Senescent-like microglia limit remyelination through the senescence associated secretory phenotype
Open accessPublished version of a preprint
Abstract
The capacity to regenerate myelin in the central nervous system (CNS) diminishes with age. This decline is particularly evident in multiple sclerosis (MS), which has been suggested to exhibit features of accelerated biological aging. Whether cellular senescence, a hallmark of aging, contributes to remyelination impairment remains unknown. Here, we show that senescent cells (SCs) accumulate within demyelinated lesions after injury, and their elimination enhances remyelination in young mice but not in aged mice. In young mice, we observed the upregulation of senescence-associated transcripts primarily in microglia after demyelination, followed by their reduction during remyelination. However, in aged mice, senescence-associated factors persisted within lesions, correlating with inefficient remyelination. We found that SC elimination enhanced remyelination in young mice but was ineffective in aged mice. Proteomic analysis of senescence-associated secretory phenotype (SASP) revealed elevated levels of CCL11/Eotaxin-1 in lesions, which was found to inhibit efficient oligodendrocyte maturation. These results suggest therapeutic targeting of SASP components, such as CCL11, may improve remyelination in aging and MS.
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Written from the paper’s full text.
TL;DR
Senescent-like microglia/macrophages accumulate in demyelinated lesions, peak early after injury, and persist with age, where SASP factors such as CCL11 impair oligodendrocyte maturation and remyelination. Senolytic treatment improves remyelination in young and middle-aged mice but not aged mice, while CCL11 inhibition partially mimics senolytic benefits.
Key findings
- In young mice, p16tdt+ senescent cells increased at 5 days post lesion (dpl) and declined by 10, 20, and 60 dpl; p16tdt predominantly colocalized with CD11b+ cells, accounting for 62% of p16tdt+ cells and 20% of myeloid cells in lesions.
- Aged lesions showed persistent senescence and SASP: at 20 dpl, 434 differentially expressed genes were identified between young and aged lesions, including 14 SenMayo senescence-associated transcripts; aged lesions had increased CSF1, CCL4, CCL5, CCL11, CXCL1, CXCL2, and decreased IL2.
- Senolytic treatment increased remyelination in young and middle-aged mice but not aged mice: AP20187 increased Olig2+ and CC1+ cells and modestly increased remyelination by SEM in young mice; AP increased MBP in 12-month-old mice; AP did not affect oligodendrocyte lineage cells, mature oligodendrocytes, or MBP in 18–22-month-old mice.
- CCL11/Eotaxin-1 was elevated in aged lesions and reduced by AP treatment; CCL11 neutralizing antibody increased MBP+ area without changing mature oligodendrocyte number, and recombinant CCL11 in vitro increased the percentage of low-MBP oligodendrocytes (20.7 ± 2.2% vs 10.5 ± 2.5%) and decreased high-MBP cells (79.3 ± 2.2% vs 89.5 ± 2.5%).
Methods
- Focal demyelination was induced by LPC injection into mouse spinal cord white matter in young (3 months), middle-aged (12 months), and aged (18–22 months) mice, using p16-tdTomato, INK-ATTAC, and C57BL/6 mice; treatments included AP20187 (2 mg/kg), dasatinib/quercetin (5/50 mg/kg), CCL11 neutralizing antibody (50 µg/kg), and recombinant CCL11 (10 µg/kg).
- Analyses included immunohistochemistry, MERFISH spatial transcriptomics with a 400-gene panel, bulk RNA-sequencing, reanalysis of mouse and human snRNA-sequencing datasets, SASP multiplex protein assays, scanning electron microscopy with g-ratio quantification, primary rat oligodendrocyte cultures, and human plasma CCL11 ELISA.
- Statistics were performed in GraphPad Prism 10 using t-tests, one-way or two-way ANOVA with multiple-comparison corrections, Wilcoxon tests, and Wald tests as appropriate.
Limitations
- Stated: the authors could not confirm senolytic efficacy in clearing senescent cells, possibly due to unreliable common senescent marker antibodies (P16, P21, β-galactosidase); transcriptomic experiments had small sample sizes; and the study lacked statistical power to differentiate sex effects.
- Stated: senolytics did not improve remyelination in aged mice despite modifying the lesion environment, possibly due to incomplete senescent cell clearance, lingering SASP factors, or other age-related inhibitors of regeneration; systemic recombinant CCL11 also had no detectable effect, possibly due to saturated CCL11 levels or delivery route.
- Evident from the text: several key experiments used very small group sizes, such as MERFISH with n = 2 per group and CCL11 lesion quantification with n = 2 per group, and human plasma CCL11 comparisons were uncorrected for age.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
14 of 17 cited sources checked · 9 supported · 0 flagged · accuracy not yet measured
- Premisecitation
Microglia are the primary cell-type in the CNS responsive to CCL11.
“evidence suggests microglia are the primary cell-type in the CNS responsive to CCL1158.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [58] Fernández-Castañeda, A. et al. Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation. Cell 185, 2452–2468.e16 (2022). source
- Findingown data
CCL11/Eotaxin-1 inhibits oligodendrocyte maturation.
“which is found to inhibit oligodendrocyte maturation.”
Quote in the paperSubstantial claim - Findingown data
In young mice, senescence-associated transcripts are upregulated primarily in microglia and macrophages after demyelination and then reduced during remyelination.
“In young mice, we observe the upregulation of senescence-associated transcripts, primarily in microglia and macrophages, after demyelination, followed by a reduction during remyelination.”
Quote in the paperSubstantial claim - Findingown data
In 12-month-old mice, a two-week regimen of dasatinib and quercetin (D/Q) after LPC-induced demyelination resulted in a pro-myelinating effect, indicated by increased MBP staining.
“Similar to AP treatment, we found a two week regiment of D/Q treatment (Fig. 4c) resulted in a pro-myelinating effect as indicated by increased MBP staining (Fig. 4q–t and Supplementary Fig. 7c, f).”
Quote in the paperSubstantial claim - Findingown data
Inhibiting CCL11 in mice partially mimics the beneficial effects of treatment with senolytics on remyelination.
“Furthermore, inhibiting CCL11 in mice partially mimics the beneficial effects of treatment with senolytics on remyelination.”
Quote in the paperSubstantial claim
- Findingown data
No differential expression of SenMayo or DAM genes was observed in AP-treated 18-month-old mouse lesions compared to 3-month-old mouse lesions.
“Additionally, no differential expression of SenMayo or DAM genes was observed in AP treated 18 months old mouse lesions compared to 3 months old mouse lesions (Supplementary Fig. 8b, c).”
Quote in the paperSubstantial claim - Findingown data
AP treatment reduced CCL11 expression in 18-month-old mouse lesions to levels comparable to 3-month-old mice.
