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Cited by 198Telomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model OrganismsPhagocytosis and Immune Regulation

Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases

Open access
Song, Ping, An, Junqing, Zou, Ming-Hui·2020·Cells
DOI 10.3390/cells9030671PMC PMC7140645
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Abstract

Senescent cells are generally characterized by permanent cell cycle arrest, metabolic alteration and activation, and apoptotic resistance in multiple organs due to various stressors. Excessive accumulation of senescent cells in numerous tissues leads to multiple chronic diseases, tissue dysfunction, age-related diseases and organ ageing. Immune cells can remove senescent cells. Immunaging or impaired innate and adaptive immune responses by senescent cells result in persistent accumulation of various senescent cells. Although senolytics—drugs that selectively remove senescent cells by inducing their apoptosis—are recent hot topics and are making significant research progress, senescence immunotherapies using immune cell-mediated clearance of senescent cells are emerging and promising strategies to fight ageing and multiple chronic diseases. This short review provides an overview of the research progress to date concerning senescent cell-caused chronic diseases and tissue ageing, as well as the regulation of senescence by small-molecule drugs in clinical trials and different roles and regulation of immune cells in the elimination of senescent cells. Mounting evidence indicates that immunotherapy targeting senescent cells combats ageing and chronic diseases and subsequently extends the healthy lifespan.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that excessive senescent cells drive ageing and chronic diseases, and that immune-mediated clearance by macrophages, NK cells, cytotoxic T cells, and dendritic cells is a promising anti-ageing strategy. It surveys senolytics and small-molecule drugs in preclinical and clinical development and outlines immune mechanisms and future directions for senescence immunotherapy.

Key findings

  • Senescent cells accumulate with age and causally contribute to tissue dysfunction, organ ageing, and chronic diseases including cardiovascular disease, cancer, neurodegenerative diseases, and osteoarthritis; immune cells can remove them, but immunosenescence and impaired innate/adaptive responses promote persistent accumulation.
  • Senescence immunotherapy is emerging as an alternative or complement to senolytics: macrophages, NK cells, cytotoxic T cells, and dendritic cells recognize distinct senescent-cell ligands, such as NKG2D ligands MICA/ULBP2 on senescent cells, while HLA-E–NKG2A interaction inhibits NK/CD8+ T-cell clearance.
  • Small molecules and senolytics show reported benefits: dasatinib plus quercetin (D + Q) eliminates senescent cells in human adipose tissue and skin and improves physical function in idiopathic pulmonary fibrosis; nicotinamide mononucleotide (NMN) was safe after single oral administration in healthy men; topical rapamycin reduced p16 expression in human skin; metformin has entered multiple clinical trials including MILES and TAME.
  • In human immune ageing, supercentenarians older than 110 years had increased CD4+ cytotoxic T lymphocytes (~25.3% of total T cells) versus only 2.8% in young controls (~50–80 year olds), with a dramatic reduction in B-cell number compared with controls.

Methods

  • Narrative review synthesizing preclinical animal models, human samples, mechanistic studies, and clinical trials; no systematic review or meta-analysis is described.
  • Main analysis is qualitative and organized around senescent-cell features, senescent-cell-driven diseases and tissue ageing, small-molecule regulation of senescence, and immune cell types involved in senescent-cell clearance.
  • Clinical trial examples cited include NCT03151239 for NMN safety, NCT03103893 for topical rapamycin, the Metformin in Longevity Study (MILES), NCT02570672 for metformin and frailty, NCT02915198 for metformin in pre-diabetes and atherosclerotic cardiovascular disease, and the proposed TAME trial.

Limitations

  • The paper states that the precise mechanism underlying senescent cell accumulation within tissues is still debatable, and it is unknown whether this is due to senescent cell increase exceeding immune clearance or immune cell dysfunction.
  • The paper states that whether macrophages remove senescent cells in aged or diseased systems remains to be elucidated, and it remains extremely unknown whether and how dendritic cells eliminate apoptotic or senescent cells to prevent chronic diseases including atherosclerosis.
  • The paper states that senescence immunotherapy is not cost-free and does have side effects, and future investigations are needed for personal ageing biomarkers, unique senescent-cell antigens or ligands, and inclusion of both genders; evident from the text, many proposed immunotherapies such as CAR-T/CAR-NK targeting senescent cells and anti-NKG2A strategies are still speculative or not yet established in clinical senescence settings.

