Cellular senescence in brain aging and neurodegenerative diseases: evidence and perspectives
Open accessAbstract
Along with a general decline in overall health, most chronic degenerative human diseases are inherently associated with increasing age. Age-associated cognitive impairments and neurodegenerative diseases, such as Parkinson's and Alzheimer's diseases, are potentially debilitating conditions that lack viable options for treatment, resulting in a tremendous economic and societal cost. Most high-profile clinical trials for neurodegenerative diseases have led to inefficacious results, suggesting that novel approaches to treating these pathologies are needed. Numerous recent studies have demonstrated that senescent cells, which are characterized by sustained cell cycle arrest and production of a distinct senescence-associated secretory phenotype, accumulate with age and at sites of age-related diseases throughout the body, where they actively promote tissue deterioration. Cells with features of senescence have been detected in the context of brain aging and neurodegenerative disease, suggesting that they may also promote dysfunction. Here, we discuss the evidence implicating senescent cells in neurodegenerative diseases, the mechanistic contribution of these cells that may actively drive neurodegeneration, and how these cells or their effects may be targeted therapeutically.
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- Premisecitation
Senescent cells accumulate in multiple tissues during aging and in disease.
“Recent work has demonstrated that senescent cells, characterized by an arrested cell cycle that is triggered by a variety of stresses, accumulate in various tissues of age and disease (4)(5)(6)(7)(8)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites (4)(5)(6)(7)(8)
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- Premisecitation
Aging leads to chronic low-grade inflammation in the brain in the absence of an obvious pathogen.
“Just like in peripheral tissues, aging leads to a chronic low-grade inflammation in the brain (42), which occurs in the absence of any obvious pathogen.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [42] Frank-Cannon, 2009, Does neuroinflammation fan the flame in neurodegenerative diseases?, Mol Neurodegener source
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- Premisenone given
The markers currently used to identify senescent cells are not unique to senescent cells.
“As these markers are not truly unique to senescent cells, it is imperative to establish that these changes occur in the context of senescence and not just as a result of inflammation, for example.”
Quote in the paperSubstantial claim - Premisecitation
With age, human brain tissue displays an increase in astrocytes positive for p16 and MMP3.
“With age, human brain tissue displays an increase in the number of astrocytes positive for p16 INK4A and matrix metalloproteinase 3 (MMP3) (57), a common SASP-associated protease.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [57] source
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- Premisecitation
Microglia from aged mice produce increased IL-6, IL-1β, and TNF-α, all factors upregulated in senescent cells.
“Microglia from aged mice exhibit increased production of the proinflammatory cytokines IL-6, IL-1β, and TNF-α (48, 49), all of which are factors upregulated in senescent cells (9).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [48] source
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- cites [49] Bachstetter, 2011, Microglial p38α MAPK is a key regulator of proinflammatory cytokine up-regulation induced by toll-like receptor (TLR) ligands or beta-amyloid (Aβ), J Neuroinflammation source
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- cites [9] Coppé, 2008, Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor, PLoS Biol source
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- Premisecitation
Microglia from AD patients possess shorter telomeres compared with age-matched controls.
“For example, microglia from AD patients possess shorter telomeres compared with age-matched controls (50).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [50] source
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- Interpretationreasoning
Telomere attrition is unlikely to occur in postmitotic cells such as neurons and oligodendrocytes under normal circumstances because it is linked to proliferation.
“Telomere attrition is inherently linked to proliferation; therefore this process is unlikely to occur in postmitotic cells, such as neurons and oligodendrocytes, under normal circumstances.”
Quote in the paperNot a substantial claim - Premisecitation
Treating primary astrocytes in vitro with antiretroviral drugs promotes senescence.
“Indeed, treating primary astrocytes in vitro with these drugs promotes senescence (87,88).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisenone given
Current methods for identifying senescent cells depend on a combination of markers.
“Current methods rely on a combination of markers, including those described in Figure 1.”
Quote in the paperSubstantial claim - Premisecitation
Astrocytes cultured from AD patients express more p16, MMP1, and IL-6 than age-matched controls.
“Astrocytes cultured from patients with AD express not only more of the CDKi p16 INK4A than age-matched controls, but also more MMP1 and IL-6 (57).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [57] source
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- Premisecitation
Chronically activated microglia in vitro exhibit features of senescence including SA β-gal activity, heterochromatic foci formation, and growth arrest.
“In vitro, chronically activated microglia exhibit various features of senescence, including SA β-gal activity, heterochromatic foci formation, and growth arrest (51).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [51] source
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- Premisecitation
Several senolytic molecules have already been identified.
