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Cited by 235Telomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model OrganismsSirtuins and Resveratrol in Medicine

Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies

Open access
Wyld, Lynda, Bellantuono, Ilaria, Tchkonia, Tamara, Morgan, Jenna, Turner, Olivia, Foss, Fiona, George, Jayan, Danson, Sarah +1 more·2020·Cancers
DOI 10.3390/cancers12082134PMC PMC7464619
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Abstract

Cellular senescence is a key component of human aging that can be induced by a range of stimuli, including DNA damage, cellular stress, telomere shortening, and the activation of oncogenes. Senescence is generally regarded as a tumour suppressive process, both by preventing cancer cell proliferation and suppressing malignant progression from pre-malignant to malignant disease. It may also be a key effector mechanism of many types of anticancer therapies, such as chemotherapy, radiotherapy, and endocrine therapies, both directly and via bioactive molecules released by senescent cells that may stimulate an immune response. However, senescence may contribute to reduced patient resilience to cancer therapies and may provide a pathway for disease recurrence after cancer therapy. A new group of drugs, senotherapies, (drugs which interact with senescent cells to interfere with their pro-aging impacts by either selectively destroying senescent cells (senolytic drugs) or inhibiting their function (senostatic drugs)) are under active investigation to determine whether they can enhance the efficacy of cancer therapies and improve resilience to cancer treatments. Senolytic drugs include quercetin, navitoclax, and fisetin and preclinical and early phase clinical data are emerging of their potential role in cancer treatments, although none are yet in routine use clinically. This article provides a review of these issues.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review summarizes how cellular senescence is both tumour-suppressive and potentially tumour-promoting, and how therapy-induced senescence may affect cancer treatment response, recurrence, and patient resilience. It reviews emerging senotherapies—senolytics and senostatics—as potential adjuncts to cancer therapy, noting that none are yet in routine clinical use.

Key findings

  • Senescence is generally tumour suppressive by preventing proliferation and blocking progression from premalignant to malignant disease, but chronic senescent cells release SASP factors that may promote tumour recurrence, progression, inflammation, and fibrosis.
  • Therapy-induced senescence is common: in breast cancer treated with neoadjuvant CAF chemotherapy, 41% of tumours stained by senescence markers versus 10% of untreated cases; Adriamycin treatment for 5 days induced 60% of breast cancer cells to become senescent.
  • Senotherapies include senolytics (e.g., quercetin, navitoclax, fisetin) and senostatics (e.g., metformin); preclinical and early-phase data suggest potential to enhance cancer therapy and reduce frailty, but none are in routine clinical use.
  • Navitoclax is limited by toxicity, especially thrombocytopenia; dasatinib plus quercetin reduces senescent cells in models and improved physical dysfunction and lifespan in aged mice; fisetin is roughly twice as potent as quercetin, with an average daily dietary intake of 0.4 mg and a phase 2 trial using 20 mg/kg orally for 2 days.

Methods

  • Design: narrative review of the clinical implications of senescence and senotherapies in cancer.
  • Data/sample: published literature on senescence biology, cancer prognosis, chemotherapy, radiotherapy, hormonal therapy, surgery, frailty, and senotherapies, including preclinical mouse models and human cancer studies; no primary patient cohort is reported.
  • Main analysis: narrative synthesis with summary tables; no systematic search strategy, meta-analysis, or formal quality appraisal is described.

Limitations

  • Stated: the interactions between senescence and cancer are “complex and poorly understood,” and more research is needed to clarify them.
  • Stated: variation in SASP composition means findings may not be extrapolated to other cancers or treatment types; no senotherapies are yet approved for clinical use, and there are no published studies of senotherapies on acute wound healing.
  • Evident: as a narrative review, it does not describe a systematic literature search or formal evidence grading, and many cited data are preclinical, small, or early-phase.

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

Integrity signals

Registry

Crossref · 10.3390/cancers12082134

Cites

123 of 123 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 84 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Senescence surveillance has been shown to suppress the progression of malignancy in hepatocytes in a mouse model.

    “This has been shown to suppress the progression of malignancy in hepatocytes in a mouse model [34].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Kang, 2011, Senescence surveillance of pre-malignant hepatocytes limits liver cancer development, Nature source

      Not checked in the free run.