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

Integrity signals

Registry

Crossref · 10.3390/cells9030671

Cites

165 of 165 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 107 cited sources checked · 0 supported · 0 flagged

  • Interpretationreasoning

    Senescence immunotherapies using immune cell-mediated clearance of senescent cells are emerging and promising strategies to fight ageing and multiple chronic diseases.

    “Although senolytics—drugs that selectively remove senescent cells by inducing their apoptosis—are recent hot topics and are making significant research progress, senescence immunotherapies using immune cell-mediated clearance of senescent cells are emerging and promising strategies to fight ageing and multiple chronic diseases.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Cellular senescence plays beneficial critical roles in numerous biological processes, such as tumor suppression, embryonic tissue remodeling and wound healing after injury.

    “Cellular senescence plays beneficial critical roles in numerous biological processes [5], such as tumor suppression [6,7], embryonic tissue remodeling [8] and wound healing after injury [9].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [5] Burton, 2014, Physiological and pathological consequences of cellular senescence, Cell Mol. Life Sci. source

      Not checked in the free run.

    • cites [6] Lin, 2010, Skp2 targeting suppresses tumorigenesis by arf-p53-independent cellular senescence, Nature source

      Not checked in the free run.

    • cites [7] Braig, 2005, Oncogene-induced senescence as an initial barrier in lymphoma development, Nature source

      Not checked in the free run.

    • cites [8] Canamero, 2013, Programmed cell senescence during mammalian embryonic development, Cell source

      Not checked in the free run.

  • Premisecitation

    Immune cells can remove senescent cells.

    “Immune cells can remove senescent cells.”
    • Also stated in: § 3. Immunosurveillance of Senescent Cells · plain
      “Generally, senescent cells can be removed by apoptosis and the immune system [121,122].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [121] Ovadya, 2018, Strategies targeting cellular senescence, J. Clin. Investig. source

      Not checked in the free run.

    • cites [122] Prata, 2018, Senescent cell clearance by the immune system: Emerging therapeutic opportunities, Semin. Immunol. source

      Not checked in the free run.

  • Premisecitation

    Impaired innate and adaptive immune responses by senescent cells result in persistent accumulation of various senescent cells.

    “Immunaging or impaired innate and adaptive immune responses by senescent cells result in persistent accumulation of various senescent cells.”
    • Also stated in: § 3. Immunosurveillance of Senescent Cells · plain
      “Senescent cells recruit and make immune cells senescent and dysfunctional via SASP, leading to persistent and excessive accumulation of senescent cells [122].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [122] Prata, 2018, Senescent cell clearance by the immune system: Emerging therapeutic opportunities, Semin. Immunol. source

      Not checked in the free run.

  • Premisecitation

    Senescent cells in patients with idiopathic pulmonary fibrosis drive physical dysfunction.

    “Senescent cells in patients with idiopathic pulmonary fibrosis (IPF) drive physical dysfunction [45].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Justice, 2019, Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study, EBioMedicine source

      Not checked in the free run.

  • May combine two claims. 25
  • Classified as probably not a substantial claim. 5

  • May combine two claims.

    Premisecitation

    Excessive accumulation of senescent cells causally shortens the healthy lifespan and drives organ ageing, age-related organ deterioration/disorders, tissue dysfunction and chronic diseases, including cardiovascular diseases, cancer, neurodegenerative diseases and osteoarthritis.

    “However, excessive accumulation of senescent cells causally shortens the healthy lifespan [11] and drives organ ageing [12], age-related organ deterioration/disorders [13,14], tissue dysfunction and chronic diseases, including cardiovascular diseases (CVDs) [15,16], cancer [2], neurodegenerative diseases [17,18] and osteoarthritis [19].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [11] Baker, 2016, Naturally occurring p16(ink4a)-positive cells shorten healthy lifespan, Nature source

      Not checked in the free run.

    • cites [12] Childs, 2015, Cellular senescence in aging and age-related disease: From mechanisms to therapy, Nat. Med. source

      Not checked in the free run.

    • cites [13] Baker, 2011, Clearance of p16ink4a-positive senescent cells delays ageing-associated disorders, Nature source

      Not checked in the free run.

    • cites [14] Childs, 2017, Senescent cells: An emerging target for diseases of ageing, Nat. Rev. Drug Discov. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Immunotherapy targeting senescent cells combats ageing and chronic diseases and subsequently extends the healthy lifespan.

