CoChat
Sign Up
Cited by 69Neuroinflammation and Neurodegeneration MechanismsGenetics, Aging, and Longevity in Model OrganismsTelomeres, Telomerase, and Senescence

Untangling senescent and damage‐associated microglia in the aging and diseased brain

Open access
Ng, Pei Y., McNeely, Taylor L., Baker, Darren J.·2023·The FEBS Journal
DOI 10.1111/febs.16315PMC PMC9167891
Open this paper in CoChat — free account

Abstract

Microglial homeostasis has emerged as a critical mediator of health and disease in the central nervous system. In their neuroprotective role as the predominant immune cells of the brain, microglia surveil the microenvironment for debris and pathogens, while also promoting neurogenesis and performing maintenance on synapses. Chronological ageing, disease onset, or traumatic injury promotes irreparable damage or deregulated signaling to reinforce neurotoxic phenotypes in microglia. These insults may include cellular senescence, a stable growth arrest often accompanied by the production of a distinctive pro‐inflammatory secretory phenotype, which may contribute to age‐ or disease‐driven decline in neuronal health and cognition and is a potential novel therapeutic target. Despite this increased scrutiny, unanswered questions remain about what distinguishes senescent microglia and non‐senescent microglia reacting to insults occurring in ageing, disease, and injury, and how central the development of senescence is in their pivot from guardian to assailant. To intelligently design future studies to untangle senescent microglia from other primed and reactionary states, specific criteria must be developed that define this population and allow for comparisons between different model systems. Comparing microglial activity seen in homeostasis, ageing, disease, and injury allows for a more coherent understanding of when and how senescent and other harmful microglial subpopulations should be targeted.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that senescent microglia constitute a distinct cellular state from the non-senescent "activated" or primed microglia seen in aging, neurodegenerative disease, and traumatic brain injury, but that current markers cannot reliably separate the two. It proposes a combinatorial, criteria-based approach—cell-cycle arrest, p16/p21, macromolecular damage, SASP profiling, and senolytic sensitivity—to define and target senescent microglia therapeutically.

Key findings

  • Microglial phenotypes overlap heavily across aging, neurodegenerative disease (ND), and TBI: all feature loss of homeostatic genes (Tmem119, P2ry12, Cx3cr1) and a pro-inflammatory profile (TNFα, IL-6, IL-1β), with no marker or secretome component specific to any one context.
  • Senescent microglia have been reported in aged rodents in vivo and ex vivo, in mouse models of AD/tauopathy, and preliminarily after TBI in adult mice, but evidence in aged human brain is described as limited.
  • Pharmacological clearance of senescent cells mitigated pathology in mouse models of tauopathy (p16-expressing cells, with microglia identified as a senescent population), AD (oligodendrocyte progenitor senescence), and ALS-associated gliosis; a Phase II senolytic trial in AD is noted as underway.
  • Proposed discriminators between senescent and "activated" microglia include cell-cycle arrest (activated microglia show increased proliferation, whereas senescence is defined by arrest), p16/p21 upregulation, and susceptibility to senolytics—though the review stresses that p21 has non-cell-cycle roles, p21 can decline in late senescence, and p16 can be upregulated in non-senescent contexts.

Methods

  • Narrative review; no primary data, sample, or statistical analysis is reported.
  • Synthesizes literature on microglial phenotypes in homeostasis, aging, ND, and TBI, and evaluates candidate senescence assays (SA-β-gal, Sudan Black B/lipofuscin, p16/p21, EdU proliferation tracking, single-cell RNA sequencing, senescence gene ontology pathway analysis, and senolytic response).
  • Cites the International Cell Senescence Association recommendation (cell-cycle arrest, macromolecular damage, deregulated metabolism, SASP) and a separate two-step senescence assessment algorithm as proposed frameworks.

Limitations

  • Stated by the paper: no single unambiguous senescence biomarker exists; SASP composition varies by cell type, senescence inducer, and senescence stage, and overlaps with the secretome of non-senescent activated microglia; SA-β-gal may be non-specific in microglia due to phagocytic/lysosomal activity; single-cell studies are highly sensitive to model, isolation, and preparation method and often lack functional validation; evidence for microglial senescence after TBI remains preliminary; the specificity of Sudan Black B in microglia is not thoroughly investigated.
  • Evident from the text: the review is conceptual and proposes criteria rather than testing them, so the central claim that senescence is a distinct microglial state remains a postulate ("We postulate that senescence is a distinct cellular state") rather than a demonstrated finding; the authors also note that current senolytics have potential off-target effects and that correct dose/class for selective microglial clearance is undetermined.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1111/febs.16315

Cites

172 of 172 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 155 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Senescent cells produce a distinct inflammatory secretome.

    “Senescent cells produce a distinct inflammatory secretome and have been found to accumulate with age and in many diseases; potentially contributing to pathology [17–21].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [17] Childs BG, Gluscevic M, Baker DJ, Laberge R-M, Marquess D, Dananberg J & van Deursen JM (2017) Senescent cells: an emerging target for diseases of ageing. Nat Rev Drug Discov 16, 718– 735. 28729727 PMC5942225 source

      Not checked in the free run.

    • cites [18] Sharpless NE & Sherr CJ (2015) Forging a signature of in vivo senescence. Nature Reviews Cancer 15, 397– 408. 26105537 source

      Not checked in the free run.

    • cites [19] Campisi J & Robert L (2014) Cell senescence: Role in aging and age-related diseases. In Aging: Facts and Theories pp. 45– 61. S. Karger AG. PMC4211612 24862014 source

      Not checked in the free run.

    • cites [20] Baker DJ & Petersen RC (2018) Cellular senescence in brain aging and neurodegenerative diseases: evidence and perspectives. J Clin Invest 128, 1208– 1216. 29457783 PMC5873891 source

      Not checked in the free run.

    • cites [21] Guerrero A, De Strooper B & Arancibia-Cárcamo IL (2021) Cellular senescence at the crossroads of inflammation and Alzheimer’s disease. Trends Neurosci, S0166–2236(21)00119–3. 34366147 source

      Not checked in the free run.

  • Premisecitation

    Aged microglia in humans and mice adopt a pro-inflammatory profile including higher expression of TNFα, IL-6, IL-1β, and markers of priming such as CD11b and MHC-II.

    “In both humans [62] and mice [52,63,64], aged microglia adopt a pro-inflammatory profile including higher expression of genes including TNFα, IL-6, and IL-1β, as well as markers of ‘priming’ such as CD11b and MHC-II (Figure 1).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [62] Primiani CT, Ryan VH, Rao JS, Cam MC, Ahn K, Modi HR & Rapoport SI (2014) Coordinated gene expression of neuroinflammatory and cell signaling markers in dorsolateral prefrontal cortex during human brain development and aging. PLoS One 9, e110972. 25329999 PMC4203852 source

      Not checked in the free run.

    • cites [52] Sierra A, Gottfried-Blackmore AC, McEwen BS & Bulloch K (2007) Microglia derived from aging mice exhibit an altered inflammatory profile. Glia 55, 412– 424. 17203473 source

      Not checked in the free run.

    • cites [63] Henry CJ, Huang Y, Wynne AM & Godbout JP (2009) Peripheral lipopolysaccharide (LPS) challenge promotes microglial hyperactivity in aged mice that is associated with exaggerated induction of both pro-inflammatory IL-1β and anti-inflammatory IL-10 cytokines. Brain, Behavior, and Immunity 23, 309– 317. 18814846 PMC2692986 source

      Not checked in the free run.