  • Findingcitation

    Telomere shortening in peripheral blood T cells was linked to the development of cancer.

    “This was shown in a study where telomere shortening in peripheral blood T cells, was linked to the development of cancer [37].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Falci, 2013, Immune senescence and cancer in elderly patients: Results from an exploratory study, Exp. Gerontol. source

      Not checked in the free run.

  • Findingcitation

    The treatment of breast cancer cells with Adriamycin for 5 days induces 60% of cells to become senescent.

    “The treatment of breast cancer cells with Adriamycin for 5 days induces 60% of cells to become senescent [61].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] You, R., Dai, J., Zhang, P., Barding, G.A., and Raftery, D. (2018). Dynamic Metabolic Response to Adriamycin-Induced Senescence in Breast Cancer Cells. Metabolites, 8. source

      Not checked in the free run.

  • Findingcitation

    In a range of cancer types, including breast, lymphoma, colon, sarcoma and lung, senescence markers were linked to better prognosis.

    “Another study of a range of cancer types, including breast, lymphoma, colon, sarcoma and lung, found that senescence markers were linked to better prognosis [29].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] Althubiti, 2014, Characterization of novel markers of senescence and their prognostic potential in cancer, Cell Death Dis. source

      Not checked in the free run.

  • Findingcitation

    In colon and endometrial cancers, senescence markers are linked to improved prognosis.

    “Colon and endometrial cancers have also been studied, as well as senescence markers linked to improved prognosis [44,45].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [44] Jung, 2001, The invasion front of human colorectal adenocarcinomas shows co-localization of nuclear beta-catenin, cyclin D1, and p16INK4A and is a region of low proliferation, Am. J. Pathol. source

      Not checked in the free run.

    • cites [45] Horree, 2007, The invasive front in endometrial carcinoma: Higher proliferation and associated derailment of cell cycle regulators, Hum. Pathol. source

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  • May combine two claims. 38
  • Classified as probably not a substantial claim. 12

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    Findingcitation

    Studies have demonstrated high levels of senescence in premalignant lesions and lower levels in invasive disease, suggesting a role for senescence in blocking malignant progression.

    “Studies have demonstrated high levels of senescence in premalignant lesions and lower levels in invasive disease, suggesting a role for senescence in blocking malignant progression [2,31,32].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [2] Collado, 2005, Tumour biology: Senescence in premalignant tumours, Nature source

      Not checked in the free run.

    • cites [31] Chen, 2005, Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis, Nature source

      Not checked in the free run.

    • cites [32] Michaloglou, 2005, BRAFE600-associated senescence-like cell cycle arrest of human naevi, Nature source

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  • May combine two claims.

    Findingcitation

    In breast cancer cases treated with neoadjuvant chemotherapy, 41% of tumours were stained by senescence markers compared to only 10% of untreated cases, showing that senescence is induced by CAF chemotherapy.

    “In breast cancer cases treated with neoadjuvant chemotherapy, 41% of tumours were stained by senescence markers compared to only 10% of untreated cases, showing that senescence is induced by CAF (cyclophosphamide, Adriamycin, and fluorouracil) chemotherapy [53].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [53] Okorokov, 2002, DNA damage is able to induce senescence in tumor cells in vitro and in vivo, Cancer Res.

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    In breast cancer, p16 levels correlate with breast cancer subtype, proliferative status, and prognosis.

    “In breast cancer, p16 levels correlate with breast cancer subtype, proliferative status, and prognosis [42].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Shin, 2015, Expression of p16 and pRB in invasive breast cancer, Int. J. Clin. Exp. Pathol.

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisenone given

    None of the senolytic drugs are yet in routine use clinically.

    “although none are yet in routine use clinically.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Acute senescence is a short-term process, often triggered to limit an inflammatory response or physiological process, such as wound healing or embryological development.

    “Acute senescence is a short-term process, often triggered to limit an inflammatory response or physiological process, such as wound healing or embryological development [12].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Davaapil, 2017, Conserved and novel functions of programmed cellular senescence during vertebrate development, Development

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Senescence is generally regarded as a tumour suppressive process, both by preventing cancer cell proliferation and suppressing malignant progression from pre-malignant to malignant disease.

