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Cited by 139Telomeres, Telomerase, and SenescenceSingle-cell and spatial transcriptomicsGenetics, Aging, and Longevity in Model Organisms

Spatial mapping of cellular senescence: emerging challenges and opportunities

Open access
Gurkar, Aditi U., Gerencser, Akos A., Mora, Ana L., Nelson, Andrew C., Zhang, Anru R., Lagnado, Anthony B., Enninful, Archibald, Benz, Christopher +37 more·2023·Nature Aging
DOI 10.1038/s43587-023-00446-6PMC PMC10505496
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Abstract

Cellular senescence is a well-established driver of aging and age-related diseases. There are many challenges to mapping senescent cells in tissues such as the absence of specific markers and their relatively low abundance and vast heterogeneity. Single-cell technologies have allowed unprecedented characterization of senescence; however, many methodologies fail to provide spatial insights. The spatial component is essential, as senescent cells communicate with neighboring cells, impacting their function and the composition of extracellular space. The Cellular Senescence Network (SenNet), a National Institutes of Health (NIH) Common Fund initiative, aims to map senescent cells across the lifespan of humans and mice. Here, we provide a comprehensive review of the existing and emerging methodologies for spatial imaging and their application toward mapping senescent cells. Moreover, we discuss the limitations and challenges inherent to each technology. We argue that the development of spatially resolved methods is essential toward the goal of attaining an atlas of senescent cells.

AI snapshot

Written from the paper’s full text.

TL;DR

This review from the SenNet imaging working group argues that mapping senescent cells in tissues requires spatially resolved, multi-marker approaches because no single marker is specific and senescent cells are rare and heterogeneous. It surveys low-plex to high-plex imaging, spatial transcriptomics, image analysis, and deep learning, emphasizing limitations and opportunities toward a senescence atlas.

Key findings

  • Senescent cells lack a stand-alone specific marker; commonly used markers such as SA-β-Gal, p16INK4a, and p21CIP1 can appear in non-senescent contexts, so the field favors multi-marker detection. Senescent cells may be present below 5% in aged tissues, making rare-cell detection difficult.
  • Spatial context is essential because senescent cells communicate with neighbors through the SASP, influencing immune recruitment, proliferation, angiogenesis, inflammation, epithelial-to-mesenchymal transition, tissue repair, and wound healing.
  • High-plex spatial proteomics can measure roughly 10–60 proteins with tagged antibodies, barcoded platforms may exceed 100 targets, and mass-spectrometry platforms can use up to 40 metal-conjugated antibodies; however, platforms differ in resolution, throughput, tissue area, antibody validation needs, and whether they destroy the sample.
  • Spatial transcriptomics spans targeted FISH-based methods with hundreds of genes (for example, Xenium panels of 300–400 genes plus up to 100 custom probes), unbiased Visium with spots around 50 μm and 100 μm spacing over a 6.5 × 6.5 mm area (version 2: 11 × 11 mm), and ultra-high-resolution methods such as Seq-Scope, Stereo-seq, and PIXEL-seq reaching up to about 23 unique transcripts per μm². Deep learning applied to H&E and DAPI images predicted senescence; breast tissue from 67 healthy individuals scored 460,000 nuclei, and skin biopsies from more than 160 individuals showed predicted dermal senescence increasing with age.

Methods

  • Narrative review by the SenNet imaging mapping working group, synthesizing existing and emerging spatial imaging, spatial omics, image-analysis, and deep-learning methods for detecting senescent cells.
  • No primary experimental cohort or new data are reported; the work draws on cited literature and consortium examples, with tables comparing platforms and figures illustrating workflows.
  • The main analysis is a qualitative comparison of technologies by plex level, resolution, throughput, tissue compatibility, and suitability for rare senescent cells.

Limitations

  • Stated: no universal senescence marker exists; markers are nonspecific; senescent cells are rare (below 5% in aged tissues) and heterogeneous; antibody validation is problematic, especially for mouse p16INK4a; platform constraints include limited tissue area, low throughput, long acquisition, cost, autofluorescence, fixation effects, destructive mass imaging, and inability to resolve single cells for some methods.
  • Stated: computational challenges include segmentation errors, deconvolution difficulty distinguishing senescent from non-senescent cells within a cell type, lack of annotated reference scRNA-seq datasets, and unknown benchmark performance for senescent-cell deconvolution.
  • Evident from the text: as a review, it provides no new experimental validation or systematic benchmarking; many proposed integrations and deep-learning pipelines are described as future or in-progress rather than fully validated.

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

Integrity signals

Registry

Crossref · 10.1038/s43587-023-00446-6

Cites

109 of 109 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

66 of 81 cited sources checked · 45 supported · 1 flagged · accuracy not yet measured

  • Premisereasoning

    There is no single, stand-alone marker to identify a senescent cell.

    “One major challenge is that there is no single, stand-alone marker to identify a senescent cell.”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [6] Severino, J., Allen, R. G., Balin, S., Balin, A. & Cristofalo, V. J. Is β-galactosidase staining a marker of senescence in vitro and in vivo? Exp. Cell Res. 257, 162–171 (2000). source
    • cites [7] Hall, B. M. et al. Aging of mice is associated with p16Ink4a- and β-galactosidase-positive macrophage accumulation that can be induced in young mice by senescent cells. Aging 8, 1294–1315 (2016). source
    • cites [8] Ogrodnik, M., Salmonowicz, H., Jurk, D. & Passos, J. F. Expansion and cell-cycle arrest: common denominators of cellular senescence. Trends Biochem. Sci. 44, 996–1008 (2019). source
  • Premisecitation

    Several studies have used single-cell technologies to successfully identify senescence-associated signatures in the context of aging.

