Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline
Open accessAbstract
Cellular senescence, which is characterized by an irreversible cell-cycle arrest 1 accompanied by a distinctive secretory phenotype 2, can be induced through various intracellular and extracellular factors. Senescent cells that express the cell cycle inhibitory protein p16 INK4A have been found to actively drive naturally occurring age-related tissue deterioration 3,4 and contribute to several diseases associated with ageing, including atherosclerosis 5 and osteoarthritis 6. Various markers of senescence have been observed in patients with neurodegenerative diseases 7-9; however, a role for senescent cells in the aetiology of these pathologies is unknown. Here we show a causal link between the accumulation of senescent cells and cognition-associated neuronal loss. We found that the MAPT P301S PS19 mouse model of tau-dependent neurodegenerative disease 10 accumulates p16 INK4A-positive senescent astrocytes and microglia. Clearance of these cells as they arise using INK-ATTAC transgenic mice prevents gliosis, hyperphosphorylation of both soluble and insoluble tau leading to neurofibrillary tangle deposition, and degeneration of cortical and hippocampal neurons, thus preserving cognitive function. Pharmacological intervention with a first-generation senolytic modulates tau aggregation. Collectively, these results show that senescent cells have a role in the initiation and progression of tau-mediated disease, and suggest that targeting senescent cells may provide a therapeutic avenue for the treatment of these pathologies.
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Senescence has been observed in neurons, astrocytes, microglia, oligodendrocytes, and oligodendrocyte progenitor cells.
“Senescence has been observed in neurons, astrocytes, microglia, oligodendrocytes, and oligodendrocyte progenitor cells (57–59).”
From Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span (2021) · cites this paper as [58]
The main text reports senescence-associated findings in astrocytes and microglia of PS19 mice. It reports no comparable induction in oligodendrocytes or neuron-enriched cells, and does not report senescence in oligodendrocyte progenitor cells. Thus this source supports two of the five cell types listed, not the full sentence. (LLM, conf=0.90)
Experimental — accuracy not yet measuredIn mice, removing senescent cells genetically or pharmacologically improves function in models of neurodegenerative diseases such as Parkinson's and Alzheimer's.
“Importantly, clearance of Sncs either genetically or pharmacologically in mice leads to functional improvements in models of neurodegenerative diseases such as PD and AD (57–59).”
From Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span (2021) · cites this paper as [58]
In the main text (page unavailable), genetic clearance of senescent cells in PS19 tauopathy mice mitigated short-term memory loss. The ABT263 experiment in the same model reduced tau phosphorylation, but the paper does not report a functional improvement from pharmacological clearance. It does not test clearance in a Parkinson’s disease model or identify PS19 as a separate Alzheimer’s disease model. (LLM, conf=0.88)
Experimental — accuracy not yet measuredGenetic clearance of senescent cells or senolytic treatment in tauopathy mouse models mitigates cognitive decline and neurodegeneration.
“Genetic clearance of senescent cells or senolytic treatment in tauopathy mouse models mitigated cognitive decline and neurode-generation158,159”
From Telomere dysfunction in ageing and age-related diseases (2022) · cites this paper as [158]
The paper’s main text (page not specified) reports that genetic clearance in PS19 tauopathy mice prevented neurodegeneration and mitigated memory loss. Its senolytic ABT263 experiment reports reduced tau phosphorylation, but does not report that treatment mitigated cognitive decline or neurodegeneration. (LLM, conf=0.90)
Experimental — accuracy not yet measuredThe INK-ATTAC and p16-3MR mouse models have substantially advanced knowledge about whether senescent cells contribute to ageing and age-related diseases in model organisms, covering conditions such as Parkinson disease, Alzheimer disease, atherosclerosis, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and osteoarthritis.
“These two mouse models have greatly accelerated our understanding of whether senescent cells contribute to ageing and age-related diseases, at least in model organisms, for numerous diseases, including Parkinson disease196, Alzheimer disease197,198, atherosclerosis175, idiopathic pulmonary fibrosis199, chronic obstructive pulmonary disease200 and osteoarthritis201.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [197]
The main text (page not available) reports that clearing senescent cells with INK-ATTAC in PS19 mice prevented tau pathology, neurodegeneration and cognitive decline. That supports this citation’s contribution to the Alzheimer-disease example, but the study tests a tauopathy model, not Alzheimer disease as a whole, and does not test p16-3MR or the other listed diseases. (LLM, conf=0.82)
Experimental — accuracy not yet measuredCellular senescence is involved in the pathogenesis of Alzheimer's disease.