“Several senolytic molecules have already been identified.”
Quote in the paperNot a substantial claim - Premisecitation
Senescent cells participate in starting and maturing atheromas in atherosclerosis.
“In atherosclerosis, senescent cells contribute atheroma initiation and maturation, and navitoclax administration reduces plaque burden (30).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30] source
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- Premisereasoning
Two related but distinct mouse models exist for detecting and clearing senescent cells.
“To circumvent this problem, two similar yet unique mouse models have been developed to detect and eliminate senescent cells.”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
These models have greatly sped up knowledge about how senescent cells contribute to age-related changes and diseases such as osteoarthritis and atherosclerosis.
“Use of these models has dramatically accelerated our understanding of the contribution of senescent cells to various age-associated alterations and pathologies, including osteoarthritis and atherosclerosis (30,31).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
Navitoclax administration reduces plaque burden in atherosclerosis.
“In atherosclerosis, senescent cells contribute atheroma initiation and maturation, and navitoclax administration reduces plaque burden (30).”
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- Premisereasoning
A number of senolytic drugs act on the anti-apoptotic pathways that senescent cells upregulate.
“Many of these agents target the antiapoptotic machinery that is upregulated in senescent cells.”
Quote in the paperNot a substantial claim - Interpretationreasoning
The SASP probably has favorable effects in the nearby tissue where senescent cells are located.
“These “senolytic” approaches eliminate not only the senescent cell but also the accompanying SASP, which likely exerts beneficial effects in the local environment where senescent cells reside.”
Quote in the paperNot a substantial claim - Premisecitation
In naturally aged mice, clearing senescent cells with the INK-ATTAC construct produced no obvious adverse effects.
“In the study using naturally aged mice, senescent cell elimination with the INK-ATTAC transgenic construct had no discernible negative side effects (98).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [98] source
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- Premisecitation
Under conditions like wounding, failure to rapidly induce senescent cells slows wound closure.
“In response to certain conditions, such as wounding, the inability to acutely induce senescent cells results in a retarded rate of wound closure (91,98).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
In mice, removing senescent cells genetically or with senolytics has generally helped across many diseases and conditions.
“Using mouse models, elimination of these cells, through either genetic means or senolytic therapies, has largely shown beneficial impacts, irrespective of the disease or condition investigated (29-31, 99, 100).”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [29] source
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- cites [30] source
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- cites [31] source
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- cites [99] source
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- cites [100] Schafer, 2017, Cellular senescence mediates fibrotic pulmonary disease, Nat Commun source
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- Premisecitation
Aging and age-related diseases cause senescent cells to build up in many tissues of humans and mice.
“Organismal aging and age-related diseases promote an accumulation of senescent cells in a variety of tissues in both humans and mice (8).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [8] source
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- Premisecitation
Numerous candidate treatments for clearing senescent cells in aging and disease have been found, such as piperlongumine, dasatinib, quercetin, UBX0101, a FOXO4 peptide, and HSP90 inhibitors.
“Other potentially senolytic molecules and strategies, including piperlongumine (94), dasatinib (95), quercetin (95), the proprietary compound UBX0101 (31), a FOXO4 peptide that promotes p53-dependent apoptosis (96), and HSP90 inhibitors (97), have also been identified”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisereasoning
Whatever method is used, attacking senescent cells generally benefits age-related pathologies and diseases.
“Interestingly, these various studies demonstrate that whatever means is employed, targeting of senescent cells has largely beneficial impacts for pathologies of aging and age-related disease.”
Quote in the paperSubstantial claim - Premisenone given
Key findings about how well senescent cell removal works have come from cell culture or mouse studies.
“Several important insights into the effectiveness of senescent cell elimination strategies have used tissue culture conditions or mouse models.”
Quote in the paperNot a substantial claim - Premisenone given
Trials for neurodegeneration based on older molecular targets have repeatedly failed.
“many clinical trials to combat neurodegeneration using previously established molecular targets have consistently failed”
Quote in the paperNot a substantial claim - Premisenone given
Signs and identity of senescent cells are seen in neurological aging and disease.
“Senescent cell evidence and identity are observed in neurological aging and pathology.”
Quote in the paperSubstantial claim - Premisenone given
Weak, indirect evidence points to possible buildup of senescent cells with aging and dysfunction.
“Limited and indirect evidence suggests a potential accumulation of these cells with age and dysfunction.”