“Furthermore, AP treatment reduced its expression in 18 months old mouse lesions to levels comparable to 3 months old mice (Fig. 5d).”
Quote in the paperSubstantial claim - Findingown data
Proteomic analysis of the SASP reveals elevated levels of CCL11/Eotaxin-1 in lesions of aged mice.
“Proteomic analysis of the senescence-associated secretory phenotype (SASP) reveals elevated levels of CCL11/Eotaxin-1 in lesions of aged mice”
Quote in the paperSubstantial claim - Findingown data
Treatment with senolytics reduces the levels of SASP proteins within aged lesions.
“RNA-sequencing and protein multiplexing analyses revealed treatment with senolytics reduces the levels of SASP proteins within aged lesions.”
Quote in the paperSubstantial claim - Findingown data
CCL11 co-labels with IBA1+ microglia in lesions of both 3-month-old and 18-month-old mice.
“and found that CCL11 co-labeled with IBA1+ microglia in lesions of both 3 months old and 18 months old mice (Fig. 5b).”
Quote in the paperSubstantial claim - Findingown data
In individuals with MS and healthy controls, the increase in CCL11 concentration with age paralleled disease progression.
“and interestingly, the increase in CCL11 concentration with age also paralleled disease progression (Fig. 5e).”
- Also stated in: § Discussion · plain
“Interestingly, an elevation of plasma CCL11 level was observed in MS patients with age, concurrent with disease progression.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Findingown data
In mouse lesions at 20 dpl, there were 434 differentially expressed genes between 3-month-old and 18-month-old mice after vehicle treatment, compared to only 70 differentially expressed genes after AP treatment.
“We identified 434 differentially expressed genes between 3 months old and 18 months old mouse lesions following vehicle treatment (Fig. 3j), compared to only 70 differentially expressed genes after AP treatment (Supplementary Fig. 8a).”
Quote in the paperSubstantial claim - Findingown data
Systemic administration of CCL11 neutralizing antibody twice a week during remyelination in 3-month-old mice after LPC-induced demyelination increased MBP staining in lesions at 20 dpl compared to isotype control.
“At 20 dpl, increased MBP staining was observed in lesions of mice treated with CCL11na compared to the isotype control (Fig. 5g, i).”
Quote in the paperSubstantial claim- Rests on an assumption: The CCL11 neutralizing antibody specifically neutralizes CCL11 in vivo.
- Findingown data
CCL11 co-localizes with p16tdt in LPC-induced demyelinated lesions but not in naive control tissue.
“We observed co-localization of CCL11 with p16tdt in lesions but not naïve control tissue (Fig. 5a and Supplementary Fig. 9a)”
Quote in the paperSubstantial claim - Findingown data
CCL11na administration did not affect the number of mature oligodendrocytes in lesions.
“However, CCL11na administration did not affect the number of mature oligodendrocytes in the lesions (Fig. 5h, j)”
Quote in the paperSubstantial claim- Rests on an assumption: The CCL11 neutralizing antibody specifically neutralizes CCL11 in vivo.
- Findingown data
Treatments with senolytics enhance remyelination in young and middle-aged mice but not aged mice.
“treatments with senolytics enhances remyelination in young and middle-aged mice but not aged mice.”
Quote in the paperSubstantial claim - Findingown data
In plasma of individuals with MS and healthy controls, there is a significant association between age and CCL11 concentration across all samples.
“We found a significant association between age and CCL11 concentration across all samples (Supplementary Fig. 9c)”
Quote in the paperNot a substantial claim - Findingown data
Systemic administration of recombinant CCL11 twice a week during remyelination in 3-month-old mice after LPC-induced demyelination did not have any detectable effect on remyelination compared to vehicle.
“We found that rCCL11 administration did not have any detectable effect on remyelination compared to vehicle”
Quote in the paperNot a substantial claim - Findingown data
In SASP protein multiplex data of demyelinated lesions at 20 dpl, CCL11 was upregulated in lesions of 18-month-old mice compared to 3-month-old mice.
“We also analyzed our SASP protein multiplex data of demyelinated lesions at 20 dpl and found that CCL11 was upregulated in the lesions of 18 months old mice compared to those of 3 months old mice (Fig. 5d).”
Quote in the paperSubstantial claim - Findingown data
Elevated CCL11 levels correlate with disease severity in MS.
“we find elevated CCL11 levels correlate with disease severity in MS”
Quote in the paperSubstantial claim - Findingown data
Reanalyzed snRNA-sequencing data show increased myeloid cell expression in the lesion of many anti-apoptotic genes that D/Q targets.
“our reanalyzed snRNA-sequencing data31 shows increased myeloid cell expression in the lesion of many of the anti-apoptotic genes D/Q targets (Supplementary Fig. 7g).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [31] Melchor, G. S., Baydyuk, M., Manavi, Z., Hu, J. & Huang, J. K. Dissecting the evolving cellular landscape of a remyelinating microenvironment. BioRxiv. https://doi.org/10.1101/2024.12.25.630253 (2024). source
- Findingown data
Senescent cells accumulate within demyelinated lesions after injury.
“Here, we show that senescent cells accumulate within demyelinated lesions after injury”
Quote in the paperSubstantial claim - Findingown data
Following CCL11 inhibition during remyelination in young mice, similar beneficial remyelinating effects were observed as when senescent cells were treated with AP and D/Q.
“Additionally, following CCL11 inhibition during remyelination in young mice, we observed similar beneficial remyelinating effects as when senescent cells were treated with AP and D/Q.”
Quote in the paperSubstantial claim- Rests on an assumption: The CCL11 neutralizing antibody specifically neutralizes CCL11 in vivo.
- Findingown data
In an age-dependent manner, there is an increased and prolonged senescence response to demyelination.
“In an age dependent manner, we observe an increased and prolonged senescence response to demyelination”
Quote in the paperSubstantial claim - Findingown data
CCL11/Eotaxin-1 is one of the most drastically altered SASP proteins following senolytic treatment.
“In particular, we found that CCL11/Eotaxin-1 is one of the most drastically altered SASP proteins following senolytic treatment.”
Quote in the paperNot a substantial claim - Findingreasoning
Artificially raising the levels of CCL11 with recombinant protein did not show an effect.
“However, we did not see an effect of artificially raising the levels of CCL11 with recombinant protein.”
Quote in the paperNot a substantial claim - Findingown data
The senescence phenomenon following demyelination increases with age.
“We also find this phenomenon increases with age, which is known to be associated with a reduced capacity to remyelinate.”
Quote in the paperSubstantial claim - Findingown data
Almost all commonly associated DAM genes were upregulated in young lesions at 20 dpl compared to naive control white matter.