“Cellular senescence contributes to Alzheimer’s disease (AD) pathogenesis.”
From Senolytic therapy in mild Alzheimer's disease: a phase 1 feasibility trial (2023) · cites this paper as [8]
The main text (page not provided) reports that clearing senescent glial cells prevented tau pathology, neurodegeneration, and cognitive decline in a PS19 mouse model. This supports a role for senescence in tau-mediated disease, but the study does not establish that it contributes to Alzheimer’s disease pathogenesis generally. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Preclinical studies in various CNS disorders show reduced gliosis and neuroinflammation with senescent cell clearance.
“However, studies in preclinical models of various CNS disorders have demonstrated reduced gliosis and neuroinflammation with senescent cell clearance, for example,6,8,17,19,25,50.”
From Senolytic therapy in mild Alzheimer's disease: a phase 1 feasibility trial (2023) · cites this paper as [8]
The Results (page unavailable) report that clearing senescent glial cells prevented gliosis in a PS19 mouse model of tauopathy. The paper does not report a reduction in neuroinflammation as a separate outcome, so that part of the claim is not established by this source. (LLM, conf=0.85)
Experimental — accuracy not yet measuredPostmortem AD brain tissue has senescent astrocytes, and mouse models show they are cleared with senolytic treatment.
“Furthermore, prior research conducted on postmortem brain tissue from individuals with AD has identified senescent astrocytes16, and mouse models have demonstrated that they are cleared with senolytic treatment8,17.”
From Senolytic therapy in mild Alzheimer's disease: a phase 1 feasibility trial (2023) · cites this paper as [8]
The citation to this paper is attached to the mouse-model claim, not the preceding claim about postmortem AD tissue. In the main text (Fig. 1; page unavailable), the authors identify senescent astrocytes in PS19 mice and report their clearance with AP in a genetic model. Their senolytic ABT263 experiment (Fig. 4; page unavailable) shows reduced senescence-associated gene expression, but does not directly show that senescent astrocytes were cleared by the drug. (LLM, conf=0.82)
Experimental — accuracy not yet measuredPreclinical studies using different models have suggested that senolytic treatments can reduce the abundance of senescent cells, disease-relevant pathology and cognitive deficits.
“Preclinical studies using different models have suggested that senolytic treatments can reduce the abundance of senescent cells, disease-relevant pathology and cognitive deficits [8, 56, 80].”
From Characterisation of premature cell senescence in Alzheimer's disease using single nuclear transcriptomics (2024) · cites this paper as [8]
In the main text (page unavailable), ABT263 treatment in PS19 mice prevented an increase in senescence-associated genes and attenuated tau phosphorylation. The paper reports reduced short-term memory loss after genetic clearance of senescent cells, but does not report a cognitive benefit from ABT263. It therefore supports the pathology finding and the cognitive finding for a different intervention, not all three outcomes for senolytic drug treatment. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSenescent 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 [12]
The paper’s opening section says senescent cells drive age-related tissue deterioration and contribute to age-associated diseases; it also reports their accumulation in a mouse model of tau-dependent disease. Its references name a study finding that p16-positive cells shorten healthy lifespan, but our copy does not state that senescent cells limit overall lifespan in mice. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn aged organisms, senescent cells can contribute to a variety of age-related pathologies, including pulmonary fibrosis, biliary liver damage, arteriosclerosis, retinopathy, osteoarthritis, dementia and diabetes mellitus.
“In aged organisms, senescent cells can contribute to a variety of age- related pathologies, including pulmonary fibrosis, biliary liver damage, arteriosclerosis, retinopathy, osteoarthritis, dementia and diabetes mellitus 13-19 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [17]
The paper’s opening passage says senescent cells contribute to atherosclerosis and osteoarthritis, and its tauopathy mouse study links senescent glial cells to cognitive decline. It does not address pulmonary fibrosis, biliary liver damage, retinopathy, or diabetes mellitus; nor does the mouse finding establish a contribution to dementia in aged organisms. No page number is available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThese cells are implicated in sterile inflammation, wound healing, and age-related processes, including neurodegeneration.