    “Senescence is generally regarded as a tumour suppressive process, both by preventing cancer cell proliferation and suppressing malignant progression from pre-malignant to malignant disease.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Campisi, 2005, Senescent cells, tumor suppression, and organismal aging: Good citizens, bad neighbors, Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chronic senescence is triggered by feedback loops when the senescent stimulus is prolonged, and may cause diseases such as atherosclerosis, arthritis, neurodegenerative disease, and diabetes as well as age-related decline in tissue function.

    “Chronic senescence is triggered by feedback loops when the senescent stimulus is prolonged, and may cause diseases such as atherosclerosis, arthritis, neurodegenerative disease, and diabetes [13] as well as effecting classical age-related decline in tissue function [14].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [13] Calcinotto, 2019, Cellular Senescence: Aging, Cancer, and Injury, Physiol. Rev. source

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    • cites [14] Xu, 2018, Senolytics improve physical function and increase lifespan in old age, Nat. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aging is integral to the causation of many cancers and impacts on treatment response, prognosis, treatment allocation, and treatment tolerance.

    “Aging is integral to the causation of many cancers and also impacts on treatment response, prognosis, treatment allocation, and treatment tolerance.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [6] Partridge, 2018, Facing up to the global challenges of ageing, Nature source

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    • cites [7] Hanahan, 2011, Hallmarks of cancer: The next generation, Cell source

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  • May combine two claims.

    Premisenone given

    Senescent cells release a complex, cell type-specific mixture of bioactive molecules (SASP), which impacts adjacent cells and extracellular matrix and contributes to age-related tissue degeneration.

    “Senescent cells release a complex, cell type-specific, mixture of bioactive molecules (senescence-associated secretory phenotype or SASP), which impacts on the adjacent cells and extracellular matrix and contributes to age-related tissue degeneration.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Senescent cells are rare in tissues of young organisms but become more common as tissues age, especially in adipose tissue, muscle, and skin.

    “Senescent cells are rare in the tissues of young organisms but become more common as tissues age, especially in adipose tissue, muscle, and skin [10].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Tchkonia, 2010, Fat tissue, aging, and cellular senescence, Aging Cell source

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

    Premisenone given

    A range of factors may trigger senescence, including cell stressors, reactive oxygen species, DNA damage, radiation, genotoxic substances, telomere shortening, adverse growth conditions, tumour suppressor gene activation, and oncogene activity.

    “A range of factors may trigger senescence, including cell stressors, such as reactive oxygen species, DNA damage due to aging, radiation, and genotoxic substances (including many chemotherapy agents), age-related telomere shortening, adverse growth conditions, tumour suppressor gene activation, and oncogene activity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Cells have a finite ability to replicate (the Hayflick Limit) and once this limit is reached, they lose the ability to divide but remain alive and metabolically active as senescent cells.

    “Cells have a finite ability to replicate (the Hayflick Limit [26]) and once this limit is reached, they lose the ability to divide but remain alive and metabolically active as senescent cells.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Hayflick, 1961, The serial cultivation of human diploid cell strains, Exp. Cell Res. source

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  • May combine two claims.

    Premisereasoning

    If DNA damage cannot be repaired, the cell may die via apoptosis or enter senescence via the p53/cyclin E/CDK2/RB signaling pathway; whether apoptosis or senescence occurs depends on the degree of damage and whether it is repairable.

    “Again, if this DNA damage cannot be repaired, the cell may die (usually via apoptosis) or enter senescence via the p53/cyclin E/CDK2/RB signaling pathway. Whether a cell undergoes apoptosis or senescence depends on the degree of damage, and whether it is repairable.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    As telomere shortening is irreversible in normal cells and cannot be repaired, it triggers senescence rather than temporary proliferative arrest.

    “As telomere shortening is irreversible in normal cells and cannot be repaired, it triggers senescence rather than temporary proliferative arrest.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Mild stimulation induces senescence whereas severe stimulation induces cell death.

    “Once again, mild stimulation induces senescence whereas severe stimulation induces cell death.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Some oncogenes, such as BRAF, may trigger senescence acting via mitochondrial pyruvate kinase metabolism to regulate cell cycle progression.