“Indeed, we found that almost all commonly associated DAM genes were upregulated in young lesions at 20 dpl compared to naive control white matter (Supplementary Fig. 9g).”
Quote in the paperNot a substantial claim - Findingown data
Differing proportions of cell types show features of senescence with age.
“Analogously, we found differing proportions of cell types showing features of senescence with age (Fig. 2h).”
Quote in the paperNot a substantial claim - Interpretationown data
CCL11 inhibits efficient MBP expression in maturing oligodendrocytes in a cell-autonomous manner.
“This observation suggests CCL11 inhibits efficient MBP expression in maturing oligodendrocytes in a cell-autonomous manner.”
- Also stated in: § Discussion · plain
“Here, we found treatment with recombinant CCL11 in vitro resulted in reduced MBP production in maturing oligodendrocytes in a cell-autonomous manner.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Interpretationown data
Inhibition of CCL11 may prevent senescence-mediated remyelination failure in MS.
“and suggests inhibition of CCL11 may prevent senescence-mediated remyelination failure in MS.”
Quote in the paperSubstantial claim- Rests on an assumption: Plasma CCL11 concentration reflects CNS CCL11 activity relevant to MS lesion remyelination.
- Interpretationown data
Depletion of CCL11 enhances oligodendrocyte maturation by increasing MBP expression.
“and that depletion of CCL11 enhances oligodendrocyte maturation by increasing MBP expression.”
Quote in the paperSubstantial claim- Rests on an assumption: The CCL11 neutralizing antibody specifically neutralizes CCL11 in vivo.
- Interpretationown data
The SASP factor CCL11 contributes to the inhibitory effects of senescent cells on remyelination.
“Taken together, our results suggest the SASP factor CCL11 contributes to the inhibitory effects of senescent cells on remyelination”
Quote in the paperSubstantial claim- Rests on an assumption: The CCL11 neutralizing antibody specifically neutralizes CCL11 in vivo.
- Interpretationreasoning
Therapeutic targeting of SASP components, such as CCL11, may improve remyelination in aging and MS.
“These results suggest therapeutic targeting of SASP components, such as CCL11, may improve remyelination in aging and MS.”
Quote in the paperSubstantial claim - Interpretationreasoning
CCL11 may play a central role in senescence-associated remyelination delay.
“These observations, combined with our findings, suggests CCL11 may play a central role in senescence-associated remyelination delay.”
Quote in the paperSubstantial claim - Interpretationown data
Systemic delivery of rCCL11 into mice may not be sufficient to impact remyelination.
“suggesting systemic delivery of rCCL11 into mice may not be sufficient to impact remyelination (Fig. 5g–j).”
Quote in the paperSubstantial claim - Interpretationown data
The increase in MBP levels following CCL11na treatment was not due to myelin debris accumulation, as indicated by minimal overlap between MBP and LAMP1 in lesions at 20 dpl.
“Analysis of LAMP1, a marker for early lysosomes, in lesions at 20 dpl revealed minimal overlap between MBP and LAMP1, indicating that the increase in MBP levels following CCL11na treatment was not due to myelin debris accumulation (Supplementary Fig. 9e, f).”
Quote in the paperSubstantial claim- Rests on an assumption: The CCL11 neutralizing antibody specifically neutralizes CCL11 in vivo.
- Interpretationown data
SCs limit remyelination through the accumulation of SASP in demyelinated lesions.
“Our results suggest SCs limit remyelination through the accumulation of SASP in demyelinated lesions”
Quote in the paperSubstantial claim - Interpretationown data
Treatment with senolytics alone may not be sufficient to enhance remyelination with age.
“Our study suggests treatment with senolytics alone may not be sufficient to enhance remyelination with age”
Quote in the paperSubstantial claim - Interpretationown data
The blank barcode differential expression pattern supports that there is not an increase of probe identification in either condition.
“further supporting that there is not an increase of probe identification in either condition”
Quote in the paperNot a substantial claim - Interpretationown data
The lack of differential expression of these cell type markers supports that the observed differences are biologically meaningful.
“further supporting that the observed differences are biologically meaningful.”
Quote in the paperNot a substantial claim - Interpretationown data
In the context of remyelination, senescent microglia and macrophages limit remyelination.
“we show here that in the context of remyelination, senescent microglia and macrophages limit remyelination.”
Quote in the paperSubstantial claim - Interpretationown data
The blank barcode differential expression pattern supports that there was not a random increase in gene detection in one condition vs the other.
“and that there was not a random increase in gene detection in one condition vs the other.”
Quote in the paperNot a substantial claim - Interpretationreasoning
The presence of senescent cells is only one of multiple factors limiting remyelination in the aged nervous system.
“Additionally, it is likely that the presence of SCs is only one of multiple factors limiting remyelination in the aged nervous system.”
Quote in the paperNot a substantial claim - Study design and conductcitation
Despite multiple attempts to verify reduction of senescent cells, the efficacy of the treatments in clearing senescent cells could not be confirmed.
“Despite multiple attempts to verify reduction of senescent cells, we were unable to confirm the efficacy of the treatments in clearing senescent cells.”
Quote in the paperSubstantial claim
- May combine two claims. 22
- Classified as probably not a substantial claim. 16
May combine two claims.
PremisecitationCCL11/Eotaxin1 is a chemokine that selectively recruits eosinophils, is elevated with age in humans and mice, and promotes senescence.
“CCL11/Eotaxin1 is a chemokine that selectively recruits eosinophils, is elevated with age in humans and mice52–54, and has been shown to promote senescence55.”
Quote in the paperSubstantial claim4 of 4 sources checked- cites [52] Hoefer, J. et al. The “Aging Factor” Eotaxin-1 (CCL11) Is Detectable in Transfusion Blood Products and Increases with the Donor’s Age. Front. Aging Neurosci. 9, 402 (2017). source
- cites [53] Tashiro, R. et al. Young Astrocytic Mitochondria Attenuate the Elevated Level of CCL11 in the Aged Mice, Contributing to Cognitive Function Improvement. Int. J. Mol. Sci. 24, 5187 (2023). source
- cites [54] Villeda, S. A. et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477, 90–94 (2011). source
- cites [55] Lavandoski, P. et al. Eotaxin-1/CCL11 promotes cellular senescence in human-derived fibroblasts through pro-oxidant and pro-inflammatory pathways. Front. Immunol. 14, 1243537 (2023). source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationD/Q is currently being used in several clinical trials to deplete senescent cells.