    • cites [64] Hart AD, Wyttenbach A, Perry VH & Teeling JL (2012) Age related changes in microglial phenotype vary between CNS regions: grey versus white matter differences. Brain Behav Immun 26, 754– 765. 22155499 PMC3381227 source

      Not checked in the free run.

  • Premisecitation

    Accumulation of microglia with a dystrophic appearance or de-ramified microglia with cytoplasmic fragmentations has been noted in aged human brains.

    “An accumulation of microglia with a ‘dystrophic’ appearance or de-ramified microglia with cytoplasmic fragmentations have been noted in aged human brains [42,51].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [42] Streit WJ, Sammons NW, Kuhns AJ & Sparks DL (2004) Dystrophic Microglia in the Aging Human Brain. GLIA 45, 208– 212. 14730714 source

      Not checked in the free run.

    • cites [51] Flanary BE, Sammons NW, Nguyen C, Walker D & Streit WJ (2007) Evidence That Aging And Amyloid Promote Microglial Cell Senescence. Rejuvenation Research 10, 61– 74. 17378753 source

      Not checked in the free run.

  • Premisecitation

    In a reactionary or dystrophic state, microglia contribute to the pathogenesis of various NDs and post-TBI syndromes.

    “However, in a reactionary or dystrophic state, microglia also contribute to the pathogenesis of various NDs and post-TBI syndromes [43–45].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [43] Hansen DV, Hanson JE & Sheng M (2018) Microglia in Alzheimer’s disease. J Cell Biol 217, 459– 472. 29196460 PMC5800817 source

      Not checked in the free run.

    • cites [44] Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, David E, Baruch K, Lara-Astaiso D, Toth B, Itzkovitz S, Colonna M, Schwartz M & Amit I (2017) A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease. Cell 169, 1276– 1290.e17. 28602351 source

      Not checked in the free run.

    • cites [45] Hammond TR, Dufort C, Dissing-Olesen L, Giera S, Young A, Wysoker A, Walker AJ, Gergits F, Segel M, Nemesh J, Marsh SE, Saunders A, Macosko E, Ginhoux F, Chen J, Franklin RJM, Piao X, McCarroll SA & Stevens B (2019) Single-Cell RNA Sequencing of Microglia throughout the Mouse Lifespan and in the Injured Brain Reveals Complex Cell-State Changes. Immunity 50, 253– 271.e6. 30471926 PMC6655561 source

      Not checked in the free run.

  • Interpretationcitation

    The overlapping phenotypes of reactive and senescent microglia, together with heterogeneity of microglial phenotypes in aging and disease, present a challenge to defining senescent microglia and parsing their contribution to dysfunction.

    “The overlapping phenotypes of reactive and senescent microglia together with the heterogeneity of microglial phenotypes described in aging and disease [45,46] present a nuanced challenge to defining senescent microglia and parsing out their contribution to dysfunction.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [45] Hammond TR, Dufort C, Dissing-Olesen L, Giera S, Young A, Wysoker A, Walker AJ, Gergits F, Segel M, Nemesh J, Marsh SE, Saunders A, Macosko E, Ginhoux F, Chen J, Franklin RJM, Piao X, McCarroll SA & Stevens B (2019) Single-Cell RNA Sequencing of Microglia throughout the Mouse Lifespan and in the Injured Brain Reveals Complex Cell-State Changes. Immunity 50, 253– 271.e6. 30471926 PMC6655561 source

      Not checked in the free run.

    • cites [46] Greenwood EK & Brown DR (2021) Senescent microglia: The key to the ageing brain? International Journal of Molecular Sciences 22. PMC8122783 33922383 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. 18
  • May combine two claims. 34

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Cellular senescence is a stable growth arrest often accompanied by a distinctive pro-inflammatory secretory phenotype.

    “These insults may include cellular senescence, a stable growth arrest often accompanied by the production of a distinctive pro-inflammatory secretory phenotype”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Chronological aging, disease onset, or traumatic injury promotes irreparable damage or deregulated signaling that reinforces neurotoxic phenotypes in microglia.

    “Chronological aging, disease onset, or traumatic injury promotes irreparable damage or deregulated signaling to reinforce neurotoxic phenotypes in microglia.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Senescence is a cellular state of irreversible cell-cycle arrest induced by expression of p21 and/or p16.

    “Senescence describes a cellular state where an irreversible cell-cycle arrest is induced by the expression of cyclin-dependent kinase inhibitors Cdkn1a (p21CIP1, hereafter p21) and/or Cdkn2a (p16INK4a, hereafter p16) [14–16].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [14] Stein GH, Drullinger LF, Soulard A & Dulić V (1999) Differential roles for cyclin-dependent kinase inhibitors p21 and p16 in the mechanisms of senescence and differentiation in human fibroblasts. Mol Cell Biol 19, 2109– 2117. 10022898 PMC84004 source

      Not checked in the free run.

    • cites [15] Herbig U, Jobling WA, Chen BPC, Chen DJ & Sedivy JM (2004) Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a). Mol Cell 14, 501– 513. 15149599 source

      Not checked in the free run.

    • cites [16] Serrano M, Lin AW, McCurrach ME, Beach D & Lowe SW (1997) Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593– 602. 9054499 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Senescent cells accumulate with age and in many diseases, potentially contributing to pathology.

    “Senescent cells produce a distinct inflammatory secretome and have been found to accumulate with age and in many diseases; potentially contributing to pathology [17–21].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [17] Childs BG, Gluscevic M, Baker DJ, Laberge R-M, Marquess D, Dananberg J & van Deursen JM (2017) Senescent cells: an emerging target for diseases of ageing. Nat Rev Drug Discov 16, 718– 735. 28729727 PMC5942225 source

      Not checked in the free run.

    • cites [18] Sharpless NE & Sherr CJ (2015) Forging a signature of in vivo senescence. Nature Reviews Cancer 15, 397– 408. 26105537 source

      Not checked in the free run.

    • cites [19] Campisi J & Robert L (2014) Cell senescence: Role in aging and age-related diseases. In Aging: Facts and Theories pp. 45– 61. S. Karger AG. PMC4211612 24862014 source

      Not checked in the free run.

    • cites [20] Baker DJ & Petersen RC (2018) Cellular senescence in brain aging and neurodegenerative diseases: evidence and perspectives. J Clin Invest 128, 1208– 1216. 29457783 PMC5873891 source

      Not checked in the free run.

    • cites [21] Guerrero A, De Strooper B & Arancibia-Cárcamo IL (2021) Cellular senescence at the crossroads of inflammation and Alzheimer’s disease. Trends Neurosci, S0166–2236(21)00119–3. 34366147 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Vascular and endothelial cells of the blood-brain barrier have demonstrated senescence properties.

    “Vascular and endothelial cells of the blood-brain barrier have also demonstrated senescence properties [37,38].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [37] Kiss T, Nyúl-Tóth Á, Balasubramanian P, Tarantini S, Ahire C, DelFavero J, Yabluchanskiy A, Csipo T, Farkas E, Wiley G, Garman L, Csiszar A & Ungvari Z (2020) Single-cell RNA sequencing identifies senescent cerebromicrovascular endothelial cells in the aged mouse brain. Geroscience 42, 429– 444. 32236824 PMC7205992 source

      Not checked in the free run.

    • cites [38] Rojas-Vázquez S, Blasco-Chamarro L, López-Fabuel I, Martínez-Máñez R & Fariñas I (2021) Vascular Senescence: A Potential Bridge Between Physiological Aging and Neurogenic Decline. Front Neurosci 15, 666881. 33958987 PMC8093510 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Multiple cell types likely become senescent in complex diseases, complicating the cause-effect relationship between specific senescent populations and disease processes.

