Cellular senescence in ageing: from mechanisms to therapeutic opportunities

Genetic and pharmacological removal of p16-expressing senescent cells improves heart function in aged mice.

“genetic and pharmacological clearance of p16-expressing senescent cells ameliorated heart functions in aged mice140.”

• cites [140] Anderson, R. et al. Length-independent telomere damage drives post-mitotic cardiomyocyte senescence. EMBO J. https://doi.org/10.15252/embj.2018100492 (2019). sourceDisputed

  In Results, ‘Senescent-cell clearance reduces cardiac hypertrophy and fibrosis’ (Figs 7G, EV5B–C), genetic clearance reduced hypertrophy and fibrosis in aged mice but did not change ejection fraction. The same Results section (Figs 8E–G) says pharmacological treatment with navitoclax had no significant impact on cardiac function. The paper reports improved cardiac remodelling, not improved heart function. (LLM, conf=0.91)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

TGF-β improves liver regeneration after injury by blocking paracrine senescence in neighbouring uninjured hepatocytes.

“Similarly, transforming growth factor-β improves liver regeneration on injury by blocking paracrine senescence in neighbouring uninjured hepatocytes188.”

• cites [188] Bird, T. G. et al. TGFbeta inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence. Sci. Transl Med. https://doi.org/10.1126/scitranslmed.aan1230 (2018). sourceDisputed

  The Introduction says macrophage-derived TGFβ drives the spread of senescence between hepatocytes. The Results section on TGFβR1 inhibition reports that blocking TGFβ signaling—not TGFβ itself—reduced hepatocellular senescence and improved regeneration after acute liver injury. Page numbers are not provided in our copy. (LLM, conf=0.94)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

Persistent DNA damage causes prolonged DNA damage response signalling and protracted proliferative arrest in the form of cellular senescence.

“If DNA damage persists, it causes prolonged DDR signalling and protracted proliferative arrest in the form of cellular senescence22”

• cites [22] Fumagalli, M., Rossiello, F., Mondello, C. & d’Adda di Fagagna, F. Stable cellular senescence is associated with persistent DDR activation. PLoS ONE 9, e110969 (2014). sourceSupported

Some DNA damage response factors accumulate at damage sites and form nuclear foci containing H2AX phosphorylation and associated proteins such as MDC1, 53BP1 and activated ATM.

“Some DDR factors accumulate at sites of DNA damage and form cytologically detectable nuclear foci composed of extended chromatin modification events, such as the phosphorylation of histone H2AX, and the proteins associated with them, including MDC1, 53BP1 and the activated form of the kinase ataxia telangiectasia mutated (ATM)21”

• cites [21] Jackson, S. P. & Bartek, J. The DNA-damage response in human biology and disease. Nature 461, 1071–1078 (2009). sourcePartly supported

  The DNA-damage signaling and cell-cycle checkpoints section (page unavailable) describes H2AX phosphorylation on chromatin flanking double-strand breaks, recruitment of DDR factors, and ATM recruitment and activation at breaks. It does not identify MDC1 or 53BP1 among those factors or state that they form cytologically detectable nuclear foci with activated ATM. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

Senescent cells resist apoptotic death more than normal cells because survival pathways, including BCL-2 family antiapoptotic proteins, are upregulated, even after exogenous stress.

“Senescent cells have increased resistance to apoptotic cell death owing to upregulation of cell survival pathways, including the BCL-2 family of antiapoptotic proteins, even on exogenous stress exposure14,15”

• cites [14] Yosef, R. et al. Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nat. Commun. 7, 11190 (2016). sourceSupported
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• cites [15] Chang, J. et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat. Med. 22, 78–83 (2016). sourcePartly supported

  In the passage labeled Abstract (page unavailable), the paper reports increased BCL-xL in senescent cells and experiments suggesting that BCL-2 and BCL-xL protect them from apoptosis. It does not establish greater resistance to apoptotic death than normal cells after exogenous stress exposure; it also reports no increase in BCL-2 expression. (LLM, conf=0.83)

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Persistent DNA damage response foci in cultured senescent cells contain unrepaired double-strand breaks.

“The recent demonstration that persistent DDR foci observed in cultured senescent cells contain unrepaired DSBs23 supports the notion that cellular senescence is akin to prolonged checkpoint activation”

• cites [23] Galbiati, A., Beausejour, C. & d’Adda di Fagagna, F. A novel single-cell method provides direct evidence of persistent DNA damage in senescent cells and aged mammalian tissues. Aging Cell 16, 422–427 (2017). sourceSupported

Inhibiting the DNA damage response kinases ATM, ATR, CHK1 and CHK2 allows senescent cells to re-enter the cell cycle.

“Inhibition of DDR signalling kinases (ATM, ATR, CHK1 and CHK2) allows senescent cells to re-enter the cell cycle7,24,25”

• cites [7] Di Micco, R. et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444, 638–642 (2006). sourceNot checked — no full text of the source
• cites [24] d’Adda di Fagagna, F. et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 426, 194–198 (2003). This study demonstrates that the activation of the DDR pathways by critically short telomeres is key in the enforcement of cellular senescence. sourceNot checked — no full text of the source
• cites [25] Mallette, F. A. & Ferbeyre, G. The DNA damage signaling pathway connects oncogenic stress to cellular senescence. Cell Cycle 6, 1831–1836 (2007). sourcePartly supported

  The Conclusions (page unavailable) identify ATM, ATR, Chk1 and Chk2 as required for the senescence program and say that interfering with the DDR can bypass oncogene-induced senescence. But the authors report rescuing that response only when the Rb pathway was also inactivated. The paper does not establish that inhibiting those kinases makes already-senescent cells re-enter the cell cycle. (LLM, conf=0.87)

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Senescence-associated heterochromatin foci enforce a DNA damage response-resistant heterochromatin structure that restrains DDR signalling.

“Rather, SAHF enforce a DDR-resistant heterochromatin structure that restrains DDR signalling52”

• cites [52] Di Micco, R. et al. Interplay between oncogene-induced DNA damage response and heterochromatin in senescence and cancer. Nat. Cell Biol. 13, 292–302 (2011). sourceSupported
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Reactivation of transposable elements contributes to the non-cell-autonomous functions of senescent cells.

“the reactivation of transposable elements also contributes to mediate the non-cell-autonomous functions of senescent cells as detailed later62”

• cites [62] De Cecco, M. et al. L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature 566, 73–78 (2019). sourceSupported

PTEN loss-induced cellular senescence was initially not linked to DNA damage response activation but was later found to involve hyperproliferation, DDR engagement and senescence in vivo.

“Although initially PTEN loss-induced cellular senescence was not associated with DDR activation40, it was later found to be associated with hyperproliferation, DDR engagement and cellular senescence in vivo41”

• cites [40] Alimonti, A. et al. A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis. J. Clin. Invest. 120, 681–693 (2010). sourceSupported
• cites [41] Parisotto, M. et al. PTEN deletion in luminal cells of mature prostate induces replication stress and senescence in vivo. J. Exp. Med. 215, 1749–1763 (2018). sourceSupported

A core SASP programme comprising mainly IL-6, CXCL8/IL-8 and MCP1/CCL2 was reported in all types of in vitro-generated senescent cells.

“a core SASP programme comprising mainly proinflammatory interleukin-6 (IL-6), CXC chemokine ligand 8 (CXCL8, hereafter named IL-8) and monocyte chemoattractant protein 1 (MCP1; also known as CCL2) was reported in all types of in vitro-generated senescent cells75”

• cites [75] Coppe, J. P. et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 6, 2853–2868 (2008). sourcePartly supported

  The Discussion describes IL-6, IL-8 and MCP-1 as core SASP features, and the Results report substantial overlap among the senescent fibroblast and epithelial cells studied (page numbers unavailable). But the paper lists other core factors, notes differences between cell types, and only suggests—not establishes—that a conserved programme occurs in any cell undergoing senescence. It therefore does not support ‘mainly’ those three factors or ‘all types’ as stated. (LLM, conf=0.86)

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Genome-wide analysis of H3K4me3, H3K27me3 and H3K27ac in senescent cells reveals dynamic acquisition and depletion of large-scale chromatin domains proposed to regulate key senescence downstream effectors.

“Genome-wide analysis of H3 Lys4 trimethylation, H3 Lys27 trimethylation and H3 Lys27 acetylation in senescent cells has also revealed the dynamic acquisition and depletion of large-scale chromatin domains that have been proposed to regulate the expression of key senescence downstream effectors68–72”

• cites [68] Shah, P. P. et al. Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape. Genes Dev. 27, 1787–1799 (2013). sourcePartly supported

  The Results (pages not available in our copy) report genome-wide gains and losses of large H3K4me3 and H3K27me3 domains, with changes associated with expression of senescence-related genes. The study analyzed those two modifications, but did not report a genome-wide analysis of dynamic H3K27ac domains; it mentions H3K27ac only when identifying active enhancers. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [69] Freund, A., Laberge, R. M., Demaria, M. & Campisi, J. Lamin B1 loss is a senescence-associated biomarker. Mol. Biol. Cell 23, 2066–2075 (2012). sourceCould not verify

  The Introduction (page unavailable) discusses chromatin rearrangement in senescent cells and its correlation with gene-expression changes, while the Discussion focuses on lamin B1 loss. Searches for H3K4me3, H3K27me3, H3K27ac, genome-wide analysis, and large-scale chromatin domains found no passage in our copy addressing the claimed acquisition or depletion of histone-mark domains. (LLM, conf=0.77)

  Experimental — accuracy not yet measured
• cites [70] Shimi, T. et al. The role of nuclear lamin B1 in cell proliferation and senescence. Genes Dev. 25, 2579–2593 (2011). sourceCould not verify

  The Discussion proposes that lamin B1 might affect chromatin organization and gene expression, and the methods describe a targeted senescence-gene expression assay. Our copy does not report a genome-wide analysis of H3K4me3, H3K27me3, or H3K27ac, or the acquisition and depletion of large-scale domains; searches for those marks and domain changes found no supporting passage. No page numbers were available in the indexed passages. (LLM, conf=0.74)

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• cites [71] Tasdemir, N. et al. BRD4 connects enhancer remodeling to senescence immune surveillance. Cancer Discov. 6, 612–629 (2016). sourcePartly supported

  The Results sections on enhancer remodeling and the SASP transcriptional profile report genome-wide H3K27ac changes in senescent IMR90 cells, including gains and losses at super-enhancers associated with senescence-related gene expression. The Methods describe analysis of H3K27ac and H3K4me1, but not the claimed H3K4me3 or H3K27me3 analyses. Page numbers are unavailable in our copy. (LLM, conf=0.88)

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• cites [72] Sen, P. et al. Histone acetyltransferase p300 induces de novo super-enhancers to drive cellular senescence. Mol. Cell 73, 684–698 e688 (2019). sourceSupported
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Dysfunctional mitochondria may be important in senescence establishment, since depleting mitochondrial sirtuins or chemically inhibiting mitochondrial function triggers senescence.

“Dysfunctional mitochondria may play an important role in senescence establishment, as depletion of mitochondrial sirtuins, a group of evolutionarily conserved proteins that regulate ageing across different species, as well as selective chemical inhibition of mitochondrial function, triggers senescence47”

• cites [47] Wiley, C. D. et al. Mitochondrial dysfunction induces senescence with a distinct secretory phenotype. Cell Metab. 23, 303–314 (2016). sourceSupported

Loss of nuclear lamina can release cytosolic chromatin fragments into the cytoplasm of senescent cells.

“Loss of nuclear lamina can lead to the release of cytosolic chromatin fragments (CCFs) in the cytoplasm of senescent cells58–60”

• cites [58] Ivanov, A. et al. Lysosome-mediated processing of chromatin in senescence. J. Cell Biol. 202, 129–143 (2013). sourceSupported
• cites [59] Dou, Z. et al. Autophagy mediates degradation of nuclear lamina. Nature 527, 105–109 (2015). sourceSupported
• cites [60] Dou, Z. et al. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature 550, 402–406 (2017). This study demonstrates that cytoplasmic chromatin in senescent and cancer cells activates the innate immunity through the cGAS–STING pathway. sourceSupported

Oncogene-induced reactive oxygen species generated by NADPH oxidases can induce senescence by boosting the initial hyperproliferative phase with altered DNA replication and DNA damage accumulation.

“oncogene-induced ROS, generated by NADPH oxidases, can induce cellular senescence by boosting the initial hyperproliferative phase associated with altered DNA replication and DNA damage accumulation45”

• cites [45] Ogrunc, M. et al. Oncogene-induced reactive oxygen species fuel hyperproliferation and DNA damage response activation. Cell Death Differ. 21, 998–1012 (2014). sourceSupported

Persistent DNA damage response activation also occurs at telomeres that are not critically shortened in non-dividing cells exposed to genotoxic treatments and in non-dividing ageing cells, because repair is less efficient at telomeric double-strand breaks.

“Persistent DDR activation occurs also at telomeres that are not critically shortened, in non-dividing cells exposed to exogenous genotoxic treatments and in non-dividing ageing cells, because repair is much less efficient when DSBs are localized within telomeres35–37”

• cites [35] Fumagalli, M. et al. Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat. Cell Biol. 14, 355–365 (2012). sourceSupported
• cites [36] Hewitt, G. et al. Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence. Nat. Commun. 3, 708 (2012). sourcePartly supported

  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 [37] Bae, N. S. & Baumann, P. A RAP1/TRF2 complex inhibits nonhomologous end-joining at human telomeric DNA ends. Mol. Cell 26, 323–334 (2007). sourceNot checked — no full text of the source

Oncogene-induced senescent cells and late replicatively senescent fibroblasts show increased nucleosomal chromatin accessibility, with most open regions mapping to regulatory elements and repeats.

