (2014) Longitudinal neurochemical modifications in the aging mouse brain measured in vivo by 1H magnetic resonance spectroscopy. Neurobiol Aging 35:1660–1668. https://doi.org/10.1016/j.neurobiolaging.2014.01.135

    Article  CAS  PubMed  Google Scholar 

  46. Duncombe J, Lennen RJ, Jansen MA, Marshall I, Wardlaw JM, Horsburgh K (2017) Ageing causes prominent neurovascular dysfunction associated with loss of astrocytic contacts and gliosis. Neuropathol Appl Neurobiol 43:477–491. https://doi.org/10.1111/nan.12375

    Article  CAS  PubMed  Google Scholar 

  47. Early AN, Gorman AA, Van Eldik LJ, Bachstetter AD, Morganti JM (2020) Effects of advanced age upon astrocyte-specific responses to acute traumatic brain injury in mice. J Neuroinflammation 17:115. https://doi.org/10.1186/s12974-020-01800-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Emir UE, Raatz S, McPherson S, Hodges JS, Torkelson C, Tawfik P, White T, Terpstra M (2011) Noninvasive quantification of ascorbate and glutathione concentration in the elderly human brain. NMR Biomed 24:888–894. https://doi.org/10.1002/nbm.1646

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Evans RJ, Wyllie FS, Wynford-Thomas D, Kipling D, Jones CJ (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

    CAS  PubMed  Google Scholar 

  50. Fabricius K, Jacobsen JS, Pakkenberg B (2013) Effect of age on neocortical brain cells in 90+ year old human females--a cell counting study. Neurobiol Aging 34:91–99. https://doi.org/10.1016/j.neurobiolaging.2012.06.009

    Article  PubMed  Google Scholar 

  51. Ferrer I (2017) Diversity of astroglial responses across human neurodegenerative disorders and brain aging. Brain Pathol 27:645–674. https://doi.org/10.1111/bpa.12538

    Article  CAS  PubMed  Google Scholar 

  52. Filosa JA, Bonev AD, Straub SV, Meredith AL, Wilkerson MK, Aldrich RW, Nelson MT (2006) Local potassium signaling couples neuronal activity to vasodilation in the brain. Nat Neurosci 9:1397–1403. https://doi.org/10.1038/nn1779

    Article  CAS  PubMed  Google Scholar 

  53. Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, Panourgia MP, Invidia L, Celani L, Scurti M, Cevenini E, Castellani GC, Salvioli S (2007) Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev 128:92–105. https://doi.org/10.1016/j.mad.2006.11.016

    Article  CAS  PubMed  Google Scholar 

  54. Garaschuk O, Verkhratsky A (2019) GABAergic astrocytes in Alzheimer’s disease. Aging (Albany NY) 11:1602–1604. https://doi.org/10.18632/aging.101870

    Article  Google Scholar 

  55. Gavrilov N, Golyagina I, Brazhe A, Scimemi A, Turlapov V, Semyanov A (2018) Astrocytic coverage of dendritic spines, dendritic shafts, and axonal boutons in hippocampal neuropil. Front Cell Neurosci 12:248. https://doi.org/10.3389/fncel.2018.00248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ge WP, Jia JM (2016) Local production of astrocytes in the cerebral cortex. Neuroscience 323:3–9. https://doi.org/10.1016/j.neuroscience.2015.08.057

    Article  CAS  PubMed  Google Scholar 

  57. Ge WP, Miyawaki A, Gage FH, Jan YN, Jan LY (2012) Local generation of glia is a major astrocyte source in postnatal cortex. Nature 484:376–380. https://doi.org/10.1038/nature10959

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Geinisman Y, Bondareff W, Dodge JT (1978) Hypertrophy of astroglial processes in the dentate gyrus of the senescent rat. Am J Anat 153:537–543. https://doi.org/10.1002/aja.1001530405

    Article  CAS  PubMed  Google Scholar 

  59. Gomez-Gonzalo M, Martin-Fernandez M, Martinez-Murillo R, Mederos S, Hernandez-Vivanco A, Jamison S, Fernandez AP, Serrano J, Calero P, Futch HS, Corpas R, Sanfeliu C, Perea G, Araque A (2017) Neuron-astrocyte signaling is preserved in the aging brain. Glia 65:569–580. https://doi.org/10.1002/glia.23112

    Article  PubMed  PubMed Central  Google Scholar 

  60. Goss JR, Finch CE, Morgan DG (1991) Age-related changes in glial fibrillary acidic protein mRNA in the mouse brain. Neurobiol Aging 12:165–170. https://doi.org/10.1016/0197-4580(91)90056-p

    Article  CAS  PubMed  Google Scholar 

  61. Grubman A, Chew G, Ouyang JF, Sun G, Choo XY, McLean C, Simmons RK, Buckberry S, Vargas-Landin DB, Poppe D, Pflueger J, Lister R, Rackham OJL, Petretto E, Polo JM (2019) A single-cell atlas of entorhinal cortex from individuals with Alzheimer’s disease reveals cell-type-specific gene expression regulation. Nat Neurosci 22:2087–2097. https://doi.org/10.1038/s41593-019-0539-4

    Article  CAS  PubMed  Google Scholar 

  62. Hardy RN, Simsek ZD, Curry B, Core SL, Beltz T, Xue B, Johnson AK, Thunhorst RL, Curtis KS (2018) Aging affects isoproterenol-induced water drinking, astrocyte density, and central neuronal activation in female Brown Norway rats. Physiol Behav 192:90–97. https://doi.org/10.1016/j.physbeh.2018.03.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Harris JL, Choi IY, Brooks WM (2015) Probing astrocyte metabolism in vivo: proton magnetic resonance spectroscopy in the injured and aging brain. Front Aging Neurosci 7:202. https://doi.org/10.3389/fnagi.2015.00202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Harris JL, Yeh HW, Swerdlow RH, Choi IY, Lee P, Brooks WM (2014) High-field proton magnetic resonance spectroscopy reveals metabolic effects of normal brain aging. Neurobiol Aging 35:1686–1694. https://doi.org/10.1016/j.neurobiolaging.2014.01.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Haug H, Eggers R (1991) Morphometry of the human cortex cerebri and corpus striatum during aging. Neurobiol Aging 12:336–338 discussion 352-335

    Article  CAS  Google Scholar 

  66. Hayakawa K, Esposito E, Wang X, Terasaki Y, Liu Y, Xing C, Ji X, Lo EH (2016) Transfer of mitochondria from astrocytes to neurons after stroke. Nature 535:551–555. https://doi.org/10.1038/nature18928

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Hayakawa N, Kato H, Araki T (2007) Age-related changes of astorocytes, oligodendrocytes and microglia in the mouse hippocampal CA1 sector. Mech Ageing Dev 128:311–316. https://doi.org/10.1016/j.mad.2007.01.005

    Article  CAS  PubMed  Google Scholar 

  68. Hayflick L, Moorhead PS (1961) The serial cultivation of human diploid cell strains. Exp Cell Res 25:585–621. https://doi.org/10.1016/0014-4827(61)90192-6