    “It is also likely that multiple cell types become senescent in complex diseases, which further complicates the cause-effect relationship between specific populations of senescent cells and disease processes.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Microglia are the resident mononuclear phagocytes of the CNS and play key roles in immune surveillance and defense, synaptic remodeling, and homeostasis.

    “Microglia, the resident mononuclear phagocytes of the CNS, play key roles in immune surveillance and defense [39], synaptic remodeling [40], and homeostasis [41].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [39] Yang I, Han SJ, Kaur G, Crane C & Parsa AT (2010) The Role of Microglia in Central Nervous System Immunity and Glioma Immunology. J Clin Neurosci 17, 6– 10. 19926287 PMC3786731 source

      Not checked in the free run.

    • cites [40] Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, Ransohoff RM, Greenberg ME, Barres BA & Stevens B (2012) Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74, 691– 705. 22632727 PMC3528177 source

      Not checked in the free run.

    • cites [41] Ginhoux F & Prinz M (2015) Origin of microglia: Current concepts and past controversies. Cold Spring Harbor Perspectives in Biology 7. PMC4526747 26134003 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The International Cell Senescence Association recommends determining the presence of senescence by a combination of cell-cycle arrest, macromolecular damage, deregulated metabolism, and production of a SASP.

    “the International Cell Senescence Association recently put forth a recommendation for determining the presence of senescence, describing a combination of cell-cycle arrest, macromolecular damage, deregulated metabolism, and the production of a senescent-associated secretory phenotype (SASP) [25].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Gorgoulis V, Adams PD, Alimonti A, Bennett DC, Bischof O, Bishop C, Campisi J, Collado M, Evangelou K, Ferbeyre G, Gil J, Hara E, Krizhanovsky V, Jurk D, Maier AB, Narita M, Niedernhofer L, Passos JF, Robbins PD, Schmitt CA, Sedivy J, Vougas K, von Zglinicki T, Zhou D, Serrano M & Demaria M (2019) Cellular Senescence: Defining a Path Forward. Cell 179, 813– 827. 31675495 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microglia have been identified as a putative senescent population in natural aging in humans and mice, mouse models of AD pathology, and in TBI.

    “They have also been identified as a putative senescent population in natural aging in both humans [42] and mice [27], mouse models of AD pathology [26], and in TBI [28,29].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [42] Streit WJ, Sammons NW, Kuhns AJ & Sparks DL (2004) Dystrophic Microglia in the Aging Human Brain. GLIA 45, 208– 212. 14730714 source

      Not checked in the free run.

    • cites [27] Ogrodnik M, Evans SA, Fielder E, Victorelli S, Kruger P, Salmonowicz H, Weigand BM, Patel AD, Pirtskhalava T, Inman CL, Johnson KO, Dickinson SL, Rocha A, Schafer MJ, Zhu Y, Allison DB, von Zglinicki T, LeBrasseur NK, Tchkonia T, Neretti N, Passos JF, Kirkland JL & Jurk D (2021) Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice. Aging Cell 20, e13296– e13296. 33470505 PMC7884042 source

      Not checked in the free run.

    • cites [26] Bussian TJ, Aziz A, Meyer CF, Swenson BL, van Deursen JM & Baker DJ (2018) Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature 562, 578– 582. 30232451 PMC6206507 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Senescence is heterogeneous: a variety of insults may incite senescence, the inflammatory secretory phenotype is modified depending on cell type, and the senescent phenotype may change based on the stage of senescence.

    “A challenge in targeting senescence is the apparent heterogeneity of this cellular state, wherein a variety of insults may incite senescence, the inflammatory secretory phenotype is modified depending on cell type, and the senescent phenotype may even change based on the stage of senescence [22–24].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [22] Wiley CD, Flynn JM, Morrissey C, Lebofsky R, Shuga J, Dong X, Unger MA, Vijg J, Melov S & Campisi J (2017) Analysis of individual cells identifies cell-to-cell variability following induction of cellular senescence. Aging Cell 16, 1043– 1050. 28699239 PMC5595671 source

      Not checked in the free run.

    • cites [23] Childs BG, Durik M, Baker DJ & Van Deursen JM (2015) Cellular senescence in aging and age-related disease: From mechanisms to therapy. Nature Medicine 21, 1424– 1435. PMC4748967 26646499 source

      Not checked in the free run.

    • cites [24] Kohli J, Wang B, Brandenburg SM, Basisty N, Evangelou K, Varela-Eirin M, Campisi J, Schilling B, Gorgoulis V & Demaria M (2021) Algorithmic assessment of cellular senescence in experimental and clinical specimens. Nat Protoc 16, 2471– 2498. 33911261 PMC8710232 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aged microglia tend to accumulate lipofuscin, which has been associated with dysfunction and inflammation.

    “Aged microglia also tend to accumulate lipofuscin [52–54], aggregations of highly oxidized proteins cross-linked with sugars and lipids [55], which have been associated with dysfunction and inflammation [56,57].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [52] Sierra A, Gottfried-Blackmore AC, McEwen BS & Bulloch K (2007) Microglia derived from aging mice exhibit an altered inflammatory profile. Glia 55, 412– 424. 17203473 source

      Not checked in the free run.

    • cites [53] Tremblay M-È, Zettel ML, Ison JR, Allen PD & Majewska AK (2012) Effects of aging and sensory loss on glial cells in mouse visual and auditory cortices. Glia 60, 541– 558. 22223464 PMC3276747 source

      Not checked in the free run.

    • cites [54] Xu H, Chen M, Manivannan A, Lois N & Forrester JV (2008) Age-dependent accumulation of lipofuscin in perivascular and subretinal microglia in experimental mice. Aging Cell 7, 58– 68. 17988243 source

      Not checked in the free run.

    • cites [56] Ma W, Coon S, Zhao L, Fariss RN & Wong WT (2013) A2E accumulation influences retinal microglial activation and complement regulation. Neurobiology of Aging 34, 943– 960. 22819137 PMC3480997 source

      Not checked in the free run.

    • cites [57] Singh Kushwaha S, Patro N & Kumar Patro I (2018) A Sequential Study of Age-Related Lipofuscin Accumulation in Hippocampus and Striate Cortex of Rats. AON 25, 223– 233. PMC6470335 31000961 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Putative senescent states have been suggested in microglia, neurons, astrocytes, and oligodendrocyte progenitor cells with aging and in various disease contexts.

    “Putative senescent states have been suggested in a variety of neural subpopulations with aging and in various disease contexts, including microglia [26–30], neurons [31–33], astrocytes [26,34,35], and oligodendrocyte progenitor cells [36].”
    Quote in the paperSubstantial claim0 of 9 sources checked
    • cites [26] Bussian TJ, Aziz A, Meyer CF, Swenson BL, van Deursen JM & Baker DJ (2018) Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature 562, 578– 582. 30232451 PMC6206507 source

      Not checked in the free run.

    • cites [27] Ogrodnik M, Evans SA, Fielder E, Victorelli S, Kruger P, Salmonowicz H, Weigand BM, Patel AD, Pirtskhalava T, Inman CL, Johnson KO, Dickinson SL, Rocha A, Schafer MJ, Zhu Y, Allison DB, von Zglinicki T, LeBrasseur NK, Tchkonia T, Neretti N, Passos JF, Kirkland JL & Jurk D (2021) Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice. Aging Cell 20, e13296– e13296. 33470505 PMC7884042 source

      Not checked in the free run.