“oncogene-induced senescent cells and late replicatively senescent fibroblasts exhibit a marked increase in chromatin accessibility at the nucleosomal level, with most of the open chromatin regions mapping to regulatory elements and repeats66,67”

• cites [66] Parry, A. J. et al. NOTCH-mediated non-cell autonomous regulation of chromatin structure during senescence. Nat. Commun. 9, 1840 (2018). sourceSupported
  Experimental — accuracy not yet measured
• cites [67] 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). sourcePartly supported

  The Discussion (page unavailable) describes relatively more open chromatin at repeats and other gene-poor regions in replicatively senescent cells, with changes most evident after prolonged senescence. It also describes reduced accessibility at active regulatory regions. This paper does not establish the claim for oncogene-induced senescence or show that most open regions map to regulatory elements and repeats. (LLM, conf=0.88)

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Mitochondrial dysfunction-associated senescence has a distinct phenotype and a unique cell-non-autonomous programme potentially responsible for altered metabolism and aberrant adipocyte differentiation in aged animals.

“mitochondrial dysfunction-associated senescence (MiDAs), which is characterized by a distinct phenotype, exhibits a unique cell-non-autonomous programme that is potentially responsible for the altered metabolism and aberrant adipocyte differentiation observed in aged animals47”

• cites [47] Wiley, C. D. et al. Mitochondrial dysfunction induces senescence with a distinct secretory phenotype. Cell Metab. 23, 303–314 (2016). sourcePartly supported

  The Discussion (page unavailable) describes MiDAS as a distinct senescence response with a distinct secretory phenotype. Results (‘MiDAS in POLG Mice’; page unavailable) show that conditioned medium from mitochondrially impaired cells blocked adipogenesis in cell culture, supporting a potential cell-non-autonomous effect. The paper does not establish that this programme accounts for altered metabolism or aberrant adipocyte differentiation observed in normally aged animals; its in-vivo evidence comes from progeroid mice. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Chromatin loosening at genomic repeats increases expression of transposable elements, which are normally epigenetically silenced and dormant in unstressed cells.

“Chromatin loosening at genomic repeats results in increased expression levels of transposable elements, which are normally epigenetically silenced and dormant in unstressed cells67”

• cites [67] 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). sourceSupported

Senescence-associated heterochromatin foci are organized heterochromatic domains detected as dense DAPI-positive nuclear structures enriched in repressive marks and proteins including H3K9me3, HP1, HMGA factors, macroH2A, HIRA and ASF1A.

“Senescence-associated heterochromatin foci (SAHF) are spatially organized heterochromatic domains that can be detected as dense 4′,6-diamidino-2-phenylindole (DAPI)-positive nuclear structures that are enriched in repressive chromatin marks and proteins, including trimethylated histone H3 Lys9 (H3K9me3), heterochromatin protein 1 (HP1), high mobility group protein A (HMGA) factors, histone variant”

• cites [49] Narita, M. et al. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 113, 703–716 (2003). sourcePartly supported

  The Results (page not provided) identify SAHF as DNA foci seen with DAPI staining and report enrichment of lysine-9-methylated histone H3 and HP1. The passages do not specify trimethylation, and the searched passages do not support enrichment of HMGA factors, macroH2A, HIRA, or ASF1A. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [50] Zhang, R. et al. Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA. Dev. Cell 8, 19–30 (2005). sourceNot checked — no full text of the source
• cites [51] Chandra, T. et al. Independence of repressive histone marks and chromatin compaction during senescent heterochromatic layer formation. Mol. Cell 47, 203–214 (2012). sourcePartly supported

  The Introduction describes SAHFs as DAPI-dense foci, and the Results (‘Multilayer Structure of Chromatin in SAHFs’; page not provided) show spatially organized H3K9me3-rich regions containing HP1γ. The paper also identifies HMGA1 as a structural component. Our copy does not establish enrichment of macroH2A, HIRA, or ASF1A in SAHFs; searches for those terms found no supporting passages. (LLM, conf=0.86)

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Persistent DNA damage response activation at telomeres can trigger senescence both after telomere shortening in proliferating cells and after telomeric DNA damage in non-proliferating cells, independently of telomere length.

“persistent DDR activation at telomeres, which is a trigger of cellular senescence, can occur both upon telomere shortening in proliferating cells and upon telomeric DNA damage also in non-proliferating (quiescent or terminally differentiated) cells, independently of telomere length38”

• cites [38] Rossiello, F. et al. DNA damage response inhibition at dysfunctional telomeres by modulation of telomeric DNA damage response RNAs. Nat. Commun. 8, 13980 (2017). sourcePartly supported

  The Results (‘Telomere deprotection triggers both strands’ transcription’; page unavailable) report DDR activation after experimental telomere deprotection, supporting the general link between dysfunctional telomeres and DDR. Our copy does not establish the claimed routes through shortening in proliferating cells or damage in non-proliferating cells, nor that this occurs independently of telomere length and triggers senescence. (LLM, conf=0.82)

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There is evidence for reciprocal influence between nuclear DNA damage and mitochondrial dysfunction.

“There is evidence in support of a reciprocal influence between nuclear DNA damage and mitochondrial dysfunction48”

• cites [48] Correia-Melo, C. et al. Mitochondria are required for pro-ageing features of the senescent phenotype. EMBO J. 35, 724–742 (2016). sourcePartly supported

  The Results sections on PGC-1β-dependent biogenesis and ROS-driven DNA damage foci (page not provided) show influence in both directions: DNA damage response increases mitochondrial mass, while mitochondrial biogenesis and ROS help maintain DNA damage foci. The paper does not establish that nuclear DNA damage causes mitochondrial dysfunction specifically; the mitochondrial change it demonstrates is increased biogenesis. (LLM, conf=0.84)

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Another chromatin feature of senescent cells is unfolding of constitutive heterochromatin domains, mainly distension of pericentromeric satellite sequences, observed across species and senescence modes.

“Another chromatin feature of senescent cells is the unfolding of constitutive heterochromatin domains characterized mainly by distension of pericentromeric satellite sequences, which was observed in different species and following different modes of senescence induction57”

• cites [57] Swanson, E. C., Manning, B., Zhang, H. & Lawrence, J. B. Higher-order unfolding of satellite heterochromatin is a consistent and early event in cell senescence. J. Cell Biol. 203, 929–942 (2013). sourceSupported

JAK inhibitors reduce frailty in aged mice.

“Furthermore, JAK inhibitors alleviated frailty in aged mice99.”

• cites [99] Xu, M. et al. JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age. Proc. Natl Acad. Sci. USA 112, E6301–E6310 (2015). sourceSupported
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In that PTEN-loss senescence model, JAK/STAT inhibitors reprogram the SASP so that chemotherapy and T cell-mediated removal of cancer senescent cells are enhanced.

“In this context, JAK/STAT inhibitors were effective in reprogramming the SASP to enhance chemotherapy and T cell-mediated clearance of cancer senescent cells98.”

• cites [98] Toso, A. et al. Enhancing chemotherapy efficacy in Pten-deficient prostate tumors by activating the senescence-associated antitumor immunity. Cell Rep. 9, 75–89 (2014). sourceSupported

Exosomes are key mediators of the paracrine senescence effects of SASP and of its protumorigenic properties.

“Exosomes were recently identified as key mediators of the paracrine senescence effects of SASP as well as of its protumorigenic properties83,84”

• cites [83] Borghesan, M. et al. Small extracellular vesicles are key regulators of non-cell autonomous intercellular communication in senescence via the interferon protein IFITM3. Cell Rep. 27, 3956–3971 e3956 (2019). sourcePartly supported

  The Discussion (page not available) reports that small extracellular vesicles mediate paracrine senescence, supporting the first part of the claim. The Introduction says SASP can promote cancer proliferation, but the passages do not establish that these vesicles mediate that protumorigenic effect. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [84] Jakhar, R. & Crasta, K. Exosomes as emerging pro-tumorigenic mediators of the senescence-associated secretory phenotype. Int. J. Mol. Sci. https://doi.org/10.3390/ijms20102547 (2019). sourcePartly supported

  Section 4.2 says exosomes are SASP components that can mediate paracrine signaling, and describes their pro-tumorigenic role as emerging. Section 4.1 says SASP factors can induce senescence in neighbouring cells, but our copy does not establish that exosomes are key mediators of that specific effect. The claim also states their pro-tumorigenic role more definitively than the review does. (LLM, conf=0.85)

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Changes in NOTCH1 activity over the course of senescence alter the makeup of the SASP.

“temporal changes in NOTCH1 activity during senescence have been reported to modulate the composition of SASP.”

• cites [94] Hoare, M. et al. NOTCH1 mediates a switch between two distinct secretomes during senescence. Nat. Cell Biol. 18, 979–992 (2016). sourceSupported

In a PTEN-loss senescence model, the JAK2-STAT3 pathway turns on a subset of SASP factors that have immunosuppressive properties.

“The JAK2–STAT3 pathway activates a subset of SASP factors with immunosuppressive properties in a model of senescence induced by PTEN loss.”

• cites [98] Toso, A. et al. Enhancing chemotherapy efficacy in Pten-deficient prostate tumors by activating the senescence-associated antitumor immunity. Cell Rep. 9, 75–89 (2014). sourceSupported

EZH2 overexpression blocks entry into OIS through several mechanisms, including DDR regulation and suppression of the SASP gene expression programme.

“overexpression of EZH2 prevents entry into OIS through a variety of mechanisms, including DDR regulation and inhibition of the SASP gene expression programme106.”

• cites [106] Ito, T., Teo, Y. V., Evans, S. A., Neretti, N. & Sedivy, J. M. Regulation of cellular senescence by polycomb chromatin modifiers through distinct DNA damage- and histone methylation-dependent pathways. Cell Rep. 22, 3480–3492 (2018). sourcePartly supported

  The Results section “EZH2 Suppresses Entry into Oncogene-Induced Senescence” reports that ectopic EZH2 strongly alleviated entry into OIS and broadly alleviated SASP-gene induction; it does not say entry was completely prevented. The paper links EZH2 depletion to DNA damage and a DDR, but the cited passages do not establish DDR regulation as a demonstrated mechanism by which EZH2 overexpression suppresses OIS. (LLM, conf=0.84)

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Comprehensive quantitative proteomics identified additional diverse SASP effectors released as soluble molecules or in exosomes, including components previously enriched in human plasma during ageing and age-associated diseases.

“a comprehensive unbiased quantitative proteomic characterization of SASP led to the identification of additional and diverse SASP effectors, released as soluble molecules or in exosomes79–81 with a set of components previously reported to be enriched in human plasma during ageing and age-associated diseases82”

• cites [79] Ozcan, S. et al. Unbiased analysis of senescence associated secretory phenotype (SASP) to identify common components following different genotoxic stresses. Aging 8, 1316–1329 (2016). sourcePartly supported

  The Results section (‘Identification of senescent secretome specific proteins’; page unavailable) reports LC-MS/MS analysis of mesenchymal stromal cell secretomes and identifies 11 proteins exclusive to the senescent phenotypes. Our copy does not establish that these proteins were released in exosomes or previously found enriched in human plasma during ageing or age-associated diseases. (LLM, conf=0.86)

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• cites [80] Basisty, N. et al. A proteomic atlas of senescence-associated secretomes for aging biomarker development. PLoS Biol. 18, e3000599 (2020). sourcePartly supported

  The Discussion describes an unbiased quantitative proteomic analysis of diverse SASP components, and the Methods describe separating soluble proteins from exosomes/EVs. The Results section on aging and disease biomarkers reports overlap between newly identified soluble SASP factors and human plasma markers of aging. It does not establish that those factors were enriched in human plasma during age-associated diseases; it discusses disease biomarkers as potential applications. (LLM, conf=0.86)

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• cites [81] Faget, D. V., Ren, Q. & Stewart, S. A. Unmasking senescence: context-dependent effects of SASP in cancer. Nat. Rev. Cancer 19, 439–453 (2019). sourceNot checked — no full text of the source
• cites [82] Tanaka, T. et al. Plasma proteomic signature of age in healthy humans. Aging Cell 17, e12799 (2018). sourcePartly supported

  The Results (Association of proteins with chronological age; page unavailable) report that 21 of 72 measured SASP proteins were associated with age in plasma, with significant enrichment overall. The Discussion links some age-associated proteins to age-related conditions, but this study of healthy humans does not establish that the SASP components were enriched in plasma during those diseases. The claims about comprehensive SASP characterization and exosomal release are attached to other citations, not this one. (LLM, conf=0.84)

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ATM indirectly regulates SASP gene expression by mediating removal of macroH2A1.1 from SASP genes in response to DNA damage and oncogenic stress.

“ATM was found to regulate expression of SASP genes indirectly by mediating the removal of the histone variant macroH2A1.1 from SASP genes in response to DNA damage and oncogenic stress87”

• cites [87] Chen, H. et al. MacroH2A1 and ATM play opposing roles in paracrine senescence and the senescence-associated secretory phenotype. Mol. Cell 59, 719–731 (2015). sourcePartly supported

  The Results section on ATM-mediated SASP gene repression reports that ATM activity triggers removal of macroH2A1 from SASP genes during oncogene-induced senescence, through a pathway involving DNA-damage signaling. The paper separately shows that macroH2A1.1 can stimulate SASP expression, but the ATM-removal experiments identify macroH2A1 generally, not the macroH2A1.1 splice variant specifically; that specificity is unsupported. (LLM, conf=0.85)

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SASP includes proinflammatory molecules and extracellular matrix-remodelling enzymes such as MMPs, SERPINs and TIMPs.