    Article  CAS  PubMed  Google Scholar 

  69. Henrik Heiland D, Ravi VM, Behringer SP, Frenking JH, Wurm J, Joseph K, Garrelfs NWC, Strahle J, Heynckes S, Grauvogel J, Franco P, Mader I, Schneider M, Potthoff AL, Delev D, Hofmann UG, Fung C, Beck J, Sankowski R, Prinz M, Schnell O (2019) Tumor-associated reactive astrocytes aid the evolution of immunosuppressive environment in glioblastoma. Nat Commun 10:2541. https://doi.org/10.1038/s41467-019-10493-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Hertz L, Dringen R, Schousboe A, Robinson SR (1999) Astrocytes: glutamate producers for neurons. J Neurosci Res 57:417–428

    Article  CAS  Google Scholar 

  71. Hulse RE, Winterfield J, Kunkler PE, Kraig RP (2001) Astrocytic clasmatodendrosis in hippocampal organ culture. Glia 33:169–179. https://doi.org/10.1002/1098-1136(200102)33:2<169::aid-glia1016>3.0.co;2-b

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Iadecola C (2017) The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease. Neuron 96:17–42. https://doi.org/10.1016/j.neuron.2017.07.030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, Benveniste H, Vates GE, Deane R, Goldman SA, Nagelhus EA, Nedergaard M (2012) A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Transl Med 4:147ra111. https://doi.org/10.1126/scitranslmed.3003748

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Itoh N, Itoh Y, Tassoni A, Ren E, Kaito M, Ohno A, Ao Y, Farkhondeh V, Johnsonbaugh H, Burda J, Sofroniew MV, Voskuhl RR (2018) Cell-specific and region-specific transcriptomics in the multiple sclerosis model: focus on astrocytes. Proc Natl Acad Sci U S A 115:E302–E309. https://doi.org/10.1073/pnas.1716032115

    Article  CAS  PubMed  Google Scholar 

  75. Jackson FR (2011) Glial cell modulation of circadian rhythms. Glia 59:1341–1350. https://doi.org/10.1002/glia.21097

    Article  PubMed  Google Scholar 

  76. Jessen SB, Mathiesen C, Lind BL, Lauritzen M (2017) Interneuron deficit associates attenuated network synchronization to mismatch of energy supply and demand in aging mouse brains. Cereb Cortex 27:646–659. https://doi.org/10.1093/cercor/bhv261

    Article  PubMed  Google Scholar 

  77. Jeyapalan JC, Sedivy JM (2008) Cellular senescence and organismal aging. Mech Ageing Dev 129:467–474. https://doi.org/10.1016/j.mad.2008.04.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Jiang T, Cadenas E (2014) Astrocytic metabolic and inflammatory changes as a function of age. Aging Cell. https://doi.org/10.1111/acel.12268

  79. Jo S, Yarishkin O, Hwang YJ, Chun YE, Park M, Woo DH, Bae JY, Kim T, Lee J, Chun H, Park HJ, Lee DY, Hong J, Kim HY, Oh SJ, Park SJ, Lee H, Yoon BE, Kim Y, Jeong Y, Shim I, Bae YC, Cho J, Kowall NW, Ryu H, Hwang E, Kim D, Lee CJ (2014) GABA from reactive astrocytes impairs memory in mouse models of Alzheimer’s disease. Nat Med 20:886–896. https://doi.org/10.1038/nm.3639

    Article  CAS  PubMed  Google Scholar 

  80. John Lin CC, Yu K, Hatcher A, Huang TW, Lee HK, Carlson J, Weston MC, Chen F, Zhang Y, Zhu W, Mohila CA, Ahmed N, Patel AJ, Arenkiel BR, Noebels JL, Creighton CJ, Deneen B (2017) Identification of diverse astrocyte populations and their malignant analogs. Nat Neurosci 20:396–405. https://doi.org/10.1038/nn.4493

    Article  CAS  PubMed  Google Scholar 

  81. Johnson ECB, Dammer EB, Duong DM, Ping L, Zhou M, Yin L, Higginbotham LA, Guajardo A, White B, Troncoso JC, Thambisetty M, Montine TJ, Lee EB, Trojanowski JQ, Beach TG, Reiman EM, Haroutunian V, Wang M, Schadt E, Zhang B, Dickson DW, Ertekin-Taner N, Golde TE, Petyuk VA, De Jager PL, Bennett DA, Wingo TS, Rangaraju S, Hajjar I, Shulman JM, Lah JJ, Levey AI, Seyfried NT (2020) Large-scale proteomic analysis of Alzheimer’s disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat Med 26:769–780. https://doi.org/10.1038/s41591-020-0815-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Jyothi HJ, Vidyadhara DJ, Mahadevan A, Philip M, Parmar SK, Manohari SG, Shankar SK, Raju TR, Alladi PA (2015) Aging causes morphological alterations in astrocytes and microglia in human substantia nigra pars compacta. Neurobiol Aging 36:3321–3333. https://doi.org/10.1016/j.neurobiolaging.2015.08.024

    Article  CAS  PubMed  Google Scholar 

  83. Kanaan NM, Kordower JH, Collier TJ (2010) Age-related changes in glial cells of dopamine midbrain subregions in rhesus monkeys. Neurobiol Aging 31:937–952. https://doi.org/10.1016/j.neurobiolaging.2008.07.006

    Article  CAS  PubMed  Google Scholar 

  84. Kawano H, Katsurabayashi S, Kakazu Y, Yamashita Y, Kubo N, Kubo M, Okuda H, Takasaki K, Kubota K, Mishima K, Fujiwara M, Harata NC, Iwasaki K (2012) Long-term culture of astrocytes attenuates the readily releasable pool of synaptic vesicles. PLoS One 7:e48034. https://doi.org/10.1371/journal.pone.0048034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Keleshian VL, Modi HR, Rapoport SI, Rao JS (2013) Aging is associated with altered inflammatory, arachidonic acid cascade, and synaptic markers, influenced by epigenetic modifications, in the human frontal cortex. J Neurochem 125:63–73. https://doi.org/10.1111/jnc.12153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Kettenmann H, Kirchhoff F, Verkhratsky A (2013) Microglia: new roles for the synaptic stripper. Neuron 77:10–18. https://doi.org/10.1016/j.neuron.2012.12.023

    Article  CAS  PubMed  Google Scholar 

  87. Kettenmann H, Ransom B (eds) (2013) Neuroglia. Oxford Unversity Press, Oxford

    Google Scholar 

  88. Kirischuk S, Parpura V, Verkhratsky A (2012) Sodium dynamics: another key to astroglial excitability? Trends Neurosci 35:497–506. https://doi.org/10.1016/j.tins.2012.04.003

    Article  CAS  PubMed  Google Scholar 

  89. Kisler K, Nelson AR, Montagne A, Zlokovic BV (2017) Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease. Nat Rev Neurosci 18:419–434. https://doi.org/10.1038/nrn.2017.48