“These cells are implicated in sterile inflammation, wound healing, and age-related processes, including neurodegeneration”
From Cross-Species Single-Cell Analysis Reveals Divergence of the Primate Microglia Program (2019) · cites this paper as Bussian et al., 2018
The paper’s opening section (page not provided) links senescent cells to age-related tissue deterioration and reports a role for senescent glial cells in a mouse model of tau-dependent neurodegeneration. It does not address wound healing or implicate these cells in sterile inflammation; the Methods describe experimentally induced inflammatory responses, which do not establish that part of the claim. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCellular senescence has a causative effect in tauopathy pathology.
“which suggests that cellular senescence has a causative effect in this pathology”
From Telomere dysfunction in ageing and age-related diseases (2022) · cites this paper as [158]
Senescent cells accumulate in multiple central nervous system cell types in aging and neurodegenerative disease.
“In the context of aging and neurodegenerative disease, senescent cell accumulation has been identified in multiple cell types within the central nervous system (CNS), including neurons6,7,14,15, astrocytes16,17, microglia8,18, oligodendrocyte precursor cells19 and endothelial cells20.”
From Senolytic therapy in mild Alzheimer's disease: a phase 1 feasibility trial (2023) · cites this paper as [8]
Experimental — accuracy not yet measuredOther teams confirmed the association between tau and senescence in PS19 mice and effective senescent cell clearance by dasatinib plus quercetin in the Tg(APP/PS1) mouse model.
“Other research teams confirmed the association between tau and senescence in PS19 tau transgenic mice8 and the effective clearance of senescent cells using D + Q in the Tg(APP/PS1) Aβ-producing mouse model19.”
From Senolytic therapy in mild Alzheimer's disease: a phase 1 feasibility trial (2023) · cites this paper as [8]
Increased numbers of p16-positive astrocytes and microglia have been reported with tau-mediated disease initiation and progression in a mouse model.
“Increased numbers of p16-positive astrocytes and microglia also have been reported with tau-mediated disease initiation and progression in a mouse model [8].”
From Characterisation of premature cell senescence in Alzheimer's disease using single nuclear transcriptomics (2024) · cites this paper as [8]
Fibroblasts present papillary and reticular phenotypes and heterogeneous populations at the single-cell level.
“fibroblasts present not only papillary and reticular phenotypes, but also heterogeneous populations if studied at the single-cell level58,59.”
From Guidelines for minimal information on cellular senescence experimentation in vivo (2024) · cites this paper as [59]
The Methods (‘Single cell preparation and FACS’) and Extended Data Figures 4–5 describe sorting and identifying brain cell populations, not fibroblast populations. Searches for papillary and reticular fibroblasts and single-cell fibroblast heterogeneity found no passage addressing either part of the claim. (LLM, conf=0.78)
Experimental — accuracy not yet measuredKeratinocytes display different properties across different strata of the epidermis.
“Keratinocytes display different properties across different strata of the epidermis”
From Guidelines for minimal information on cellular senescence experimentation in vivo (2024) · cites this paper as [59]
The Extended Data passages discuss astrocytes, microglia, and other brain cells, not keratinocytes. Searches for keratinocytes, epidermal strata, and skin layers found no passage in our copy addressing how keratinocyte properties vary across the epidermis. (LLM, conf=0.77)
Experimental — accuracy not yet measuredKeratinocytes and fibroblasts can be divided into different subtypes.
“Keratinocytes and fibroblasts can be further divided into different subtypes.”
From Guidelines for minimal information on cellular senescence experimentation in vivo (2024) · cites this paper as [59]
The Methods section on single-cell preparation and Extended Data Figure 4 describe sorting brain cells, including astrocytes and microglia, rather than classifying skin cells. Searches for keratinocytes, fibroblasts, and skin-cell subpopulations found no passage in our copy addressing whether keratinocytes or fibroblasts have subtypes. (LLM, conf=0.75)
Experimental — accuracy not yet measuredRetrotransposon expression has been shown to have a role in DNA damage, cellular senescence, and inflammatory signaling, which are well-described features of both aging and some neurodegenerative disorders.
“retrotransposon expression has in fact been shown to have a role in DNA damage (Yousefzadeh et al. 2021), cellular senescence (Bussian et al. 2018, De Cecco et al. 2019b, Li et al. 2013, Musi et al. 2018), and inflammatory signaling (Franceschi et al. 2018, Gulen et al. 2023), which are well-described features of both aging and some neurodegenerative disorders”
From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Bussian et al. 2018
The main text reports senescent glial cells in a mouse model of tau-dependent neurodegeneration, but does not address whether retrotransposon expression has a role in cellular senescence. Searches for “retrotransposon expression” and “LINE-1 transposable element” found no passage addressing that link. (LLM, conf=0.76)
Experimental — accuracy not yet measuredOther common facets of neurodegeneration, such as mitochondrial dysfunction and abnormal proteostasis, may also promote neuronal and glial senescent phenotypes.