“SASP not only includes proinflammatory molecules but also enzymes involved in ECM remodelling, such as matrix metalloproteinases (MMPs)77, serine/cysteine proteinase inhibitors (SERPINs)78 and tissue inhibitors of metalloproteinases (TIMPs)79”

• cites [77] Coppe, J. P. et al. A human-like senescence-associated secretory phenotype is conserved in mouse cells dependent on physiological oxygen. PLoS ONE 5, e9188 (2010). sourceSupported
• cites [78] Eren, M. et al. PAI-1-regulated extracellular proteolysis governs senescence and survival in Klotho mice. Proc. Natl Acad. Sci. USA 111, 7090–7095 (2014). sourceNot checked — no full text of the source
• cites [79] Ozcan, S. et al. Unbiased analysis of senescence associated secretory phenotype (SASP) to identify common components following different genotoxic stresses. Aging 8, 1316–1329 (2016). sourcePartly supported

  The Discussion (page unavailable) identifies PAI-1 (SERPINE1) in senescent secretomes and says it prevents proteolysis of IGFBP3. That supports the citation attached to SERPINs, but the paper does not establish that SERPINE1 remodels the extracellular matrix; it discusses ECM remodelling chiefly in relation to MMPs. (LLM, conf=0.83)

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A small molecule that degrades BRD4 has senolytic activity.

“However, a recent chemical screen identified a small molecule that degrades BRD4 and has senolytic activity104.”

• cites [104] Wakita, M. et al. A BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells. Nat. Commun. 11, 1935 (2020). sourcePartly supported

  The Results section reports that ARV825 degrades BRD4 and has strong senolytic activity. However, the high-throughput screen identified BET inhibitors; ARV825 was tested afterward to confirm and extend the screening results, not identified as a screen hit. (LLM, conf=0.88)

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BRD4 positively regulates telomere elongation in mouse and human cell cultures.

“Moreover, BRD4 was shown to positively regulate telomere elongation in murine and human cultures105.”

• cites [105] Wang, S. et al. BRD4 inhibitors block telomere elongation. Nucleic Acids Res. 45, 8403–8410 (2017). sourceSupported

Ageing is consistently associated with increased DNA damage response in proliferating and non-proliferating cells, contributing to senescent cell accumulation with age.

“Ageing is one of the factors that is consistently associated with an increase in DDR in proliferating and non-proliferating cells, thus contributing significantly to the accumulation of senescent cells with age35,89”

• cites [35] Fumagalli, M. et al. Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat. Cell Biol. 14, 355–365 (2012). sourcePartly supported

  The Abstract reports more DDR-positive cells with age across tissues and cell types, and the Results section on physiological ageing in primates reports persistent DDR foci in non-dividing neurons and hepatocytes. The Discussion proposes that persistent telomeric DDR leads to senescence, but does not establish that increased DDR contributes significantly to the accumulation of senescent cells with age. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [89] White, R. R., Vijg, J. & Do, D. N. A. Double-strand breaks drive aging? Mol. Cell 63, 729–738 (2016). sourcePartly supported

  In “DSBs, DSB processing and aging” (page unavailable), the paper reports that DNA-damage-associated γH2AX foci increase with age in multiple tissues, including fibroblasts and brain, and in senescent cells. The Abstract says DSB-triggered DDR can lead to senescence. But the paper does not establish that DDR activity consistently increases in both proliferating and non-proliferating cells or that this significantly causes senescent-cell accumulation; “DSB processing and repair as a function of age” also describes declines in some damage responses. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

SASP gene expression changes over time.

“SASP gene expression is temporally dynamic100, and temporal changes in NOTCH1 activity during senescence have been reported to modulate the composition of SASP.”

• cites [100] Hernandez-Segura, A. et al. Unmasking transcriptional heterogeneity in senescent cells. Curr. Biol. 27, 2652–2660 e2654 (2017). sourceSupported

Higher nuclear pore density during OIS, needed for SAHF formation, regulates SASP expression by reorganizing heterochromatin.

“Furthermore, increased nuclear pore density during OIS, which is key to establish SAHF, regulates SASP expression by mediating heterochromatin reorganization111.”

• cites [111] 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). sourcePartly supported

  The Results and Discussion sections report that nuclear pore density rises during OIS, that reducing it decreases SAHF formation, and that disrupting pores or SAHFs impairs the SASP (pages not supplied). The paper supports heterochromatin reorganization as the link, but says it cannot completely rule out a separate effect of nuclear pores on SASP activation; the claim states that mechanism more definitively than the source does. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

Persistent DNA damage response signalling is often required to initiate inflammatory cytokine secretion.

“persistent DDR signalling is often required to initiate inflammatory cytokine secretion86”

• cites [86] Rodier, F. et al. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat. Cell Biol. 11, 973–979 (2009). This study demonstrates that persistent DDR activation controls SASP induction in senescent cells. sourceSupported

Incomplete DNA repair may contribute to accumulation of DNA lesions, DDR activation and widespread chromatin changes during ageing.

“Incomplete DNA repair may further contribute to the accumulation of DNA lesions and DDR activation as well as to the widespread chromatin changes seen in different cell types and at the organismal level during ageing90,91”

• cites [90] Ou, H. L. & Schumacher, B. DNA damage responses and p53 in the aging process. Blood 131, 488–495 (2018). sourcePartly supported

  In “Persistent DNA damage: a driving force of aging” (page unavailable), the paper says unrepaired lesions can persist and activate the DDR, and that limited repair in aged hematopoietic stem cells leads to gradual DNA-damage accumulation. Our copy does not link incomplete repair to widespread chromatin changes across cell types or at the organismal level during aging. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [91] Gorbunova, V. & Seluanov, A. DNA double strand break repair, aging and the chromatin connection. Mutat. Res. 788, 2–6 (2016). sourcePartly supported

  “DNA DSB repair declines with age” reports less efficient repair in aged tissues, and “Shared responsibilities: factors involved in DNA repair, chromatin and aging” links DNA damage to broad chromatin and transcriptional changes. The copy does not establish that incomplete repair causes sustained DDR activation, so that part of the claim remains unsupported. Page numbers were not available in the indexed passages. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

DNA replication stress accumulation in HSCs from aged mice was associated with limited but detectable HSC senescence, unbalanced haematopoietic differentiation and myeloid skewing.

“accumulation of DNA replication stress in HSCs from aged mice was linked to limited yet detectable HSC senescence, unbalanced haematopoietic differentiation and myeloid skewing127.”

• cites [127] Flach, J. et al. Replication stress is a potent driver of functional decline in ageing haematopoietic stem cells. Nature 512, 198–202 (2014). sourceSupported

In an Alzheimer disease mouse model, tau-containing neurons show a transcriptomic profile consistent with cellular senescence.

“In a mouse model of Alzheimer disease, transcriptomic analyses of tau-containing neurons indicated an expression profile consistent with cellular senescence136.”

• cites [136] Musi, N. et al. Tau protein aggregation is associated with cellular senescence in the brain. Aging Cell 17, e12840 (2018). sourcePartly supported

  The Results section on tau transgenic mice reports that hippocampal gene-expression patterns after neurofibrillary tangle formation were enriched for senescence-associated regulators. But the mouse analysis used hippocampal expression data, not transcriptomic analyses of isolated tau-containing neurons; the Results section describes that neuron-specific analysis for postmortem human AD tissue. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

In irradiated mice, lineage tracing confirmed differentiation marker expression in the brain subventricular zone, where neural stem cells normally reside.

“Lineage tracing experiments in vivo in irradiated mice confirmed the induction of expression of differentiation markers in the subventricular zone of the brain, normally populated by neural stem cells128.”

• cites [128] Schneider, L. et al. DNA damage in mammalian neural stem cells leads to astrocytic differentiation mediated by BMP2 signaling through JAK-STAT. Stem Cell Rep. 1, 123–138 (2013). sourceSupported

Senescent cells that persist for long periods in culture or in vivo show strong activation of the type I interferon response and its downstream targets.

“Senescent cells, especially when persisting for extended periods in culture or in vivo, display a profound activation of type I interferon response and downstream targets.”

• cites [62] De Cecco, M. et al. L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature 566, 73–78 (2019). sourceSupported

The inflammasome and Toll-like receptors promote maturation and secretion of SASP factors during OIS.

“The inflammasome, a multiprotein complex comprising caspase 1 and key regulators of the defence mechanisms against pathogens117, and Toll-like receptors, which regulate the inflammasome, have been reported to promote maturation and secretion of SASP factors during OIS73,118.”

• cites [73] Acosta, J. C. et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat. Cell Biol. 15, 978–990 (2013). sourcePartly supported

  The section “Activation of the inflammasome controls SASP production” (page unavailable) reports that cells undergoing OIS secrete mature IL-1α and IL-1β and show caspase-1 activity, supporting the inflammasome portion of the claim. The retrieved passages do not establish that Toll-like receptors regulate the inflammasome or promote SASP-factor maturation and secretion during OIS. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [118] Hari, P. et al. The innate immune sensor Toll-like receptor 2 controls the senescence-associated secretory phenotype. Sci. Adv. 5, eaaw0254 (2019). sourceSupported

Obesity in mice is associated with senescence marker expression in neurons of particular brain regions.

“Conversely, obesity in mice was associated with the expression of senescence markers in neurons of specific parts of the brain135.”

• cites [135] Ogrodnik, M. et al. Obesity-induced cellular senescence drives anxiety and impairs neurogenesis. Cell Metab. 29, 1061–1077.e1068 (2019). sourceSupported

DNA damage-induced cellular senescence can occur together with cell differentiation.

“Thus, DNA damage-induced cellular senescence can coincide with cell differentiation128,129.”

• cites [128] Schneider, L. et al. DNA damage in mammalian neural stem cells leads to astrocytic differentiation mediated by BMP2 signaling through JAK-STAT. Stem Cell Rep. 1, 123–138 (2013). sourceSupported
• cites [129] Zou, Y. et al. Responses of human embryonic stem cells and their differentiated progeny to ionizing radiation. Biochem. Biophys. Res. Commun. 426, 100–105 (2012). sourceSupported

A distinct form of cellular senescence occurs in the mammalian developing embryo and placenta to control growth and patterning.

“A distinct form of cellular senescence occurs in the mammalian developing embryo and in the placenta to control growth and patterning131,132,142,143.”

• cites [131] Storer, M. et al. Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell 155, 1119–1130 (2013). sourcePartly supported

  The Summary (p. 1) describes senescence as a normal developmental mechanism throughout the embryo, including signaling centers involved in patterning; the Introduction (p. 2) also identifies a role in tissue development and patterning. The cited paper does not establish the claim about senescence in the placenta; a search for “placenta” found no matching passage in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [132] Munoz-Espin, D. et al. Programmed cell senescence during mammalian embryonic development. Cell 155, 1104–1118 (2013). sourcePartly supported

  The Abstract and Introduction report a distinct, developmentally programmed form of senescence in mammalian embryos. The Abstract links it to tissue remodeling and developmental abnormalities, supporting a role in embryonic development. The passages do not establish senescence in the placenta or a placental role in growth and patterning. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [142] Chuprin, A. et al. Cell fusion induced by ERVWE1 or measles virus causes cellular senescence. Genes Dev. 27, 2356–2366 (2013). sourcePartly supported

  The Results (page unavailable) show senescence markers in human placental syncytiotrophoblast cells, and the Discussion links their senescence to placental function during embryonic development. The paper does not show senescence in the developing embryo itself or establish that it controls embryonic growth and patterning; it also says the reason senescence is necessary in placental development remains to be determined. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

Evidence is emerging, mainly from neurons, that cellular senescence can be associated with terminally differentiated cells.

“Although not extensively investigated, and mainly studied in neurons, evidence is emerging that cellular senescence can be associated with terminally differentiated cells133,134.”

• cites [133] Sapieha, P. & Mallette, F. A. Cellular senescence in postmitotic cells: beyond growth arrest. Trends Cell Biol. 28, 595–607 (2018). sourceNot checked — no full text of the source
• cites [134] Jurk, D. et al. Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response. Aging Cell 11, 996–1004 (2012). sourceSupported

In amphibians, cellular senescence occurs at specific developmental steps to shape body growth.

“Similarly, in amphibians, cellular senescence occurs at specific steps during development to shape body growth144.”

• cites [144] Davaapil, H., Brockes, J. P. & Yun, M. H. Conserved and novel functions of programmed cellular senescence during vertebrate development. Development 144, 106–114 (2017). sourceSupported

Senescence can be viewed as a stress response that evolved to carry out essential beneficial functions.

“Senescence can be regarded as a stress response that evolved to perform essential and beneficial functions141 (FIG. 3).”

• cites [141] Burton, D. G. & Krizhanovsky, V. Physiological and pathological consequences of cellular senescence. Cell. Mol. Life Sci. 71, 4373–4386 (2014). sourcePartly supported

  The Overview describes senescence as a response to cellular stress and identifies beneficial short-term roles in tumor suppression and wound healing. The Abstract calls it an essential mechanism, but says only that its pro-survival phenotype *may* have evolved to aid short-term wound healing; it does not establish that senescence itself evolved to perform beneficial functions generally. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Persistent telomeric DNA damage in cardiomyocytes drives a senescence phenotype with p16 and p21 induction and a non-canonical SASP programme that contributes to cardiac hypertrophy and fibrosis.