    “Some oncogenes, such as the BRAF oncogene (which is commonly mutated in melanoma), may trigger senescence acting via mitochondrial pyruvate kinase metabolism to regulate cell cycle progression.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Acute senescence is largely beneficial in the regulation of transient injury or stress; if a cell experiences prolonged non-lethal stress, a chronic senescent state is entered where continued production of SASP perpetuates cellular and extracellular matrix damage and results in an aging or disease linked phenotype.

    “Whereas acute senescence is largely beneficial in the regulation of transient injury or stress, if a cell experiences prolonged non-lethal stress, a chronic senescent state is entered where the continued production of SASP perpetuates cellular and extracellular matrix damage and results in the acquisition of an aging or disease linked phenotype.”
    Quote in the paperSubstantial claim

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

    Premisenone given

    The precise content of the SASP released by a senescent cell may vary according to the host tissue and the degree and type of senescent stimulus.

    “The precise content of the SASP released by a senescent cell may vary according to the host tissue and the degree and type of senescent stimulus.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Non-lethal DNA damage activates the DDR; DNA damage accumulates progressively with age but also occurs in the majority of cancers, where a key initiation event is often loss of function of critical DNA repair pathways via loss of function of tumour suppressor genes.

    “The same pathway is triggered by non-lethal DNA damage, which again activates the DDR. DNA damage accumulates progressively with age but also occurs in the majority of cancers, where a key initiation event is often the loss of function of critical DNA repair pathways via loss of function of tumour suppressor genes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Radiotherapy and chemotherapy may trigger either cell death at high doses or senescence at non-lethal doses.

    “There are also potential interactions with cancer therapies, in particular, radiotherapy and chemotherapy, which may trigger either cell death at high doses or senescence at non-lethal doses.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [20] Saleh, 2019, Tumor Cell Escape from Therapy-Induced Senescence as a Model of Disease Recurrence after Dormancy, Cancer Res. source

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    • cites [21] Bharadwaj, 2020, Senescence in polyploid giant cancer cells: A road that leads to chemoresistance, Cytokine Growth Factor Rev. source

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    • cites [22] Lee, 2019, The dynamic nature of senescence in cancer, Nat. Cell Biol. source

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

    Premisenone given

    The p53 and BRCA genes are key tumour suppressor genes that are mutated and lose function at an early stage in cancer development.

    “For example, the p53 and BRCA genes are key tumour suppressor genes that are mutated and lose function at an early stage in the process of cancer development.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Stromal cell senescence may have a tumour promoting effect in some models, possibly because of the proangiogenic influence of some components of SASP, such as VEGF, or the impact of senescent fibroblasts on adjacent tumour cells.

    “In contrast there is also evidence that stromal cell senescence may have a tumour promoting effect in some models—this may be because of the proangiogenic influence of some components of SASP, such as vascular endothelial growth factor (VEGF) or the impact of senescent fibroblasts on adjacent tumour cells [17,36].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [17] Coppe, 2006, Secretion of vascular endothelial growth factor by primary human fibroblasts at senescence, J. Biol. Chem. source

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    • cites [36] Bavik, 2006, The gene expression program of prostate fibroblast senescence modulates neoplastic epithelial cell proliferation through paracrine mechanisms, Cancer Res. source

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  • May combine two claims.

    Premisecitation

    Senescence may impact on these same pathways via positive or negative feedback loops as well as other intracellular pathways and extracellular processes, such as immune modulation, inflammation, extracellular matrix regulation, and angiogenesis.

    “In turn, senescence may impact on these same pathways via positive or negative feedback loops as well as other intracellular pathways and extracellular processes, such as the immune modulation, inflammation [16], regulation, and maintenance of the extracellular matrix, and angiogenesis [17].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [16] Freund, 2010, Inflammatory networks during cellular senescence: Causes and consequences, Trends Mol. Med. source

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    • cites [17] Coppe, 2006, Secretion of vascular endothelial growth factor by primary human fibroblasts at senescence, J. Biol. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductcitation

    No one marker alone is sufficient to identify senescence; most researchers use a panel of biomarkers, such as senescence-associated β-galactosidase, p21, and p16INK4A, combined with a marker of cellular proliferation.