    “Several studies have used single-cell technologies to successfully identify senescence-associated signatures in the context of aging12,13.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [12] Zhang, X. et al. Characterization of cellular senescence in aging skeletal muscle. Nat. Aging 2, 601–615 (2022). source
    • cites [13] Ogrodnik, M. et al. Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice. Aging Cell 20, e13296 (2021). source
  • Premisecitation

    p16INK4a and p21CIP1 can be expressed irrespectively of senescence in certain contexts.

    “For example, the commonly used marker senescence-associated β-galactosidase (SA-β-Gal) at pH 6 can be detected in vitro in confluent and immortalized cells6 and in activated macrophages7, while cell cycle kinase inhibitors p16INK4a and p21CIP1 can be expressed irrespectively of senescence in certain contexts7,8.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [7] Hall, B. M. et al. Aging of mice is associated with p16Ink4a- and β-galactosidase-positive macrophage accumulation that can be induced in young mice by senescent cells. Aging 8, 1294–1315 (2016). source

      The Discussion (page unavailable) reports p16INK4a expression in non-senescent macrophages, supporting the claim for p16INK4a. The Introduction lists p21 as a senescence-associated marker but does not establish that it can be expressed independently of senescence, so that part is not supported by this paper. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [8] Ogrodnik, M., Salmonowicz, H., Jurk, D. & Passos, J. F. Expansion and cell-cycle arrest: common denominators of cellular senescence. Trends Biochem. Sci. 44, 996–1008 (2019). source
  • Premisecitation

    Elimination of senescent cells in mice either genetically or by senolytics alleviates several pathologies during aging and age-related disorders.

    “Importantly, several studies have shown that elimination of senescent cells in mice either genetically or by using drugs that can kill senescent cells (senolytics) alleviates several pathologies during aging and age-related disorders2.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [2] Robbins, P. D. et al. Senolytic drugs: reducing senescent cell viability to extend health span. Annu. Rev. Pharmacol. Toxicol. 61, 779–803 (2021). source
  • Premisecitation

    None of the markers used to detect senescent cells are individually specific.

    “None of the markers used to detect senescent cells are individually specific.”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [6] Severino, J., Allen, R. G., Balin, S., Balin, A. & Cristofalo, V. J. Is β-galactosidase staining a marker of senescence in vitro and in vivo? Exp. Cell Res. 257, 162–171 (2000). source
    • cites [7] Hall, B. M. et al. Aging of mice is associated with p16Ink4a- and β-galactosidase-positive macrophage accumulation that can be induced in young mice by senescent cells. Aging 8, 1294–1315 (2016). source
    • cites [8] Ogrodnik, M., Salmonowicz, H., Jurk, D. & Passos, J. F. Expansion and cell-cycle arrest: common denominators of cellular senescence. Trends Biochem. Sci. 44, 996–1008 (2019). source
  • May combine two claims. 41
  • Classified as probably not a substantial claim. 23

  • May combine two claims.

    Premisecitation

    Innovations for unbiased mass spectrometry-based studies are evolving to query a larger swath of the proteome and metabolome with spatial orientation in tissues, although these methods are still fairly limited in throughput and resolution, restricting their application to mapping rare senescent cells.

    “As an alternative to antibody-based methods, innovations for unbiased mass spectrometry-based studies are evolving to query a larger swath of the proteome and metabolome with spatial orientation in tissues, although these methods are still fairly limited in throughput and resolution43,44, restricting their application to mapping rare senescent cells.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [43] Taylor, M. J., Liyu, A., Vertes, A. & Anderton, C. R. Ambient single-cell analysis and native tissue imaging using laser-ablation electrospray ionization mass spectrometry with increased spatial resolution. J. Am. Soc. Mass Spectrom. 32, 2490–2494 (2021). source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 1 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [44] Buczak, K. et al. Spatially resolved analysis of FFPE tissue proteomes by quantitative mass spectrometry. Nat. Protoc. 15, 2956–2979 (2020). source

  • May combine two claims.

    Premisecitation

    SA-β-Gal at pH 6 can be detected in vitro in confluent and immortalized cells and in activated macrophages.

    “For example, the commonly used marker senescence-associated β-galactosidase (SA-β-Gal) at pH 6 can be detected in vitro in confluent and immortalized cells6 and in activated macrophages7, while cell cycle kinase inhibitors p16INK4a and p21CIP1 can be expressed irrespectively of senescence in certain contexts7,8.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [6] Severino, J., Allen, R. G., Balin, S., Balin, A. & Cristofalo, V. J. Is β-galactosidase staining a marker of senescence in vitro and in vivo? Exp. Cell Res. 257, 162–171 (2000). source
    • cites [7] Hall, B. M. et al. Aging of mice is associated with p16Ink4a- and β-galactosidase-positive macrophage accumulation that can be induced in young mice by senescent cells. Aging 8, 1294–1315 (2016). source

      The Results (Nature of cells attracted by SCs into peritoneal cavity; page unavailable) report elevated β-galactosidase activity at pH 6 in macrophages elicited by senescent cells. That supports detection in some macrophages, but the reported macrophage finding is in mice, not an in-vitro demonstration. The Discussion (page unavailable) also cautions that β-galactosidase activity does not increase with every type of macrophage activation. The confluent and immortalized cell clause is attached to a different citation and is not judged here. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Senescent cells have important physiological roles and their clearance may be detrimental in certain conditions.