“persistent telomeric DNA damage in cardiomyocytes drives a senescence phenotype characterized by induction of p16 and p21 and a non-canonical SASP programme that contributes to cardiac hypertrophy and fibrosis140.”

• cites [140] Anderson, R. et al. Length-independent telomere damage drives post-mitotic cardiomyocyte senescence. EMBO J. https://doi.org/10.15252/embj.2018100492 (2019). sourceSupported

In mouse embryonic stem cells, a p53-induced programme activates differentiation genes and represses pluripotency genes.

“Notably, in mouse embryonic stem cells, a p53-induced programme is associated with transcriptional activation of a differentiation programme and the repression of pluripotent stem cell genes130.”

• cites [130] Li, M. et al. Distinct regulatory mechanisms and functions for p53-activated and p53-repressed DNA damage response genes in embryonic stem cells. Mol. Cell 46, 30–42 (2012). sourceSupported

Aberrant cGAS-STING activation may be linked to reduced DNases such as DNase 2 and TREX1, causing nuclear DNA to accumulate in the cytosol during senescence establishment.

“it was reported that aberrant activation of the cGAS–STING pathway could be linked to the downregulation of DNases (for example, DNase 2 and TREX1) that are normally devoted to cytoplasmic DNA degradation, resulting in cytosolic accumulation of nuclear DNA during senescence establishment115.”

• cites [115] Takahashi, A. et al. Downregulation of cytoplasmic DNases is implicated in cytoplasmic DNA accumulation and SASP in senescent cells. Nat. Commun. 9, 1249 (2018). sourceSupported

During ageing, terminally differentiated cells can accumulate persistent DNA damage and DDR markers.

“during ageing terminally differentiated cells can accumulate persistent DNA damage and DDR markers35,89”

• cites [35] Fumagalli, M. et al. Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat. Cell Biol. 14, 355–365 (2012). sourceSupported
• cites [89] White, R. R., Vijg, J. & Do, D. N. A. Double-strand breaks drive aging? Mol. Cell 63, 729–738 (2016). sourcePartly supported

  In “DSBs, DSB processing and aging” (page unavailable), the paper reports that persistent γH2AX foci, a DNA-damage-response marker, increase with age in several cells and tissues, including brain and liver. It also says unrepaired DSBs may accumulate with age, but does not establish that the observed foci represent unrepaired DNA damage or specifically identify terminally differentiated cells as the affected population. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

In salamanders, senescent cells have been linked to limb regeneration.

“in salamanders, senescent cells have been associated with limb regeneration150.”

• cites [150] Yun, M. H., Davaapil, H. & Brockes, J. P. Recurrent turnover of senescent cells during regeneration of a complex structure. eLife https://doi.org/10.7554/eLife.05505 (2015). sourceSupported
  Experimental — accuracy not yet measured

During cancer development with senescent cell accumulation, SASP can recruit immature myeloid cells that promote tumorigenesis in a paracrine manner.

“By contrast, during cancer development associated with accumulation of senescent cells, SASP can recruit immature myeloid cells to promote tumorigenesis in a paracrine manner160,161.”

• cites [160] Di Mitri, D. et al. Tumour-infiltrating Gr-1+ myeloid cells antagonize senescence in cancer. Nature 515, 134–137 (2014). sourceNot checked — no full text of the source
• cites [161] Eggert, T. et al. Distinct functions of senescence-associated immune responses in liver tumor surveillance and tumor progression. Cancer Cell 30, 533–547 (2016). sourceSupported

Atherosclerotic plaques in LDL receptor-null mice accumulate high amounts of SA-β-Gal and p16-positive endothelial cells, vascular smooth muscle cells and macrophages.

“Recently, atherosclerotic plaques from LDL receptor-null mice were found to accumulate high amounts of SA-β-Gal and p16-positive endothelial cells, vascular smooth muscle cells and macrophages.”

• cites [175] Childs, B. G. et al. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science 354, 472–477 (2016). sourcePartly supported

  The paper reports SA β-Gal–positive lesions and elevated p16Ink4a transcripts in plaque-rich aortic arches of Ldlr−/− mice. Its plaque microscopy passage (Fig. 1A; page unavailable) identifies three senescent cell types resembling endothelial cells, VSMCs, and macrophages, but explicitly says their origins cannot be accurately determined. The claim overstates those cell identities as definitive. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Cellular senescence helps maintain tissue structure and function after injury.

“Cellular senescence contributes to the maintenance of the structure and the function of tissues following injury.”

• cites [145] Krizhanovsky, V. et al. Senescence of activated stellate cells limits liver fibrosis. Cell 134, 657–667 (2008). This study demonstrates that immune cell targeting of senescent cells limits dysfunction in the liver. sourcePartly supported

  The Discussion reports that senescence of activated hepatic stellate cells limits fibrosis after liver damage and describes it as a homeostatic mechanism that helps tissue return to its pre-damaged state. It says this mechanism may apply to other wound-healing responses, but does not establish maintenance of tissue structure and function after injury generally. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [146] Kim, K. H., Chen, C. C., Monzon, R. I. & Lau, L. F. Matricellular protein CCN1 promotes regression of liver fibrosis through induction of cellular senescence in hepatic myofibroblasts. Mol. Cell. Biol. 33, 2078–2090 (2013). sourceNot checked — no full text of the source

Induction of a senescence programme limits fibrosis progression in the pancreas.

“Moreover, induction of a senescence programme limits fibrosis progression in the pancreas148.”

• cites [148] Fitzner, B. et al. Senescence determines the fate of activated rat pancreatic stellate cells. J. Cell Mol. Med. 16, 2620–2630 (2012). sourcePartly supported

  The Introduction (page unavailable) proposes a role for senescence in regulating pancreatic fibrogenesis, and the Discussion (page unavailable) describes it as a possible component of pancreatic wound healing. But the rat study reports that senescent cells correlated with the extent of fibrosis; it does not show that inducing senescence limits fibrosis progression in the pancreas. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

NK cells, T cells and macrophages can physically interact with senescent cells in both pathological and physiological conditions.

“Among these cell types, NK cells, T cells and macrophages can physically interact with senescent cells in pathological and physiological conditions131,132,145,150,153–156.”

• cites [131] Storer, M. et al. Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell 155, 1119–1130 (2013). sourcePartly supported

  The developmental-limb findings (p. 7) show macrophages surrounding senescent cells, and the Discussion (p. 10) describes immune-mediated clearance. This supports the macrophage component in a physiological setting, but the paper does not identify NK- or T-cell interactions with senescent cells or establish physical interactions by all three cell types in both pathological and physiological conditions. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [132] Munoz-Espin, D. et al. Programmed cell senescence during mammalian embryonic development. Cell 155, 1104–1118 (2013). sourcePartly supported

  The “Clearance of Senescent Cells and Compensatory Mechanisms” section reports that macrophages surround senescent embryonic tubules and describes macrophage clearance of senescent tumor cells. It does not establish the claimed physical interactions involving NK cells or T cells. Page numbers were not available in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [145] Krizhanovsky, V. et al. Senescence of activated stellate cells limits liver fibrosis. Cell 134, 657–667 (2008). This study demonstrates that immune cell targeting of senescent cells limits dysfunction in the liver. sourcePartly supported

  The Results section, “Senescent stellate cells are selectively targeted by NK cells” (page unavailable), shows NK cells attacking senescent cells in vitro. The Results section, “Immune cells are found in proximity to senescent cells in fibrotic livers” (page unavailable), reports macrophages and activated lymphocytes near senescent-marker-positive cells in diseased mice, but does not identify those lymphocytes as T cells or establish physical contact by T cells or macrophages. It does not demonstrate these interactions under physiological conditions. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

Senescence immunosurveillance is essential to limit pathological fibrotic conditions and ageing.

“Senescence immunosurveillance is also essential to limit pathological fibrotic conditions and ageing20,145,151,157.”

• cites [20] Ovadya, Y. et al. Impaired immune surveillance accelerates accumulation of senescent cells and aging. Nat. Commun. 9, 5435 (2018). sourceSupported
• cites [145] Krizhanovsky, V. et al. Senescence of activated stellate cells limits liver fibrosis. Cell 134, 657–667 (2008). This study demonstrates that immune cell targeting of senescent cells limits dysfunction in the liver. sourcePartly supported

  The Results section ('Senescent stellate cells are selectively targeted by NK cells'; page unavailable) reports that inhibiting NK-cell activity delayed clearance of senescent cells and left significantly more liver fibrosis, supporting a role for immune surveillance in limiting fibrosis. The Discussion (page unavailable) only speculates that declining immune function may contribute to senescent-cell accumulation in aged tissues; it does not establish that senescence immunosurveillance is essential to limit ageing or fibrotic conditions generally. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [151] Sagiv, A. & Krizhanovsky, V. Immunosurveillance of senescent cells: the bright side of the senescence program. Biogerontology 14, 617–628 (2013). sourceNot checked — no full text of the source

Specialized SASP chemokines attract distinct immune cell subsets, including NK cells, neutrophils, dendritic cells, monocytes/macrophages, B cells and T cells.

“Specialized SASP chemokines are able to attract distinct subsets of immune cells, including NK cells, neutrophils, dendritic cells, monocytes/macrophages, B cells and T cells75,151,152.”

• cites [75] Coppe, J. P. et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 6, 2853–2868 (2008). sourcePartly supported

  The Discussion passage says that SASP cytokines and chemokines might contribute to infiltration by innate immune cells in senescing mouse tumors. It does not identify distinct recruited subsets or support the full list of NK cells, neutrophils, dendritic cells, monocytes/macrophages, B cells, and T cells. Page information is unavailable in our copy. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [151] Sagiv, A. & Krizhanovsky, V. Immunosurveillance of senescent cells: the bright side of the senescence program. Biogerontology 14, 617–628 (2013). sourceNot checked — no full text of the source
• cites [152] Freund, A., Orjalo, A. V., Desprez, P. Y. & Campisi, J. Inflammatory networks during cellular senescence: causes and consequences. Trends Mol. Med. 16, 238–246 (2010). sourcePartly supported

  The sections “Senescent cells as a source of chronic inflammation” and “Multiple roles of the SASP” say that the SASP includes chemokines and can stimulate immune clearance, including clearance by NK cells. “Chronic inflammation might propel basic aging processes” also describes senescent-cell cytokines as attractors of innate immune cells. The paper does not establish that specialized SASP chemokines attract each of the other listed subsets—neutrophils, dendritic cells, monocytes/macrophages, B cells and T cells. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

Immune surveillance and clearance of senescent cells is necessary to limit tumorigenesis in premalignant lesions and after cancer therapy.

“The surveillance and clearance of senescent cells by the immune system is necessary in order to limit tumorigenesis in premalignant lesions and following cancer therapy155,156,159.”

• cites [155] Xue, W. et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445, 656–660 (2007). sourcePartly supported

  The passages labeled Abstract report that suppressing innate immune cells delayed clearance of murine liver tumours after p53 reactivation, supporting a role for immune surveillance in that setting. The paper says clearance may reinforce tumour suppression in premalignant settings or after senescence-promoting treatment; it does not establish that immune clearance is necessary to limit tumorigenesis in those broader settings. No page numbers are provided in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [156] Kang, T. W. et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479, 547–551 (2011). sourceNot checked — no full text of the source
• cites [159] Ruscetti, M. et al. NK cell-mediated cytotoxicity contributes to tumor control by a cytostatic drug combination. Science 362, 1416–1422 (2018). sourcePartly supported

  In the paper’s discussion of combination-treated KRAS-mutant lung tumors (section labeled Abstract; page unavailable), NK-cell depletion prevented tumor regression and reduced the treatment’s survival benefit, supporting a role for immune clearance after this therapy. The discussion of premalignant cells concerns RB-mediated restraint of proliferation, not a demonstrated need for immune clearance of senescent cells in premalignant lesions. The claim also generalizes beyond the specific therapy and mouse models studied. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

In liver fibrosis, senescence restricts proliferation and expansion of ECM-producing activated hepatic stellate cells, limiting progression of the pathology after liver damage.

“in liver fibrosis, a condition associated with scarring of the liver and decrease in its function, senescence limits the proliferation and expansion of ECM-producing activated hepatic stellate cells145,146. This response limits the progression of the pathology following liver damage.”

• cites [145] Krizhanovsky, V. et al. Senescence of activated stellate cells limits liver fibrosis. Cell 134, 657–667 (2008). This study demonstrates that immune cell targeting of senescent cells limits dysfunction in the liver. sourceSupported
• cites [146] Kim, K. H., Chen, C. C., Monzon, R. I. & Lau, L. F. Matricellular protein CCN1 promotes regression of liver fibrosis through induction of cellular senescence in hepatic myofibroblasts. Mol. Cell. Biol. 33, 2078–2090 (2013). sourceNot checked — no full text of the source

The homeostatic role of senescent cells depends on their removal by the immune system after their beneficial functions are completed.

“The homeostatic function of senescent cells is dependent on their elimination by the immune system, once their beneficial functions have been performed145,151.”