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Klein M, Lohr C, Droste D (2020) Age-dependent heterogeneity of murine olfactory bulb astrocytes. Front Aging Neurosci 12:172. https://doi.org/10.3389/fnagi.2020.00172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Kobayashi E, Nakano M, Kubota K, Himuro N, Mizoguchi S, Chikenji T, Otani M, Mizue Y, Nagaishi K, Fujimiya M (2018) Activated forms of astrocytes with higher GLT-1 expression are associated with cognitive normal subjects with Alzheimer pathology in human brain. Sci Rep 8:1712. https://doi.org/10.1038/s41598-018-19442-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Kohama SG, Goss JR, Finch CE, McNeill TH (1995) Increases of glial fibrillary acidic protein in the aging female mouse brain. Neurobiol Aging 16:59–67. https://doi.org/10.1016/0197-4580(95)80008-f

    Article  CAS  PubMed  Google Scholar 

  93. Kress BT, Iliff JJ, Xia M, Wang M, Wei HS, Zeppenfeld D, Xie L, Kang H, Xu Q, Liew JA, Plog BA, Ding F, Deane R, Nedergaard M (2014) Impairment of paravascular clearance pathways in the aging brain. Ann Neurol 76:845–861. https://doi.org/10.1002/ana.24271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Kriauciunaite K, Kausyle A, Pajarskiene J, Tunaitis V, Lim D, Verkhratsky A, Pivoriunas A (2020) Immortalised hippocampal astrocytes from 3xTG-AD mice fail to support BBB integrity in vitro: role of extracellular vesicles in glial-endothelial communication. Cell Mol Neurobiol. https://doi.org/10.1007/s10571-020-00871-w

  95. Kumar MJ, Andersen JK (2004) Perspectives on MAO-B in aging and neurological disease: where do we go from here? Mol Neurobiol 30:77–89. https://doi.org/10.1385/MN:30:1:077

    Article  CAS  PubMed  Google Scholar 

  96. Lalo U, Bogdanov A, Pankratov Y (2019) Age- and experience-related plasticity of ATP-mediated signaling in the neocortex. Front Cell Neurosci 13:242. https://doi.org/10.3389/fncel.2019.00242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Lalo U, Palygin O, North RA, Verkhratsky A, Pankratov Y (2011) Age-dependent remodelling of ionotropic signalling in cortical astroglia. Aging Cell 10:392–402. https://doi.org/10.1111/j.1474-9726.2011.00682.x

    Article  CAS  PubMed  Google Scholar 

  98. Landfield PW, Rose G, Sandles L, Wohlstadter TC, Lynch G (1977) Patterns of astroglial hypertrophy and neuronal degeneration in the hippocampus of ages, memory-deficient rats. J Gerontol 32:3–12. https://doi.org/10.1093/geronj/32.1.3

    Article  CAS  PubMed  Google Scholar 

  99. Lebedeva A, Plata A, Nosova O, Tyurikova O, Semyanov A (2018) Activity-dependent changes in transporter and potassium currents in hippocampal astrocytes. Brain Res Bull 136:37–43. https://doi.org/10.1016/j.brainresbull.2017.08.015

    Article  CAS  PubMed  Google Scholar 

  100. Lee M, McGeer EG, McGeer PL (2011) Mechanisms of GABA release from human astrocytes. Glia 59:1600–1611. https://doi.org/10.1002/glia.21202

    Article  PubMed  Google Scholar 

  101. Lei M, Hua X, Xiao M, Ding J, Han Q, Hu G (2008) Impairments of astrocytes are involved in the d-galactose-induced brain aging. Biochem Biophys Res Commun 369:1082–1087. https://doi.org/10.1016/j.bbrc.2008.02.151

    Article  CAS  PubMed  Google Scholar 

  102. Leon M, Woo C (2018) Environmental enrichment and successful aging. Front Behav Neurosci 12:155. https://doi.org/10.3389/fnbeh.2018.00155

    Article  PubMed  PubMed Central  Google Scholar 

  103. Levitt P, Pintar JE, Breakefield XO (1982) Immunocytochemical demonstration of monoamine oxidase B in brain astrocytes and serotonergic neurons. Proc Natl Acad Sci U S A 79:6385–6389. https://doi.org/10.1073/pnas.79.20.6385

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Long JM, Kalehua AN, Muth NJ, Calhoun ME, Jucker M, Hengemihle JM, Ingram DK, Mouton PR (1998) Stereological analysis of astrocyte and microglia in aging mouse hippocampus. Neurobiol Aging 19:497–503. https://doi.org/10.1016/s0197-4580(98)00088-8

    Article  CAS  PubMed  Google Scholar 

  105. Ma B, Buckalew R, Du Y, Kiyoshi CM, Alford CC, Wang W, McTigue DM, Enyeart JJ, Terman D, Zhou M (2016) Gap junction coupling confers isopotentiality on astrocyte syncytium. Glia 64:214–226. https://doi.org/10.1002/glia.22924

    Article  PubMed  Google Scholar 

  106. Maher P (2005) The effects of stress and aging on glutathione metabolism. Ageing Res Rev 4:288–314. https://doi.org/10.1016/j.arr.2005.02.005

    Article  CAS  PubMed  Google Scholar 

  107. Makar TK, Nedergaard M, Preuss A, Gelbard AS, Perumal AS, Cooper AJ (1994) Vitamin E, ascorbate, glutathione, glutathione disulfide, and enzymes of glutathione metabolism in cultures of chick astrocytes and neurons: evidence that astrocytes play an important role in antioxidative processes in the brain. J Neurochem 62:45–53

    Article  CAS  Google Scholar 

  108. Mansour H, Chamberlain CG, Weible MW 2nd, Hughes S, Chu Y, Chan-Ling T (2008) Aging-related changes in astrocytes in the rat retina: imbalance between cell proliferation and cell death reduces astrocyte availability. Aging Cell 7:526–540. https://doi.org/10.1111/j.1474-9726.2008.00402.x

    Article  CAS  PubMed  Google Scholar 

  109. Marina N, Christie IN, Korsak A, Doronin M, Brazhe A, Hosford PS, Wells JA, Sheikhbahaei S, Humoud I, Paton JFR, Lythgoe MF, Semyanov A, Kasparov S, Gourine AV (2020) Astrocytes monitor cerebral perfusion and control systemic circulation to maintain brain blood flow. Nat Commun 11:131. https://doi.org/10.1038/s41467-019-13956-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Mathiesen C, Brazhe A, Thomsen K, Lauritzen M (2013) Spontaneous calcium waves in Bergman glia increase with age and hypoxia and may reduce tissue oxygen. J Cereb Blood Flow Metab 33:161–169. https://doi.org/10.1038/jcbfm.2012.175

    Article  CAS  PubMed  Google Scholar 

  111. Mathur R, Ince PG, Minett T, Garwood CJ, Shaw PJ, Matthews FE, Brayne C, Simpson JE, Wharton SB (2015) A reduced astrocyte response to beta-amyloid plaques in the ageing brain associates with cognitive impairment. PLoS One 10:e0118463. https://doi.org/10.1371/journal.pone.0118463

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Mattison JA, Colman RJ, Beasley TM, Allison DB, Kemnitz JW, Roth GS, Ingram DK, Weindruch R, de Cabo R, Anderson RM (2017) Caloric restriction improves health and survival of rhesus monkeys. Nat Commun 8:14063. https://doi.org/10.1038/ncomms14063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Mauch DH, Nagler K, Schumacher S, Goritz C, Muller EC, Otto A, Pfrieger FW (2001) CNS synaptogenesis promoted by glia-derived cholesterol. Science 294:1354–1357. https://doi.org/10.1126/science.294.5545.1354