    “It should be noted, however, that senescent cells also have important physiological roles and that their clearance may be detrimental in certain conditions3–5.”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [3] Demaria, M. et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev. Cell 31, 722–733 (2014). source
    • cites [4] Born, E. et al. Eliminating senescent cells can promote pulmonary hypertension development and progression. Circulation 147, 650–666 (2023). source
    • cites [5] Reyes, N. S. et al. Sentinel p16INK4a+ cells in the basement membrane form a reparative niche in the lung. Science 378, 192–201 (2022). source

  • May combine two claims.

    Premisecitation

    Senescent cells can induce senescence in neighboring cells and, through the SASP, recruit immune cells to their vicinity.

    “Senescent cells can induce senescence in neighboring cells14,15 and, through the SASP, recruit immune cells to their vicinity.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [14] Acosta, J. C. et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat. Cell Biol. 15, 978–990 (2013). source
    • cites [15] Xu, M. et al. Senolytics improve physical function and increase lifespan in old age. Nat. Med. 24, 1246–1256 (2018). source

  • May combine two claims.

    Premisecitation

    Expression of p21CIP1, p16INK4A, p53, DDR components (γH2A.X and 53BP1), decreased lamin B1, loss of nuclear HMGB1 and expression of GLB1 are common senescence-associated markers assessed in tissues by immunohistochemistry and immunofluorescence.

    “Expression of p21CIP1, p16INK4A, p53, components of the DNA damage response (DDR; for example, γH2A.X and 53BP1)22, decreased lamin B1 (ref. 23), loss of nuclear high-mobility group box 1 (HMGB1)24 and expression of GLB1 (ref. 25) (which encodes lysosomal β-d-galactosidase) are common senescence-associated markers assessed in tissues by immunohistochemistry and immunofluorescence.”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [22] Wang, C. et al. DNA damage response and cellular senescence in tissues of aging mice. Aging Cell 8, 311–323 (2009). source
    • cites [23] Freund, A., Laberge, R. M., Demaria, M. & Campisi, J. Lamin B1 loss is a senescence-associated biomarker. Mol. Biol. Cell 23, 2066–2075 (2012). source
    • cites [24] Davalos, A. R. et al. p53-dependent release of alarmin HMGB1 is a central mediator of senescent phenotypes. J. Cell Biol. 201, 613–629 (2013). source

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

    Premisecitation

    Structured illumination microscopy was used to estimate the density of nuclear pores.

    “For example, structured illumination microscopy was used to estimate the density of nuclear pores33.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [33] Boumendil, C., Hari, P., Olsen, K. C. F., Acosta, J. C. & Bickmore, W. A. Nuclear pore density controls heterochromatin reorganization during senescence. Genes Dev. 33, 144–149 (2019). source

  • May combine two claims.

    Premisecitation

    Lipofuscin detection can be applied to FFPE tissues and combined with other immunohistochemical techniques.

    “Advantages of this method are that it can be applied to FFPE tissues and combined with other immunohistochemical techniques.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [21] Georgakopoulou, E. A. et al. Specific lipofuscin staining as a novel biomarker to detect replicative and stress-induced senescence. A method applicable in cryo-preserved and archival tissues. Aging 5, 37–50 (2013). source

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

    Premisecitation

    RNA-ISH methods can be applied to both frozen and FFPE tissue sections.

    “These methods can be applied to both frozen and FFPE tissue sections.”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [13] Ogrodnik, M. et al. Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice. Aging Cell 20, e13296 (2021). source

      The Methods > RNA-ISH section describes applying RNAscope to paraffin tissue sections, supporting the FFPE portion of the claim. It does not describe RNA-ISH on frozen sections; searches for frozen sections and FFPE found no such passage. Page numbers are not available in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [16] Lagnado, A. et al. Neutrophils induce paracrine telomere dysfunction and senescence in ROS-dependent manner. EMBO J. 40, e106048 (2021). source

      The Materials and Methods section (page unavailable) describes RNA-ISH on paraffin tissue sections, supporting its use on FFPE sections. It does not describe RNA-ISH on frozen sections; the frozen liver tissue mentioned elsewhere was reserved for biochemical analyses. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [31] Ogrodnik, M. et al. Obesity-induced cellular senescence drives anxiety and impairs neurogenesis. Cell Metab. 29, 1061–1077 (2019). source

      The STAR★Methods section on RNA in situ hybridization describes applying RNA-ISH to paraffin sections. It does not describe RNA-ISH on frozen sections, and it does not explicitly say the paraffin sections were formalin-fixed, so the claim about both frozen and FFPE tissue is not fully supported. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Super-resolution microscopy permits imaging cellular compartments at a resolution beyond the diffraction limit of light (<200 nm).

    “Super-resolution microscopy has emerged as having great potential to investigate biological samples at unprecedented levels of detail, as new and powerful fluorescence-based methods now permit imaging cellular compartments at a resolution beyond that of the diffraction limit of light (<200 nm).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [32] Valli, J. et al. Seeing beyond the limit: a guide to choosing the right super-resolution microscopy technique. J. Biol. Chem. 297, 100791 (2021). source

  • May combine two claims.

    Premisecitation

    Thorough in situ characterization of DDR foci requires high-resolution imaging to detect and quantify distinct intranuclear puncta, as DDR foci are often under 1 μm.