• cites [145] Krizhanovsky, V. et al. Senescence of activated stellate cells limits liver fibrosis. Cell 134, 657–667 (2008). This study demonstrates that immune cell targeting of senescent cells limits dysfunction in the liver. sourcePartly supported

  The Results section reports that reducing NK-cell activity left more senescent stellate cells and more fibrosis, supporting immune clearance as a contributor to fibrosis resolution. The Discussion describes this as a homeostatic mechanism but cautions that not all senescent cells are immune targets. The paper does not establish that homeostatic function generally depends on clearance, or that clearance occurs only after beneficial functions are complete. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [151] Sagiv, A. & Krizhanovsky, V. Immunosurveillance of senescent cells: the bright side of the senescence program. Biogerontology 14, 617–628 (2013). sourceNot checked — no full text of the source

During wound healing, the SASP component PDGF-AA speeds wound closure.

“During wound healing, the SASP component PDGF-AA accelerates wound closure12.”

• cites [12] 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). sourceSupported

Shortened telomere length during ageing correlates with metabolic and cardiac dysfunction.

“Moreover, shortened telomere length, observed during ageing, correlates with metabolic and cardiac dysfunctions171,172.”

• cites [171] D’Mello, M. J. et al. Association between shortened leukocyte telomere length and cardiometabolic outcomes: systematic review and meta-analysis. Circ. Cardiovasc. Genet. 8, 82–90 (2015). sourceNot checked — no full text of the source
• cites [172] Benetos, A. et al. Tracking and fixed ranking of leukocyte telomere length across the adult life course. Aging Cell 12, 615–621 (2013). sourcePartly supported

  The Introduction (page unavailable) reports that shorter leukocyte telomere length is associated with atherosclerosis risk and, in some studies, higher BMI. The Results report telomere shortening over time, but the paper does not establish correlations with metabolic and cardiac dysfunction as broadly stated. Its Discussion also cautions against assuming that adult telomere shortening explains aging-related disease. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

In vitro, cellular senescence is a potent cell-autonomous barrier to OSKM transcription factor-mediated reprogramming, similar to its tumour suppressor role.

“In vitro studies demonstrated that cellular senescence is a potent cell-autonomous barrier for transcription factor-mediated reprograming using OCT4, SOX2, KLF4 and MYC (commonly referred to as OSKM), in a manner similar to its role in tumour suppression181–183.”

• cites [181] Krizhanovsky, V. & Lowe, S. W. Stem cells: The promises and perils of p53. Nature 460, 1085–1086 (2009). sourcePartly supported

  The Abstract says that senescence may be a barrier to reprogramming in cultured cells and compares p53’s effects on reprogramming and tumour formation. But it says the senescence mechanism is suggested rather than demonstrated, and does not establish senescence specifically as a cell-autonomous barrier to OSKM-mediated reprogramming. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [182] Banito, A. et al. Senescence impairs successful reprogramming to pluripotent stem cells. Genes Dev. 23, 2134–2139 (2009). sourceSupported
• cites [183] Li, H. et al. The Ink4/Arf locus is a barrier for iPS cell reprogramming. Nature 460, 1136–1139 (2009). sourcePartly supported

  The paper’s main text (indexed under Abstract; page unavailable) reports that loss of Ink4a/Arf improves reprogramming, including when c-Myc is added to Oct4, Sox2 and Klf4. Its concluding passage draws a parallel between the locus’s roles as a barrier to malignancy and to de-differentiation. The experiments establish a barrier involving this senescence-associated locus, but do not directly demonstrate that cellular senescence itself is the cell-autonomous barrier claimed. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

Macrophages with senescence-like features occur in lesions of patients with cell histiocytoses, haematological neoplasms with oncogene activation and multiorgan dissemination of inflamed p16-positive myeloid cells.

“Macrophages with senescence-like features have also been identified in lesions from patients with cell histiocytoses, haematological neoplasms associated with oncogene activation characterized by multiorgan dissemination of highly inflamed, p16-positive myeloid cells177,178.”

• cites [177] Cavalli, G., Biavasco, R., Borgiani, B. & Dagna, L. Oncogene-induced senescence as a new mechanism of disease: the paradigm of erdheim-chester disease. Front. Immunol. 5, 281 (2014). sourcePartly supported

  The Introduction (page unavailable) describes Erdheim–Chester disease as a multisystem histiocytosis involving tissue-infiltrating macrophages with an activating BRAF mutation. Figure 1 shows p16-positive infiltrating histiocytes, and Figure 2 links that marker to oncogene-induced senescence and inflammation. The paper does not establish Erdheim–Chester disease as a haematological neoplasm; its Abstract says whether the disease is inflammatory or clonal has long been debated. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [178] Cangi, M. G. et al. BRAFV600E-mutation is invariably present and associated to oncogene-induced senescence in Erdheim-Chester disease. Ann. Rheum. Dis. 74, 1596–1602 (2015). sourceNot checked — no full text of the source

Clinically approved antibiotics have been reported to kill DNA-damage-induced senescent cells via metabolic alterations.

“More recently, clinically approved antibiotics have been reported to have senolytic activity towards DNA-damage induced senescent cells through metabolic changes217.”

• cites [217] Ozsvari, B., Nuttall, J. R., Sotgia, F. & Lisanti, M. P. Azithromycin and roxithromycin define a new family of “senolytic” drugs that target senescent human fibroblasts. Aging 10, 3294–3307 (2018). sourcePartly supported

  The Results report that azithromycin and roxithromycin preferentially eliminated BrdU-induced senescent human fibroblasts. The Abstract and Discussion report metabolic changes with azithromycin, but say these changes could explain its senolytic activity; they do not establish that the antibiotics kill cells through those changes. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

The INK-ATTAC and p16-3MR mouse models have substantially advanced knowledge about whether senescent cells contribute to ageing and age-related diseases in model organisms, covering conditions such as Parkinson disease, Alzheimer disease, atherosclerosis, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and osteoarthritis.

“These two mouse models have greatly accelerated our understanding of whether senescent cells contribute to ageing and age-related diseases, at least in model organisms, for numerous diseases, including Parkinson disease196, Alzheimer disease197,198, atherosclerosis175, idiopathic pulmonary fibrosis199, chronic obstructive pulmonary disease200 and osteoarthritis201.”

• cites [196] Chinta, S. J. et al. Cellular senescence is induced by the environmental neurotoxin paraquat and contributes to neuropathology linked to Parkinson’s disease. Cell Rep. 22, 930–940 (2018). sourceSupported
• cites [197] Bussian, T. J. et al. Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature 562, 578–582 (2018). sourcePartly supported

  The main text (page not available) reports that clearing senescent cells with INK-ATTAC in PS19 mice prevented tau pathology, neurodegeneration and cognitive decline. That supports this citation’s contribution to the Alzheimer-disease example, but the study tests a tauopathy model, not Alzheimer disease as a whole, and does not test p16-3MR or the other listed diseases. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites [198] Zhang, P. et al. Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nat. Neurosci. 22, 719–728 (2019). sourcePartly supported

  The Discussion reports that removing senescent cells with senolytic treatment improved learning and memory in APP/PS1 Alzheimer’s disease mice, supporting the Alzheimer’s disease portion of the cited sentence. But the Methods describe a p16-ZsGreen reporter rather than INK-ATTAC or p16-3MR, and the Discussion proposes testing selective genetic elimination in Alzheimer’s disease mice as future work. This source therefore does not show that those two mouse models produced the Alzheimer’s disease finding attributed to it. (LLM, conf=0.89)

  Experimental — accuracy not yet measured
• cites [175] Childs, B. G. et al. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science 354, 472–477 (2016). sourceSupported

The peptide proxofim induces senolysis by disrupting the interaction between p53 and FOXO4.

“Administration of proxofim (a peptide) promotes senolysis by interfering with the binding of p53 to forkhead box protein O4 (FOXO4)206.”

• cites [206] Baar, M. P. et al. Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell 169, 132–147 e116 (2017). sourcePartly supported

  The Results section reports that the peptide FOXO4-DRI competes with FOXO4 for p53 binding and selectively induces apoptosis in senescent cells. Our copy does not name the peptide proxofim or establish that proxofim is FOXO4-DRI, so it does not verify that part of the claim. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Specific SASP components, soluble or in extracellular vesicles, can induce senescence in a paracrine manner, including DDR activation.

“In addition, specific SASP components, either soluble or in extracellular vesicles186, can induce senescence in a paracrine manner — which includes DDR activation73,83.”

• cites [73] Acosta, J. C. et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat. Cell Biol. 15, 978–990 (2013). sourcePartly supported

  The sections “Multiple components of the SASP mediate paracrine senescence” and “Paracrine senescence is a stable arrest mediated by secreted factors” support induction by secreted factors. “Paracrine senescence resembles a full senescence response” reports increased DNA damage in neighboring cells, but does not explicitly establish activation of the DNA-damage response. The extracellular-vesicle qualifier has its own citation (186) in the citing sentence and is not attributed to this paper. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites [83] Borghesan, M. et al. Small extracellular vesicles are key regulators of non-cell autonomous intercellular communication in senescence via the interferon protein IFITM3. Cell Rep. 27, 3956–3971 e3956 (2019). sourceSupported
• cites [186] Takasugi, M. et al. Small extracellular vesicles secreted from senescent cells promote cancer cell proliferation through EphA2. Nat. Commun. 8, 15729 (2017). sourceSupported

A-1331852 and A-1155463, believed to inhibit BCL-XL, have demonstrated senolytic activity.

“Additionally, A-1331852 and A-1155463, which are thought to inhibit BCL-XL, have also been shown to exhibit senolytic activity202.”

• cites [202] Zhu, Y. et al. New agents that target senescent cells: the flavone, fisetin, and the BCL-X(L) inhibitors, A1331852 and A1155463. Aging 9, 955–963 (2017). sourceSupported

In a phase I clinical trial, dasatinib plus quercetin lowered p16 and SA-β-gal expression in patients with diabetic kidney disease and idiopathic pulmonary disease.

“Importantly, the administration of dasatinib and quercetin has shown effectiveness in reducing the expression of p16 and SA-β-gal in a phase I clinical trial among patients with diabetic kidney disease211 and idiopathic pulmonary disease212.”

• cites [211] Hickson, L. J. et al. Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease. EBioMedicine 47, 446–456 (2019). sourceSupported
• cites [212] Justice, J. N. et al. Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study. EBioMedicine 40, 554–563 (2019). sourcePartly supported

  The Abstract (Interpretation; page unavailable) confirms that this was a first-in-human trial of dasatinib plus quercetin in patients with idiopathic pulmonary fibrosis. But the Discussion (Limitations; page unavailable) says the trial could not test senescent-cell clearance in patients’ lungs and that changes in circulating markers were inconclusive. The reported reduction in lung p16 expression was in mice, not trial participants; the paper does not establish a reduction in SA-β-gal in these patients. The diabetic kidney disease portion is attached to citation 211, not this source. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

Nanoparticles coated with galacto-oligosaccharides and carrying fluorophores or cytotoxic agents preferentially deliver their cargo to senescent cells due to elevated SA-β-gal activity.

“Nanoparticles containing either fluorophores or cytotoxic agents coated with galacto-oligosaccharides were found to preferentially deliver cytotoxic cargo to senescent cells because of the higher level of SA-β-gal activity in these cells218.”

• cites [218] Munoz-Espin, D. et al. A versatile drug delivery system targeting senescent cells. EMBO Mol. Med. https://doi.org/10.15252/emmm.201809355 (2018). sourceSupported

Adipose tissue, skeletal muscle and eyes of BubR1 hypomorphic mice express high p16 levels and other senescence-associated features.

“Adipose tissue, skeletal muscle and the eyes of BubR1 hypomorphic mice express high levels of p16 and other senescence-associated features192.”

• cites [192] Baker, D. J., Jin, F. & van Deursen, J. M. The yin and yang of the Cdkn2a locus in senescence and aging. Cell Cycle 7, 2795–2802 (2008). sourceSupported

Additional senolytics such as HSP90 inhibitors and piperlongumine have been shown to act selectively on senescent cells.

“Other senolytics, including HSP90 inhibitors213,214 and piperlongumine215,216, have also been demonstrated to be selective towards senescent cells.”

• cites [213] Fuhrmann-Stroissnigg, H., Niedernhofer, L. J. & Robbins, P. D. Hsp90 inhibitors as senolytic drugs to extend healthy aging. Cell Cycle 17, 1048–1055 (2018). sourceSupported
• cites [214] Fuhrmann-Stroissnigg, H. et al. Identification of HSP90 inhibitors as a novel class of senolytics. Nat. Commun. 8, 422 (2017). sourceSupported
• cites [215] Wang, Y. et al. Discovery of piperlongumine as a potential novel lead for the development of senolytic agents. Aging 8, 2915–2926 (2016). sourceSupported
• cites [216] Liu, X. et al. Senolytic activity of piperlongumine analogues: synthesis and biological evaluation. Bioorg. Med. Chem. 26, 3925–3938 (2018). sourceSupported

Natural flavonoids such as quercetin and fisetin, used alone or with dasatinib, can promote senolysis in multiple in vitro and in vivo settings.

“The use of various natural flavonoids, including quercetin and fisetin, either alone or in combination with dasatinib, a pan-tyrosine kinase inhibitor, can stimulate senolysis in a variety of contexts in vitro and in vivo199,207–210.”