“D/Q is currently being used in several clinical trials to deplete senescent cells46,50”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [46] Zhu, Y. et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14, 644–658 (2015). source
The Results sections on candidate senolytic drugs in vitro and on reducing senescent cells in vivo report that D+Q selectively killed senescent cells in culture and reduced senescence markers in mice. The copy does not report D+Q being used in several clinical trials to deplete senescent cells; a search for “clinical trial” found no such passage. The Discussion says only that D and Q are approved for human use, which does not establish the clinical-trial claim. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [50] Gonzales, M. M. et al. Senolytic therapy in mild Alzheimer’s disease: a phase 1 feasibility trial. Nat. Med. 29, 2481–2488 (2023). source
The paper reports its own D/Q clinical trial and, in the Discussion, identifies one ongoing placebo-controlled D/Q trial (NCT04685590). It also mentions earlier human studies for other conditions, but does not establish that several D/Q trials were ongoing at the time. The trials’ aim of targeting senescent cells is supported; actual depletion in this trial was not established. (LLM, conf=0.83)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationCCL11 efficiently crosses the blood brain barrier, has been implicated in neuroinflammatory disorders and SARS-CoV-2 cognitive impairment, and impairs neurogenesis.
“CCL11 efficiently crosses the blood brain barrier56, has been implicated in neuroinflammatory disorders and SARS-CoV-2 (COVID-19) cognitive impairment57,58, and impairs neurogenesis54,58,59.”
Quote in the paperNot a substantial claim4 of 5 sources checked- cites [56] Erickson, M. A., Morofuji, Y., Owen, J. B. & Banks, W. A. Rapid Transport of CCL11 across the Blood-Brain Barrier: Regional Variation and Importance of Blood Cells. J. Pharmacol. Exp. Ther. 349, 497–507 (2014). source
- cites [57] Huber, A. K., Giles, D. A., Segal, B. M. & Irani, D. N. An emerging role for eotaxins in neurodegenerative disease. Clin. Immunol. 189, 29–33 (2018). source
- cites [58] Fernández-Castañeda, A. et al. Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation. Cell 185, 2452–2468.e16 (2022). source
- cites [54] Villeda, S. A. et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477, 90–94 (2011). source
- cites [59] Büttner, R. et al. Inflammaging impairs peripheral nerve maintenance and regeneration. Aging Cell 17, e12833 (2018). source
This source is cited for the neurogenesis clause. The Results section reports that CCL11 reduces Schwann-cell myelination and remyelination, but those processes are not neurogenesis. Searches for neurogenesis and the generation of new neurons found no passage in our copy establishing that CCL11 impairs neurogenesis; the blood–brain barrier and COVID-19 clauses carry other citations. (LLM, conf=0.76)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationOPCs have been suggested to express the primary CCL11 receptor CCR3, and elevated CCL11 levels are associated with MS disease duration and severity.
“Moreover, OPCs have been suggested to express the primary CCL11 receptor, CCR360 and elevated CCL11 levels are associated with MS disease duration and severity61,62.”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [60] Maysami, S. et al. Oligodendrocyte precursor cells express a functional chemokine receptor CCR3: Implications for myelination. J. Neuroimmunol. 178, 17–23 (2006). source
- cites [61] Tejera-Alhambra, M. et al. Plasma Biomarkers Discriminate Clinical Forms of Multiple Sclerosis. PLOS ONE 10, e0128952 (2015). source
The Results report that plasma CCL11 was higher in progressive than relapsing-remitting MS and correlated with EDSS, a measure of disability. The paper notes that progressive patients had longer disease duration, but our copy does not report a direct association between CCL11 levels and disease duration. The OPC/CCR3 statement is attached to a different citation, not this source. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [62] Huang, J. et al. Inflammation-related plasma and CSF biomarkers for multiple sclerosis. Proc. Natl. Acad. Sci. 117, 12952–129960 (2020). source
The Results section on clinical course reports that CCL11 increased with MS disease duration and showed a suggestive increase in secondary progressive versus relapsing–remitting disease. It does not report an association between CCL11 and measured disease severity; the Results and Discussion instead identify CCL20 as associated with severity. The separate CCR3 statement is attached to citation 60, not this source. (LLM, conf=0.90)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim.
Study design and conductcitationThe study utilized multiple complementary methods to characterize and confirm a senescence phenotype following demyelination, in line with recently released guidance for studying senescence.
“With this in mind, here we utilized multiple complementary methods to characterize and confirm a senescence phenotype following demyelination, in line with recently released guidance for studying senescence76.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [76] Ogrodnik, M. et al. Guidelines for minimal information on cellular senescence experimentation in vivo. Cell 187, 4150–4175 (2024). source
May combine two claims.
Findingown dataCCL11 expression level is significantly higher in lesions of 18-month-old mice compared to 3-month-old mice and is relatively absent in naive control tissue of both ages.
“Moreover, the expression level of CCL11 was significantly higher in lesions of 18 months old mice compared to 3 months old mice (Fig. 5c) and is relatively absent in naïve control tissue of both ages (Supplementary Fig. 9a).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataFollowing AP treatment in 18-month-old mice at 20 dpl, multiple SASP factors in lesions, including CCL11, CXCL9, and CCL5, decreased and IL2 increased, and these factors were no longer differentially expressed compared to control naive tissue.
“Following AP treatment, we observed a decrease in multiple SASP factors in lesions, including CCL11, CXCL9, and CCL5, and an increase in IL2, which were no longer differentially expressed compared to control naive tissue (Fig. 4u).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn rat primary oligodendrocyte cultures treated with recombinant CCL11 during differentiation from DIV2 to DIV5, more cells had low MBP expression and fewer cells had high MBP expression compared to control.
“In the rCCL11-treated group, we observed more cells with low MBP expression (Fig. 5m) and fewer cells with high MBP expression (Fig. 5n).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataSenescent microglia and macrophage cells emerge following demyelination and are gradually cleared throughout remyelination.
“Here, we report the emergence of senescent microglia and macrophage cells following demyelination, with gradual clearance throughout remyelination.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn young lesions at 5 dpl, astrocytes and myeloid cells showed the highest percentage of senescent cells, while in aged lesions myeloid cells increased their percentages.
“In young lesions at 5 dpl, astrocytes and myeloid cells showed the highest percentage of senescent cells, while in aged lesions myeloid cells increased their percentages.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingnone givenTreatment with genetic and pharmacologic senolytic methods resulted in increased numbers of mature oligodendrocytes and improved remyelination in lesions of young and middle-aged mice.
“Treatment with genetic and pharmacologic senolytic methods resulted in increased numbers of mature oligodendrocytes and improved remyelination in lesions of young and middle-aged mice.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataTmem119, Aldhl1l, Plp1, Cspg4, Pdgfra, Pecam1 and Cldn5 are not differentially expressed when young and old conditions are compared within lesion and non-lesion areas.