    • cites [28] Schwab N, Ju Y & Hazrati LN (2021) Early onset senescence and cognitive impairment in a murine model of repeated mTBI. Acta Neuropathologica Communications, 1– 27. 33964983 PMC8106230 source

      Not checked in the free run.

    • cites [29] Ritzel RM, Doran SJ, Glaser EP, Meadows VE, Faden AI, Stoica BA & Loane DJ (2019) Old age increases microglial senescence, exacerbates secondary neuroinflammation, and worsens neurological outcomes after acute traumatic brain injury in mice. Neurobiol Aging 77, 194– 206. 30904769 PMC6486858 source

      Not checked in the free run.

    • cites [30] Hu Y, Fryatt GL, Ghorbani M, Obst J, Menassa DA, Martin-Estebane M, Muntslag TAO, Olmos-Alonso A, Guerrero-Carrasco M, Thomas D, Cragg MS & Gomez-Nicola D (2021) Replicative senescence dictates the emergence of disease-associated microglia and contributes to Aβ pathology. Cell Rep 35, 109228. 34107254 PMC8206957 source

      Not checked in the free run.

    • cites [31] Jurk D, Wang C, Miwa S, Maddick M, Korolchuk V, Tsolou A, Gonos ES, Thrasivoulou C, Saffrey MJ, 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. 22882466 PMC3533793 source

      Not checked in the free run.

    • cites [32] 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. 20457127 source

      Not checked in the free run.

    • cites [33] Musi N, Valentine JM, Sickora KR, Baeuerle E, Thompson CS, Shen Q & Orr ME (2018) Tau protein aggregation is associated with cellular senescence in the brain. Aging Cell 17, 12840– 12840. PMC6260915 30126037 source

      Not checked in the free run.

    • cites [36] Zhang P, Kishimoto Y, Grammatikakis loannis, Gottimukkala K, Cutler RG, Zhang S, Abdelmohsen K, Bohr VA, Sen JM, Gorospe M & Mattson MP (2019) Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nat Neurosci 22, 719– 728. 30936558 PMC6605052 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    An accumulation of senescent microglia with age has been shown in rodents both in vivo and ex vivo, although evidence in aged human brains is limited.

    “An accumulation of senescent microglia with age has been shown in rodents both in vivo [72] and ex vivo [51,72], although the evidence of senescent microglia accumulation in aged human brains is limited [42].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [72] Stojiljkovic MR, Ain Q, Bondeva T, Heller R, Schmeer C & Witte OW (2019) Phenotypic and functional differences between senescent and aged murine microglia. Neurobiology of Aging 74, 56– 69. 30439594 source

      Not checked in the free run.

    • cites [51] Flanary BE, Sammons NW, Nguyen C, Walker D & Streit WJ (2007) Evidence That Aging And Amyloid Promote Microglial Cell Senescence. Rejuvenation Research 10, 61– 74. 17378753 source

      Not checked in the free run.

    • cites [42] Streit WJ, Sammons NW, Kuhns AJ & Sparks DL (2004) Dystrophic Microglia in the Aging Human Brain. GLIA 45, 208– 212. 14730714 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Microglia could mechanistically contribute to ND through aberrant synaptic pruning via the complement system.

    “It has also been suggested that microglia could mechanistically contribute to ND through aberrant synaptic pruning via the complement system [81].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [81] Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, Merry KM, Shi Q, Rosenthal A, Barres BA, Lemere CA, Selkoe DJ & Stevens B (2016) Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352, 712– 716. 27033548 PMC5094372 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the minutes following TBI, microglia are recruited via purinergic signaling to clear necrotic debris and adopt a phagocytic state.

    “In the minutes following TBI, microglia are recruited via purinergic signaling to clear necrotic debris and adopt a phagocytic state [100,107,108].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [100] Loane DJ, Kumar A, Stoica BA, Cabatbat R & Faden AI (2014) Progressive neurodegeneration after experimental brain trauma: association with chronic microglial activation. J Neuropathol Exp Neurol 73, 14– 29. 24335533 PMC4267248 source

      Not checked in the free run.

    • cites [107] Roth TL, Nayak D, Atanasijevic T, Koretsky AP, Latour LL & McGavern DB (2014) Transcranial amelioration of inflammation and cell death after brain injury. Nature 505, 223– 228. 24317693 PMC3930079 source

      Not checked in the free run.

    • cites [108] Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, Littman DR, Dustin ML & Gan W-B (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 8, 752– 758. 15895084 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    As time passes following primary injury, neuroprotective functions are lost, and microglia become the prime motivators of neuroinflammatory gene expression in the post-TBI brain.

    “However, as time passes following the primary injury the neuroprotective functions are lost, and microglia become the prime motivators of neuroinflammatory gene expression in the post-TBI brain [112].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [112] Witcher KG, Bray CE, Chunchai T, Zhao F, O’Neil SM, Gordillo AJ, Campbell WA, McKim DB, Liu X, Dziabis JE, Quan N, Eiferman DS, Fischer AJ, Kokiko-Cochran ON, Askwith C & Godbout JP (2021) Traumatic Brain Injury Causes Chronic Cortical Inflammation and Neuronal Dysfunction Mediated by Microglia. J Neurosci 41, 1597– 1616. 33452227 PMC7896020 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The mode of microglial activation following TBI is somewhat age-dependent and may be less neuroprotective and more toxic in older animals.

    “The mode of activation following TBI is somewhat age-dependent and may be less neuroprotective and more toxic in older animals [109].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [109] Kumar A, Stoica BA, Sabirzhanov B, Burns MP, Faden AI & Loane DJ (2013) Traumatic brain injury in aged animals increases lesion size and chronically alters microglial/macrophage classical and alternative activation states. Neurobiol Aging 34, 1397– 1411. 23273602 PMC3572914 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the initial week following injury, the microglia population adopts a balanced distribution between pro- and anti-inflammatory states to promote neurogenesis and enhance the immune response to injury.

    “In the initial week following injury, the microglia population adopts a balanced distribution between pro- and anti-inflammatory states to promote neurogenesis and enhance the immune response to injury [89,110,111].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [89] Song W, Hooli B, Mullin K, Jin SC, Cella M, Ulland TK, Wang Y, Tanzi RE & Colonna M (2017) Alzheimer’s disease-associated TREM2 variants exhibit either decreased or increased ligand-dependent activation. Alzheimers Dement 13, 381– 387. 27520774 PMC5299056 source

      Not checked in the free run.

    • cites [110] Turtzo LC, Lescher J, Janes L, Dean DD, Budde MD & Frank JA (2014) Macrophagic and microglial responses after focal traumatic brain injury in the female rat. J Neuroinflammation 11, 82. 24761998 PMC4022366 source

      Not checked in the free run.

    • cites [111] Wang G, Zhang J, Hu X, Zhang L, Mao L, Jiang X, Liou AK-F, Leak RK, Gao Y & Chen J (2013) Microglia/macrophage polarization dynamics in white matter after traumatic brain injury. J Cereb Blood Flow Metab 33, 1864– 1874. 23942366 PMC3851898 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Downregulation of homeostatic genes Tmem119, P2ry12, and Cx3cr1 has been identified in many murine models representing AD, ALS, and multiple sclerosis, suggesting similar signaling pathways are present.

    “The downregulation of genes associated with microglial homeostasis, Tmem119, P2ry12, and Cx3cr1, have been identified in many murine models representing AD [44,77–80], amyotrophic lateral sclerosis (ALS) [44,77,79], and multiple sclerosis [79]; suggesting similar signaling pathways are present.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [44] Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, David E, Baruch K, Lara-Astaiso D, Toth B, Itzkovitz S, Colonna M, Schwartz M & Amit I (2017) A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease. Cell 169, 1276– 1290.e17. 28602351 source

      Not checked in the free run.