    “No one marker alone is sufficient to identify senescence and most researchers use a panel of biomarkers, such as senescence-associated β-galactosidase, p21, and p16INK4A, as well as a number of other biomarkers, such as heterochromatin and proliferation markers (Table 1) combined [24] with a marker of cellular proliferation (Ki-67, for instance).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [23] Gorgoulis, 2019, Cellular Senescence: Defining a Path Forward, Cell source

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    • cites [24] Matjusaitis, 2016, Biomarkers to identify and isolate senescent cells, Ageing Res. Rev. source

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  • May combine two claims.

    Premisecitation

    Immune senescence associated with the aging of the immune system in older age may contribute to the failure of immune surveillance and contribute to cancer development in older people.

    “There is also evidence that “immune senescence”, associated with the aging of the immune system in older age may contribute to the failure of immune surveillance and contribute to cancer development in older people.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Falci, 2013, Immune senescence and cancer in elderly patients: Results from an exploratory study, Exp. Gerontol. source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    The SASP of a particular senescent cell type may have a tumour suppressive function and trigger immune activation or promote tumour growth and inflammation depending on the host tissue.

    “The SASP of a particular senescent cell type may have a tumour suppressive function and trigger immune activation or promote tumour growth and inflammation depending on the host tissue.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Senescent cells release SASP factors that damage nearby non-senescent cells and the extracellular matrix, triggering inflammation, fibrosis, and apoptosis of adjacent healthy cells, but the senescent cells themselves are resistant to these effects and accumulate, thus generating more SASP factors.

    “Senescent cells release SASP factors that damage nearby non-senescent cells and the extracellular matrix, triggering inflammation, fibrosis, and apoptosis of adjacent healthy cells, but the senescent cells themselves are resistant to these effects and accumulate, thus generating more SASP factors.”
    Quote in the paperSubstantial claim

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

    Premisenone given

    Several key pathways into senescence have been described: replicative senescence, oncogene-induced senescence, stress-induced senescence, and therapy-induced senescence.

    “Several key pathways into senescence have been described: replicative senescence, oncogene-induced senescence, stress-induced senescence, and therapy-induced senescence.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    The SASP of chronically senescent cells may promote tumour recurrence or progression.

    “It has been proposed that, whilst senescence itself is largely tumour suppressive [18], the SASP of chronically senescent cells may promote tumour recurrence or progression [19].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Campisi, 2011, Cellular senescence: A link between cancer and age-related degenerative disease?, Semin. Cancer Biol.

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

    Premisenone given

    The SASP is a melange of over 100 molecules, including inflammatory cytokines, growth factors, and proteases.

    “The SASP is a melange of over 100 molecules, including inflammatory cytokines, growth factors, and proteases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    The p16 INK4 pathway inhibits CDK4/6 and cyclin 2 and blocks cell cycle progression via the RB protein; it may be stimulated by loss of tumour suppressor function, oncogene activation, epigenetic changes, or damage to microtubules.

    “Another regulatory pathway for senescence activation is via the p16 inhibitor of kinase 4(INK4), a regulatory protein that inhibits CDK4/6 and cyclin 2 and so blocks cell cycle progression via the RB protein. This pathway may be stimulated by the loss of tumour suppressor function, oncogene activation, epigenetic changes (DNA methylation, for example, which may alter gene expression), or damage to”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Senescence induced by some cancer therapies may be harmful and promote tumour growth.

    “Consequently, senescence induced by some cancer therapies may be harmful and promote tumour growth.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] Basisty, N., Kale, A., Jeon, O.H., Kuehnemann, C., Payne, T., Rao, C., Holtz, A., Shah, S., Sharma, V., and Ferrucci, L. (2020). A proteomic atlas of senescence-associated secretomes for aging biomarker development. PLoS Biol., 18. source

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  • May combine two claims.

    Premisereasoning

    Cyclophosphamide causes DNA cross linking, which may trigger a DDR.

    “Cyclophosphamide causes DNA cross linking, which again may trigger a DDR.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    Senescence is a complex process closely related to cell cycle regulatory processes and is integral to human aging and the genesis of many human diseases.

    “senescence is a complex process closely related to cell cycle regulatory processes and is integral to human aging and the genesis of many human diseases.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Metformin has senostatic properties and reduces the stimulatory effect of SASP intermediates on prostate cancer cells.