    Article  CAS  PubMed  Google Scholar 

  114. Medvedev N, Popov V, Henneberger C, Kraev I, Rusakov DA, Stewart MG (2014) Glia selectively approach synapses on thin dendritic spines. Philos Trans R Soc Lond Ser B Biol Sci 369:20140047. https://doi.org/10.1098/rstb.2014.0047

    Article  Google Scholar 

  115. Meng Q, Lin MS, Tzeng IS (2020) Relationship between exercise and Alzheimer’s disease: a narrative literature review. Front Neurosci 14:131. https://doi.org/10.3389/fnins.2020.00131

    Article  PubMed  PubMed Central  Google Scholar 

  116. Miranda CJ, Braun L, Jiang Y, Hester ME, Zhang L, Riolo M, Wang H, Rao M, Altura RA, Kaspar BK (2012) Aging brain microenvironment decreases hippocampal neurogenesis through Wnt-mediated survivin signaling. Aging Cell 11:542–552. https://doi.org/10.1111/j.1474-9726.2012.00816.x

    Article  PubMed  PubMed Central  Google Scholar 

  117. Mirzadeh Z, Merkle FT, Soriano-Navarro M, Garcia-Verdugo JM, Alvarez-Buylla A (2008) Neural stem cells confer unique pinwheel architecture to the ventricular surface in neurogenic regions of the adult brain. Cell Stem Cell 3:265–278. https://doi.org/10.1016/j.stem.2008.07.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Montagne A, Barnes SR, Sweeney MD, Halliday MR, Sagare AP, Zhao Z, Toga AW, Jacobs RE, Liu CY, Amezcua L, Harrington MG, Chui HC, Law M, Zlokovic BV (2015) Blood-brain barrier breakdown in the aging human hippocampus. Neuron 85:296–302. https://doi.org/10.1016/j.neuron.2014.12.032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Mora F (2013) Successful brain aging: plasticity, environmental enrichment, and lifestyle. Dialogues Clin Neurosci 15:45–52

    Article  Google Scholar 

  120. Mora F, Segovia G, del Arco A (2007) Aging, plasticity and environmental enrichment: structural changes and neurotransmitter dynamics in several areas of the brain. Brain Res Rev 55:78–88. https://doi.org/10.1016/j.brainresrev.2007.03.011

    Article  CAS  PubMed  Google Scholar 

  121. Moss J, Gebara E, Bushong EA, Sanchez-Pascual I, O'Laoi R, El M'Ghari I, Kocher-Braissant J, Ellisman MH, Toni N (2016) Fine processes of Nestin-GFP-positive radial glia-like stem cells in the adult dentate gyrus ensheathe local synapses and vasculature. Proc Natl Acad Sci U S A 113:E2536–E2545. https://doi.org/10.1073/pnas.1514652113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Mosso A (1880) Sulla circolazione del sangue nel cervello dell’uomo. Mem Real Acc Lincei 5:237–358

    Google Scholar 

  123. Mouton PR, Long JM, Lei DL, Howard V, Jucker M, Calhoun ME, Ingram DK (2002) Age and gender effects on microglia and astrocyte numbers in brains of mice. Brain Res 956:30–35. https://doi.org/10.1016/s0006-8993(02)03475-3

    Article  CAS  PubMed  Google Scholar 

  124. Mulligan SJ, MacVicar BA (2004) Calcium transients in astrocyte endfeet cause cerebrovascular constrictions. Nature 431:195–199. https://doi.org/10.1038/nature02827

    Article  CAS  PubMed  Google Scholar 

  125. Munoz-Espin D, Serrano M (2014) Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol 15:482–496. https://doi.org/10.1038/nrm3823

    Article  CAS  PubMed  Google Scholar 

  126. Nation DA, Sweeney MD, Montagne A, Sagare AP, D'Orazio LM, Pachicano M, Sepehrband F, Nelson AR, Buennagel DP, Harrington MG, Benzinger TLS, Fagan AM, Ringman JM, Schneider LS, Morris JC, Chui HC, Law M, Toga AW, Zlokovic BV (2019) Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat Med 25:270–276. https://doi.org/10.1038/s41591-018-0297-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Navarrete M, Perea G, Maglio L, Pastor J, Garcia de Sola R, Araque A (2013) Astrocyte calcium signal and gliotransmission in human brain tissue. Cereb Cortex 23:1240–1246. https://doi.org/10.1093/cercor/bhs122

    Article  PubMed  Google Scholar 

  128. Nedergaard M (2013) Neuroscience. Garbage truck of the brain. Science 340:1529–1530. https://doi.org/10.1126/science.1240514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Nicaise AM, Willis CM, Crocker SJ, Pluchino S (2020) Stem cells of the aging brain. Front Aging Neurosci 12:247

    Article  CAS  Google Scholar 

  130. Nichols NR, Day JR, Laping NJ, Johnson SA, Finch CE (1993) GFAP mRNA increases with age in rat and human brain. Neurobiol Aging 14:421–429. https://doi.org/10.1016/0197-4580(93)90100-p

    Article  CAS  PubMed  Google Scholar 

  131. Norenberg MD, Martinez-Hernandez A (1979) Fine structural localization of glutamine synthetase in astrocytes of rat brain. Brain Res 161:303–310

    Article  CAS  Google Scholar 

  132. Ohtani N (2019) Deciphering the mechanism for induction of senescence-associated secretory phenotype (SASP) and its role in aging and cancer development. J Biochem. https://doi.org/10.1093/jb/mvz055

  133. Okamoto M, Inoue K, Iwamura H, Terashima K, Soya H, Asashima M, Kuwabara T (2011) Reduction in paracrine Wnt3 factors during aging causes impaired adult neurogenesis. FASEB J 25:3570–3582. https://doi.org/10.1096/fj.11-184697

    Article  CAS  PubMed  Google Scholar 

  134. Olabarria M, Noristani HN, Verkhratsky A, Rodriguez JJ (2011) Age-dependent decrease in glutamine synthetase expression in the hippocampal astroglia of the triple transgenic Alzheimer’s disease mouse model: mechanism for deficient glutamatergic transmission? Mol Neurodegener 6:55. https://doi.org/10.1186/1750-1326-6-55

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Olsen ML, Khakh BS, Skatchkov SN, Zhou M, Lee CJ, Rouach N (2015) New insights on astrocyte ion channels: critical for homeostasis and neuron-glia signaling. J Neurosci 35:13827–13835. https://doi.org/10.1523/JNEUROSCI.2603-15.2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Olude MA, Mustapha OA, Aderounmu OA, Olopade JO, Ihunwo AO (2015) Astrocyte morphology, heterogeneity, and density in the developing African giant rat (Cricetomys gambianus). Front Neuroanat 9:67. https://doi.org/10.3389/fnana.2015.00067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Ormel L, Lauritzen KH, Schreiber R, Kunzelmann K, Gundersen V (2020) GABA, but not Bestrophin-1, is localized in astroglial processes in the mouse hippocampus and the cerebellum. Front Mol Neurosci 13:135