    • cites [77] Holtman IR, Raj DD, Miller JA, Schaafsma W, Yin Z, Brouwer N, Wes PD, Möller T, Orre M, Kamphuis W, Hol EM, Boddeke EW & Eggen BJ (2015) Induction of a common microglia gene expression signature by aging and neurodegenerative conditions: a co-expression meta-analysis. Acta neuropathologica communications 3, 31. 26001565 PMC4489356 source

      Not checked in the free run.

    • cites [78] Friedman BA, Srinivasan K, Ayalon G, Meilandt WJ, Lin H, Huntley MA, Cao Y, Lee S-H, Haddick PCG, Ngu H, Modrusan Z, Larson JL, Kaminker JS, van der Brug MP & Hansen DV (2018) Diverse Brain Myeloid Expression Profiles Reveal Distinct Microglial Activation States and Aspects of Alzheimer’s Disease Not Evident in Mouse Models. Cell Reports 22, 832– 847. 29346778 source

      Not checked in the free run.

    • cites [79] Krasemann S, Madore C, Cialic R, Baufeld C, Calcagno N, El Fatimy R, Beckers L, O’Loughlin E, Xu Y, Fanek Z, Greco DJ, Smith ST, Tweet G, Humulock Z, Zrzavy T, Conde-Sanroman P, Gacias M, Weng Z, Chen H, Tjon E, Mazaheri F, Hartmann K, Madi A, Ulrich JD, Glatzel M, Worthmann A, Heeren J, Budnik B, Lemere C, Ikezu T, Heppner FL, Litvak V, Holtzman DM, Lassmann H, Weiner HL, Ochando J, Haass C & Butovsky O (2017) The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases. Immunity 47, 566– 581.e9. 28930663 PMC5719893 source

      Not checked in the free run.

    • cites [80] Sobue A, Komine O, Hara Y, Endo F, Mizoguchi H, Watanabe S, Murayama S, Saito T, Saido TC, Sahara N, Higuchi M, Ogi T & Yamanaka K (2021) Microglial gene signature reveals loss of homeostatic microglia associated with neurodegeneration of Alzheimer’s disease. Acta Neuropathologica Communications 9, 1. 33402227 PMC7786928 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Whole-body clearance of p16-expressing cells in a mouse model of tauopathy led to amelioration of disease, with microglia identified as a senescent cell population.

    “Whole-body clearance of p16-expressing cells in a mouse model of tauopathy led to an amelioration of disease, with microglia identified as a senescent cell population in this disease model [26].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] Bussian TJ, Aziz A, Meyer CF, Swenson BL, van Deursen JM & Baker DJ (2018) Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature 562, 578– 582. 30232451 PMC6206507 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TBI is a biphasic injury: after the mechanical primary injury, a secondary dystrophic state produces long-term dysfunction including elevated neuroinflammation due to blood-brain barrier disruption, increased oxidative stress, and persistent changes in the microglial population.

    “TBI is a biphasic injury: after the mechanical primary injury, a secondary dystrophic state produces long-term dysfunction in the brain that includes elevated neuroinflammation as a result of blood-brain barrier disruption, increased oxidative stress, and persistent changes in the microglial population [100–106].”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [100] Loane DJ, Kumar A, Stoica BA, Cabatbat R & Faden AI (2014) Progressive neurodegeneration after experimental brain trauma: association with chronic microglial activation. J Neuropathol Exp Neurol 73, 14– 29. 24335533 PMC4267248 source

      Not checked in the free run.

    • cites [101] Gentleman SM, Leclercq PD, Moyes L, Graham DI, Smith C, Griffin WST & Nicoll JAR (2004) Long-term intracerebral inflammatory response after traumatic brain injury. Forensic Science International 146, 97– 104. 15542269 source

      Not checked in the free run.

    • cites [102] Johnson VE, Stewart JE, Begbie FD, Trojanowski JQ, Smith DH & Stewart W (2013) Inflammation and white matter degeneration persist for years after a single traumatic brain injury. Brain 136, 28– 42. 23365092 PMC3562078 source

      Not checked in the free run.

    • cites [103] Soares HD, Hicks RR, Smith D & McIntosh TK (1995) Inflammatory leukocytic recruitment and diffuse neuronal degeneration are separate pathological processes resulting from traumatic brain injury. J Neurosci 15, 8223– 8233. 8613756 PMC6577921 source

      Not checked in the free run.

    • cites [104] Nonaka M, Chen XH, Pierce JE, Leoni MJ, McIntosh TK, Wolf JA & Smith DH (1999) Prolonged activation of NF-kappaB following traumatic brain injury in rats. J Neurotrauma 16, 1023– 1034. 10595819 source

      Not checked in the free run.

    • cites [105] Nagamoto-Combs K, McNeal DW, Morecraft RJ & Combs CK (2007) Prolonged microgliosis in the rhesus monkey central nervous system after traumatic brain injury. J Neurotrauma 24, 1719– 1742. 18001202 source

      Not checked in the free run.

    • cites [106] Clarke GJB, Skandsen T, Zetterberg H, Einarsen CE, Feyling C, Follestad T, Vik A, Blennow K & Håberg AK (2021) One-Year Prospective Study of Plasma Biomarkers From CNS in Patients With Mild Traumatic Brain Injury. Front Neurol 12, 643743. 33967940 PMC8097004 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The primed state is thought to make aged microglia disproportionately reactive to immunological challenges, leading to prolonged neuroinflammation and cognitive deficits associated with age.

    “This state of ‘priming’ is thought to make aged microglia disproportionately reactive to immunological challenges, leading to prolonged neuroinflammation and the cognitive deficits associated with age [65,66].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [65] Norden DM & Godbout JP (2013) Microglia of the Aged Brain: Primed to be Activated and Resistant to Regulation. Neuropathol Appl Neurobiol 39, 19– 34. 23039106 PMC3553257 source

      Not checked in the free run.

    • cites [66] Perry VH & Holmes C (2014) Microglial priming in neurodegenerative disease. Nat Rev Neurol 10, 217– 224. 24638131 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A SASP factor specific to senescent microglia has not been identified, and several components of the SASP can be attributed to the secreted inflammatory milieu of non-senescent 'activated' microglia.

    “However, a SASP factor specific to senescent microglia has not been identified, and several components of the SASP can be attributed to the secreted inflammatory milieu of non-senescent ‘activated’ microglia [93].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [93] Wyss-Coray T & Rogers J (2012) Inflammation in Alzheimer Disease—A Brief Review of the Basic Science and Clinical Literature. Cold Spring Harb Perspect Med 2, a006346. 22315714 PMC3253025 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Sudan Black B has a high overlap with SA-β-gal staining, which is relevant in contexts where SA-β-gal is not suitable such as formalin-fixed, paraffin-embedded tissues, or in microglia where SA-β-gal is likely to stain false positive.

    “It has been suggested that Sudan Black B has a high overlap with SA-β-gal staining, which is especially relevant in contexts where the latter is not suitable such as in formalin-fixed, paraffin-embedded tissues [151,152], or in microglia where SA-β-gal is likely to stain false positive.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [151] Georgakopoulou E, Tsimaratou K, Evangelou K, Fernandez M-P, Zoumpourlis V, Trougakos I, Kletsas D, Bartek J, Serrano M & Gorgoulis V (2012) Specific lipofuscin staining as a novel biomarker to detect replicative and stress-induced senescence. A method applicable in cryo-preserved and archival tissues. Aging (Albany NY) 5, 37– 50. PMC3616230 23449538 source

      Not checked in the free run.