    “the diabetic drug, metformin has senostatic properties and reduces the stimulatory effect of SASP intermediates on prostate cancer cells [123]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [123] Moiseeva, 2013, Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-kappaB activation, Aging Cell source

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  • May combine two claims.

    Premisecitation

    Senescent cells are present in cancer and in premalignant lesions and have been evaluated as prognostic markers.

    “They are also present in cancer and in premalignant lesions and have been evaluated as prognostic markers [41].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Pare, R., Soon, P.S., Shah, A., and Lee, C.S. (2019). Differential expression of senescence tumour markers and its implications on survival outcomes of breast cancer patients. PLoS ONE, 14. source

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  • May combine two claims.

    Interpretationnone given

    Senescence may be a route to tumour resistance and recurrence if senescent cells reacquire the ability to proliferate when they may become more stem-cell like or via the proinflammatory and apoptosis inhibitory effects of the SASP.

    “Conversely, it may be a route to tumour resistance and recurrence if the senescent cells reacquire the ability to proliferate when they may become more stem-cell like or via the proinflammatory and apoptosis inhibitory effects of the SASP.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Moderate chemotherapy doses are more likely to cause senescence and higher doses more likely to cause cell death.

    “Moderate chemotherapy doses are more likely to cause senescence and higher doses more likely to cause cell death [54].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Roninson, 2003, Tumor cell senescence in cancer treatment, Cancer Res.

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  • May combine two claims.

    Premisecitation

    Doxorubicin prevents the resealing of the DNA double helix by inhibiting topoisomerase 2, which triggers a DDR and thereby may cause senescence.

    “For example, doxorubicin prevents the resealing of the DNA double helix by inhibiting topoisomerase 2, which triggers a DDR and thereby may cause senescence [54].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Roninson, 2003, Tumor cell senescence in cancer treatment, Cancer Res.

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

    Premisenone given

    Vinca alkaloids and taxanes work by causing damage to the mitotic spindle during mitosis, resulting in cell death.

    “Others, such as vinca alkaloids and taxanes, work by causing damage to the mitotic spindle during mitosis, resulting in cell death.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Senolytics may impact cancer outcomes by enhancing resilience and reducing frailty.

    “There is another way in which senolytics may impact on cancer outcomes—by enhancing resilience and reducing frailty.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Long-term survivors of cancer have increased rates of frailty and reduced longevity.
    • Rests on an assumption: Some of the increased frailty and reduced longevity in long-term cancer survivors is due to direct and indirect induction of senescent cells by cancer therapies (chemotherapy and radiotherapy).
    • Rests on an assumption: Treatments such as surgery and chemotherapy have a significant negative impact on physical function, with studies showing an increase in measures of frailty after treatment, which may never recover back to baseline levels.
    • Rests on an assumption: This loss of function is one of the reasons that older patients require longer hospital admission after surgery and sometimes require social care support in the longer term after surgery.
    • Rests on an assumption: Physical dysfunction is a major burden on both the NHS and social care resources and is a research priority for the UK government.

  • May combine two claims.

    Premisecitation

    Many types of chemotherapy cause DNA damage, which can, if severe, cause cell death via the DNA damage response, or they may trigger a non-lethal DDR, leading to acute or chronic senescence, depending on the extent and duration of the stimulus.

    “Many types of chemotherapy cause DNA damage (DNA strand breaks or cross linking), which can, if severe, cause cell death via the DNA damage response, or they may trigger a non-lethal DDR, leading to acute or chronic senescence, depending on the extent and duration of the stimulus [52].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] 2014, The role of senescent cells in ageing, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A 100 mg dose of fisetin has been used in a colorectal cancer chemotherapy study and has been shown to reduce inflammatory markers, although numbers were small and no clinical cancer end points were assessed.

    “In terms of clinical trials, this 100 mg dose has been used in a colorectal cancer chemotherapy study and has been shown to reduce inflammatory markers, although numbers were small and no clinical cancer end points were assessed [121].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [121] Alizadeh, 2018, Effect of fisetin supplementation on inflammatory factors and matrix metalloproteinase enzymes in colorectal cancer patients, Food Funct. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Senescence is an important mechanism of efficacy in the treatment of breast cancer with PARP inhibitors and many typical chemotherapy agents used to treat breast cancer, such as epirubicin and cyclophosphamide.