“when we compared the cells within the lesion and non-lesion areas in the old and young conditions, we observed that Tmem119, Aldhl1l, Plp1, Cspg4, Pdgfra, Pecam1 and Cldn5, all cell type markers used to identify the observed populations, are not differentially expressed when young and old conditions are compared”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
FindingreasoningThe study involved both females and males with a female:male ratio of 3:1.
“The study involved both females and males with a female:male ratio of 3:1”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataMultiple SASP factors are dysregulated in aged mouse lesions and were returned to younger levels with treatment of senolytics.
“We also showed that multiple SASP factors are dysregulated in aged mouse lesions and were returned to younger levels with treatment of senolytics.”
Quote in the paperSubstantial claimMay combine two claims.
FindingreasoningTreatment with senolytics did not significantly improve remyelination in aged mice, despite modifying the lesion environment.
“However, we found that treatment with senolytics did not significantly improve remyelination in aged mice, despite modifying the lesion environment.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAP treatment modified SASP profiles within aged lesions but several factors remained elevated.
“Indeed, AP treatment modified SASP profiles within the aged lesions but several factors remained elevated (Fig. 4u).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataOut of the 62 blank barcodes, 95.15% were not differentially expressed between the old and young samples.
“Out of the 62 blank barcodes, 95.15% were not differentially expressed between the old and young samples.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataOf the three blank barcodes that are differentially expressed between old and young conditions, two are upregulated and one downregulated.
“Out of the three blank barcodes that are differentially expressed between old and young conditions, two are upregulated and one downregulated”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataAP treatment reduces senescent cell activity in aged mouse lesions despite the lack of significant improvement in remyelination.
“These findings suggest AP treatment reduces SC activity in aged mouse lesions despite the lack of significant improvement in remyelination.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataCCL11 inhibition influences oligodendrocyte maturation and myelination, but not differentiation.
“suggesting that CCL11 inhibition influences oligodendrocyte maturation and myelination, but not differentiation.”
Quote in the paperSubstantial claim- Rests on an assumption: The CCL11 neutralizing antibody specifically neutralizes CCL11 in vivo.
May combine two claims.
Interpretationown dataIn contrast to aged lesions, which exhibit sustained upregulation of senescence and DAM associated transcripts at 20 dpl, AP treatment reduces these transcripts to levels similar to those in young mice.
“These results suggest that in contrast to lesions in aged mice, which exhibit sustained upregulation of senescence and DAM associated transcripts at 20 dpl, AP treatment reduces these transcripts to levels similar to those in young mice.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataIn aged mice, senescence-associated factors persist within lesions, correlating with inefficient remyelination.
“However, in aged mice, senescence-associated factors persist within lesions, correlating with inefficient remyelination.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataCCL11 level increases with age and MS disease progression.
“These results indicate CCL11 level increases with age and MS disease progression”
Quote in the paperSubstantial claim- Rests on an assumption: Plasma CCL11 concentration reflects CNS CCL11 activity relevant to MS lesion remyelination.
Probably not a substantial claim: may not pass S2 (checkable).
InterpretationreasoningInhibiting lingering SASP activity, such as CCL11, may be a better strategy to improving the lesion environment for remyelination.
“and that inhibiting lingering SASP activity, such as CCL11, may be a better strategy to improving the lesion environment for remyelination.”
Quote in the paperNot a substantial claim- Rests on an assumption: Plasma CCL11 concentration reflects CNS CCL11 activity relevant to MS lesion remyelination.
May combine two claims.
InterpretationreasoningThis study provides an important step to understand how demyelination promotes the accumulation of senescent cells in lesions, and how especially with age, these cells limit remyelination through SASP production.
“In conclusion, this study provides an important step to understand how demyelination promotes the accumulation of senescent cells in lesions, and how especially with age, these cells limit remyelination through SASP production.”
Quote in the paperSubstantial claim- Rests on an assumption: MS exhibits features of increased aging.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenSamples were blinded by cage number and ear-tag where applicable.
“Samples were blinded by cage number and ear-tag where applicable.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenDespite MS predominantly occurring in females, the study did not have statistical power to differentiate the effects of sex.
“Despite MS predominantly occurring in females, we did not have statistical power to differentiate the effects of sex.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe study protocol (2016-1123) was approved by the Institutional Animal Care and Use Committee at Georgetown University.
“The study protocol (2016-1123) was approved by the Institutional Animal Care and Use Committee at Georgetown University.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenSex was not included in the analyses as a covariate to adjust for any effects it may have.
“Sex was not included in the analyses as a covariate to adjust for any effects it may have.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenEach value represents an individual biological sample, where technical replicates have been averaged.
“Each value represents an individual biological sample, where technical replicates have been averaged.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenMBP expression analysis was performed manually, with sample conditions blinded.
“MBP expression analysis was performed manually, with sample conditions blinded.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Interpretationnone givenThe results may apply to both females and males.
“The results may apply to both females and males.”
Quote in the paperNot a substantial claim- Rests on an assumption: Sex does not meaningfully affect the results, so they apply to both females and males.
May combine two claims.
InterpretationreasoningSenescent cells are effectively cleared from demyelinated lesions in young mice, resulting in a transient phenomenon, while the aged immune system may be less adept, leading to inefficient remyelination.
“While SCs are effectively cleared from demyelinated lesions in young mice, resulting in a transient phenomenon, the aged immune system may be less adept, leading to inefficient remyelination.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe small sample sizes for the transcriptomic experiments limit the scope of conclusions that can be inferred.
“The small sample sizes for these transcriptomic experiments limit the scope of conclusions that can be inferred”
Quote in the paperNot a substantial claim
The paper relies on this without support.
MS exhibits features of increased aging.
“Together, since MS exhibits features of increased aging, it is possible that elevated levels of SCs with chronic disease result in increased SASP including CCL11, which inhibit remyelination and promote the deterioration of symptoms.”
The paper relies on this without support.
Plasma CCL11 concentration reflects CNS CCL11 activity relevant to MS lesion remyelination.
“To validate our findings clinically, we also assessed the concentration of CCL11 in the plasma of individuals with MS and healthy controls (Supplementary Fig. 9b).”
The paper relies on this without support.
The CCL11 neutralizing antibody specifically neutralizes CCL11 in vivo.
“we administered a CCL11 neutralizing antibody (CCL11na) systemically twice a week during the remyelination phase in 3 months old mice following LPC-induced demyelination (Fig. 5f).”
The paper relies on this without support.
Sex does not meaningfully affect the results, so they apply to both females and males.
“Sex was not included in the analyses as a covariate to adjust for any effects it may have. The results may apply to both females and males.”
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?
Multiplexed Error-Robust Fluorescence In Situ Hybridization (MERFISH) has mapped senescent-like microglia within demyelinating lesions, linking a localized senescence-associated state to impaired remyelination.