    “Thorough in situ characterization of DDR foci also requires high-resolution imaging to detect and quantify distinct intranuclear puncta, as DDR foci are often under 1 μm34,35.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [34] Rodier, F. et al. DNA-SCARS: distinct nuclear structures that sustain damage-induced senescence growth arrest and inflammatory cytokine secretion. J. Cell Sci. 124, 68–81 (2011). source

      The Introduction says DNA damage foci can be detected in cell nuclei by fluorescence microscopy, and the Results describe monitoring and distinguishing small from enlarged foci. However, our copy does not establish that high-resolution imaging is required or that DDR foci are often under 1 μm (searched for size, resolution, and imaging requirements). (LLM, conf=0.78)

      Experimental — accuracy not yet measured
    • cites [35] Anderson, R. et al. Length-independent telomere damage drives post-mitotic cardiomyocyte senescence. EMBO J. 38, e100492 (2019). source

      The Discussion (page unavailable) says super-resolution STED microscopy improved the resolution of clustered telomere signals, supporting the need for higher-resolution imaging to distinguish nearby signals. It does not establish that DDR foci are often under 1 μm or that this size is why high-resolution imaging is required for their in situ characterization. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    HMGB1, a ubiquitous and predominantly nuclear protein, localizes to the cytoplasm and is secreted during senescence.

    “For example, HMGB1, a ubiquitous and predominantly nuclear protein, localizes to the cytoplasm and is secreted during senescence24.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [24] Davalos, A. R. et al. p53-dependent release of alarmin HMGB1 is a central mediator of senescent phenotypes. J. Cell Biol. 201, 613–629 (2013). source

  • May combine two claims.

    Premisecitation

    Visium has been used to investigate the spatial characteristics of cellular senescence in mouse and human brains and to decipher age-dependent tissue-regeneration capabilities.

    “Already there are reports of Visium being used to investigate the spatial characteristics of cellular senescence in mouse52 and human brains53 as well as to decipher age-dependent tissue-regeneration capabilities54.”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [52] Kiss, T. et al. Spatial transcriptomic analysis reveals inflammatory foci defined by senescent cells in the white matter, hippocampi and cortical grey matter in the aged mouse brain. GeroScience 44, 661–681 (2022). source
    • cites [53] Xu, P. et al. The landscape of human tissue and cell type specific expression and co-regulation of senescence genes. Mol. Neurodegener. 17, 5 (2022). source
    • cites [54] Tower, R. J. et al. Spatial transcriptomics reveals metabolic changes underly age-dependent declines in digit regeneration. eLife 11, e71542 (2022). source

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

    Premisecitation

    Loss of lamin-associated domains has been primarily investigated via electron microscopy techniques.

    “The ability of STORM to provide a detailed rendering of the structure of chromatin fibers37 makes it ideal to investigate changes in heterochromatin distribution within senescent nuclei, such as the loss of lamin-associated domains38, which has been primarily investigated via electron microscopy techniques39.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [39] De Cecco, M. et al. Genomes of replicatively senescent cells undergo global epigenetic changes leading to gene silencing and activation of transposable elements. Aging Cell 12, 247–256 (2013). source

      The Results (page not provided) report using electron microscopy to find reduced staining of peripheral heterochromatin in senescent nuclei. The paper does not establish that lamin-associated domains themselves were lost or that their loss has primarily been investigated by electron microscopy. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Levels of lamin B1, a component of the nuclear lamina, decrease during senescence, and its detection requires sufficient resolution to visualize a 30-100-nm-thick structure.

    “Similarly, levels of lamin B1, which is a component of the nuclear lamina, decrease during senescence23, and its detection requires sufficient resolution to visualize a 30–100-nm-thick structure.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [23] Freund, A., Laberge, R. M., Demaria, M. & Campisi, J. Lamin B1 loss is a senescence-associated biomarker. Mol. Biol. Cell 23, 2066–2075 (2012). source

  • May combine two claims.

    Premisecitation

    Methods such as CyCIF and 4i, which do not require proprietary instrumentation, allow elution of antibodies in relatively mild conditions that preserve sample structure up to and possibly over 20 rounds of elution and imaging, allowing detection of over 40 protein targets.

    “Methods such as cyclic immunofluorescence (CyCIF)45 and iterative indirect immunofluorescence imaging (4i)46, which do not require proprietary instrumentation, allow the elution of antibodies in relatively mild conditions that preserve the sample structure up to and possibly over 20 rounds of elution and imaging, allowing the detection of over 40 protein targets.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [45] Lin, J. R., Fallahi-Sichani, M., Chen, J. Y. & Sorger, P. K. Cyclic immunofluorescence (CycIF), a highly multiplexed method for single-cell imaging. Curr. Protoc. Chem. Biol. 8, 251–264 (2016). source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [46] Gut, G., Herrmann, M. D. & Pelkmans, L. Multiplexed protein maps link subcellular organization to cellular states. Science 361, eaar7042 (2018). source

  • May combine two claims.

    Premisecitation

    p21CIP1-positive nuclei exhibited higher predicted levels of senescence in multiple tissues, while proliferating cells showed lower levels.

    “Interestingly, p21CIP1-positive nuclei exhibited higher predicted levels of senescence in multiple tissues, while proliferating cells (indicated by 5-ethynyl-2′-deoxyuridine (EdU) incorporation) showed lower levels65.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [65] Heckenbach, I. et al. Nuclear morphology is a deep learning biomarker of cellular senescence. Nat. Aging 2, 742–755 (2022). source

  • May combine two claims.

    Premisecitation

    PIXEL-seq uses DNA arrays called 'polony gels' that capture tissue RNA from a single-cell layer touching the gel, improving single-cell resolution.

    “Furthermore, PIXEL-seq uses DNA arrays called ‘polony gels’, which capture tissue RNA from a single-cell layer touching the gel, similar to confocal microscopy, and restrain template diffusion, thus improving single-cell resolution63.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [63] Fu, X. et al. Polony gels enable amplifiable DNA stamping and spatial transcriptomics of chronic pain. Cell 185, 4621–4633 (2022). source

  • May combine two claims.

    Premisecitation

    High-resolution methods Seq-Scope, Stereo-seq and PIXEL-seq provide submicrometer resolution and highly efficient transcriptome-capture efficiency up to ~23 unique transcripts per μm2.