Quote in the paperSubstantial claim
- May combine two claims. 20
- Classified as probably not a substantial claim. 5
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PremisecitationSenescent cells drive various natural age-related pathologies, shorten life, and promote atherosclerosis and osteoarthritis.
“Subsequent studies using the INK-ATTAC model determined that senescent cells drive various natural age-related pathologies, shorten life, and promote the age-associated diseases atherosclerosis and osteoarthritis (20,(29)(30)(31).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites (20,(29)(30)(31)
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Premisecitationp16 is a biomarker of natural aging, with expression increasing in various tissues over time.
“Importantly, p16 INK4A is a biomarker of natural aging, as its expression increases in a variety of tissues with time (28).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [28] source
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InterpretationcitationChronic low-grade brain inflammation contributes to decreased pre- and postsynaptic densities, fewer synapses and dendritic spines, and cognitive impairment and memory loss in aged individuals.
“This contributes to decreased pre-and postsynaptic densities, as well as decreased synapses and dendritic spines overall (43), resulting in cognitive impairments and memory loss in aged individuals.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [43] source
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PremisecitationNeurons of aged mice accumulate high amounts of DNA damage and display elevated proinflammatory molecules and SA β-gal activity.
“Studies have demonstrated that neurons of aged mice accumulate high amounts of DNA damage (16) and display elevated expression of proinflammatory molecules and SA β-gal activity (41), characteristics typical of senescence.”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisereasoningNo single marker can independently define a senescent cell, so multiple hallmarks are needed.
“It is important to note that while these changes are indicative of senescence, there is currently no single marker that can be used independently to define a senescent cell.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationSenescence is a distinct proinflammatory cell fate with a secretome of cytokines, chemokines, proteases, and growth factors known as SASP.
“Unlike a normally programmed terminal differentiation process, senescence is a distinct proinflammatory fate in which cells acquire a distinctive secretome of cytokines, chemokines, proteases, and growth factors collectively known as the senescence-associated secretory phenotype (SASP) (9).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [9] Coppé, 2008, Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor, PLoS Biol source
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May combine two claims.
PremisecitationBUBR1 hypomorphic mice display blood-brain barrier leakage that correlates with premature senescence of neural endothelial cells and pericytes, which become SA β-gal positive and express p16.
“BUBR1 hypomorphic mice display leakage across the BBB that correlates with a propensity for neural endothelial cells and pericytes to prematurely senesce, become SA β-gal positive, and express p16 INK4A (66).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [66] source
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PremisereasoningWith aging and at brain pathology sites, senescent cells might build up.
“The above studies suggest that senescent cells may accumulate with age and at sites of pathology in the brain.”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitationp16 INK4A-deficient mice develop many tumors and die before normal mice show cognitive decline.
“One limitation of genetic inactivation experiments is that mice lacking p16 INK4A are highly tumor prone and therefore die before the cognitive decline is observed in normal mice (90).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [90] source
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PremisecitationA common feature of PD patients and mouse models is accumulation of activated microglia and astrocytes, which would promote increased local concentrations of inflammatory mediators and ROS.
“Interestingly, a common feature of PD patients and mouse models is the accumulation of activated microglia and astrocytes, which would promote increased local concentrations of inflammatory mediators and ROS (84).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [84] source
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InterpretationreasoningCausal proof that senescent cells drive neuropathology could come from blocking senescence entry via p16 INK4A genetic inactivation or from removing senescent cells with engineered mice.
“A true demonstration that senescent cells causally drive neuropathology can be achieved either by prevention of senescence entry through genetic inactivation of p16 INK4A or by direct elimination of senescent cells using genetically engineered mice.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationNavitoclax clears senescent cells appearing in early atherosclerotic plaques and after sublethal irradiation in skeletal muscle and bone marrow.
“Navitoclax treatment has been shown to eliminate senescent cells that arise in early atherosclerotic plaques (30) and upon sublethal irradiation in both skeletal muscle and the bone marrow (93).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisereasoningRemoving senescent cells is feasible and can modulate inflammatory diseases.
“The finding that senescent cell elimination is not only possible but also effective at modulating inflammatory diseases has triggered profound interest in developing therapeutic strategies to eliminate senescent cells in the absence of genetic modifications.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationGanciclovir is converted by HSV-TK into a toxic DNA chain terminator within p16 INK4A-expressing cells, causing senescent cells to undergo mitochondria-dependent apoptosis.