“Multiplexed Error-Robust Fluorescence In Situ Hybridization (MERFISH) has mapped senescent-like microglia within demyelinating lesions, linking a localized senescence-associated state to impaired remyelination [12].”
From Fluorescence-Guided Spatial Mapping of p21-Expressing Senescent Cells in Aged Liver at Single-Cell Resolution (2026) · cites this paper as [12]
Only three cytokines, associated with apoptosis (FasL), adaptive immune system signaling (CD8+ T cells, CCL5) and cellular senescence (SerpinE1), were significantly upregulated in lesions with foamy microglia compared to nonfoamy.
“Only three cytokines, associated with apoptosis (FasL)5,35, adaptive immune system signaling36 (CD8+ T cells, CCL5) and cellular senescence (SerpinE1)37,38, were significantly upregulated in lesions with foamy microglia compared to nonfoamy.”
From Foamy microglia link oxylipins to disease progression in multiple sclerosis (2026) · cites this paper as [37]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Conflicting ages for the 5-day lesion comparison
MinorThe Fig. 3 caption describes the 5-day comparison as young versus middle-aged mice (12 months), but its sample counts identify the older mice as 18 months old.
“c Immunofluorescent staining of p16tdt in young and middle-aged lesions at 5 dpl. d Quantification of p16tdt+ cells in (c) (n = 3 3 m, 2 18 m).”
“Similarly, we observed increased p16tdt+ staining in 12 months old (middle-aged) lesions compared to 3 months old (young) lesions at 10 dpl (Fig. 3a, b), but no difference between ages at 5 dpl (Fig. 3c, d).”
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“Moreover, demyelinated lesions exhibited a signi fi cant increase in transcripts associated with senescence, such as Lgals3 42,43 , Spp1 , and Ctsb , compared to naive tissues (Fig.”
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“Interestingly, MS has been shown to affect chronological aging 23 , and recent evidence of SCs in MS lesions has been reported 24 – 27 .”
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Impact of Age on Multiple Sclerosis Disease Activity and Progression
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Senolytic therapy alleviates physiological human brain aging and COVID-19 neuropathology
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Targeting senescent cells improves functional recovery after spinal cord injury
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Microglia promote remyelination independent of their role in clearing myelin debris
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“Although Cd11b does not distinguish between peripheral myeloid cells and microglia in lesions, previous lineage tracing experiments indicate that microglia are the predominantimmunecellsinthelesionsby10dpl 33,34 .”
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Age is a critical determinant in recovery from multiple sclerosis relapses
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Replication stress as a driver of cellular senescence and aging
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“However, a subset of microglia may proliferate too vigorously, leading to the accumulation of replication stress 82 and the triggering of senescence programming.”
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“…upregulation of genes associated with cellular senescence and microglial activation, including Spp1 and C3 , both part of the SenMayo and DAM genesets, Irf7 , whichhas been shown to inducesenescence 44 , Ccnd1 ,whichishyper-expressed inSCs 45 ,and Efnb3 , which isnecessary for SC survival 46 (Fig.”
Plasma Biomarkers Discriminate Clinical Forms of Multiple Sclerosis
Tejera-Alhambra, M., Casrouge, A., de Andrés, C., Seyfferth, A., Ramos-Medina, R., Alonso, B., Vega, J., Fernández-Paredes, L., Albert, M. L., & Sánchez-Ramón, S. (2015) · PLOS ONE · doi:10.1371/journal.pone.0128952 · Cited by 55 · cited 2× · see citing works
“Moreover, OPCs have been suggested to express the primary CCL11 receptor, CCR3 60 and elevated CCL11 levels are associated with MS disease duration and severity 61,62 .”
BURTON, D. G. A., SHEERIN, A. N., OSTLER, E. L., SMITH, K., GILES, P. J., LOWE, J., RHYS‐WILLIAMS, W., KIPLING, D. G., & FARAGHER, R. G. A. (2007) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1404.026 · Cited by 49 · cited 1× · see citing works
“…upregulation of genes associated with cellular senescence and microglial activation, including Spp1 and C3 , both part of the SenMayo and DAM genesets, Irf7 , whichhas been shown to inducesenescence 44 , Ccnd1 ,whichishyper-expressed inSCs 45 ,and Efnb3 , which isnecessary for SC survival 46 (Fig.”
Timing and cell specificity of senescence drives postnatal lung development and injury
Yao, H., Wallace, J., Peterson, A. L., Scaffa, A., Rizal, S., Hegarty, K., Maeda, H., Chang, J. L., Oulhen, N., Kreiling, J. A., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-35985-4 · Cited by 48 · see citing works
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Identification of distinct and age‐dependent p16<sup>High</sup> microglia subtypes
Talma, N., Gerrits, E., Wang, B., Eggen, B. J. L., & Demaria, M. (2021) · Aging Cell · doi:10.1111/acel.13450 · Cited by 46 · see citing works
Glial aging and its impact on central nervous system myelin regeneration
Rawji, K. S., Neumann, B., & Franklin, R. J. M. (2022) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.14933 · Cited by 46 · cited 2× · see citing works
“Similarly, changes in OPCs with age result in reduced recruitment 72 and limited intrinsic capacity to differentiate 71,73 .”
Zia, S., Hammond, B. P., Zirngibl, M., Sizov, A., Baaklini, C. S., Panda, S. P., Ho, M. F. S., Lee, K. V., Mainali, A., Burr, M. K., et al. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00584-2 · Cited by 40 · see citing works
Self-citationTracking the evolution of CNS remyelinating lesion in mice with neutral red dye
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InfluentialSelf-citationSenescent Microglia Represent a Subset of Disease-Associated Microglia in P301S Mice
Ng, P. Y., Zhang, C., Li, H., & Baker, D. J. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-230109 · Cited by 38 · cited 2× · see citing works
“While the relationship between these phenotypes remains unclear, recent studies suggest DAM are highly proliferative before becoming senescent 77 and that inhibiting microglial proliferation limits DAM and senescent microglia accumulation 37 .”
Drake, S., Zaman, A., Gianfelice, C., Hua, E. M.-L., Heale, K., Afanasiev, E., Klément, W., Stratton, J. A., Prat, A., Zandee, S., et al. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03278-2 · Cited by 36 · cited 2× · see citing works
“Further, it has been shown that P16 could be observed in microglia within the brains of individuals with MS 25 and recently senolytic treatment in a mouse model of MS resulted in reduced microglia and disease severity 27 .”