    Article  CAS  Google Scholar 

  138. Orre M, Kamphuis W, Osborn LM, Jansen AHP, Kooijman L, Bossers K, Hol EM (2014) Isolation of glia from Alzheimer’s mice reveals inflammation and dysfunction. Neurobiol Aging 35:2746–2760. https://doi.org/10.1016/j.neurobiolaging.2014.06.004

    Article  CAS  PubMed  Google Scholar 

  139. Orre M, Kamphuis W, Osborn LM, Melief J, Kooijman L, Huitinga I, Klooster J, Bossers K, Hol EM (2014) Acute isolation and transcriptome characterization of cortical astrocytes and microglia from young and aged mice. Neurobiol Aging 35:1–14. https://doi.org/10.1016/j.neurobiolaging.2013.07.008

    Article  CAS  PubMed  Google Scholar 

  140. Otsu Y, Couchman K, Lyons DG, Collot M, Agarwal A, Mallet JM, Pfrieger FW, Bergles DE, Charpak S (2015) Calcium dynamics in astrocyte processes during neurovascular coupling. Nat Neurosci 18:210–218. https://doi.org/10.1038/nn.3906

    Article  CAS  PubMed  Google Scholar 

  141. Palmer AL, Ousman SS (2018) Astrocytes and aging. Front Aging Neurosci 10:337. https://doi.org/10.3389/fnagi.2018.00337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Payne BA, Chinnery PF (2015) Mitochondrial dysfunction in aging: much progress but many unresolved questions. Biochim Biophys Acta 1847:1347–1353. https://doi.org/10.1016/j.bbabio.2015.05.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Pekny M, Pekna M, Messing A, Steinhauser C, Lee JM, Parpura V, Hol EM, Sofroniew MV, Verkhratsky A (2016) Astrocytes: a central element in neurological diseases. Acta Neuropathol 131:323–345. https://doi.org/10.1007/s00401-015-1513-1

    Article  CAS  PubMed  Google Scholar 

  144. Pekny M, Wilhelmsson U, Pekna M (2014) The dual role of astrocyte activation and reactive gliosis. Neurosci Lett 565:30–38. https://doi.org/10.1016/j.neulet.2013.12.071

    Article  CAS  PubMed  Google Scholar 

  145. Pelvig DP, Pakkenberg H, Stark AK, Pakkenberg B (2008) Neocortical glial cell numbers in human brains. Neurobiol Aging 29:1754–1762. https://doi.org/10.1016/j.neurobiolaging.2007.04.013

    Article  CAS  PubMed  Google Scholar 

  146. Penfield W (1928) Neuroglia and microglia-the interstitial tissue of the central nervous system. In: Cowdry EV (ed) Special cytology, the form and function of the cell in health and disease. New York, Hoeber, pp 1033–1068

    Google Scholar 

  147. Peng W, Achariyar TM, Li B, Liao Y, Mestre H, Hitomi E, Regan S, Kasper T, Peng S, Ding F, Benveniste H, Nedergaard M, Deane R (2016) Suppression of glymphatic fluid transport in a mouse model of Alzheimer’s disease. Neurobiol Dis 93:215–225. https://doi.org/10.1016/j.nbd.2016.05.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. 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. https://doi.org/10.1111/j.1471-4159.2006.04369.x

    Article  CAS  PubMed  Google Scholar 

  149. Peters A, Sethares C (2004) Oligodendrocytes, their progenitors and other neuroglial cells in the aging primate cerebral cortex. Cereb Cortex 14:995–1007. https://doi.org/10.1093/cercor/bhh060

    Article  PubMed  Google Scholar 

  150. Peters O, Schipke CG, Philipps A, Haas B, Pannasch U, Wang LP, Benedetti B, Kingston AE, Kettenmann H (2009) Astrocyte function is modified by Alzheimer’s disease-like pathology in aged mice. J Alzheimers Dis 18:177–189. https://doi.org/10.3233/JAD-2009-1140

    Article  CAS  PubMed  Google Scholar 

  151. Plata A, Lebedeva A, Denisov P, Nosova O, Postnikova TY, Pimashkin A, Brazhe A, Zaitsev AV, Rusakov DA, Semyanov A (2018) Astrocytic atrophy following status epilepticus parallels reduced Ca2+ activity and impaired synaptic plasticity in the rat Hippocampus. Front Mol Neurosci 11:215. https://doi.org/10.3389/fnmol.2018.00215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Popov A, Brazhe A, Denisov P, Sutyagina O, Lazareva N, Verkhratsky A, Semyanov A (2020) Astrocytes dystrophy in ageing brain parallels impaired synaptic plasticity. bioRxiv. https://doi.org/10.1101/2020.08.05.237420

  153. Popov A, Denisov P, Bychkov M, Brazhe A, Lyukmanova E, Shenkarev Z, Lazareva N, Verkhratsky A, Semyanov A (2020) Caloric restriction triggers morphofunctional remodeling of astrocytes and enhances synaptic plasticity in the mouse hippocampus. Cell Death Dis 11:208. https://doi.org/10.1038/s41419-020-2406-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Potier B, Billard JM, Riviere S, Sinet PM, Denis I, Champeil-Potokar G, Grintal B, Jouvenceau A, Kollen M, Dutar P (2010) Reduction in glutamate uptake is associated with extrasynaptic NMDA and metabotropic glutamate receptor activation at the hippocampal CA1 synapse of aged rats. Aging Cell 9:722–735. https://doi.org/10.1111/j.1474-9726.2010.00593.x

    Article  CAS  PubMed  Google Scholar 

  155. Ramon-y-Cajal S (1892) El nuevo concepto de la histología de los centros nerviosos. Rev Cienc Méd Barcelona 18:361–376 457,-476, 505,-520, 529-541

    Google Scholar 

  156. Rawji KS, Gonzalez Martinez GA, Sharma A, Franklin RJM (2020) The role of astrocytes in remyelination. Trends Neurosci 43:596–607. https://doi.org/10.1016/j.tins.2020.05.006

    Article  CAS  PubMed  Google Scholar 

  157. Reichenbach A, Derouiche A, Kirchhoff F (2010) Morphology and dynamics of perisynaptic glia. Brain Res Rev 63:11–25. https://doi.org/10.1016/j.brainresrev.2010.02.003

    Article  PubMed  Google Scholar 

  158. Robillard KN, Lee KM, Chiu KB, MacLean AG (2016) Glial cell morphological and density changes through the lifespan of rhesus macaques. Brain Behav Immun 55:60–69. https://doi.org/10.1016/j.bbi.2016.01.006

    Article  PubMed  PubMed Central  Google Scholar 

  159. Rockstein M, Brandt KF (1963) Enzyme changes in flight muscle correlated with aging and flight ability in the male housefly. Science 139:1049–1051. https://doi.org/10.1126/science.139.3559.1049

    Article  CAS  PubMed  Google Scholar 

  160. Rodriguez-Vieitez E, Saint-Aubert L, Carter SF, Almkvist O, Farid K, Scholl M, Chiotis K, Thordardottir S, Graff C, Wall A, Langstrom B, Nordberg A (2016) Diverging longitudinal changes in astrocytosis and amyloid PET in autosomal dominant Alzheimer’s disease. Brain 139:922–936. https://doi.org/10.1093/brain/awv404