    “Recently, several ultra-high-resolution technologies such as Seq-Scope61, Stereo-seq62 and polony-indexed library sequencing (PIXEL-seq)63 have been developed, which could prove ideal for identification and characterization of senescent cells and their interactions with the environment. In addition to providing submicrometer resolution, which is comparable to that of optical microscopy, these meth”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [61] Cho, C.-S. et al. Microscopic examination of spatial transcriptome using Seq-Scope. Cell 184, 3559–3572 (2021). source
    • cites [62] Chen, A. et al. Spatiotemporal transcriptomic atlas of mouse organogenesis using DNA nanoball-patterned arrays. Cell 185, 1777–1792 (2022). source
    • cites [63] Fu, X. et al. Polony gels enable amplifiable DNA stamping and spatial transcriptomics of chronic pain. Cell 185, 4621–4633 (2022). source

      The Introduction identifies this paper as the report of Pixel-seq and describes high-resolution tissue mapping with efficient RNA capture; the mouse olfactory-bulb Results likewise report high capture efficiency. But the Results describe Pixel-seq’s assay feature resolution as 1 μm, while the submicrometer figure refers to gel-to-gel replication. Our copy does not report ~23 unique transcripts per μm² or establish that figure for all three named methods; pages are not provided in the indexed copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Deep learning methods have been developed to detect senescent cells in culture with phase-contrast imaging and tissues with H&E and DAPI staining.

    “Deep learning methods have been recently developed to detect senescent cells in culture with phase-contrast imaging99 and tissues with H&E and DAPI staining65.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [99] Kusumoto, D. et al. Anti-senescent drug screening by deep learning-based morphology senescence scoring. Nat. Commun. 12, 257 (2021). source
    • cites [65] Heckenbach, I. et al. Nuclear morphology is a deep learning biomarker of cellular senescence. Nat. Aging 2, 742–755 (2022). source

  • May combine two claims.

    Premisecitation

    Predicted senescence in the dermis of more than 160 individuals increased with age and showed expected associations with disease outcomes.

    “Further analysis of skin biopsies revealed that predicted senescence in the dermis of more than 160 individuals increased with age and showed expected associations with disease outcomes.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [65] Heckenbach, I. et al. Nuclear morphology is a deep learning biomarker of cellular senescence. Nat. Aging 2, 742–755 (2022). source

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

    Premisecitation

    DBiT-seq is an unbiased multiomic approach that allows for spatial barcoding of the transcriptome in tissues.

    “DBiT-seq is an unbiased multiomic approach that allows for spatial barcoding of the transcriptome in tissues57.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [57] Liu, Y. et al. High-spatial-resolution multi-omics sequencing via deterministic barcoding in tissue. Cell 183, 1665–1681 (2020). source

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

    Interpretationnone given

    There are many challenges to mapping senescent cells in tissues, including the absence of specific markers, their relatively low abundance, and their vast heterogeneity.

    “There are many challenges to mapping senescent cells in tissues such as the absence of specific markers and their relatively low abundance and vast heterogeneity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The spatial component is essential in understanding senescence because senescent cells communicate with neighboring cells, impacting their function and the composition of extracellular space.

    “The spatial component is essential, as senescent cells communicate with neighboring cells, impacting their function and the composition of extracellular space.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    Single-cell technologies have allowed unprecedented characterization of senescence.

    “Single-cell technologies have allowed unprecedented characterization of senescence; however, many methodologies fail to provide spatial insights.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    Low-plex methods have advantages: they are established, widely used, inexpensive, relatively easy to apply, and generally reproducible.

    “There are, however, several advantages: these techniques are established, widely used and inexpensive; as such, protocols are relatively easy to apply and are generally reproducible.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Factors such as tissue processing and autofluorescence greatly affect image quality and readout accuracy.

    “Factors such as tissue processing and autofluorescence greatly affect image quality and readout accuracy.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    All low-plex methods mentioned have the limitation of detecting one or relatively few biomolecules simultaneously and are therefore not adequate to characterize the molecular heterogeneity of senescent cells in a spatially resolved manner.

    “All methods mentioned here have the limitation of detecting one or relatively few biomolecules simultaneously and are therefore not adequate to characterize the molecular heterogeneity of senescent cells in a spatially resolved manner.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Preparation and preservation of the cell suspension can affect the final proportion of cells that are sampled.

    “Preparation and preservation of the cell suspension can affect the final proportion of cells that are sampled.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    In immunohistochemical techniques, common challenges in visualizing senescence-associated markers include low antigen expression, lack of primary antibody specificity, variability between antibodies, cross-reactivity, autofluorescence, and tissue fixation quality.

    “In immunohistochemical techniques, common challenges in visualizing senescence-associated markers are low levels of antigen expression, lack of specificity of the primary antibody, variability between antibodies even from the same manufacturer, cross-reactivity between primary and/or secondary antibodies, autofluorescence, quality of tissue fixation and others.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Detection of SA-β-Gal activity at pH 6.0 is a common method used to detect senescent cells.

    “Detection of the activity of the lysosomal enzyme SA-β-Gal at pH 6.0 is a common method used to detect senescent cells20.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Dimri, G. P. et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl Acad. Sci. USA 92, 9363–9367 (1995). source

  • May combine two claims.

    Premisecitation

    SA-β-Gal detection requires frozen tissue sections and is not applicable to formalin-fixed paraffin-embedded (FFPE) samples.