Lavandoski, P., Pierdoná, V., Maurmann, R. M., Grun, L. K., Guma, F. T. C. R., & Barbé-Tuana, F. M. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1243537 · Cited by 34 · see citing works
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“Moreover, OPCs have been suggested to express the primary CCL11 receptor, CCR3 60 and elevated CCL11 levels are associated with MS disease duration and severity 61,62 .”
Tashiro, R., Ozaki, D., Bautista-Garrido, J., Sun, G., Obertas, L., Mobley, A. S., Kim, G. S., Aronowski, J., & Jung, J. E. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24065187 · Cited by 15 · see citing works
Senescent and disease-associated microglia are modifiable features of aged brain white matterPreprint
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“Moreover, demyelinated lesions exhibited a signi fi cant increase in transcripts associated with senescence, such as Lgals3 42,43 , Spp1 , and Ctsb , compared to naive tissues (Fig.”
Dissecting the evolving cellular landscape of a remyelinating microenvironment
Melchor, G. S., Baydyuk, M., Manavi, Z., Hu, J., & Huang, J. K. (2024) · doi:10.1101/2024.12.25.630253 · Cited by 3 · cited 4× · see citing works
“D/Q is currently being used in several clinical trials to deplete senescent cells 46,50 , and our reanalyzed snRNA-sequencing data 31 shows increased myeloid cell expression in the lesion of many of the anti-apoptotic genes D/Q targets ( Supplementary Fig.”
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Therapeutic approaches targeting aging and cellular senescence in Huntington's disease
Bhat, A. A., Moglad, E. H. O., Afzal, M., Thapa, R., Almalki, W. H., Kazmi, I. A., Alzarea, S. I., Ali, H., Pant, K., Singh, T. G., et al. (2024) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.70053 · Cited by 32 · see citing works
Immune aging and infectious diseases
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“The accumulation of senescent cells, which undergo stable cell cycle arrest and produce a distinct senescence-associated secretory phenotype (SASP), has been reported in age-related diseases, where they actively promote low-grade tissue in fl ammation and further disruption of tissue homeostasis 9 .”
InfluentialChen, Z., Mao, Z., Tang, W., Shi, Y., Liu, J., & You, Y. (2025) · Translational Neurodegeneration · doi:10.1186/s40035-025-00517-1 · Cited by 21 · see citing works
“This result underscores a key role of micro-glial senescence in the pathogenesis of MS. Additionally, the senescence-associated phenotypes in microglia persist within demyelinated lesions during aging, contributing to inefficient remyelination and progressive myelin damage [229].”
Senotherapeutics for Brain Aging Management
Saliev, T. M., & Singh, P. B. (2025) · Neurology International · doi:10.3390/neurolint17120204 · Cited by 15 · see citing works
Cellular Senescence in Glial Cells: Implications for Multiple Sclerosis
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Self-citationFoamy microglia link oxylipins to disease progression in multiple sclerosis
van der Vliet, D., Di, X., Shamorkina, T. M., Coulon-Bainier, C., Pavlovic, A., van der Vliet, I. A. C. M., Zeng, Y., Macnair, W., van Egmond, N., Chen, J. Q. A., et al. (2026) · Nature Neuroscience · doi:10.1038/s41593-026-02302-3 · Cited by 9 · see citing works
Microglial States Are Susceptible to Senescence and Cholesterol Dysregulation in Alzheimer's Disease
Li, B., Wang, S., Kerman, B. E., Hugo, C., Shwab, E. K., Shu, C., Chiba‐Falek, O., Arvanitakis, Z., & Yassine, H. N. (2025) · Aging Cell · doi:10.1111/acel.70189 · Cited by 9 · see citing works
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“Markers of SASPs, such as CCL11, were found to be elevated in lesions of aged mice, suggesting that targeting SnCs can prove to be a beneficial therapeutic option for MS treatment [57].”
Bertoni, G., Ristori, S., & Monti, D. (2026) · Cells · doi:10.3390/cells15080657 · Cited by 9 · see citing works
Interplay Between Aging and Glial Cell Dysfunction: Implications for CNS Health
García‐Domínguez, M. (2025) · Life · doi:10.3390/life15101498 · Cited by 8 · see citing works
“This impairment in the clearance of myelin debris promotes the recruitment and activation of peripheral and CNS resident inflammatory cells, accompanied by sustained microglial activation (Table 1) [136,137].”
Pursuing healthy aging and longevity through natural product and stem cell-driven rejuvenation
Wu, D., Xu, Q., Wu, S., Tan, J., Khan, F. A., Pandupuspitasari, N. S., & Huang, C. (2025) · Biochemical Pharmacology · doi:10.1016/j.bcp.2025.117359 · Cited by 9 · see citing works
Kumar, M., Ray, S., & Sil, S. (2025) · Extracellular Vesicles and Circulating Nucleic Acids · doi:10.20517/evcna.2025.65 · Cited by 8 · see citing works
Microglia Mitochondrial Metabolism in Neurological Diseases
Wang, J., Gao, Y., Chen, Q., Xiong, X., Miao, S., Chen, X., Tang, Y., & Gu, L. (2026) · Molecular Neurobiology · doi:10.1007/s12035-025-05640-8 · Cited by 9 · see citing works
Immunosenescence in multiple sclerosis: New insights and clinical implications
Laroni, A., Vigo, T., Inglese, M., & Uccelli, A. (2025) · Multiple Sclerosis Journal · doi:10.1177/13524585251367611 · Cited by 5 · see citing works
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Targeting senescent microglia in progressive multiple sclerosis: a geroscience-informed approach
Atkinson, J., Dokiburra, A., Groover, H., Godbout, J. P., Segal, B. M., & Zhang, Y. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1681724 · Cited by 6 · see citing works
Evolving insights into the identity and function of dark microglia
Flury, A. G., St‐Pierre, M., Ayata, P., & Tremblay, M. (2025) · Trends in Neurosciences · doi:10.1016/j.tins.2025.11.002 · Cited by 7 · see citing works
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Reversing coma by senolytics and stem cells: the future is now
Ichim, T. E., Ramos, R. A., Rath, A. V., Castellano, J., Azimi, N. A., Veltmeyer, J. D., Koumjian, M. P., Nicole, E. U., Bajnath, A., Lin, E. S., et al. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-07099-6 · Cited by 4 · see citing works
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Microglia States are Susceptible to Senescence and Cholesterol Dysregulation in Alzheimer’s DiseasePreprint
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Potential connections between senescence and chemobrain: An early overview of literature
Melhem, N. Y., Qutifan, S., Alsalem, M., & Saleh, T. (2025) · Ageing Research Reviews · doi:10.1016/j.arr.2025.102896 · Cited by 4 · see citing works
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Alameen, A. A. M., Al‐kuraishy, H. M., Fawzy, M. N., & Batiha, G. E. (2026) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-026-05309-6 · Cited by 3 · see citing works
Neurovascular unit remodeling: focusing on glial cells in stroke injury and recovery
Gong, M., Li, X., Yuan, Q., Lina, P. A. N. G., Ye, X., Li, S., Li, Y., Guo, H., & Jin, S. (2026) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2026.1821227 · Cited by 2 · see citing works
“Aged microglia adopt a senescence-associated secretory phenotype (SASP), characterized by reduced phagocytic activity, impaired resolution of inflammation, and sustained secretion of IL-6, TNF-α , and matrix metalloproteinases (Baixauli-Martín et al., 2025; Gross et al., 2025).”