    • cites [152] Myrianthopoulos V, Evangelou K, Vasileiou PVS, Cooks T, Vassilakopoulos TP, Pangalis GA, Kouloukoussa M, Kittas C, Georgakilas AG & Gorgoulis VG (2019) Senescence and senotherapeutics: a new field in cancer therapy. Pharmacology & Therapeutics 193, 31– 49. 30121319 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Increased ferritin accumulation in human microglia in ND but not old age has been suggested, and altered iron homeostasis has been proposed as a distinguishing factor between aged 'healthy' microglia and those associated with neurodegeneration.

    “One study by Shahidehpour et al. suggests that there is increased ferritin accumulation in human microglia in ND but not old age, and proposed altered iron homeostasis as a distinguishing factor between aged ‘healthy’ microglia and those associated with neurodegeneration [132].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [132] Shahidehpour RK, Higdon RE, Crawford NG, Neltner JH, Ighodaro ET, Patel E, Price D, Nelson PT & Bachstetter AD (2021) Dystrophic microglia are associated with neurodegenerative disease and not healthy aging in the human brain. Neurobiol Aging 99, 19– 27. 33422891 PMC8293930 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    There is a large overlap between microglial phenotypes in aging, neurodegenerative disease, and injury - mainly a loss of homeostasis and a pro-inflammatory phenotype.

    “There is a large overlap between microglial phenotypes in aging, neurodegenerative disease, and injury – mainly a loss of homeostasis and a pro-inflammatory phenotype.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The SASP can differ based on cell type, cause of senescence, or even stage of senescence.

    “To add extra confusion, the SASP can also differ based on cell type, cause of senescence, or even stage of senescence [37,95].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [37] Kiss T, Nyúl-Tóth Á, Balasubramanian P, Tarantini S, Ahire C, DelFavero J, Yabluchanskiy A, Csipo T, Farkas E, Wiley G, Garman L, Csiszar A & Ungvari Z (2020) Single-cell RNA sequencing identifies senescent cerebromicrovascular endothelial cells in the aged mouse brain. Geroscience 42, 429– 444. 32236824 PMC7205992 source

      Not checked in the free run.

    • cites [95] Coppé J-P, Desprez P-Y, Krtolica A & Campisi J (2010) The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol 5, 99– 118. 20078217 PMC4166495 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Increased cellular iron accumulation has been posited as a feature of senescence, although it is not critical to maintaining this fate.

    “Additionally, increased cellular iron accumulation has been posited as a feature of senescence, although it’s not critical to maintaining this fate [136,137].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [136] Masaldan S, Clatworthy SAS, Gamell C, Meggyesy PM, Rigopoulos A-T, Haupt S, Haupt Y, Denoyer D, Adlard PA, Bush AI & Cater MA (2017) Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis. Redox Biol 14, 100– 115. 28888202 PMC5596264 source

      Not checked in the free run.

    • cites [137] Killilea DW, Wong SL, Cahaya HS, Atamna H & Ames BN (2004) Iron accumulation during cellular senescence. Ann N Y Acad Sci 1019, 365– 367. 15247045 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Microglia associated with the long-term inflammatory phenotype following TBI are commonly defined as MHC-II/CD86/Cd11b positive, with upregulated expression of NOX24, Tlr4, Trem2, CD68, Clec7a, and Stat1, and higher expression of interferon- and immune-associated signaling genes.

    “Microglia associated with the long-term inflammatory phenotype following TBI are commonly defined as MHC-II/CD86/Cd11b positive, with upregulated expression of NOX24, Tlr4, Trem2, CD68, Clec7a, and Stat1, and higher expression of interferon- and immune-associated signaling genes [100,112,115,116].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [100] Loane DJ, Kumar A, Stoica BA, Cabatbat R & Faden AI (2014) Progressive neurodegeneration after experimental brain trauma: association with chronic microglial activation. J Neuropathol Exp Neurol 73, 14– 29. 24335533 PMC4267248 source

      Not checked in the free run.

    • cites [112] Witcher KG, Bray CE, Chunchai T, Zhao F, O’Neil SM, Gordillo AJ, Campbell WA, McKim DB, Liu X, Dziabis JE, Quan N, Eiferman DS, Fischer AJ, Kokiko-Cochran ON, Askwith C & Godbout JP (2021) Traumatic Brain Injury Causes Chronic Cortical Inflammation and Neuronal Dysfunction Mediated by Microglia. J Neurosci 41, 1597– 1616. 33452227 PMC7896020 source

      Not checked in the free run.

    • cites [115] Izzy S, Liu Q, Fang Z, Lule S, Wu L, Chung JY, Sarro-Schwartz A, Brown-Whalen A, Perner C, Hickman SE, Kaplan DL, Patsopoulos NA, El Khoury J & Whalen MJ (2019) Time-Dependent Changes in Microglia Transcriptional Networks Following Traumatic Brain Injury. Front Cell Neurosci 13, 307. 31440141 PMC6694299 source

      Not checked in the free run.

    • cites [116] Jin X, Ishii H, Bai Z, Itokazu T & Yamashita T (2012) Temporal changes in cell marker expression and cellular infiltration in a controlled cortical impact model in adult male C57BL/6 mice. PLoS One 7, e41892. 22911864 PMC3404031 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A study by Hammond et al. identified two microglial populations highly concentrated in aged mice - one defined by Ccl4, and another enriched in several interferon-response genes - and a cluster predominantly in injured mice characterized by Ifi27l2a.

    “For example, a study by Hammond et al. compared microglia from developing, aged, and mice injured from a focal white matter injury and identified two populations highly concentrated in aged mice – one defined by Ccl4, and another enriched in several interferon-response genes [45]. In addition, a cluster predominantly in injured mice characterized by Ifi27l2a was also identified [45].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Hammond TR, Dufort C, Dissing-Olesen L, Giera S, Young A, Wysoker A, Walker AJ, Gergits F, Segel M, Nemesh J, Marsh SE, Saunders A, Macosko E, Ginhoux F, Chen J, Franklin RJM, Piao X, McCarroll SA & Stevens B (2019) Single-Cell RNA Sequencing of Microglia throughout the Mouse Lifespan and in the Injured Brain Reveals Complex Cell-State Changes. Immunity 50, 253– 271.e6. 30471926 PMC6655561 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pharmacological clearance of microglia post-injury in mice is neuroprotective and reduces cognitive impairment.

    “Importantly, a recent study in mice demonstrated pharmacological clearance of microglia post-injury is neuroprotective and reduces cognitive impairment [112].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [112] Witcher KG, Bray CE, Chunchai T, Zhao F, O’Neil SM, Gordillo AJ, Campbell WA, McKim DB, Liu X, Dziabis JE, Quan N, Eiferman DS, Fischer AJ, Kokiko-Cochran ON, Askwith C & Godbout JP (2021) Traumatic Brain Injury Causes Chronic Cortical Inflammation and Neuronal Dysfunction Mediated by Microglia. J Neurosci 41, 1597– 1616. 33452227 PMC7896020 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In vitro, conditioned media derived from microglia in an induced pro-inflammatory M1-like state reduces survival of oligodendrocytes, whereas conditioned media from microglia in an induced anti-inflammatory M2-like state promotes remyelination.