“When ganciclovir is administered, HSV-TK converts this compound into a toxic DNA chain terminator in p16 INK4A -expressing cells, triggering apoptosis in senescent cells through mitochondria-dependent cell death (92).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [92] Laberge, 2013, Mitochondrial DNA damage induces apoptosis in senescent cells, Cell Death Dis source
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Premisenone givenSenolytic treatments remove both the senescent cell and its SASP.
“These “senolytic” approaches eliminate not only the senescent cell but also the accompanying SASP, which likely exerts beneficial effects in the local environment where senescent cells reside.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationABT-737 and navitoclax bind the inhibitory pockets of BCL-2 family proteins, blocking their anti-apoptotic function.
“The senolytic molecules ABT-737 (37) and navitoclax (ABT-263) (93) occupy the inhibitory binding regions of members of the BCL-2 family of proteins, thereby canceling their antiapoptotic activity.”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningFor some senolytic compounds, the blood-brain barrier might prevent systemic delivery from reaching the target.
“The BBB may preclude systemic administration for some of these compounds to get to the target site.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningIn the short term senescence helps tissue repair and remodeling, but over the long term its effects seem mostly harmful.
“The aforementioned studies demonstrate a beneficial role for senescence in tissue repair and remodeling in the short term, whereas the long-term consequences appear to be largely detrimental.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningShould senolytics be used for neurological conditions, several candidates probably reach the brain in both aging and disease.
“Therefore, if these approaches are to be implemented in neurological conditions, there are likely a number of candidates that demonstrate bioavailability in the brain, in the context of both aging and disease.”
Quote in the paperSubstantial claimMay combine two claims.
PremisereasoningTreatments have been short and follow-up brief, so studies so far have not detected long-term adverse effects.
“Furthermore, the duration of treatments has been brief with relatively short follow-up assessments, so long-term negative consequences have not been observed in studies to date.”
Quote in the paperNot a substantial claimMay combine two claims.
Study design and conductnone givenThat study's animals lived in a controlled setting and received no external stressors.
“It is important to keep in mind that the animals used in this study were in a controlled environment without any exogenous stresses applied.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisenone givenAfter cells become senescent, several distinguishing features appear, varying by cell type and inducing stimulus.
“Once they have entered into this state, a number of distinguishing qualities can be observed.depending on the cell type and senescence-inducing stimuli.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisenone givenVarious internal and external stressors can push normal cells to become senescent.
“A number of stressors, both intrinsic and extrinsic, can stimulate the conversion of otherwise normal cells into senescent cells.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
The risk of developing neurodegenerative diseases increases dramatically with age.
“The risk of developing many pathological conditions, including neurodegenerative diseases, increases dramatically with age.”
The paper relies on this without support.
None of the numerous clinical trials to treat Alzheimer's disease have demonstrated a beneficial impact for patients.
“Unfortunately, of the numerous clinical trials to treat AD, none have been able to demonstrate beneficial impact for patients.”
The paper relies on this without support.
The role of senescent cells in causing and worsening neurodegenerative disorders remains unknown.
“However, the significance of senescent cells in both the induction and exacerbation of neurodegenerative disorders is unknown.”
The paper relies on this without support.
Determining the overall importance and mechanism of senescent cells in neuropathology has been very hard because tools to identify, isolate, or remove these cells are lacking.
“To date, it has been extremely difficult to discern the overall significance and mechanistic contribution of senescent cells to neuropathology because of a lack of tools to identify, isolate, and/or eliminate these cells.”
The paper relies on this without support.
These methods have not yet been used in relevant neurodegenerative disease studies.
“To date, these approaches have not been employed for relevant studies of neurodegenerative disease.”
The paper relies on this without support.
Whether and how senolytics can be translated into clinical practice is currently unclear.
“It is currently unclear how these various senolytics can be translated into clinical strategies, if at all.”
The paper relies on this without support.
No reliable method currently exists to detect the early signs of neurodegenerative diseases.
“as there is currently no reliable way to identify the early signs of these devastating diseases.”
The paper relies on this without support.
The molecular features that accompany normal aging and CNS disease remain incompletely characterized.
“The molecular correlates of normal aging and CNS disease are not fully defined.”
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 contribute to aging and age-related pathologies through SASP.
“Senescent cells contribute to aging and age-related pathologies21,22,23 through their senescence-associated secretory phenotype (SASP).24,25,26”
From Uncovering the signatures of aging and senescence in the human dorsolateral prefrontal cortex (2026) · cites this paper as [22]
The Introduction (page unavailable) says senescent cells accumulate with age and disease and may contribute to pathology; it also identifies their secretory phenotype as the SASP. The discussion of senescent-cell properties (page unavailable) calls the SASP-mediated link to age-related disease plausible, rather than establishing that senescent cells cause aging and age-related pathologies through SASP. (LLM, conf=0.84)
Experimental — accuracy not yet measuredCellular senescence can augment glial function and accelerate brain aging.