    Article  PubMed  PubMed Central  Google Scholar 

  161. Rodriguez JJ, Butt AM, Gardenal E, Parpura V, Verkhratsky A (2016) Complex and differential glial responses in Alzheimer’s disease and ageing. Curr Alzheimer Res 13:343–358. https://doi.org/10.2174/1567205013666160229112911

    Article  CAS  PubMed  Google Scholar 

  162. Rodriguez JJ, Jones VC, Tabuchi M, Allan SM, Knight EM, LaFerla FM, Oddo S, Verkhratsky A (2008) Impaired adult neurogenesis in the dentate gyrus of a triple transgenic mouse model of Alzheimer’s disease. PLoS One 3:e2935. https://doi.org/10.1371/journal.pone.0002935

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Rodriguez JJ, Noristani HN, Olabarria M, Fletcher J, Somerville TD, Yeh CY, Verkhratsky A (2011) Voluntary running and environmental enrichment restores impaired hippocampal neurogenesis in a triple transgenic mouse model of Alzheimer’s disease. Curr Alzheimer Res 8:707–717. https://doi.org/10.2174/156720511797633214

    Article  CAS  PubMed  Google Scholar 

  164. Rodriguez JJ, Terzieva S, Olabarria M, Lanza RG, Verkhratsky A (2013) Enriched environment and physical activity reverse astrogliodegeneration in the hippocampus of AD transgenic mice. Cell Death Dis 4:e678. https://doi.org/10.1038/cddis.2013.194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Rodriguez JJ, Verkhratsky A (2011) Neurogenesis in Alzheimer's disease. J Anat 219:78–89. https://doi.org/10.1111/j.1469-7580.2011.01343.x

    Article  PubMed  PubMed Central  Google Scholar 

  166. Rodriguez JJ, Yeh CY, 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. https://doi.org/10.1016/j.neurobiolaging.2013.07.002

    Article  CAS  PubMed  Google Scholar 

  167. Rose CF, Verkhratsky A, Parpura V (2013) Astrocyte glutamine synthetase: pivotal in health and disease. Biochem Soc Trans 41:1518–1524. https://doi.org/10.1042/BST20130237

    Article  CAS  PubMed  Google Scholar 

  168. Rose CR, Verkhratsky A (2016) Principles of sodium homeostasis and sodium signalling in astroglia. Glia 64:1611–1627. https://doi.org/10.1002/glia.22964

    Article  PubMed  Google Scholar 

  169. Rose CR, Ziemens D, Verkhratsky A (2020) On the special role of NCX in astrocytes: translating Na+-transients into intracellular Ca2+ signals. Cell Calcium 86:102154. https://doi.org/10.1016/j.ceca.2019.102154

    Article  CAS  PubMed  Google Scholar 

  170. Roy CS, Sherrington CS (1890) On the regulation of the blood-supply of the brain. J Physiol Lond 11:85–108

    Article  CAS  Google Scholar 

  171. Sack I, Streitberger KJ, Krefting D, Paul F, Braun J (2011) The influence of physiological aging and atrophy on brain viscoelastic properties in humans. PLoS One 6:e23451. https://doi.org/10.1371/journal.pone.0023451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Sahlas DJ, Bilbao JM, Swartz RH, Black SE (2002) Clasmatodendrosis correlating with periventricular hyperintensity in mixed dementia. Ann Neurol 52:378–381. https://doi.org/10.1002/ana.10310

    Article  PubMed  Google Scholar 

  173. Salminen LE, Conturo TE, Laidlaw DH, Cabeen RP, Akbudak E, Lane EM, Heaps JM, Bolzenius JD, Baker LM, Cooley S, Scott S, Cagle LM, Phillips S, Paul RH (2016) Regional age differences in gray matter diffusivity among healthy older adults. Brain Imaging Behav 10:203–211. https://doi.org/10.1007/s11682-015-9383-7

    Article  PubMed  PubMed Central  Google Scholar 

  174. Salois G, Smith JS (2016) Housing complexity alters GFAP-immunoreactive astrocyte morphology in the rat dentate gyrus. Neural Plast 2016:3928726. https://doi.org/10.1155/2016/3928726

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Sampedro-Piquero P, De Bartolo P, Petrosini L, Zancada-Menendez C, Arias JL, Begega A (2014) Astrocytic plasticity as a possible mediator of the cognitive improvements after environmental enrichment in aged rats. Neurobiol Learn Mem 114:16–25. https://doi.org/10.1016/j.nlm.2014.04.002

    Article  CAS  PubMed  Google Scholar 

  176. Schousboe A, Scafidi S, Bak LK, Waagepetersen HS, McKenna MC (2014) Glutamate metabolism in the brain focusing on astrocytes. Adv Neurobiol 11:13–30. https://doi.org/10.1007/978-3-319-08894-5_2

    Article  PubMed  PubMed Central  Google Scholar 

  177. Schousboe A, Waagepetersen HS (2007) GABA: homeostatic and pharmacological aspects. Prog Brain Res 160:9–19. https://doi.org/10.1016/S0079-6123(06)60002-2

    Article  CAS  PubMed  Google Scholar 

  178. Seifert G, Henneberger C, Steinhauser C (2018) Diversity of astrocyte potassium channels: an update. Brain Res Bull 136:26–36. https://doi.org/10.1016/j.brainresbull.2016.12.002

    Article  CAS  PubMed  Google Scholar 

  179. Semyanov A (2019) Spatiotemporal pattern of calcium activity in astrocytic network. Cell Calcium 78:15–25. https://doi.org/10.1016/j.ceca.2018.12.007

    Article  CAS  PubMed  Google Scholar 

  180. Siemsen BM, Reichel CM, Leong KC, Garcia-Keller C, Gipson CD, Spencer S, McFaddin JA, Hooker KN, Kalivas PW, Scofield MD (2019) Effects of methamphetamine self-administration and extinction on astrocyte structure and function in the nucleus accumbens core. Neuroscience 406:528–541. https://doi.org/10.1016/j.neuroscience.2019.03.040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Sofroniew MV (2009) Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci 32:638–647. https://doi.org/10.1016/j.tins.2009.08.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Sofroniew MV (2014) Astrogliosis. Cold Spring Harb Perspect Biol 7:a020420. https://doi.org/10.1101/cshperspect.a020420

    Article  PubMed  Google Scholar 

  183. Sonntag WE, Deak F, Ashpole N, Toth P, Csiszar A, Freeman W, Ungvari Z (2013) Insulin-like growth factor-1 in CNS and cerebrovascular aging. Front Aging Neurosci 5:27. https://doi.org/10.3389/fnagi.2013.00027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Soreq L, Consortium UKBE, North American Brain Expression, C, Rose J, Soreq E, Hardy J, Trabzuni D, Cookson MR, Smith C, Ryten M, Patani R, Ule J (2017) Major shifts in glial regional identity are a transcriptional Hallmark of human brain aging. Cell Rep 18:557–570. https://doi.org/10.1016/j.celrep.2016.12.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Souza DG, Bellaver B, Souza DO, Quincozes-Santos A (2013) Characterization of adult rat astrocyte cultures. PLoS One 8:e60282. https://doi.org/10.1371/journal.pone.0060282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Stern Y (2009) Cognitive reserve. Neuropsychologia 47:2015–2028. https://doi.org/10.1016/j.neuropsychologia.2009.03.004