    “In vitro, conditioned media derived from microglia in an induced pro-inflammatory ‘M1-like’ state reduces survival of oligodendrocytes in vitro, whereas conditioned media from microglia in an induced anti-inflammatory ‘M2-like’ state promotes remyelination [111,113].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [111] Wang G, Zhang J, Hu X, Zhang L, Mao L, Jiang X, Liou AK-F, Leak RK, Gao Y & Chen J (2013) Microglia/macrophage polarization dynamics in white matter after traumatic brain injury. J Cereb Blood Flow Metab 33, 1864– 1874. 23942366 PMC3851898 source

      Not checked in the free run.

    • cites [113] Miron VE, Boyd A, Zhao J-W, Yuen TJ, Ruckh JM, Shadrach JL, van Wijngaarden P, Wagers AJ, Williams A, Franklin RJM & Ffrench-Constant C (2013) M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat Neurosci 16, 1211– 1218. 23872599 PMC3977045 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    For now, there is no cellular marker or component of the secretome that is specific for microglia found in aging, disease, or injury.

    “For now, there is no cellular marker or component of the secretome that is specific for microglia found in aging, disease, or injury.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Elevated iron in the CNS is associated with ND, possibly at levels higher than with normal aging.

    “Indeed, elevated iron in the CNS is associated with ND (reviewed in [133] and [134]), possibly at levels higher than with normal aging [133].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [133] Andersen HH, Johnsen KB & Moos T (2014) Iron deposits in the chronically inflamed central nervous system and contributes to neurodegeneration. Cell Mol Life Sci 71, 1607– 1622. 24218010 PMC3983878 source

      Not checked in the free run.

    • cites [134] Zucca FA, Segura-Aguilar J, Ferrari E, Muñoz P, Paris I, Sulzer D, Sarna T, Casella L & Zecca L (2017) Interactions of iron, dopamine and neuromelanin pathways in brain aging and Parkinson’s disease. Prog Neurobiol 155, 96– 119. 26455458 PMC4826627 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Elderly individuals are at greater risk to suffer significant cognitive impairment and early morbidity following TBI, potentially due to an already present dysfunction in the microglial compartment.

    “Elderly individuals are at greater risk to suffer significant cognitive impairment and early morbidity following TBI, potentially due to an already present dysfunction in the microglial compartment [109,122,123].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [109] Kumar A, Stoica BA, Sabirzhanov B, Burns MP, Faden AI & Loane DJ (2013) Traumatic brain injury in aged animals increases lesion size and chronically alters microglial/macrophage classical and alternative activation states. Neurobiol Aging 34, 1397– 1411. 23273602 PMC3572914 source

      Not checked in the free run.

    • cites [122] Hukkelhoven CWPM, Steyerberg EW, Rampen AJJ, Farace E, Habbema JDF, Marshall LF, Murray GD & Maas AIR (2003) Patient age and outcome following severe traumatic brain injury: an analysis of 5600 patients. J Neurosurg 99, 666– 673. 14567601 source

      Not checked in the free run.

    • cites [123] Mak CHK, Wong SKH, Wong GK, Ng S, Wang KKW, Lam PK & Poon WS (2012) Traumatic Brain Injury in the Elderly: Is it as Bad as we Think? Curr Transl Geriatr Exp Gerontol Rep 1, 171– 178. 24014175 PMC3758513 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Non-senescent macrophages may exhibit SA-β-gal positivity, and microglia can also stain positive in non-senescent contexts due to their phagocytic function and possible associated change in lysosomal numbers.

    “In particular, non-senescent macrophages may exhibit SA-β-gal positivity [145,146], and microglia can also stain positive in non-senescent contexts due to their phagocytic function and the possible associated change in lysosomal numbers [147].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [145] Bursuker I, Rhodes JM & Goldman R (1982) Beta-galactosidase--an indicator of the maturational stage of mouse and human mononuclear phagocytes. J Cell Physiol 112, 385– 390. 6813341 source

      Not checked in the free run.

    • cites [146] Frescas D, Hall BM, Strom E, Virtuoso LP, Gupta M, Gleiberman AS, Rydkina E, Balan V, Vujcic S, Chernova OB & Gudkov AV (2017) Murine mesenchymal cells that express elevated levels of the CDK inhibitor p16(Ink4a) in vivo are not necessarily senescent. Cell Cycle 16, 1526– 1533. 28650766 PMC5584871 source

      Not checked in the free run.

    • cites [147] Yegorov YE, Akimov SS, Hass R, Zelenin AV & Prudovsky IA (1998) Endogenous β-Galactosidase Activity in Continuously Nonproliferating Cells. Experimental Cell Research 243, 207– 211. 9716464 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lipofuscin has been shown to accumulate in aged microglia and is generally considered a hallmark of aging.

    “Lipofuscin has been shown to accumulate in aged microglia [52–54], and is generally considered a hallmark of aging [150].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [52] Sierra A, Gottfried-Blackmore AC, McEwen BS & Bulloch K (2007) Microglia derived from aging mice exhibit an altered inflammatory profile. Glia 55, 412– 424. 17203473 source

      Not checked in the free run.

    • cites [53] Tremblay M-È, Zettel ML, Ison JR, Allen PD & Majewska AK (2012) Effects of aging and sensory loss on glial cells in mouse visual and auditory cortices. Glia 60, 541– 558. 22223464 PMC3276747 source

      Not checked in the free run.

    • cites [54] Xu H, Chen M, Manivannan A, Lois N & Forrester JV (2008) Age-dependent accumulation of lipofuscin in perivascular and subretinal microglia in experimental mice. Aging Cell 7, 58– 68. 17988243 source

      Not checked in the free run.

    • cites [150] Terman A & Brunk UT (2004) Lipofuscin. Int J Biochem Cell Biol 36, 1400– 1404. 15147719 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    p21 may have roles outside of cell cycle inhibition and its upregulation is not specific to senescence.

    “For example, p21 may have roles outside of cell cycle inhibition [156] and its upregulation is not specific to senescence [157].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [156] Daszkiewicz L, Vázquez-Mateo C, Rackov G, Ballesteros-Tato A, Weber K, Madrigal-Avilés A, Di Pilato M, Fotedar A, Fotedar R, Flores JM, Esteban M, Martínez-A C & Balomenos D (2015) Distinct p21 requirements for regulating normal and self-reactive T cells through IFN-γ production. Sci Rep 5, 7691. 25573673 PMC4287747 source

      Not checked in the free run.

    • cites [157] de Mera-Rodríguez JA, Álvarez-Hernán G, Gañán Y, Martín-Partido G, Rodríguez-León J & Francisco-Morcillo J (2021) Is Senescence-Associated β-Galactosidase a Reliable in vivo Marker of Cellular Senescence During Embryonic Development? Frontiers in Cell and Developmental Biology 9, 36. PMC7876289 33585480

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    A senescent cell, by definition, is in a state of cell cycle arrest.

    “A senescent cell, by definition, is in a state of cell cycle arrest [25].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] Gorgoulis V, Adams PD, Alimonti A, Bennett DC, Bischof O, Bishop C, Campisi J, Collado M, Evangelou K, Ferbeyre G, Gil J, Hara E, Krizhanovsky V, Jurk D, Maier AB, Narita M, Niedernhofer L, Passos JF, Robbins PD, Schmitt CA, Sedivy J, Vougas K, von Zglinicki T, Zhou D, Serrano M & Demaria M (2019) Cellular Senescence: Defining a Path Forward. Cell 179, 813– 827. 31675495 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A gene specific to cellular senescence has not been identified, and different papers use different marker genes to describe their senescent cell population.