“Cellular senescence is yet another factor that can augment glial function and accelerate brain aging.”
From Connecting aging biology and inflammation in the omics era (2022) · cites this paper as [167]
Microglia, astrocytes, brain endothelial cells, and other CNS cell types show evidence of senescence and increased expression of senescence factors.
“Microglia, astrocytes, brain endothelial cells, and other CNS cell types show evidence of senescence and increased expression of senescence factors (167, 168).”
From Connecting aging biology and inflammation in the omics era (2022) · cites this paper as [167]
Cellular senescence plays a crucial role in brain aging, neurodegeneration, and dementia through the SASP, which represents a major source of inflammation.
“Among these aging hallmarks, cellular senescence plays a crucial role in brain aging, neurodegeneration, and dementia 36 through the SASP, which represents a major source of inflammation. 37”
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 [36]
The burden of senescent cells in the brain increases with advanced age and neurodegenerative diseases and occurs across neurons, microglia, astrocytes, oligodendrocyte precursor cells, and endothelial cells.
“The burden of senescent cells in the brain increases with advanced chronological age and neurodegenerative diseases, and occurs across cell types including neurons, microglia, astrocytes, oligodendrocyte precursor cells, and endothelial cells (28–32).”
From Senolytic Therapy to Modulate the Progression of Alzheimer's Disease (SToMP-AD): A Pilot Clinical Trial (2022) · cites this paper as [28]
Senescent cells accumulate with advancing age across multiple organ systems, including the brain.
“Senescent cells accumulate with advancing age throughout multiple organ systems, including the brain (17, 28).”
From Senolytic Therapy to Modulate the Progression of Alzheimer's Disease (SToMP-AD): A Pilot Clinical Trial (2022) · cites this paper as [28]
Microglia and astrocytes can acquire a senescent phenotype, promoting diffusion of the senescence-associated secretory phenotype and conversion of healthy cells to senescence.
“Microglia and astrocytes can acquire a senescent phenotype themselves (28, 31, 32), promoting further diffusion of the SASP and the conversion of healthy cells to the senescent phenotype.”
From Senolytic Therapy to Modulate the Progression of Alzheimer's Disease (SToMP-AD): A Pilot Clinical Trial (2022) · cites this paper as [28]
Across six transgenic Alzheimer's disease mouse models, orally administered senolytic drugs ablate brain senescent cells and alleviate Alzheimer's-relevant pathogenesis.
“To date, research conducted across six transgenic AD mouse models has demonstrated that orally administered senolytic drugs ablate senescent cells in the brain and alleviate AD-relevant pathogenesis (28–30, 32).”
From Senolytic Therapy to Modulate the Progression of Alzheimer's Disease (SToMP-AD): A Pilot Clinical Trial (2022) · cites this paper as [28]
Cellular senescence is a key biological process linked to aging that can contribute to or cause age-related pathologies like Alzheimer's disease.
“In this regard, cellular senescence emerges as a key biological process linked to aging that can contribute to or cause the appearance of age-related pathologies like AD [5].”
From Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology (2023) · cites this paper as [5]
Markers of cellular senescence have been found in dividing cells such as glial cells or neural stem cells in the context of aging and neurodegenerative diseases.
“Indeed, markers of cellular senescence have been found in those cell types in the context of aging and neurodegenerative diseases [5].”
From Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology (2023) · cites this paper as [5]
A variety of stressors, including oncogenic activation, reactive oxygen species and mitochondrial dysfunction, can stimulate conversion into a state of senescence, mostly through generation of DNA damage.
“It has been demonstrated that a variety of stressors, including oncogenic activation, reactive oxygen species (ROS) and mitochondrial dysfunction, can stimulate the conversion into a state of senescence, mostly through the generation of DNA damage [5].”
From Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology (2023) · cites this paper as [5]
Senescent cells are present in the brains of Alzheimer's disease patients and mouse models.
“Studies have demonstrated the presence of senescent cells in the brains of AD patients and mouse models [5]”
From Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology (2023) · cites this paper as [5]
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].”
From Untangling senescent and damage‐associated microglia in the aging and diseased brain (2023) · cites this paper as [20]
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].”