    “Senescence is also an important mechanism of efficacy in the treatment of breast cancer with PARP inhibitors [59] and many typical chemotherapy agents used to treat breast cancer, such as epirubicin and cyclophosphamide [60].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [59] Fleury, 2019, Exploiting interconnected synthetic lethal interactions between PARP inhibition and cancer cell reversible senescence, Nat. Commun. source

      Not checked in the free run.

    • cites [60] Munoz, D.P., Yannone, S.M., Daemen, A., Sun, Y., Vakar-Lopez, F., Kawahara, M., Freund, A.M., Rodier, F., Wu, J.D., and Desprez, P.Y. (2019). Targetable mechanisms driving immunoevasion of persistent senescent cells link chemotherapy-resistant cancer to aging. JCI Insight, 5. source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Chemotherapy may cause cell death, often by apoptosis, resulting clinically in tumour regression; it may also cause cellular senescence, leading clinically to tumour stasis (growth arrest).

    “Chemotherapy may cause cell death, often by apoptosis, resulting clinically in tumour regression. It may also cause cellular senescence, leading clinically to tumour stasis (growth arrest) (Figure 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Senotherapies may become a valuable adjunct to cancer therapies both by direct destruction of the chemotherapy-induced senescent cell population within a tumour and by the inhibition of the proinflammatory SASP, which may enhance treatment tolerance by the patient.

    “Senotherapies may become a valuable adjunct to cancer therapies both by direct destruction of the chemotherapy-induced senescent cell population within a tumour and by the inhibition of the proinflammatory SASP, which may enhance treatment tolerance by the patient.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Senescence is thought to be a tumour suppressive process, inhibiting both the formation of cancer by blocking transition from premalignant to malignant disease and preventing damaged cells from proliferating after suffering DNA damage or cellular stress.

    “It is thought to be a tumour suppressive process, inhibiting both the formation of cancer by blocking transition from premalignant to malignant disease and preventing damaged cells from proliferating after suffering DNA damage or cellular stress, which is one of the key events promoting cancer development.”
    Quote in the paperNot a substantial claim
47 of 47

  • The paper relies on this without support.

    Findings from mouse models of senescence and senotherapy are informative for human cancer treatment.

    “This principle was elegantly demonstrated in a mouse model, where the implantation of senescent cells into young mice induced physical dysfunction, which spread beyond the injected senescent cells and reduced lifespan.”
    “In a separate study, again in a mouse model, the elimination of senescent cells by the use of dasatinib and quercetin, reduced the impact of radiotherapy, improved cardiac function and exercise tolerance and increased life expectancy [90].”

  • The paper relies on this without support.

    Senescence biomarkers used in human studies reliably identify senescent cells in tumours.

    “The detection of senescence is complicated, as many of the molecules involved in senescence signalling are also oncogenes or tumour suppressors that may be up or down regulated as part of the carcinogenic process.”
    “The assessment of combinations of markers is therefore required in addition to a marker of proliferation, such as Ki67.”

  • The paper relies on this without support.

    Long-term survivors of cancer have increased rates of frailty and reduced longevity.

    “It is already recognised that long-term survivors of cancer have increased rates of frailty and reduced longevity”

  • The paper relies on this without support.

    Some of the increased frailty and reduced longevity in long-term cancer survivors is due to direct and indirect induction of senescent cells by cancer therapies (chemotherapy and radiotherapy).

    “some of which are thought to be due to the direct and indirect induction of senescent cells by cancer therapies (chemotherapy and radiotherapy).”

  • The paper relies on this without support.

    Treatments such as surgery and chemotherapy have a significant negative impact on physical function, with studies showing an increase in measures of frailty after treatment, which may never recover back to baseline levels.

    “It is well recognized that treatments such as surgery and chemotherapy have a significant negative impact on physical function, with studies showing an increase in measures of frailty after treatment, which may never recover back to baseline levels.”

  • The paper relies on this without support.

    This loss of function is one of the reasons that older patients require longer hospital admission after surgery and sometimes require social care support in the longer term after surgery.

    “This loss of function is one of the reasons that older patients require longer hospital admission after surgery and sometimes require social care support in the longer term after surgery.”