    “Limitations of this methodology for identification of senescent cells are that it requires frozen tissue sections (not applicable to formalin-fixed paraffin-embedded (FFPE) samples) and its diffused cytoplasmic staining can be challenging to evaluate.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Dimri, G. P. et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl Acad. Sci. USA 92, 9363–9367 (1995). source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Many commercially available antibodies targeting mouse p16INK4A are unspecific, making its detection in tissues unreliable.

    “In addition, it is well established within the senescence community that many commercially available antibodies that target mouse p16INK4A are unspecific, making its detection in tissues unreliable.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Both TAF and SADS methods require high-resolution fluorescence imaging, generation of z stacks, and have high analytical burden, and therefore are not amenable to large-scale studies.

    “Both methods require high-resolution fluorescence imaging, generation of z stacks (to acquire three-dimensional (3D) images) and have high analytical burden and therefore are not amenable to large-scale studies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Expression of p16INK4A protein ranges from undetectable to qualitatively low in aged tissues and requires a consistent and robust limit of detection sensitivity for accurate studies.

    “For instance, expression of p16INK4A protein ranges from undetectable to qualitatively low in aged tissues and is an example of a senescence-associated marker that requires a consistent and robust limit of detection sensitivity for accurate studies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Image resolution using barcoded antibody systems is similar to that of cyclical staining methods, although fluorescence-based detection may still suffer from high noise-to-signal ratios for low-expression targets such as p16INK4A, particularly in tissues that have undergone harsh fixation.

    “Image resolution using these systems is similar to that of the aforementioned cyclical staining methods, although fluorescence-based detection may still suffer from high noise-to-signal ratios for low-expression targets such as p16INK4A, particularly in tissues that have undergone harsh fixation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Iterative immunofluorescence methods, such as MACSima and CellScape, are capable of imaging with enough resolution to detect subtle changes in organelle structure and morphology (100-200 nm per pixel) and do not require specialized antibody conjugations.

    “Iterative immunofluorescence methods, such as MACSima and CellScape, are capable of imaging with enough resolution to detect subtle changes in organelle structure and morphology (100–200 nm per pixel) and do not require specialized antibody conjugations, which are time consuming and expensive and have the potential to negatively affect their ability to recognize targets.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    All iterative immunofluorescence methods share caveats: repeated rounds of staining and bleaching may alter epitope stability and are subject to incomplete fluorophore inactivation between cycles.

    “However, all iterative immunofluorescence methods share several caveats in their application. Repeated rounds of staining and bleaching may alter epitope stability and are subject to incomplete fluorophore inactivation between cycles.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Mass imaging obliterates the tissue sample, rendering multiplexed ion beam imaging (MIBI) and imaging mass cytometry (IMC) incompatible with sequential analyses.

    “Furthermore, mass imaging obliterates the tissue sample, rendering multiplexed ion beam imaging (MIBI) and imaging mass cytometry (IMC) incompatible with sequential analyses.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    Platforms that limit the imageable tissue area (CosMx, MACSima, CellScape, PhenoCycler, IMC) may altogether miss populations of senescent cells, which may be unequally distributed, in subsections of larger tissues.

    “Irrespective of staining and detection modalities, platforms that limit the imageable tissue area (CosMx, MACSima, CellScape, PhenoCycler, IMC) may altogether miss populations of senescent cells, which may be unequally distributed, in subsections of larger tissues.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    The majority of current high-plex spatial proteomic platforms use panels of tagged antibodies to detect and quantify between ten and 60 proteins, although some have reported higher numbers.

    “The majority of current high-plex spatial proteomic platforms use panels of tagged antibodies to detect and quantify between ten and 60 proteins, although some have reported higher numbers.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    The microfluidic STORM method is technically limiting and expensive.

    “This method, however, is technically limiting and expensive.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Mass spectrometry-based platforms use up to 40 different metal-conjugated antibodies in a single staining and detection step and permit highly sensitive protein detection.

    “Mass spectrometry-based platforms, which use up to 40 different metal-conjugated antibodies in a single staining and detection step, permit highly sensitive protein detection.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Visium's low resolution makes it unsuitable for profiling single cells, so isolating the senescent cell transcriptome and characterizing their spatial location will not be precise.

    “Although Visium is an unbiased spatial transcriptomic solution, its low resolution (100 μm center to center; by comparison, the naked human eye has a resolution of ~40 μm) makes it unsuitable for profiling single cells. Therefore, isolating the senescent cell transcriptome and characterizing their spatial location will not be precise.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Visium provides robust spatially resolved whole-transcriptome evaluation at relatively low resolution and discontinuous detection area.

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

    Premisereasoning

    Many laboratories have taken advantage of microfluidic systems to image multiple cycles of STORM using the same dye.

    “To overcome this limitation, many laboratories have taken advantage of microfluidic systems to image multiple cycles of STORM using the same dye.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    NanoString GeoMx is a spatial omics platform for analysis of RNA (whole transcriptome) or proteins (over 100-plex) that uses photocleavable oligonucleotide barcodes coupled to RNA probes or antibodies.

    “NanoString GeoMx is a spatial omics platform for analysis of RNA (whole transcriptome) or proteins (over 100-plex) that uses photocleavable oligonucleotide barcodes that are coupled to RNA probes or antibodies.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] Merritt, C. R. et al. Multiplex digital spatial profiling of proteins and RNA in fixed tissue. Nat. Biotechnol. 38, 586–599 (2020). source

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

    Interpretationreasoning

    A solution to overcome the analytical and storage problem is to use conventional widefield microscopy to identify putative senescent cells, which are then targeted for super-resolution imaging.

    “A solution to overcome this problem is to use conventional widefield microscopy to identify putative senescent cells, which are then targeted for super-resolution imaging.”
    Quote in the paperNot a substantial claim

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

    Premisereasoning

    In barcoded antibody platforms, the diversity of barcode conjugates makes them unparalleled in their plex limit, potentially exceeding 100 targets on a single tissue section.