• cites [199] Schafer, M. J. et al. Cellular senescence mediates fibrotic pulmonary disease. Nat. Commun. 8, 14532 (2017). sourcePartly supported

  The Results sections on DQ treatment report that dasatinib plus quercetin killed senescent fibroblasts in vitro and reduced senescence markers in bleomycin-injured mice in vivo. Our copy does not report senolysis by fisetin or by either flavonoid used alone, so it supports only the combination portion of the claim. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [207] Zhu, Y. et al. Inflammation and the depot-specific secretome of human preadipocytes. Obesity 23, 989–999 (2015). sourceCould not verify

  The Results section on JAK inhibition reports changes in chemokine secretion and monocyte attraction by human preadipocytes, not senolysis. Searches for quercetin, fisetin, dasatinib, and senolytic effects found no passage addressing flavonoid-induced senolysis in vitro or in vivo; page numbers were unavailable in our copy. (LLM, conf=0.78)

  Experimental — accuracy not yet measured
• cites [208] Roos, C. M. et al. Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell 15, 973–977 (2016). sourcePartly supported

  The age-related and hypercholesterolemia-induced vascular pathology sections report that dasatinib plus quercetin reduced senescent-cell markers in two mouse settings. This paper does not establish senolysis by fisetin, by either flavonoid alone, or in vitro, so it supports only part of the sentence attributed to it. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [209] Yousefzadeh, M. J. et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine 36, 18–28 (2018). sourceSupported
  Experimental — accuracy not yet measured
• cites [210] Zhu, Y. et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14, 644–658 (2015). sourcePartly supported

  The Results sections on candidate senolytic drugs in vitro and on dasatinib and quercetin in vivo report selective killing by quercetin alone or with dasatinib in several cell types, and reduced senescent-cell markers after the combination was given to mice. The passages do not report senolytic effects of fisetin, so this source does not support that part of the sentence. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

EF24 treatment selectively kills senescent cells by promoting proteasomal degradation of BCL-2.

“Promoting proteasomal degradation of BCL-2 through EF24 treatment also results in the selective killing of senescent cells205.”

• cites [205] Li, W., He, Y., Zhang, R., Zheng, G. & Zhou, D. The curcumin analog EF24 is a novel senolytic agent. Aging 11, 771–782 (2019). sourcePartly supported

  The Results sections report that EF24 selectively induces apoptosis in senescent cells and that proteasome inhibition blocks its reduction of Bcl-2-family proteins. But the reduction in Bcl-2 itself was not statistically significant; the significant reductions were in Bcl-xl and Mcl-1. The paper also presents proteasomal degradation as a suggested mechanism, not an established cause of the selective killing. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

The rapidly ageing BubR1 hypomorphic mouse model has been valuable for showing that senescent cells cause ageing and disease.

“The rapidly ageing BubR1 hypomorphic mouse model has been valuable to demonstrate that cellular senescent cells cause ageing and disease191,192.”

• cites [191] Baker, D. J. et al. BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice. Nat. Genet. 36, 744–749 (2004). sourceNot checked — no full text of the source
• cites [192] Baker, D. J., Jin, F. & van Deursen, J. M. The yin and yang of the Cdkn2a locus in senescence and aging. Cell Cycle 7, 2795–2802 (2008). sourcePartly supported

  The Introduction (page unavailable) identifies BubR1 hypomorphic mice as a rapidly aging model suited to investigating whether cellular senescence contributes to aging. “Linking cellular senescence in vivo to aging” reports that senescent cells accumulate in affected muscle and fat and links senescence to aging in those tissues. It does not establish the broader claim that senescent cells cause aging and disease generally; the Introduction says their direct contribution to organismal aging remains a matter of debate. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

In vitro, the SASP factors IL-8, GROα, IL-6 and IGFBP7 reinforce the senescent phenotype in an autocrine manner.

“In vitro, the SASP factors IL-8, GROα, IL-6, and IGFBP7 reinforce the senescent phenotype in an autocrine manner74,93,185.”

• cites [74] Kuilman, T. et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133, 1019–1031 (2008). sourcePartly supported

  The Discussion (page not available) says IL-6 acts in an autocrine, cell-autonomous fashion to implement oncogene-induced senescence, and identifies IL-8 as another cytokine involved in that response. Our copy does not establish autocrine reinforcement by IL-8, GROα, or IGFBP7; searches for GROα and IGFBP7 found no supporting passage. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [93] Acosta, J. C. et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133, 1006–1018 (2008). sourcePartly supported

  The Results report that knocking down or neutralizing IL-8 and GROα alleviated oncogene-induced senescence in cultured cells, supporting a reinforcing role for those factors. The Discussion says autocrine CXCR2 activation is possible, not established. This paper does not show that IL-6 reinforces senescence, and it discusses IGFBP7's senescence-related action as paracrine rather than autocrine. (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites [185] Wajapeyee, N., Serra, R. W., Zhu, X., Mahalingam, M. & Green, M. R. Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7. Cell 132, 363–374 (2008). sourceNot checked — no full text of the source

In BubR1 hypomorphic mice carrying the INK-ATTAC transgene, removing p16-expressing cells from weaning onward reduced senescent cell buildup and premature ageing in skeletal muscle, eye, and adipose tissue.

“treatment of BubR1 hypomorphic mice harbouring the INK-ATTAC transgene to remove p16-expressing cells beginning at weaning age attenuated the accumulation of senescent cells and premature ageing in skeletal muscle, eye and adipose tissue11”

• cites [11] Baker, D. J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011). This study demonstrates that selective elimination of p16-expressing senescent cells is safe and capable of modulating age-related dysfunction in a premature aged mouse model. sourceSupported

Senescent cells build up in many diseases associated with ageing.

“The literature is becoming inundated with evidence that senescent cells accumulate in a variety of age-associated diseases13.”

• cites [13] Childs, B. G. et al. Senescent cells: an emerging target for diseases of ageing. Nat. Rev. Drug Discov. 16, 718–735 (2017). sourceSupported

Senescent cells often increase negative regulators of apoptosis, such as BCL-2, BCL-W, and BCL-XL, making them resistant to apoptosis-inducing signals.

“Senescent cells frequently upregulate negative modulators of apoptosis, including members of the BCL-2 family (including BCL-2, BCL-W and BCL-XL), which confers resistance to apoptosis-inducing signals14,15.”

• cites [14] Yosef, R. et al. Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nat. Commun. 7, 11190 (2016). sourceSupported
• cites [15] Chang, J. et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat. Med. 22, 78–83 (2016). sourcePartly supported

  The paper’s results passage (indexed under Abstract; page unavailable) reports increased anti-apoptotic BCL-xL in senescent cells and suggests that BCL-2 and BCL-xL protect them from apoptotic death. It does not report increased BCL-2—indeed, it says the observed sensitivity did not correlate with increased BCL-2—or establish increased BCL-W. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

In humans, idiopathic pulmonary fibrosis is linked to telomere shortening and cellular senescence markers.

“Idiopathic pulmonary fibrosis is associated with telomere shortening and markers of cellular senescence in humans264.”

• cites [264] Alvarez, D. et al. IPF lung fibroblasts have a senescent phenotype. Am. J. Physiol. Lung Cell Mol. Physiol. 313, L1164–L1173 (2017). sourceSupported

Recent work has shown that senolytic CAR T cell therapy can reduce senescence-associated diseases.

“Exciting recent work has demonstrated that senolytic CAR T cell therapy can attenuate senescence-associated diseases226.”

• cites [226] Amor, C. et al. Senolytic CAR T cells reverse senescence-associated pathologies. Nature 583, 127–132 (2020). This study demonstrates the feasibility of targeting senescent cells in a variety of conditions by chimeric antigen receptor T cell-mediated therapy. sourceSupported

Recent work indicates that galactose-modified prodrugs or cytotoxic agents can deliver cytotoxic factors to lysosomes of senescent cells.

“Additionally, recent studies have further shown the potential of delivering cytotoxic factors to lysosomes of senescent cells by galactose-modifying prodrugs or cytotoxic agents219,220.”

• cites [219] Guerrero, A. et al. Galactose-modified duocarmycin prodrugs as senolytics. Aging Cell 19, e13133 (2020). sourcePartly supported

  The Discussion (page unavailable) reports that galactose-modified duocarmycin prodrugs are converted to cytotoxic drugs through processing by lysosomal β-galactosidase and selectively affect senescent cells. The Results (page unavailable) show that reducing this enzyme abolishes the prodrug’s selective killing. The paper does not establish that galactose modification specifically delivers the agents to lysosomes; it demonstrates dependence on a lysosomal enzyme. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites [220] González-Gualda, E. et al. Galacto-conjugation of navitoclax as an efficient strategy to increase senolytic specificity and reduce platelet toxicity. Aging Cell 19, e13142 (2020). sourceSupported

IL-21 and IL-15 have been proposed to strongly enhance NK cell-mediated immunity against cancer cells.

“The cytokines IL-21 and IL-15 have been suggested to substantially boost NK cell-mediated immunity against cancer cells222–225.”

• cites [222] McMichael, E. L. et al. IL-21 enhances natural killer cell response to cetuximab-coated pancreatic tumor cells. Clin. Cancer Res. 23, 489–502 (2017). sourcePartly supported

  The Discussion (page unavailable) reports that IL-21 enhanced NK-cell elimination of cetuximab-coated tumor cells, supporting the IL-21 part of the claim. The Introduction notes that NK cells have IL-15 receptors, and the Discussion mentions a mouse study comparing IL-15 with IL-21, but neither passage establishes that IL-15 substantially boosts NK-cell-mediated immunity against cancer cells. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [223] Brady, J. et al. The interactions of multiple cytokines control NK cell maturation. J. Immunol. 185, 6679–6688 (2010). sourceSupported
• cites [224] Elpek, K. G., Rubinstein, M. P., Bellemare-Pelletier, A., Goldrath, A. W. & Turley, S. J. Mature natural killer cells with phenotypic and functional alterations accumulate upon sustained stimulation with IL-15/IL-15Ralpha complexes. Proc. Natl Acad. Sci. USA 107, 21647–21652 (2010). sourcePartly supported

  The Abstract (page not provided) says IL-15/IL-15Rα complexes were proposed as a potent tumor immunotherapy and that transient stimulation boosted NK-cell function. The Results and Discussion (page not provided) also calls the complexes promising against cancer, while warning that sustained stimulation impairs NK-cell function. Our copy does not support the claim about IL-21. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [225] Rautela, J. & Huntington, N. D. IL-15 signaling in NK cell cancer immunotherapy. Curr. Opin. Immunol. 44, 1–6 (2017). sourceNot checked — no full text of the source

Activating the innate immune response with poly(I:C), which mimics viral infection, enhances clearance of senescent cells.

“Stimulation of innate immune response with poly(I:C), a simulator of viral infection, improves senescent cell clearance145.”

• cites [145] Krizhanovsky, V. et al. Senescence of activated stellate cells limits liver fibrosis. Cell 134, 657–667 (2008). This study demonstrates that immune cell targeting of senescent cells limits dysfunction in the liver. sourcePartly supported

  The Results section, “Senescent stellate cells are selectively targeted by NK cells” (page unavailable), says polyI:C was used to enhance the immune response and that treated mouse livers contained fewer senescent cells than controls. Our copy does not describe polyI:C as simulating viral infection, so that characterization is not supported by this source. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Sequence-specific inhibition of DDR activation using antisense oligonucleotides, and their application in cultured cells and mouse models to inhibit telomeric DDR, support this approach.

“Recently, sequence-specific inhibition of DDR activation by antisense oligonucleotides (ASOs)250 and their use in cultured cells and in mouse models to specifically inhibit telomeric DDR38 provided support for this approach.”

• cites [250] Michelini, F. et al. Damage-induced lncRNAs control the DNA damage response through interaction with DDRNAs at individual double-strand breaks. Nat. Cell Biol. 19, 1400–1411 (2017). sourceSupported
  Experimental — accuracy not yet measured
• cites [38] Rossiello, F. et al. DNA damage response inhibition at dysfunctional telomeres by modulation of telomeric DNA damage response RNAs. Nat. Commun. 8, 13980 (2017). sourceSupported
  Experimental — accuracy not yet measured

Safety concerns about forced telomerase expression in damaged tissues, especially the risk of promoting cancer, have been lessened by the recent finding that oncogene-expressing mice do not develop accelerated tumorigenesis with this treatment.

“Importantly, concerns regarding the safety of telomerase forced expression in damaged tissues, in particular by fuelling cancer progression, have been mitigated by the recent demonstration that oncogene-expressing mice do not show accelerated tumorigenesis on such treatment266.”

• cites [266] Munoz-Lorente, M. A. et al. AAV9-mediated telomerase activation does not accelerate tumorigenesis in the context of oncogenic K-Ras-induced lung cancer. PLoS Genet. 14, e1007562 (2018). sourceSupported

Emerging evidence indicates that targeted senolysis in mice may be severely toxic to the liver and perivascular tissue, due to removal of p16-expressing endothelial cells, adipocytes, and macrophages in aged organs, all of which have structural roles.

“Lastly, emerging evidence suggests that targeted senolysis in mice may be profoundly toxic in the liver and perivascular tissue, because of the eradication of p16-expressing endothelial cells, adipocytes and macrophages in aged organs, which all have structural functions254.”

• cites [254] Grosse, L. et al. Defined p16(High) senescent cell types are indispensable for mouse healthspan. Cell Metab. https://doi.org/10.1016/j.cmet.2020.05.002 (2020). sourcePartly supported

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

  Experimental — accuracy not yet measured

The serine/threonine kinase MK2 indirectly stabilizes many transcripts that encode cytokines.