  • The paper relies on this without support.

    Physical dysfunction is a major burden on both the NHS and social care resources and is a research priority for the UK government.

    “This physical dysfunction is therefore a major burden on both the NHS and social care resources and is a research priority for the UK government.”
7 of 7

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Cellular senescence is a process marked by the permanent halt of cell division and has significant implications in cancer biology, particularly in relation to MM.

    “Cellular senescence is a process marked by the permanent halt of cell division and has significant implications in cancer biology, particularly in relation to MM.”

    From Mesenchymal stromal cells in bone marrow niche of patients with multiple myeloma: a double-edged sword (2025) · cites this paper as [251]

    Section 2, “Biological Changes of Aging and Senescence,” describes loss of proliferative potential and its effects on surrounding tissue; Section 3.1, “Replicative Senescence,” links senescence to cell-cycle arrest and cancer. The claim overstates that arrest as permanent: the review says it is usually, but not always, irreversible. The passages found do not establish the claimed relevance specifically to MM. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Senescence acts as a powerful tumor suppressor by stopping damaged or stressed cells from multiplying uncontrollably and potentially developing mutations that lead to cancer.

    “While this mechanism acts as a powerful tumor suppressor by stopping damaged or stressed cells from multiplying uncontrollably and potentially developing mutations that lead to cancer, it can also paradoxically promote cancer progression in specific situations.”

    From Mesenchymal stromal cells in bone marrow niche of patients with multiple myeloma: a double-edged sword (2025) · cites this paper as [251]

  • Senescence can paradoxically promote cancer progression in specific situations.

    “While this mechanism acts as a powerful tumor suppressor by stopping damaged or stressed cells from multiplying uncontrollably and potentially developing mutations that lead to cancer, it can also paradoxically promote cancer progression in specific situations.”

    From Mesenchymal stromal cells in bone marrow niche of patients with multiple myeloma: a double-edged sword (2025) · cites this paper as [251]

  • Senescent cells, even though they do not proliferate, continue to be metabolically active and can impact their surroundings by releasing various inflammatory cytokines, growth factors, and proteases.

    “Senescent cells, even though they do not proliferate, continue to be metabolically active and can impact their surroundings by releasing various inflammatory cytokines, growth factors, and proteases.”

    From Mesenchymal stromal cells in bone marrow niche of patients with multiple myeloma: a double-edged sword (2025) · cites this paper as [251]

  • Despite its tumor-suppressive role, senescence can also facilitate cancer progression through the senescence-associated secretory phenotype (SASP).

    “Despite its tumor-suppressive role, senescence can also facilitate cancer progression through the senescence-associated secretory phenotype (SASP).”

    From Mesenchymal stromal cells in bone marrow niche of patients with multiple myeloma: a double-edged sword (2025) · cites this paper as [251]

Cites

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2 of the 125 references couldn’t be matched to a known paper.

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Related

Authors
Wyld, L., Bellantuono, I., Tchkonia, T., Morgan, J., Turner, O., Foss, F., George, J., Danson, S., & Kirkland, J. L.
Affiliations
  • University of Sheffield (GB)
  • Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA
  • Sheffield Teaching Hospitals NHS Foundation Trust (GB)
  • Mayo Clinic (US)
Corresponding author
Wyld, Lynda
ORCID
Venue
Cancers
Publisher
MDPI AG
Published
2020-07-31
Volume
12
Issue
8
Pages
2134
ISSN
2072-6694 (ISSN-L)
DOI
10.3390/cancers12082134
PMC
PMC7464619
OpenAlex
W3046779484
Semantic Scholar
010a7d02a72c6c678a15cb839c87ff57292b93d4
Cited by
235
References
125
Citations by year
2026: 21 · 2025: 35 · 2024: 42 · 2023: 44 · 2022: 57 · 2021: 29 · 2020: 7
FWCI
4.37
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancers (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institute for Health and Care Research (CL-2018-04-002)
  • National Institute on Aging (P01AG062413)
Topics
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
Keywords
cellular senescence, senotherapy, senolytics, cancer therapy resistance, tumor suppression, telomere shortening, DNA damage, oncogene activation, tumor recurrence, quercetin, navitoclax, fisetin

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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