    “In these platforms, the diversity of barcode conjugates makes them unparalleled in their plex limit, potentially exceeding 100 targets on a single tissue section.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Probes targeting SA-β-Gal stain lysosomes specifically, which vary in size from 100 nm to over 1 μm.

    “Probes targeting SA-β-Gal will stain the lysosomes specifically, which vary in size from 100 nm to over 1 μm20.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Dimri, G. P. et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl Acad. Sci. USA 92, 9363–9367 (1995). source

  • May combine two claims.

    Premisenone given

    Metal tagging can circumvent issues common to fluorescence-based approaches such as tissue autofluorescence; however, protocols for mass tagging antibodies can negatively impact their sensitivity.

    “Metal tagging can circumvent other issues common to fluorescence-based approaches such as tissue autofluorescence; however, protocols for mass tagging antibodies can negatively impact their sensitivity.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    There has been a disproportionate use of changes in mRNA levels to detect senescent cells.

    “To date, there has been a disproportionate use of changes in mRNA levels to detect senescent cells.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    High-plex imaging requires substantial time investment in the generation and optimization of conjugated antibody panels, in addition to the time required to acquire images.

    “High-plex imaging requires substantial time investment in the generation and optimization of conjugated antibody panels, in addition to the time required to acquire images.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Spatially resolved proteomic approaches have the potential to characterize the density and microanatomical location of senescent cells, define the impact of senescent cells on their microenvironment and immune cell types interacting with them, and identify the distribution of key protein senescence effectors within human tissues.

    “Spatially resolved proteomic approaches have the potential to characterize the density and microanatomical location of senescent cells, to define the impact of senescent cells on their microenvironment and the immune cell types interacting with them and to identify the distribution of key protein senescence effectors within human tissues.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    Incorporation of imaging-based deep learning into single-cell transcriptomic technologies can overcome the gene-throughput limitations of CosMx and STARmap.

    “This is particularly important as it can overcome the gene-throughput limitations of CosMx and STARmap.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Many senescence-associated transcripts are not very abundantly expressed, so high-resolution and high-capture output are essential for spatial analysis of cell senescence.

    “Furthermore, many of the senescence-associated transcripts, such as those encoding cell cycle-dependent kinase inhibitors, are not very abundantly expressed; therefore, high-resolution and high-capture output are essential for spatial analysis of cell senescence.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Many senescence-associated transcripts, such as those encoding cell cycle-dependent kinase inhibitors, are not very abundantly expressed.

  • May combine two claims.

    Interpretationreasoning

    Single cells can occupy up to 100-500 μm2, so the output of high-resolution methods is comparable to conventional scRNA-seq, enabling sensitive detection of senescent transcripts.

    “Considering that single cells can occupy up to 100–500 μm2, this output is comparable to that of conventional single-cell RNA sequencing (scRNA-seq), enabling sensitive detection of senescent transcripts.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    A benchmark is necessary to determine whether methods specifically designed for deconvoluting senescent cells are needed.

    “Such a benchmark is necessary to determine whether methods specifically designed for deconvoluting senescent cells are needed.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The performance of deconvoluting senescent cells is largely unknown.

  • May combine two claims.

    Interpretationreasoning

    While accuracy for individual nuclei is difficult to establish in tissues, deep learning predictors can offer overall assessment of senescence in tissues along with differential analysis across ages, medical conditions or other factors.

    “While the accuracy for individual nuclei is difficult to establish in tissues, deep learning predictors can offer overall assessment of senescence in tissues along with differential analysis across ages, medical conditions or other factors.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The accuracy for individual nuclei is difficult to establish in tissues.
57 of 57

  • The paper relies on this without support.

    Cellular senescence is a driver of aging and age-related diseases.

    “Cellular senescence is a well-established driver of aging and age-related diseases.”

  • The paper relies on this without support.

    Cells bearing senescence-associated markers accumulate in most tissues during aging and age-related diseases.

    “Cells bearing senescence-associated markers have been shown to accumulate in most tissues during aging and age-related diseases.”

  • The paper relies on this without support.

    Visium provides robust spatially resolved whole-transcriptome evaluation at relatively low resolution and discontinuous detection area.

    “The company 10x Genomics currently offers spatial barcoding-based transcript detection (Visium) in flash-frozen and FFPE tissues, providing robust spatially resolved whole-transcriptome evaluation at the cost of relatively low resolution and discontinuous detection area (barcoded spot diameter, ~50 μm; 100 μm between spots; 6.5 × 6.5-mm tissue-capture area).”

  • The paper relies on this without support.

    Senescent cells are typically rare in tissues.

    “This would allow for integration of transcriptomic, proteomic and epigenomic data for the positive identification of senescent cells, which are typically rare.”

  • The paper relies on this without support.

    Many senescence-associated transcripts, such as those encoding cell cycle-dependent kinase inhibitors, are not very abundantly expressed.

    “Furthermore, many of the senescence-associated transcripts, such as those encoding cell cycle-dependent kinase inhibitors, are not very abundantly expressed; therefore, high-resolution and high-capture output are essential for spatial analysis of cell senescence.”

  • The paper relies on this without support.

    Reference scRNA-seq datasets with annotated senescent cells are lacking in many types of tissues.

    “Third, reference scRNA-seq datasets with annotated senescent cells are lacking in many types of tissues.”

  • The paper relies on this without support.

    The performance of deconvoluting senescent cells is largely unknown.

    “Finally, although there are studies benchmarking the performance of deconvolution methods in a more general setting88, the performance of deconvoluting senescent cells is largely unknown.”