Demyelination and Remyelination: General Principles
Niu, J., Verkhratsky, A., Butt, A. M., & Yi, C. (2025) · Advances in neurobiology · doi:10.1007/978-3-031-87919-7_9 · Cited by 1 · see citing works
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Oligodendrocytes at the crossroads: Central players and interactive partners in white matter aging
Zhang, X., Yu, P., Chen, Y., Xu, Y., Xu, R., Yang, X., Lv, S., Shang, H., & Hu, Y. (2026) · Ageing Research Reviews · doi:10.1016/j.arr.2026.103034 · Cited by 1 · see citing works
Engineering Immune Cell to Counteract Aging and Aging‐Associated Diseases
Guo, J., Lei, L., Jin, Y., Su, L., Cui, S., & Shi, L. (2026) · Advanced Science · doi:10.1002/advs.202521776 · Cited by 3 · see citing works
Zhang, H., Li, W., Xiao, P., Lu, Z., Tian, Y., & Xu, Y. (2026) · The Journal of Pathology · doi:10.1002/path.70031 · Cited by 1 · see citing works
“Lesions initially result from an in fi l-tration of immune cells along with the expansion and activation of glial cells in the CNS [198].”
Microglial Senescence in Neurodegenerative Diseases: Mechanisms and Therapeutic Perspectives
Liu, Y., Hu, Z., Xiao, Y., Han, X., Cheng, X., & Ye, T. (2026) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.6c00016 · Cited by 1 · see citing works
The Roles of Macrophage Lineage Cells ( MLC s) in Brain Aging
Qin, Q., Zhang, L., Guo, M., Lu, D., Liu, Y., Wang, Z., Hu, M., Wang, S., Kang, X., Yi, H., et al. (2026) · CNS Neuroscience & Therapeutics · doi:10.1002/cns.70873 · Cited by 1 · see citing works
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“…senescent microglia in focal demyelination demonstrated that senescent-like myeloid cells within spinal cord lesions upregulate Lgals3 , Spp1 and other senescence-and DAM-associated markers, which are pronounced in aged mice, and senotherapy improved remyelination in adult but not old mice 58 .”
Single-cell multiomics connects 3D genome and transcriptome alterations in Alzheimer’s disease
Zhang, Y., Lu, X., Kunisky, A. K., Alam, S., Tang, J., Zhang, R., Wang, S., Zhang, H. H., Baroudi, J. K., Ichcho, W., et al. (2026) · Science · doi:10.1126/science.adz1652 · Cited by 3 · see citing works
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Systemic administration of PD-L1 blocking antibodies leads to removal of senescent microgliaPreprint
Androsova, Y., Kertser, A., Partney, H., Nathansohn, B., Ibraheem, A., Abellanas, M. A., Croese, T., Salame, T. M., Akiva, H., Krizhanovsky, V., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.22.695923 · Cited by 1 · see citing works
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“Multiplexed Error-Robust Fluorescence In Situ Hybridization (MERFISH) has mapped senescent-like microglia within demyelinating lesions, linking a localized senescence-associated state to impaired remyelination [12].”
Heitmann, N., Fiene, S., Rambuscheck, L., Eggers, B., Michel, M. F. V., Gude, A.-C., Hendek, H. H., Oberhagemann, S., Klöster, K., Hoffrogge, R., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.08.08.669252
Self-citationCellular Senescence in Multiple Sclerosis (MS)
Dahiya, R., Dahiya, S., Siddique, R., Thapa, R., Bhat, A. A., Hussain, M. S., Singh, T. G., Singh, S. K., Gupta, S., Deb, P. K., et al. (2025) · Springer eBooks · doi:10.1007/978-981-96-8873-9_11
Exercise mitigates Alzheimer’s disease by targeting ferroptosis driven by cellular senescence
Yu, Y., & Chen, K. (2026) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2025.1742209 · Cited by 3 · see citing works
Involvement of microglial aging in neurodegenerative diseases: a focus on multiple sclerosis
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Aging as a modulator of multiple sclerosis pathophysiology
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Microenvironmental Regulation of Central Nervous System Myelination and Remyelination
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Myelin Repair as a Neuroprotective Strategy for Multiple Sclerosis: From Bench to Bedside
Battah, T., Mastorodemos, V., Struecker, E., Mitsikostas, D. D., & Papadopoulos, D. (2026) · Medicina · doi:10.3390/medicina62061183
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- Authors
- Gross, P. S., Durán-Laforet, V., Ho, L. T., Melchor, G. S., Zia, S., Manavi, Z., Barclay, W. E., Lee, S. H., Shults, N., Selva, S., Alvarez, E., Plemel, J. R., Fu, M.-M., Schafer, D. P., & Huang, J. K.
- Affiliations
- Georgetown University (US)
- University of California, Berkeley (US)
- University of Alberta (CA)
- National Institutes of Health (US)
- University of Colorado Anschutz (US)
- University of Massachusetts Chan Medical School (US)
- Corresponding author
- Huang, Jeffrey K.
- ORCID
- Venue
- Nature Communications
- Published
- 2025-03-07
- Volume
- 16
- Issue
- 1
- Pages
- 2283-2283
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC11889183
- OpenAlex
- W4408231483
- Cited by
- 62
- References
- 93
- Citations by year
- 2026: 35 · 2025: 24 · 2024: 3
- FWCI
- 35.11
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (submittedVersion, cc-by-nc-nd)
- PubMed Central (submittedVersion)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- DigitalGeorgetown (Georgetown University Library) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute on Aging (R21AG072327, RF1AG068281)
- National Multiple Sclerosis Society (JF-1806-31381)
- U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (R01NS107523, 2R56NS107523-06, T32NS041218, R01NS117533)
- U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (R01MH113743)
- U.S. Department of Health & Human Services | National Institutes of Health (R24OD036199)
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- cellular senescence, senescence-associated secretory phenotype, remyelination, microglia, macrophages, multiple sclerosis, demyelination, senolytics, aging, oligodendrocyte maturation
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 2026-10-13.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-13.
Cited sources are checked by gpt-6-sol.
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 ›
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