“and the serine/threonine kinase MK2, which indirectly stabilizes many cytokine-encoding transcripts231.”

• cites [231] Laberge, R. M. et al. MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nat. Cell Biol. 17, 1049–1061 (2015). sourceCould not verify

  The Results sections on IL1A translation and NF-κB activity discuss changes in cytokine transcript abundance and translation, but do not address MK2 or stabilization of cytokine-encoding transcripts. Searches for MK2 and its full kinase name found no passage supporting the attributed mechanism. (LLM, conf=0.72)

  Experimental — accuracy not yet measured

Caloric restriction reduces DDR markers and SASP regulators in postmitotic neurons.

“Caloric restriction has also been found to reduce the levels of DDR markers and SASP regulators in postmitotic neurons134.”

• cites [134] Jurk, D. et al. Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response. Aging Cell 11, 996–1004 (2012). sourceSupported

Caloric restriction lowers p16 levels and the expression of senescence-associated genes, including SASP genes, in mice and in the colon of healthy humans.

“Nevertheless, it was reported that caloric restriction reduces p16 levels and the transcriptional expression of genes associated with cellular senescence, including SASP genes, in mice and in the colon of healthy human individuals256,257.”

• cites [256] Krishnamurthy, J. et al. Ink4a/Arf expression is a biomarker of aging. J. Clin. Invest. 114, 1299–1307 (2004). sourcePartly supported

  The section “Caloric restriction retards p16 INK4a accumulation” reports that caloric restriction significantly reduced p16 and Arf expression in mouse kidney. It does not report reduced SASP-gene expression or findings in healthy human colon; those parts of the sentence are not supported by this source. (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites [257] Fontana, L. et al. The effects of graded caloric restriction: XII. Comparison of mouse to human impact on cellular senescence in the colon. Aging Cell 17, e12746 (2018). sourceSupported

Neutralizing antibodies against key SASP components or their receptors, including IL-6, IL-1α, IL-1β, and TNF, have demonstrated senomorphic effects.

“A number of neutralizing antibodies directed against key components of the SASP or their receptors, including IL-6, IL-1α, IL-1β and TNF, also have shown senomorphic properties104,240–248 (TABLE 1).”

• cites [104] Wakita, M. et al. A BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells. Nat. Commun. 11, 1935 (2020). sourceCould not verify

  The Discussion (page unavailable) mentions that BET inhibition may downregulate SASP factors, but does not report senomorphic effects of neutralizing antibodies. The Methods (page unavailable) list an IL-6 antibody for staining, not for neutralization; searches for neutralizing antibodies against IL-6, IL-1α, IL-1β, and TNF found no supporting passage. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [240] Liu, S. et al. Simvastatin suppresses breast cancer cell proliferation induced by senescent cells. Sci. Rep. 5, 17895 (2015). sourcePartly supported

  In Results (section ‘Simvastatin suppresses SASP-induced activation of the ERK pathway in breast cancer cells’; page unavailable), an anti-IL-6 antibody slightly reduced the effect of senescent-cell conditioned medium on breast cancer cell proliferation and ERK-pathway activation. The paper does not show that the antibody changes the SASP or other properties of senescent cells, nor does it test neutralizing antibodies against IL-1α, IL-1β, TNF, or their receptors. Its evidence for SASP suppression in senescent cells concerns simvastatin, not those antibodies. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [241] Laberge, R. M. et al. Glucocorticoids suppress selected components of the senescence-associated secretory phenotype. Aging Cell 11, 569–578 (2012). sourceCould not verify

  The Results and Discussion report that the glucocorticoids corticosterone and cortisol suppress IL-1α signaling and IL-6 secretion in senescent cells. A search for neutralizing antibodies against the named SASP components or their receptors found no passage showing that such antibodies have senomorphic effects; the antibodies listed in Experimental Procedures are for protein detection. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [242] Cohen, S. et al. Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate: results of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 46, 614–624 (2002). sourceNot checked — no full text of the source
• cites [243] Kuemmerle-Deschner, J. B. et al. Canakinumab (ACZ885, a fully human IgG1 anti-IL-1β mAb) induces sustained remission in pediatric patients with cryopyrin-associated periodic syndrome (CAPS). Arthritis Res. Ther. 13, R34 (2011). sourcePartly supported

  The Introduction (page unavailable) identifies canakinumab as an antibody that neutralizes IL-1β, and the Results > Efficacy report clinical responses in children with CAPS. The paper does not assess senescence or senomorphic effects, so its therapeutic findings do not establish that part of the claim. It also provides no evidence here for antibodies targeting IL-6, IL-1α, or TNF. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [244] Hoffman, H. M. et al. Efficacy and safety of rilonacept (interleukin-1 trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebo-controlled studies. Arthritis Rheum. 58, 2443–2452 (2008). sourceNot checked — no full text of the source
• cites [245] Klareskog, L. et al. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet 363, 675–681 (2004). sourceNot checked — no full text of the source
• cites [246] Jobanputra, P., Barton, P., Bryan, S. & Burls, A. The effectiveness of infliximab and etanercept for the treatment of rheumatoid arthritis: a systematic review and economic evaluation. Health Technol. Assess. 6, 1–110 (2002). sourcePartly supported

  The References section identifies infliximab as an anti-TNFα monoclonal antibody, and the Role of TNF section discusses effects of anti-TNF therapy in rheumatoid arthritis. Our copy does not report senomorphic effects or establish that antibodies against IL-6, IL-1α, or IL-1β have such effects. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites [247] Emery, P. et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann. Rheum. Dis. 67, 1516–1523 (2008). sourcePartly supported

  The trial introduction identifies tocilizumab as an anti-IL-6 receptor monoclonal antibody, and the Results (Efficacy; page unavailable) report improved rheumatoid arthritis responses. The paper does not assess cellular senescence or senomorphic effects, so it supports the antibody example but not the attributed senomorphic property. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [248] van Rhee, F. et al. Siltuximab for multicentric Castleman’s disease: a randomised, double-blind, placebo-controlled trial. Lancet Oncol. 15, 966–974 (2014). sourceNot checked — no full text of the source

Compounds that modulate NF-κB signalling, such as metformin, apigenin, kaempferol, and BAY 11-7082, have been shown to reduce SASP production.

“Compounds that modulate NF-κB signalling, including metformin137,235–237, apigenin238, kaempferol238 and BAY 11–7082 (REF.118), have also been shown to decrease SASP production.”

• cites [137] Oubaha, M. et al. Senescence-associated secretory phenotype contributes to pathological angiogenesis in retinopathy. Sci. Transl Med. 8, 362ra144 (2016). sourceNot checked — no full text of the source
• cites [235] Moiseeva, O. et al. Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-kappaB activation. Aging Cell 12, 489–498 (2013). sourceSupported
  Experimental — accuracy not yet measured
• cites [236] Maruthur, N. M. et al. Diabetes medications as monotherapy or metformin-based combination therapy for type 2 diabetes: a systematic review and meta-analysis. Ann. Intern. Med. 164, 740–751 (2016). sourceNot checked — no full text of the source
• cites [237] Noren Hooten, N. et al. Metformin-mediated increase in DICER1 regulates microRNA expression and cellular senescence. Aging Cell 15, 572–581 (2016). sourcePartly supported

  The Results (Figure 6; page unavailable) show that metformin reduced mRNA levels of several SASP factors in the cell models studied. The paper does not establish reduced secretion or production of those factors, or link this effect to NF-κB signalling. The other named compounds have separate citations and are not attributed to this source. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [238] Lim, H., Park, H. & Kim, H. P. Effects of flavonoids on senescence-associated secretory phenotype formation from bleomycin-induced senescence in BJ fibroblasts. Biochem. Pharmacol. 96, 337–348 (2015). sourceNot checked — no full text of the source
• cites [118] Hari, P. et al. The innate immune sensor Toll-like receptor 2 controls the senescence-associated secretory phenotype. Sci. Adv. 5, eaaw0254 (2019). sourcePartly supported

  The Introduction and Results sections identify NF-κB as a regulator of the SASP and report reduced NF-κB activation after TLR2/TLR10 knockdown. But the citation is attached specifically to BAY 11–7082, and our copy does not report testing that compound or showing that it decreases SASP production. (LLM, conf=0.78)

  Experimental — accuracy not yet measured

Senescent cells are surveilled by several innate and adaptive immune cell types, including NK cells, T cells, and macrophages.

“Senescent cells are indeed subjected to immunosurveillance by multiple components of innate and adaptive immunity, including NK cells, T cells and macrophages145,151,153–156.”

• cites [145] Krizhanovsky, V. et al. Senescence of activated stellate cells limits liver fibrosis. Cell 134, 657–667 (2008). This study demonstrates that immune cell targeting of senescent cells limits dysfunction in the liver. sourcePartly supported

  The Results section, “Senescent stellate cells are selectively targeted by NK cells” (page unavailable), demonstrates NK-cell killing of senescent cells. “Immune cells are found in proximity to senescent cells in fibrotic livers” reports macrophages and activated lymphocytes nearby, but does not establish that macrophages or T cells surveil senescent cells. The paper therefore supports NK-cell surveillance, not the full list attributed to it. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [151] Sagiv, A. & Krizhanovsky, V. Immunosurveillance of senescent cells: the bright side of the senescence program. Biogerontology 14, 617–628 (2013). sourceNot checked — no full text of the source
• cites [153] Lujambio, A. et al. Non-cell-autonomous tumor suppression by p53. Cell 153, 449–460 (2013). sourceSupported
• cites [154] Soriani, A. et al. ATM-ATR-dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype. Blood 113, 3503–3511 (2009). sourcePartly supported

  The Discussion (page unavailable) proposes NK-cell surveillance of cells undergoing senescence and reports macrophage- and NK-cell-mediated clearance in a murine liver carcinoma study. It does not establish T-cell surveillance of senescent cells, so it supports the innate-cell examples but not the full claim about innate and adaptive immunity. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [155] Xue, W. et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445, 656–660 (2007). sourcePartly supported

  The supplied passages (labelled Abstract; no page given) report macrophage and natural killer cell infiltration and show that suppressing either cell type delayed clearance of senescent liver tumours. They do not establish T-cell surveillance: the mice used lacked functional T cells. The evidence supports innate immune involvement in this tumour model, not the full claim about both innate and adaptive immunity. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [156] Kang, T. W. et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479, 547–551 (2011). sourceNot checked — no full text of the source

Exposure to a younger systemic environment alleviated age-associated tissue dysfunctions in ageing telomerase-deficient mice.

“Exposure to a younger systemic environment was also shown to relieve age-associated tissue dysfunctions in ageing telomerase-deficient mice269.”

• cites [269] Conboy, I. M. & Rando, T. A. Heterochronic parabiosis for the study of the effects of aging on stem cells and their niches. Cell Cycle 11, 2260–2267 (2012). sourcePartly supported

  The Heterochronic Parabiosis section says that work in telomerase-knockout mice suggests age-related changes in the systemic environment might contribute to hematopoietic stem-cell aging. The review also reports improved tissue maintenance and repair from young systemic factors in old mammals (Is Aging of Other Adult Tissues a Stem Cell Paradigm?). It does not say that exposure to a younger environment relieved tissue dysfunction in the telomerase-deficient mice specifically; page numbers are unavailable in our copy. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

In the brain, comparable rejuvenating effects were seen when young human plasma was transferred into old animals.

“In the brain, similar rejuvenating effects were observed by a simpler procedure of young human plasma transferred into old animals268.”

• cites [268] Castellano, J. M. et al. Human umbilical cord plasma proteins revitalize hippocampal function in aged mice. Nature 544, 488–492 (2017). sourcePartly supported

  The Abstract reports that young adult human plasma was injected into aged mice and increased expression of a smaller subset of hippocampal plasticity-related genes. But young adult plasma did not significantly improve measured long-term potentiation; the reported improvements in hippocampal function and memory were primarily from umbilical cord plasma. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Heterochronic parabiosis, which surgically joins the circulation of young and old small animals, has identified systemic factors in young blood that can improve the function of several aged organs, including liver, muscle, heart, and brain.

“Over the past few decades, heterochronic parabiosis, a process by which young and old small animals are surgically connected by establishing a joined circulation, identified systemic factors that are present in young blood and can ameliorate the function of several aged organs, including liver, muscle, heart and brain267.”

• cites [267] Conboy, M. J., Conboy, I. M. & Rando, T. A. Heterochronic parabiosis: historical perspective and methodological considerations for studies of aging and longevity. Aging Cell 12, 525–530 (2013). sourcePartly supported

  The Introduction and historical-perspective section describe surgically joined young and old rodents sharing a circulation and report improved regenerative potential in aged cells exposed to youthful influences. Future perspectives discusses circulating factors with anti-aging effects. However, the paper does not establish improved function in all four organs listed: it references liver research and brain-related findings, but does not substantiate the claimed benefit to the aged heart. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Telomere shortening is one of the first and best characterized mechanisms that induce cellular senescence.

“One of the first and best characterized mechanisms of cellular senescence induction is telomere shortening”

Senescence establishment is dynamic, with overlapping but distinct molecular pathways engaged at different stages from cell cycle exit to late senescence.

“the establishment of senescence is a dynamic process, whereby overlapping but distinct molecular pathways are engaged at different stages, from immediately on cell cycle exit to late, senescence stages19”

• cites [19] Herranz, N. & Gil, J. Mechanisms and functions of cellular senescence. J. Clin. Invest. 128, 1238–1246 (2018). sourceNot checked — no full text of the source

Most senescent cells show profound epigenome and chromatin changes, which are linked to both cell-autonomous and paracrine aspects of senescence-associated proliferation arrest.