“The aggregation of misfolded proteins, including Aβ plaques and tau neurofibrillary tangles, may also promote neuronal and glial senescent phenotypes (171), as do other common facets of neurodegeneration, such as mitochondrial dysfunction and abnormal proteostasis (22, 172, 173).”
From Connecting aging biology and inflammation in the omics era (2022) · cites this paper as [22]
Persisting senescent cells have been tied to multiple chronic diseases other than atherosclerosis.
“These persisting senescent cells have been recently tied to multiple chronic diseases other than atherosclerosis, including diabetes mellitus,85 obesity,85 Alzheimer’s disease,86 heart failure,10,87 idiopathic pulmonary fibrosis,88,89 chronic obstructive pulmonary disease,90 chronic kidney disease,91 cancer,92 and osteoarthritis.93”
From Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis (2020) · cites this paper as [86]
Emerging evidence suggests that senescent cells, including p16INK4A-positive senescent astrocytes and microglia and Aβ plaque-associated p16INK4A-positive oligodendrocyte progenitor cells, have a detrimental impact on neuronal loss and cognitive impairment in Alzheimer's disease mouse models.
“Emerging evidence suggests a detrimental impact of senescent cells, including p16INK4A-positive senescent astrocytes and microglia, and Aβ plaque-associated Olig2- and NG2-expressing p16INK4A-positive oligodendrocyte progenitor cells (OPCs) in neuronal loss and cognitive impairment in mouse models of AD (Bussian et al., 2018; Zhang et al., 2019).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Bussian et al., 2018
Senolytic elimination of Aβ-associated senescent oligodendrocyte progenitor cells or Tau pathology-associated senescent glial cells ameliorates cognitive impairment in different Alzheimer's disease mouse models.
“Senolytic elimination of Aβ-associated senescent OPCs or Tau pathology-associated senescent glial cells ameliorates cognitive impairment in different AD mouse models (Bussian et al., 2018; Zhang et al., 2019).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Bussian et al., 2018
Aging is associated with increased accumulation of senescent cells in humans and animal models.
“Recent studies in humans and animal models demonstrate that aging is associated with increased accumulation of senescent cells.”
From Senescence, brain inflammation, and oligomeric tau drive cognitive decline in Alzheimer's disease: Evidence from clinical and preclinical studies (2024) · cites this paper as [22]
Various endogenous and exogenous stressors, including pathological tau aggregates, can induce senescence in different types of brain cells.
“Various endogenous and exogenous stressors (eg, pathological tau aggregates) can induce senescence in different types of brain cells. 22 , 23 , 24 , 25”
From Senescence, brain inflammation, and oligomeric tau drive cognitive decline in Alzheimer's disease: Evidence from clinical and preclinical studies (2024) · cites this paper as [22]
Selective clearance of senescent cells extends the healthy lifespan in aged animals and prevents Alzheimer's disease-associated brain pathology and cognitive decline.
“selective clearance of senescent cells extends the healthy lifespan in aged animals and also prevents AD‐associated brain pathology and cognitive decline, 22 , 23 , 24 , 25”
From Senescence, brain inflammation, and oligomeric tau drive cognitive decline in Alzheimer's disease: Evidence from clinical and preclinical studies (2024) · cites this paper as [22]
Senolytic therapy provides beneficial effects in accelerated aging, tauopathy, and AD mouse models by reducing brain inflammation.
“The involvement of senescence and SASP in MCI and AD is further strengthened by experimental evidence that senolytic therapy provides beneficial effects in accelerated aging, 106 tauopathy, 22 and AD mouse models 25 by reducing brain inflammation.”
From Senescence, brain inflammation, and oligomeric tau drive cognitive decline in Alzheimer's disease: Evidence from clinical and preclinical studies (2024) · cites this paper as [22]
Tau aggregates can trigger cellular senescence and inflammation.
“Several studies demonstrated that tau aggregates can trigger cellular senescence and inflammation”
From Senescence, brain inflammation, and oligomeric tau drive cognitive decline in Alzheimer's disease: Evidence from clinical and preclinical studies (2024) · cites this paper as [22]
Eliminating senescent cells with senolytics reduces tau aggregation and inflammation and improves cognitive performance in vivo.