    Article  PubMed  PubMed Central  Google Scholar 

  187. Streit WJ, Braak H, Xue QS, 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. https://doi.org/10.1007/s00401-009-0556-6

    Article  PubMed  PubMed Central  Google Scholar 

  188. Streit WJ, Khoshbouei H, Bechmann I (2020) Dystrophic microglia in late-onset Alzheimer’s disease. Glia 68:845–854. https://doi.org/10.1002/glia.23782

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  190. Streit WJ, Xue QS, Tischer J, Bechmann I (2014) Microglial pathology. Acta Neuropathol Commun 2:142. https://doi.org/10.1186/s40478-014-0142-6

    Article  PubMed  PubMed Central  Google Scholar 

  191. Strolin Benedetti M, Dostert P (1989) Monoamine oxidase, brain ageing and degenerative diseases. Biochem Pharmacol 38:555–561. https://doi.org/10.1016/0006-2952(89)90198-6

    Article  CAS  PubMed  Google Scholar 

  192. Sun N, Youle RJ, Finkel T (2016) The mitochondrial basis of aging. Mol Cell 61:654–666. https://doi.org/10.1016/j.molcel.2016.01.028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Sweeney MD, Zhao Z, Montagne A, Nelson AR, Zlokovic BV (2019) Blood-brain barrier: from physiology to disease and back. Physiol Rev 99:21–78. https://doi.org/10.1152/physrev.00050.2017

    Article  CAS  PubMed  Google Scholar 

  194. Sykova E, Nicholson C (2008) Diffusion in brain extracellular space. Physiol Rev 88:1277–1340. https://doi.org/10.1152/physrev.00027.2007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Tachibana M, Mohri I, Hirata I, Kuwada A, Kimura-Ohba S, Kagitani-Shimono K, Fushimi H, Inoue T, Shiomi M, Kakuta Y, Takeuchi M, Murayama S, Nakayama M, Ozono K, Taniike M (2019) Clasmatodendrosis is associated with dendritic spines and does not represent autophagic astrocyte death in influenza-associated encephalopathy. Brain and Development 41:85–95. https://doi.org/10.1016/j.braindev.2018.07.008

    Article  PubMed  Google Scholar 

  196. Tanaka M, Shih PY, Gomi H, Yoshida T, Nakai J, Ando R, Furuichi T, Mikoshiba K, Semyanov A, Itohara S (2013) Astrocytic Ca2+ signals are required for the functional integrity of tripartite synapses. Mol Brain 6:6. https://doi.org/10.1186/1756-6606-6-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Tarantini S, Tran CHT, Gordon GR, Ungvari Z, Csiszar A (2017) Impaired neurovascular coupling in aging and Alzheimer’s disease: contribution of astrocyte dysfunction and endothelial impairment to cognitive decline. Exp Gerontol 94:52–58. https://doi.org/10.1016/j.exger.2016.11.004

    Article  CAS  PubMed  Google Scholar 

  198. Toth P, Tarantini S, Ashpole NM, Tucsek Z, Milne GL, Valcarcel-Ares NM, Menyhart A, Farkas E, Sonntag WE, Csiszar A, Ungvari Z (2015) IGF-1 deficiency impairs neurovascular coupling in mice: implications for cerebromicrovascular aging. Aging Cell 14:1034–1044. https://doi.org/10.1111/acel.12372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Vanzulli I, Papanikolaou M, De-La-Rocha IC, Pieropan F, Rivera AD, Gomez-Nicola D, Verkhratsky A, Rodriguez JJ, Butt AM (2020) Disruption of oligodendrocyte progenitor cells is an early sign of pathology in the triple transgenic mouse model of Alzheimer’s disease. Neurobiol Aging 94:130–139. https://doi.org/10.1016/j.neurobiolaging.2020.05.016

    Article  CAS  PubMed  Google Scholar 

  200. Vaughan DW, Peters A (1974) Neuroglial cells in the cerebral cortex of rats from young adulthood to old age: an electron microscope study. J Neurocytol 3:405–429

    Article  CAS  Google Scholar 

  201. Verkhratsky A, Butt AM (2013) Glial physiology and pathophysiology. Wiley-Blackwell, Chichester

    Book  Google Scholar 

  202. Verkhratsky A, Marutle A, Rodriguez-Arellano JJ, Nordberg A (2015) Glial asthenia and functional paralysis: a new perspective on neurodegeneration and Alzheimer’s disease. Neuroscientist 21:552–568. https://doi.org/10.1177/1073858414547132

    Article  CAS  PubMed  Google Scholar 

  203. Verkhratsky A, Nedergaard M (2014) Astroglial cradle in the life of the synapse. Philos Trans R Soc Lond Ser B Biol Sci 369:20130595. https://doi.org/10.1098/rstb.2013.0595

    Article  CAS  Google Scholar 

  204. Verkhratsky A, Nedergaard M (2018) Physiology of Astroglia. Physiol Rev 98:239–389. https://doi.org/10.1152/physrev.00042.2016

    Article  CAS  PubMed  Google Scholar 

  205. Verkhratsky A, Olabarria M, Noristani HN, Yeh CY, Rodriguez JJ (2010) Astrocytes in Alzheimer’s disease. Neurotherapeutics 7:399–412. https://doi.org/10.1016/j.nurt.2010.05.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Verkhratsky A, Rodrigues JJ, Pivoriunas A, Zorec R, Semyanov A (2019) Astroglial atrophy in Alzheimer’s disease. Pflugers Arch 471:1247–1261. https://doi.org/10.1007/s00424-019-02310-2

    Article  CAS  PubMed  Google Scholar 

  207. Verkhratsky A, Rose CR (2020) Na+-dependent transporters: the backbone of astroglial homeostatic function. Cell Calcium 85:102136. https://doi.org/10.1016/j.ceca.2019.102136

    Article  CAS  PubMed  Google Scholar 

  208. Verkhratsky A, Steinhauser C (2000) Ion channels in glial cells. Brain Res Brain Res Rev 32:380–412. https://doi.org/10.1016/s0165-0173(99)00093-4

    Article  CAS  PubMed  Google Scholar 

  209. Verkhratsky A, Untiet V, Rose CR (2020) Ionic signalling in astroglia beyond calcium. J Physiol 598:1655–1670. https://doi.org/10.1113/JP277478

    Article  CAS  PubMed  Google Scholar 

  210. Verkhratsky A, Zorec R, Parpura V (2017) Stratification of astrocytes in healthy and diseased brain. Brain Pathol 27:629–644. https://doi.org/10.1111/bpa.12537

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Vilchez D, Saez I, Dillin A (2014) The role of protein clearance mechanisms in organismal ageing and age-related diseases. Nat Commun 5:5659. https://doi.org/10.1038/ncomms6659