    “A gene specific to cellular senescence also has not been identified, and different papers will use different marker genes to describe their senescent cell population [37,160].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [37] Kiss T, Nyúl-Tóth Á, Balasubramanian P, Tarantini S, Ahire C, DelFavero J, Yabluchanskiy A, Csipo T, Farkas E, Wiley G, Garman L, Csiszar A & Ungvari Z (2020) Single-cell RNA sequencing identifies senescent cerebromicrovascular endothelial cells in the aged mouse brain. Geroscience 42, 429– 444. 32236824 PMC7205992 source

      Not checked in the free run.

    • cites [160] Chen W, Wang X, Wei G, Huang Y, Shi Y, Li D, Qiu S, Zhou B, Cao J, Chen M, Qin P, Jin W & Ni T (2020) Single-Cell Transcriptome Analysis Reveals Six Subpopulations Reflecting Distinct Cellular Fates in Senescent Mouse Embryonic Fibroblasts. Frontiers in Genetics 11, 867. 32849838 PMC7431633 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    p21 levels may decrease in 'late' senescence or when senescence has been achieved, whereas high levels of p16 are thought to be maintained throughout senescence.

    “p21 levels may also decrease in ‘late’ senescence or when senescence has been achieved [115,158], whereas high levels of p16 are thought to be maintained throughout senescence [158,159].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [115] Izzy S, Liu Q, Fang Z, Lule S, Wu L, Chung JY, Sarro-Schwartz A, Brown-Whalen A, Perner C, Hickman SE, Kaplan DL, Patsopoulos NA, El Khoury J & Whalen MJ (2019) Time-Dependent Changes in Microglia Transcriptional Networks Following Traumatic Brain Injury. Front Cell Neurosci 13, 307. 31440141 PMC6694299 source

      Not checked in the free run.

    • cites [158] Cecco MD, Ito T, Petrashen AP, Elias AE, Skvir NJ, Criscione SW, Caligiana A, Brocculi G, Adney EM, Boeke JD, Le O, Beauséjour C, Ambati J, Ambati K, Simon M, Seluanov A, Gorbunova V, Slagboom PE, Helfand SL, Neretti N & Sedivy JM (2019) LINE-1 derepression in senescent cells triggers interferon and inflammaging. Nature 566, 73– 78. 30728521 PMC6519963 source

      Not checked in the free run.

    • cites [159] Johmura Y, Shimada M, Misaki T, Naiki-Ito A, Miyoshi H, Motoyama N, Ohtani N, Hara E, Nakamura M, Morita A, Takahashi S & Nakanishi M (2014) Necessary and Sufficient Role for a Mitosis Skip in Senescence Induction. Molecular Cell 55, 73– 84. 24910096 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Some senolytics have been effectively used in mouse models of neurological disease to alleviate pathology, including dasatinib and quercetin and navitoclax, which has led to senolytic therapies entering clinical trials for modulation of AD.

    “Nevertheless, some senolytics have been effectively used in mouse models of neurological disease to alleviate pathology including dasatinib and quercetin [36] and navitoclax [26], which has led to senolytic therapies entering clinical trials for the modulation of AD [171].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [36] Zhang P, Kishimoto Y, Grammatikakis loannis, Gottimukkala K, Cutler RG, Zhang S, Abdelmohsen K, Bohr VA, Sen JM, Gorospe M & Mattson MP (2019) Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nat Neurosci 22, 719– 728. 30936558 PMC6605052 source

      Not checked in the free run.

    • cites [26] Bussian TJ, Aziz A, Meyer CF, Swenson BL, van Deursen JM & Baker DJ (2018) Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature 562, 578– 582. 30232451 PMC6206507 source

      Not checked in the free run.

    • cites [171] Wake Forest University Health Sciences (2021) Phase II Clinical Trial to Evaluate the Safety and Feasibility of Senolytic Therapy in Alzheimer’s Disease clinicaltrials.gov.

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationnone given

    The absence of a single, unambiguous senescence biomarker complicates definitive claims.

    “This is particularly important due to the absence of a single, unambiguous senescence biomarker, which complicates definitive claims.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Senolytics are pharmacological interventions that selectively clear senescent cells, mostly by exploiting senescent cell reliance on anti-apoptotic and pro-survival pathways (SCAPs).

    “Senolytics are pharmacological interventions that selectively clear senescent cells, and mostly work by exploiting senescent cell reliance on anti-apoptotic and pro-survival pathways [162], which have been termed the Senescent Cell Anti-Apoptotic Pathways (SCAPs) [163].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [162] Wang E (1995) Senescent human fibroblasts resist programmed cell death, and failure to suppress bcl2 is involved. Cancer Res 55, 2284– 2292. 7757977

      Not checked in the free run.

    • cites [163] Zhu Y, Tchkonia T, Pirtskhalava T, Gower AC, Ding H, Giorgadze N, Palmer AK, Ikeno Y, Hubbard GB, Lenburg M, O’Hara SP, LaRusso NF, Miller JD, Roos CM, Verzosa GC, LeBrasseur NK, Wren JD, Farr JN, Khosla S, Stout MB, McGowan SJ, Fuhrmann-Stroissnigg H, Gurkar AU, Zhao J, Colangelo D, Dorronsoro A, Ling YY, Barghouthy AS, Navarro DC, Sano T, Robbins PD, Niedernhofer LJ & Kirkland JL (2015) The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14, 644– 658. 25754370 PMC4531078 source

      Not checked in the free run.

44 of 44

  • The authors state this as an assumption.

    Senescence is a distinct cellular state that can be distinguished from otherwise non-senescent inflammatory microglia.

    “We postulate that senescence is a distinct cellular state which can be distinguished from otherwise non-senescent inflammatory microglia (Figure 2).”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Senescent cells accumulate with ageing and age-associated diseases, limiting lifespan and healthspan in mice.

    “Senescent cells accumulate with ageing and age-associated diseases, limiting lifespan and healthspan in mice11–16.”

    From Senescence atlas reveals an aged-like inflamed niche that blunts muscle regeneration (2023) · cites this paper as [16]

    The Introduction (page unavailable) says senescent cells accumulate with age and in many diseases and may contribute to pathology; the Aging section reports accumulation of senescent microglia in rodents. The paper does not itself state that this accumulation limits both lifespan and healthspan in mice. Its References list a study titled “Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan,” but that title alone does not establish the full claim. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Wake Forest University Health Sciences, 2021, Phase II clinical trial to evaluate the safety and feasibility of senolytic therapy in Alzheimer’s disease

Cited by

Sorted by citations

Related

Authors
Ng, P. Y., McNeely, T. L., & Baker, D. J.
Affiliations
Mayo Clinic (US)
Corresponding author
Baker, Darren J.
ORCID
Venue
The FEBS Journal
Publisher
Wiley
Published
2021-12-14
Volume
290
Issue
5
Pages
1326-1339
ISSN
  • 1742-464X (ISSN-L)
  • 1742-4658
DOI
10.1111/febs.16315
PMC
PMC9167891
OpenAlex
W4200021353
Semantic Scholar
a50a4478ecaebadabaa6eecbc4549bf3641fa210
Cited by
68
References
172
Citations by year
2026: 12 · 2025: 16 · 2024: 24 · 2023: 12 · 2022: 4
FWCI
1.20
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • FEBS Journal (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Glenn Foundation for Medical Research
  • National Institute on Aging (AG053229, AG068076)
  • Ellison Medical Foundation
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
Keywords
microglial senescence, microglial homeostasis, brain aging, neuroinflammation, traumatic brain injury, neurodegenerative diseases, microglial subpopulations, neuroprotection, cognitive decline, microglial phenotype
MeSH terms
Brain, Central Nervous System, Cellular Senescence, Microglia

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review