  • The paper relies on this without support.

    The accuracy for individual nuclei is difficult to establish in tissues.

    “While the accuracy for individual nuclei is difficult to establish in tissues, deep learning predictors can offer overall assessment of senescence in tissues along with differential analysis across ages, medical conditions or other factors.”

  • The paper relies on this without support.

    Senescence is a cell state with temporal and phenotypic heterogeneous characteristics that depend on cell type, organ, stimulus and physiologic and temporal conditions.

    “While markers can help to identify specific cell types, senescence is a cell state with temporal and phenotypic heterogeneous characteristics that will depend on cell type, organ, stimulus and physiologic and temporal conditions.”
9 of 9

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?

  • The regulation of senescence extends beyond transcription, and prior work has reported cases in which transcriptomic changes do not align with proteomic readouts.

    “the regulation of senescence extends beyond transcription, and prior work has reported cases in which transcriptomic changes do not align with proteomic readouts [11,46,47,48].”

    From Fluorescence-Guided Spatial Mapping of p21-Expressing Senescent Cells in Aged Liver at Single-Cell Resolution (2026) · cites this paper as [11]

    The “High-plex imaging methods” section says proteomics can detect senescence-associated features that transcriptomics cannot, supporting the point that senescence extends beyond transcription. It says whether mRNA changes correspond to protein-expression changes remains unclear for many markers; it does not report cases of transcriptomic and proteomic readouts failing to align. Page numbers are unavailable in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Senescent cells release pro-inflammatory molecules, such as cytokines and chemokines, collectively known as SASP, that can harm neighboring non-senescent cells and contribute to age-related diseases.

    “Senescent cells release pro-inflammatory molecules, such as cytokines and chemokines, collectively known as the senescence-associated secretory phenotype (SASP), that can harm neighboring non-senescent cells and contribute to age-related diseases.”

    From Spatial transcriptomic landscape unveils immunoglobin-associated senescence as a hallmark of aging (2024) · cites this paper as [30]

    The paper’s Abstract describes senescent cells’ secretion of pro-inflammatory molecules as the SASP and says senescent cells can affect and induce senescence in neighboring cells. It also calls cellular senescence a driver of age-related diseases. Our copy does not specifically identify cytokines and chemokines as SASP components or establish that SASP-mediated harm to neighboring cells contributes to those diseases. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • The heterogeneous cell-type and context-specific phenotype of senescent cells has presented challenges for identifying a universal biomarker.

    “The heterogeneous cell-type and context-specific phenotype of senescent cells has presented challenges for identifying a universal biomarker [18,19].”

    From Evaluation of exploratory fluid biomarkers from a phase 1 senolytic trial in mild Alzheimer's disease (2025) · cites this paper as [19]

  • Induction of senescence is a tumor suppressor mechanism and a side effect of several chemotherapeutic drugs.

    “Induction of senescence is a tumor suppressor mechanism143–145 and a side effect of several chemotherapeutic drugs that induce a phenotype that might be considered an acquired premature progeroid syndrome in both normal and cancer cells146.”

    From Guidelines for minimal information on cellular senescence experimentation in vivo (2024) · cites this paper as [143]

    The cited paper’s Abstract discusses senescent cells in aging and their possible physiological roles, but does not address senescence as a tumor-suppressor mechanism or a side effect of chemotherapy. Searches for chemotherapy, tumor suppression, and progeroid effects found no passage supporting the attributed claim. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

Cites

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Authors
Gurkar, A. U., Gerencser, A. A., Mora, A. L., Nelson, A. C., Zhang, A. R., Lagnado, A. B., Enninful, A., Benz, C., Furman, D., Beaulieu, D., Jurk, D., Thompson, E. L., Wu, F., Rodriguez, F., Barthel, G., Chen, H., Phatnani, H., Heckenbach, I., Chuang, J. H., Horrell, J., Petrescu, J., Alder, J. K., Lee, J. H., Niedernhofer, L. J., Kumar, M., Königshoff, M., Bueno, M., Sokka, M., Scheibye-Knudsen, M., Neretti, N., Eickelberg, O., Adams, P. D., Hu, Q., Zhu, Q., Porritt, R. A., Dong, R., Peters, S., Victorelli, S., Pengo, T., Khaliullin, T., Suryadevara, V., Fu, X., Bar-Joseph, Z., Ji, Z., & Passos, J. F.
Affiliations
  • University of Pittsburgh (US)
  • Buck Institute for Research on Aging (US)
  • The Ohio State University (US)
  • Duke University (US)
  • Mayo Clinic (US)
  • Yale University (US)
  • University of Minnesota (US)
  • Carnegie Mellon University (US)
  • Columbia University Irving Medical Center (US)
  • The Jackson Laboratory for Genomic Medicine (US)
  • Brown University (US)
  • University of Michigan (US)
  • Stanford University (US)
ORCID
Venue
Nature Aging
Publisher
Springer Science and Business Media LLC
Published
2023-07-03
Volume
3
Issue
7
Pages
776-790
ISSN
2662-8465 (ISSN-L)
DOI
10.1038/s43587-023-00446-6
PMC
PMC10505496
OpenAlex
W4382989269
Cited by
139
References
110
Citations by year
2026: 37 · 2025: 46 · 2024: 44 · 2023: 10
FWCI
18.98
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Aging (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
  • The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
Topics
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords
cellular senescence, spatial imaging, senescence markers, single-cell technologies, senescence heterogeneity, extracellular space, aging, age-related diseases
MeSH terms
Aging, Animals, Humans, Longevity, United States, Cellular Senescence, Mice

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 2026-10-12.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-12.

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.

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