“eliminating senescent cells with senolytics reduces tau aggregation and inflammation and improves cognitive performance in vivo.”
From Senescence, brain inflammation, and oligomeric tau drive cognitive decline in Alzheimer's disease: Evidence from clinical and preclinical studies (2024) · cites this paper as [22]
Senolytic therapy has shown promising results in various animal models, including tauopathies.
“Senolytic therapy has shown promising results in various animal models, including tauopathies.”
From Senescence, brain inflammation, and oligomeric tau drive cognitive decline in Alzheimer's disease: Evidence from clinical and preclinical studies (2024) · cites this paper as [22]
Senescent astrocytes and microglia accumulate in a tau-dependent mouse model of AD and contribute to cognitive decline.
“Senescent astrocytes and microglia accumulate in a tau‐dependent mouse model of AD where they contribute to cognitive decline in these mice (Bussian et al, 2018; Zhang et al, 2019).”
From The struggle of a good friend getting old: cellular senescence in viral responses and therapy (2021) · cites this paper as Bussian et al, 2018
CD38 is emerging as a key enzyme involved in inflammageing and senescence, which are strongly associated with neurodegenerative diseases.
“CD38 is emerging as a key enzyme involved in inflammageing and senescence45,105,106, which are strongly associated with neurodegenerative diseases124,128,168,169.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [128]
Pharmacological and genetic elimination of senescent cells has shown therapeutic benefits for Alzheimer's disease pathology in mouse models of tau and amyloid pathology.
“the pharmacological and genetic elimination of senescent cells has shown therapeutic benefits for AD pathology in mouse models of tau and amyloid pathology [11, 83, 122].”
From Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology (2023) · cites this paper as [11]
Senotherapy ameliorated phenotypes in all of these mouse models, attenuating tau phosphorylation and aggregation, reducing neuroinflammation and amyloid β plaque load, and improving cognitive deficits.
“Senotherapy has been shown to ameliorate phenotypes in all of these mouse models, attenuating tau phosphorylation and aggregation, 39 reducing neuroinflammation and amyloid β plague load, and improving cognitive deficits.40”
From The costs and benefits of senotherapeutics for human health (2022) · cites this paper as [39]
Clearance of p16+ senescent astrocytes and microglia using INKATTAC transgene restrains gliosis, tau hyperphosphorylation, neurofibrillary tangle deposition and degeneration of cortical and hippocampal neurons, thus restoring cognitive function.
“Bussian et al. reported that clearance of p16+ senescent astrocytes and microglia using INKATTAC transgene restrains gliosis, super-phosphorylation of both soluble and insoluble tau resulting in neurofibrillary tangle deposition and degeneration of cortical and hippocampal neurons, thus restoring cognitive function.”
From Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases (2020) · cites this paper as [18]
Excessive senescent cells have been demonstrated to play a causal role in driving ageing and chronic diseases using genetic and pharmacologic approaches.
“Excessive senescent cells have been demonstrated to play a causal role in driving ageing [26] and chronic diseases [18] using genetic and pharmacologic approaches.”
From Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases (2020) · cites this paper as [18]
DNA damage may play a central role in neuroinflammation associated with neurodegenerative disease.
“work establishing a role for senescence in the aging and diseased brain reveals DNA damage may play a central role in neuroinflammation associated with neurodegenerative disease.”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Bussian et al, 2018
Senescent-like brain cells are identified in murine models of AD and tauopathy, and their removal via senolytic drugs mitigates pathology and improves cognition.
“More recently, researchers have identified senescent‐like brain cells in murine models of AD and tauopathy, and their removal via senolytic drugs seems to mitigate pathology and improve cognition (Bussian et al, 2018; Musi et al, 2018; Zhang et al, 2019; Ogrodnik et al, 2021).”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Bussian et al, 2018
Microglia, astrocytes, and neurons display senescent-like phenotypes in Tau P301S mice and have been proposed as drivers of cognitive decline and neurodegeneration.
“For example both microglia (Bussian et al, 2018), astrocytes (Bussian et al, 2018), and neurons (Musi et al, 2018) have been found to display senescent‐like phenotypes in Tau P301S mice, and have been proposed as drivers of cognitive decline and neurodegeneration.”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Bussian et al, 2018
Removal of senescent cells in the brain mitigates NFT burden, amyloid burden, neuronal loss, and cognitive decline in mouse models of tauopathy, AD, PD, and normal aging.