From Untangling senescent and damage‐associated microglia in the aging and diseased brain (2023) · cites this paper as [20]
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The Role of Glial Cell Senescence in Alzheimer's Disease
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New aspects of hepatic endothelial cells in physiology and nonalcoholic fatty liver disease
Sun, X., & Harris, E. N. (2020) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00062.2020 · Cited by 58 · see citing works
Extending human healthspan and longevity: a symposium report
DeVito, L. M., Barzilai, N., Cuervo, A. M., Niedernhofer, L. J., Milman, S., Levine, M. E., Promislow, D., Ferrucci, L., Kuchel, G. A., Mannick, J. B., et al. (2021) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.14681 · Cited by 58 · see citing works
Ionizing Radiation-Induced Brain Cell Aging and the Potential Underlying Molecular Mechanisms
Wang, Q., Yin, G., Huang, J., Xi, S.-J., Qian, F., Lee, R.-X., Peng, X., & Tang, F. R. (2021) · Cells · doi:10.3390/cells10123570 · Cited by 58 · see citing works
Ribierre, T., Bacq, A., Donneger, F., Doladilhe, M., Maletic, M., Roussel, D., Roux, I. L., Chassoux, F., Devaux, B. C., Adle‐Biassette, H., et al. (2024) · Nature Neuroscience · doi:10.1038/s41593-024-01634-2 · Cited by 62 · see citing works
Hou, J., Jeon, B.-M., Baek, J.-I., Yun, Y. J., Kim, D., Chang, B., Kim, S.-Y., & Kim, S. (2021) · Journal of Ginseng Research · doi:10.1016/j.jgr.2021.04.002 · Cited by 56 · see citing works
Scarabino, D., Peconi, M., Broggio, E., Gambina, G., Maggi, E., Armeli, F., Mantuano, E., Morello, M., Corbo, R. M., & Businaro, R. (2020) · Experimental Gerontology · doi:10.1016/j.exger.2020.110945 · Cited by 56 · see citing works
Negligible senescence in naked mole rats may be a consequence of well-maintained splicing regulation
Lee, B. P., Smith, M., Buffenstein, R., & Harries, L. W. (2020) · GeroScience · doi:10.1007/s11357-019-00150-7 · Cited by 55 · see citing works
Ginsenoside and Its Therapeutic Potential for Cognitive Impairment
Feng, H., Xue, M., Deng, H., Cheng, S., Hu, Y., & Zhou, C. (2022) · Biomolecules · doi:10.3390/biom12091310 · Cited by 58 · see citing works
Tau affects P53 function and cell fate during the DNA damage response
Sola, M., Magrin, C., Pedrioli, G., Pinton, S., Salvadè, A., Papin, S., & Paganetti, P. (2020) · Communications Biology · doi:10.1038/s42003-020-0975-4 · Cited by 55 · see citing works
Escape from senescence: molecular basis and therapeutic ramifications
Evangelou, K., Belogiannis, K., Papaspyropoulos, A., Petty, R., & Gorgoulis, V. G. (2023) · The Journal of Pathology · doi:10.1002/path.6164 · Cited by 55 · see citing works
- Authors
- Baker, D. J., & Petersen, R. C.
- Affiliations
- Mayo Clinic (US)
- Venue
- Journal of Clinical Investigation
- Published
- 2018-02-19
- Volume
- 128
- Issue
- 4
- Pages
- 1208-1216
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC5873891
- OpenAlex
- W2789191208
- Semantic Scholar
- 2532232dad192413fd93fdbee252c09f546c10ac
- Cited by
- 514
- References
- 102
- Citations by year
- 2026: 57 · 2025: 88 · 2024: 76 · 2023: 58 · 2022: 69 · 2021: 66 · 2020: 58 · 2019: 31 · 2018: 11
- FWCI
- 5.46
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ellison Medical Foundation
- Mayo Clinic (55905)
- Glenn Foundation for Medical Research
- Fondation pour la Recherche Médicale
- National Institutes of Health
- National Institute on Aging (U01AG006786, R01AG053229, P50AG016574)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- cellular senescence, brain aging, neurodegenerative diseases, Parkinson's disease, Alzheimer's disease, senescence-associated secretory phenotype, age-related cognitive impairment, senolytics, senolytic therapy, cell cycle arrest
- MeSH terms
- Aging, Alzheimer Disease, Brain, Chronic Disease, Humans, Cellular Senescence, Cell Cycle Checkpoints, Cognitive Dysfunction
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 2026-10-05.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-05.
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.
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