“Most senescent cells display profound changes in the epigenome and chromatin organization. These changes have been linked to both the cell-autonomous and paracrine aspects (that is, the effect on surrounding cells) of senescence-associated proliferation arrest”

Loss of tumour suppressor expression can induce proliferation arrest, as in PTEN loss-induced cellular senescence.

“Loss of tumour suppressor expression can also induce proliferation arrest, as exemplified by PTEN loss-induced cellular senescence (PICS)”

Cytosolic chromatin fragments drive senescence-associated paracrine functions by activating the cGAS-STING pathway.

“CCFs dictate senescence-associated paracrine functions through the activation of the cyclic GMP–AMP synthase (cGAS) and the adaptor stimulator of interferon genes (STING) pathway”

SASP activation is a dynamic process that accompanies senescence establishment.

“SASP activation is a dynamic process that accompanies senescence establishment”

GATA4 activates many immune and inflammation genes, including IL-6, IL-8, CXCL1, GM-CSF, and ECM proteases and their inhibitors.

“the transcription factor GATA4 activates a plethora of genes involved in immune response and inflammation, including those encoding IL-6, IL-8, CXCL1 (also known as GROα), granulocyte–macrophage colony-stimulating factor, and ECM proteases and their inhibitors”

Activation of the stress-inducible MAPK p38 is both necessary and sufficient to trigger growth arrest and SASP even without DNA damage.

“the activation of the stress-inducible MAPK p38 was proven both necessary and sufficient to trigger growth arrest and SASP even in the absence of DNA damage88”

• cites [88] Freund, A., Patil, C. K. & Campisi, J. p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype. EMBO J. 30, 1536–1548 (2011). sourceNot checked — no full text of the source

Regulation of SASP by the DNA damage response through multiple pathways can be one route by which DDR drives age-related inflammation.

“regulation of SASP by the DDR via multiple pathways can be one of the routes by which the DDR drives age-related inflammation”

In oncogene-induced senescence, BRD4 is recruited to superenhancers near SASP genes.

“The epigenetic reader bromodomain-containing protein 4 (BRD4), an acetylated histone-binding protein involved in oncogenesis, is recruited to superenhancers adjacent to SASP genes in OIS103.”

• cites [103] Stathis, A. & Bertoni, F. BET proteins as targets for anticancer treatment. Cancer Discov. 8, 24–36 (2018). sourceNot checked — no full text of the source

The DNA damage response drives metabolic reprogramming, which can enhance SASP.

“DDR is a driver of metabolic reprogramming, which can enhance SASP92”

• cites [92] Shmulevich, R. & Krizhanovsky, V. Cell senescence, DNA damage, and metabolism. Antioxid. Redox Signal. https://doi.org/10.1089/ars.2020.8043 (2020). sourceNot checked — no full text of the source

Cellular senescence and cell differentiation share the feature of cell cycle exit accompanied by a distinct transcriptional programme often controlled by soluble factors.

“the commonalities are striking: they both involve cell cycle exit with a distinct transcriptional programme often controlled by soluble factors.”

Ionizing radiation causes fur greying in mice through damage-induced differentiation of hair bulb melanocyte stem cells after one cell division.

“exposure of mice to ionizing radiation leads to fur greying, which is due to damage-induced differentiation of hair bulb melanocyte stem cells after one round of cell division124.”

• cites [124] Inomata, K. et al. Genotoxic stress abrogates renewal of melanocyte stem cells by triggering their differentiation. Cell 137, 1088–1099 (2009). This study demonstrates that DNA damage can induce stem cell differentiation. sourceNot checked — no full text of the source

cGAS-STING is activated mainly by recognition of self double-stranded DNA or chromatin fragments in the cytosol of senescent cells.

“cGAS–STING activation occurs mainly through recognition of ‘self’ double-stranded DNA or chromatin fragments in the cytosol of senescent cells114.”

• cites [114] Hopfner, K. P. & Hornung, V. Molecular mechanisms and cellular functions of cGAS-STING signalling. Nat. Rev. Mol. Cell Biol. 21, 501–521 (2020). sourceNot checked — no full text of the source

Retinal ganglion cells accumulate DDR activation markers, SA-β-gal, p16 and p21 in retinopathies.

“Neurons in the retina, known as retinal ganglion cells, were found to accumulate markers of DDR activation, SA-β-gal and both p16 and p21, in retinopathies137.”

• cites [137] Oubaha, M. et al. Senescence-associated secretory phenotype contributes to pathological angiogenesis in retinopathy. Sci. Transl Med. 8, 362ra144 (2016). sourceNot checked — no full text of the source

After DNA damage, DDR-regulated events can cause permanent cell cycle arrest with features of both cellular senescence and cell differentiation.

“there is evidence that, following DNA damage, events regulated by the DDR lead to permanent cell cycle arrest with features of cellular senescence and cell differentiation.”

STING inhibitors might be usable to treat age-related chronic inflammation.

“these discoveries suggest that STING inhibitors could potentially be used for the treatment of age-related chronic inflammation116.”

• cites [116] Haag, S. M. et al. Targeting STING with covalent small-molecule inhibitors. Nature 559, 269–273 (2018). sourceNot checked — no full text of the source

HSC self-renewal is inhibited by telomere dysfunction or exogenous DNA damage, followed by induction of lymphoid differentiation.

“self-renewal of haematopoietic stem cells (HSCs) is inhibited by telomere dysfunction or exogenous DNA damage followed by the induction of lymphoid differentiation125.”

• cites [125] Wang, J. et al. A differentiation checkpoint limits hematopoietic stem cell self-renewal in response to DNA damage. Cell 158, 1444 (2014). sourceNot checked — no full text of the source

Persistent genotoxic stress in stem cells, and possibly in progenitors and less differentiated cells more broadly, can produce cellular senescence with features of cell differentiation.

“Altogether, these independent observations in melanocyte stem cells, HSCs, neural stem cells, embryonic stem cells and whole embryos suggest that persistent genotoxic stress in stem cells, and possibly more broadly in the context of progenitors and less differentiated cells, can lead to cellular senescence with features of cell differentiation.”

Cellular senescence is a programme that evolved to limit tissue damage responses and facilitate repair and remodelling so that tissue function is restored.

“Altogether, these observations suggest that cellular senescence is a programme that has evolved to limit tissue damage response in the organism and facilitate tissue repair and remodelling to promptly restore the tissue to a functional state.”

SASP may contribute to dysfunction of multiple organs during ageing.

“The SASP may contribute to dysfunction of multiple aged organs.”

Higher blood levels of IL-6, IL-1RA and TNF receptor, all key SASP effectors, can predict chronic disease in old individuals.

“Indeed, increased blood levels of IL-6, IL-1 receptor antagonist (IL-1RA) and tumour necrosis factor (TNF) receptor, all key SASP effectors, can be predictors of chronic disease in old individuals173.”

• cites [173] Fabbri, E. et al. Aging and the burden of multimorbidity: associations with inflammatory and anabolic hormonal biomarkers. J. Gerontol. A Biol. Sci. Med. Sci 70, 63–70 (2015). sourceNot checked — no full text of the source

Inflammatory molecules in the blood of elderly people are associated with weight loss, muscle loss, weakness, chronic inflammation and depression, which are manifestations of frailty.

“Furthermore, the presence of inflammatory molecules in the blood of elderly individuals is associated with weight loss, muscle loss and weakness, chronic inflammation and depression — manifestations of a condition recently recognized as frailty.”

• cites [166] Franceschi, C. et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann. N. Y. Acad. Sci. 908, 244–254 (2000). sourceNot checked — no full text of the source

Senescent cells can contribute to organismal ageing through multiple mechanisms.

“Senescent cells can contribute to organismal ageing through multiple mechanisms (FIG. 3).”

Senescence limits stem and progenitor cell proliferation in a cell-autonomous manner.

“From the findings taken together, senescence limits proliferation of stem and progenitor cells in a cell-autonomous manner.”

• cites [179] Sousa-Victor, P., Garcia-Prat, L., Serrano, A. L., Perdiguero, E. & Munoz-Canoves, P. Muscle stem cell aging: regulation and rejuvenation. Trends Endocrinol. Metab. 26, 287–296 (2015). sourceNot checked — no full text of the source

With advancing age, individuals tend to develop a proinflammatory condition with high circulating inflammatory molecules, known as inflammageing.

“With advancing age, individuals tend to develop a proinflammatory condition, characterized by high circulating levels of inflammatory molecules, known as inflammageing166.”

• cites [166] Franceschi, C. et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann. N. Y. Acad. Sci. 908, 244–254 (2000). sourceNot checked — no full text of the source

In the absence of p16, age-related deterioration of adipose tissue, skeletal muscle and eye is attenuated.

“In the absence of p16, the age-related deterioration of adipose tissue, skeletal muscle and eye was attenuated193.”

• cites [193] Baker, D. J. et al. Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency. Nat. Cell Biol. 10, 825–836 (2008). sourceNot checked — no full text of the source

Mice with about 10% of normal BubR1 levels develop progeroid features early in life, including shortened lifespan, cataracts, lordokyphosis, lipodystrophy and infertility.

“Mice expressing ~10% of normal BubR1 levels develop a variety of progeroid features, including shortened lifespan, cataracts, lordokyphosis, lipodystrophy and infertility very early in life191.”

• cites [191] Baker, D. J. et al. BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice. Nat. Genet. 36, 744–749 (2004). sourceNot checked — no full text of the source

In these models, exogenous tissue damage that drives cellular senescence facilitates reprogramming.

“In these same models, exogenous tissue damage that drives cellular senescence facilitates reprogramming.”

• cites [184] Mosteiro, L. et al. Tissue damage and senescence provide critical signals for cellular reprogramming in vivo. Science https://doi.org/10.1126/science.aaf4445 (2016). sourceNot checked — no full text of the source

ABT-737 and ABT-263 (navitoclax) act as senolytics by blocking BCL-2 family activity, which allows senescent cells to undergo apoptosis.

“The senolytic agents ABT-737 and ABT-263 (also known as navitoclax) inhibit the activity of the BCL-2 family members, thereby permitting senescent cells to initiate apoptosis.”

In this context, IL-6 produced in the SASP appears crucial for generating induced pluripotent stem cells.

“IL-6 produced in the SASP appears to be crucial for the generation of induced pluripotent stem cells in this context.”

• cites [184] Mosteiro, L. et al. Tissue damage and senescence provide critical signals for cellular reprogramming in vivo. Science https://doi.org/10.1126/science.aaf4445 (2016). sourceNot checked — no full text of the source

Senescence induction is necessary for efficient cell reprogramming because SASP factor production promotes paracrine reprogramming into induced pluripotent stem cells.

“Senescence induction is necessary for efficient cell reprograming, as SASP factor production promotes reprogramming into induced pluripotent stem cells in a paracrine manner184.”

• cites [184] Mosteiro, L. et al. Tissue damage and senescence provide critical signals for cellular reprogramming in vivo. Science https://doi.org/10.1126/science.aaf4445 (2016). sourceNot checked — no full text of the source

INK-ATTAC transgenic mouse models in which senescent cells are removed show no apparent detrimental side effects.

“However, although INK-ATTAC transgenic mouse models in which senescent cells are removed exhibit no apparent detrimental side effects, it remains to be determined whether prolonged or repeated senolysis could become eventually toxic to an organism.”

Senescent cells strongly express DCR2, which blocks death receptor targeting via DR4 and DR5 by cytotoxic cells that express TRAIL.

“This mechanism is favoured because decoy receptor 2 (DCR2) is strongly expressed in senescent cells. DCR2 prevents targeting via the death receptors (DR4 and DR5) by the variety of cytotoxic cells that express their ligand TRAIL151.”

• cites [151] Sagiv, A. & Krizhanovsky, V. Immunosurveillance of senescent cells: the bright side of the senescence program. Biogerontology 14, 617–628 (2013). sourceNot checked — no full text of the source

NK cells target senescent cells through perforin-mediated granule exocytosis rather than through death receptor ligands.

“NK cells use perforin-mediated granule exocytosis and not death receptor ligands, which induce cell death by binding to these receptors, to target senescent cells151.”

• cites [151] Sagiv, A. & Krizhanovsky, V. Immunosurveillance of senescent cells: the bright side of the senescence program. Biogerontology 14, 617–628 (2013). sourceNot checked — no full text of the source

Eliminating senescent cells removes the chance that senescence bypass mutations could drive tumorigenesis in those damaged cells.

“Furthermore, the removal of senescent cells eliminates the possibility of senescence bypassing mutations that can promote tumorigenesis in these damaged cells.”

A large part of what is known about how senescent cells contribute to disease is derived from animal models of human conditions.

“Much of our understanding of the contribution of senescent cells to disease comes from animal models for human conditions.”

Long-term toxic effects or negative outcomes of senescent cell removal that need longer observation cannot be evaluated with current models and tools.

“Therefore, possible long-term toxic effects or negative consequences of senescent cell elimination that require longer observation times simply cannot be assessed with our current models and tools.”

Long-term effects of senolysis in rodents can only be studied for 2-3 years after treatment, a much shorter period than the potential duration of use in humans.

“The study of long-term effects in rodents is limited to 2–3 years after senolysis, which is a much shorter time frame than their potential use in humans.”