    Article  CAS  PubMed  Google Scholar 

  212. Viola GG, Rodrigues L, Americo JC, Hansel G, Vargas RS, Biasibetti R, Swarowsky A, Goncalves CA, Xavier LL, Achaval M, Souza DO, Amaral OB (2009) Morphological changes in hippocampal astrocytes induced by environmental enrichment in mice. Brain Res 1274:47–54. https://doi.org/10.1016/j.brainres.2009.04.007

    Article  CAS  PubMed  Google Scholar 

  213. Walhovd KB, Johansen-Berg H, Karadottir RT (2014) Unraveling the secrets of white matter - bridging the gap between cellular, animal and human imaging studies. Neuroscience 276C:2–13. https://doi.org/10.1016/j.neuroscience.2014.06.058

    Article  CAS  Google Scholar 

  214. Wardlaw JM, Benveniste H, Nedergaard M, Zlokovic BV, Mestre H, Lee H, Doubal FN, Brown R, Ramirez J, MacIntosh BJ, Tannenbaum A, Ballerini L, Rungta RL, Boido D, Sweeney M, Montagne A, Charpak S, Joutel A, Smith KJ, Black SE, colleagues from the Fondation Leducq Transatlantic Network of Excellence on the Role of the Perivascular Space in Cerebral Small Vessel, D (2020) Perivascular spaces in the brain: anatomy, physiology and pathology. Nat Rev Neurol 16:137–153. https://doi.org/10.1038/s41582-020-0312-z

    Article  PubMed  Google Scholar 

  215. Watts ME, Pocock R, Claudianos C (2018) Brain energy and oxygen metabolism: emerging role in normal function and disease. Front Mol Neurosci 11:216. https://doi.org/10.3389/fnmol.2018.00216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Weismann A (1889) Collected essays upon heredity and kindred biological problems. Clarendon, Oxford

    Google Scholar 

  217. Westlund KN, Denney RM, Rose RM, Abell CW (1988) Localization of distinct monoamine oxidase a and monoamine oxidase B cell populations in human brainstem. Neuroscience 25:439–456. https://doi.org/10.1016/0306-4522(88)90250-3

    Article  CAS  PubMed  Google Scholar 

  218. Wheeler MA, Clark IC, Tjon EC, Li Z, Zandee SEJ, Couturier CP, Watson BR, Scalisi G, Alkwai S, Rothhammer V, Rotem A, Heyman JA, Thaploo S, Sanmarco LM, Ragoussis J, Weitz DA, Petrecca K, Moffitt JR, Becher B, Antel JP, Prat A, Quintana FJ (2020) MAFG-driven astrocytes promote CNS inflammation. Nature 578:593–599. https://doi.org/10.1038/s41586-020-1999-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Wilhelmsson U, Bushong EA, Price DL, Smarr BL, Phung V, Terada M, Ellisman MH, Pekny M (2006) Redefining the concept of reactive astrocytes as cells that remain within their unique domains upon reaction to injury. Proc Natl Acad Sci U S A 103:17513–17518. https://doi.org/10.1073/pnas.0602841103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Wu Y, Zhang AQ, Yew DT (2005) Age related changes of various markers of astrocytes in senescence-accelerated mice hippocampus. Neurochem Int 46:565–574. https://doi.org/10.1016/j.neuint.2005.01.002

    Article  CAS  PubMed  Google Scholar 

  221. Wu YW, Gordleeva S, Tang X, Shih PY, Dembitskaya Y, Semyanov A (2019) Morphological profile determines the frequency of spontaneous calcium events in astrocytic processes. Glia 67:246–262. https://doi.org/10.1002/glia.23537

    Article  PubMed  Google Scholar 

  222. Wu Z, Guo Z, Gearing M, Chen G (2014) Tonic inhibition in dentate gyrus impairs long-term potentiation and memory in an Alzheimer’s [corrected] disease model. Nat Commun 5:4159. https://doi.org/10.1038/ncomms5159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Ximerakis M, Lipnick SL, Innes BT, Simmons SK, Adiconis X, Dionne D, Mayweather BA, Nguyen L, Niziolek Z, Ozek C, Butty VL, Isserlin R, Buchanan SM, Levine SS, Regev A, Bader GD, Levin JZ, Rubin LL (2019) Single-cell transcriptomic profiling of the aging mouse brain. Nat Neurosci 22:1696–1708. https://doi.org/10.1038/s41593-019-0491-3

    Article  CAS  PubMed  Google Scholar 

  224. Zamanian JL, Xu L, Foo LC, Nouri N, Zhou L, Giffard RG, Barres BA (2012) Genomic analysis of reactive astrogliosis. J Neurosci 32:6391–6410. https://doi.org/10.1523/JNEUROSCI.6221-11.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Zonta M, Angulo MC, Gobbo S, Rosengarten B, Hossmann KA, Pozzan T, Carmignoto G (2003) Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nat Neurosci 6:43–50. https://doi.org/10.1038/nn980

    Article  CAS  PubMed  Google Scholar 

  226. Zorec R, Parpura V, Verkhratsky A (2018) Preventing neurodegeneration by adrenergic astroglial excitation. FEBS J. https://doi.org/10.1111/febs.14456

Download references

Acknowledgements

AP and AV were supported by the Global Grant measure (No. 09.3.3-LMTK-712-01-0082). MAO was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Grant number 27724/2018-2) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Grant number 88887.2005.00/2018-00). AS, AP and AB were supported by Russian Science Foundation grant 20-14-00241.

Author information

Authors and Affiliations

  1. Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PT, UK

    Alexei Verkhratsky

  2. Achucarro Center for Neuroscience, IKERBASQUE, Basque Foundation for Science, 48011, Bilbao, Spain

    Alexei Verkhratsky

  3. Department of Neurosciences, University of the Basque Country UPV/EHU and CIBERNED, Leioa, Spain

    Alexei Verkhratsky

  4. Laboratório de Farmacologia Molecular, Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, 66075-110, Brazil

    Marcus Augusto-Oliveira

  5. Department of Stem Cell Biology, State Research Institute Centre for Innovative Medicine, LT-01102, Vilnius, Lithuania

    Augustas Pivoriūnas

  6. Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya street 16/10, Moscow, Russia, 117997

    Alexander Popov, Alexey Brazhe & Alexey Semyanov

  7. Faculty of Biology, Lomonosov Moscow State University, Moscow, 119234, Russia

    Alexey Brazhe

  8. Sechenov First Moscow State Medical University, Moscow, Russia

    Alexey Semyanov

Authors
  1. Alexei Verkhratsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marcus Augusto-Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Augustas Pivoriūnas
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alexander Popov
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alexey Brazhe
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alexey Semyanov
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Alexei Verkhratsky or Alexey Semyanov.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the special issue on Aging Brain in Pflügers Archiv

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Verkhratsky, A., Augusto-Oliveira, M., Pivoriūnas, A. et al. Astroglial asthenia and loss of function, rather than reactivity, contribute to the ageing of the brain. Pflugers Arch - Eur J Physiol 473, 753–774 (2021). https://doi.org/10.1007/s00424-020-02465-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-020-02465-3

Keywords

Search

Navigation