“It has since been shown that removal of senescent cells in the brain mitigates neurofibrillary tangle (NFT) burden, amyloid burden, neuronal loss, and cognitive decline in mouse models of tauopathy (Bussian et al, 2018; Musi et al, 2018), AD (Zhang et al, 2019), PD (Chinta et al, 2018), and normal aging (Ogrodnik et al, 2021).”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Bussian et al, 2018
Genetic and pharmacological clearance of senescent cells confers therapeutic benefits in models of multiple diseases.
“genetic and pharmacological clearance of senescent cells confers therapeutic benefits in models of Alzheimer’s disease”
From Skeletal muscle aging, cellular senescence, and senotherapeutics: current knowledge and future directions (2021) · cites this paper as Bussian et al., 2018
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].”
From Untangling senescent and damage‐associated microglia in the aging and diseased brain (2023) · cites this paper as [26]
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].”
From Untangling senescent and damage‐associated microglia in the aging and diseased brain (2023) · cites this paper as [26]
Each of these studies demonstrated pathology mitigation following pharmacological removal of senescent cells.
“Regardless of the hypothesized identity of the senescent population, each of these studies demonstrated pathology mitigation following pharmacological removal of senescent cells [26,33,36].”
From Untangling senescent and damage‐associated microglia in the aging and diseased brain (2023) · cites this paper as [26]
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].”
From Untangling senescent and damage‐associated microglia in the aging and diseased brain (2023) · cites this paper as [26]
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].”
From Untangling senescent and damage‐associated microglia in the aging and diseased brain (2023) · cites this paper as [26]
Senescent cells accumulate with age, neurodegenerative disease and cognitive decline, neuropsychiatric disorders, and after TBI.
“Senescent cells accumulate with age [23, 157, 175], neurodegenerative disease and cognitive decline [15], neuropsychiatric disorders [33], and have recently been discovered to accumulate after TBI [3, 123, 131, 132, 151].”
From Early onset senescence and cognitive impairment in a murine model of repeated mTBI (2021) · cites this paper as [15]
Accumulation of senescent glial cells drives tau pathology and cognitive decline in mice.
“Similarly, accumulation of senescent glial cells drives tau pathology and cognitive decline in mice [14].”
From DNA repair deficiency and senescence in concussed professional athletes involved in contact sports (2019) · cites this paper as [14]
The role of senescent cells in cognitive decline and p-tau pathology has been demonstrated in a transgenic mouse model of AD, in which eliminating senescent cells through senolytic intervention resulted in reduced tau phosphorylation, improved cognitive outcomes, and prevention of upregulation of senescence genes.
“The role of senescent cells in cognitive decline and p-tau pathology has been demonstrated in a transgenic mouse model of AD, in which eliminating senescent cells through senolytic intervention resulted in reduced tau phosphorylation, improved cognitive outcomes, and the prevention of the upregulation of senescence genes [14].”
From DNA repair deficiency and senescence in concussed professional athletes involved in contact sports (2019) · cites this paper as [14]
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- Authors
- Bussian, T. J., Aziz, A., Meyer, C. F., Swenson, B. L., van Deursen, J. M., & Baker, D. J.
- Affiliations
- Mayo Clinic (US)
- Corresponding author
- Baker, Darren J.
- Venue
- Nature
- Published
- 2018-09-19
- Volume
- 562
- Issue
- 7728
- Pages
- 578-582
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6206507
- OpenAlex
- W2890865075
- Cited by
- 1,289
- References
- 35
- Citations by year
- 2026: 140 · 2025: 165 · 2024: 185 · 2023: 161 · 2022: 173 · 2021: 157 · 2020: 169 · 2019: 127 · 2018: 12
- FWCI
- 79.93
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Funders
- National Institute on Aging (R01AG053229)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- cellular senescence, senolytics, astrocytes, microglia, tauopathy, neurofibrillary tangles, tau hyperphosphorylation, cognitive decline, neuronal loss, p16INK4a, gliosis, neurodegeneration
- MeSH terms
- Aniline Compounds, Animals, Astrocytes, Female, Gliosis, Humans, Male, Mice, Transgenic, Neuroglia, Phosphorylation, Solubility, Sulfonamides, Neurofibrillary Tangles, tau Proteins, Cellular Senescence, Transgenes, Cyclin-Dependent Kinase Inhibitor p16, Mice, Cognitive Dysfunction
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