    “Mounting evidence indicates that immunotherapy targeting senescent cells combats ageing and chronic diseases and subsequently extends the healthy lifespan.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Findings from animal models and preclinical studies of senescent cell clearance will translate to human ageing and chronic diseases.
    • Rests on an assumption: Targeting or clearing senescent cells can be done safely without eliminating beneficial functions of acute or transient senescence.

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

    Premisecitation

    Cellular senescence is a cell state in which the cell-cycle is generally irreversibly stopped, with cell-cycle reentry being a plausible scenario under specific circumstances, particularly in tumor cells.

    “Cellular senescence is a cell state in which the cell-cycle is generally irreversibly stopped [1], with cell-cycle reentry being a plausible scenario under specific circumstances, particularly in tumor cells [2].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Gorgoulis, 2019, Cellular senescence: Defining a path forward, Cell source

      Not checked in the free run.

    • cites [2] Milanovic, 2018, Senescence-associated reprogramming promotes cancer stemness, Nature source

      Not checked in the free run.

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

    Premisecitation

    p16-induced senescence of mouse and human pancreatic beta cells promotes insulin secretion.

    “p16Ink4a (encoded by the INK4a/ARF locus, also known as CDKN2a, hereafter referred to as p16)-induced senescence of mouse and human pancreatic beta cells also promotes insulin secretion [10].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Helman, 2016, P16(ink4a)-induced senescence of pancreatic beta cells enhances insulin secretion, Nat. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Senescent cells are generally characterized by permanent cell cycle arrest, metabolic alteration and activation, and apoptotic resistance in multiple organs due to various stressors.

    “Senescent cells are generally characterized by permanent cell cycle arrest, metabolic alteration and activation, and apoptotic resistance in multiple organs due to various stressors.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Gorgoulis, 2019, Cellular senescence: Defining a path forward, Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Excessive accumulation of senescent cells in numerous tissues leads to multiple chronic diseases, tissue dysfunction, age-related diseases and organ ageing.

    “Excessive accumulation of senescent cells in numerous tissues leads to multiple chronic diseases, tissue dysfunction, age-related diseases and organ ageing.”
    • Also stated in: § 1. Introduction · plain
      “However, excessive accumulation of senescent cells causally shortens the healthy lifespan [11] and drives organ ageing [12], age-related organ deterioration/disorders [13,14], tissue dysfunction and chronic diseases, including cardiovascular diseases (CVDs) [15,16], cancer [2], neurodegenerative diseases [17,18] and osteoarthritis [19].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [11] Baker, 2016, Naturally occurring p16(ink4a)-positive cells shorten healthy lifespan, Nature source

      Not checked in the free run.

    • cites [12] Childs, 2015, Cellular senescence in aging and age-related disease: From mechanisms to therapy, Nat. Med. source

      Not checked in the free run.

    • cites [13] Baker, 2011, Clearance of p16ink4a-positive senescent cells delays ageing-associated disorders, Nature source

      Not checked in the free run.

    • cites [14] Childs, 2017, Senescent cells: An emerging target for diseases of ageing, Nat. Rev. Drug Discov. source

      Not checked in the free run.

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

    Premisecitation

    There are two major types of cellular senescence: stress-induced premature cellular senescence and replicative senescence due to a repeated cell cycle, which is usually mediated by telomere shortening.

    “There are two major types of cellular senescence: stress-induced premature cellular senescence [3] and replicative senescence due to a repeated cell cycle, which is usually mediated by telomere shortening [4].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [3] Liu, 2015, Impact of er stress-regulated atf4/p16 signaling on the premature senescence of renal tubular epithelial cells in diabetic nephropathy, Am. J. Physiol. Cell Physiol. source

      Not checked in the free run.

    • cites [4] Mao, 2012, Replicatively senescent cells are arrested in g1 and g2 phases, Aging source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    cGAS recognizes cytosolic DNA in senescent cells to produce cGAMP, which triggers the generation of SASP factors via STING and promotes paracrine senescence.

    “Recently, cyclic guanosine monophosphate-adenosine monophosphate (GMP-AMP) synthase (cGAS) was shown to recognize cytosolic DNA in senescent cells to produce cGAMP, which triggers the generation of SASP factors via stimulator of interferon genes (STING) and promotes paracrine senescence [35].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Gluck, 2017, Innate immune sensing of cytosolic chromatin fragments through cgas promotes senescence, Nat. Cell Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The first-in-human open-label pilot study indicates that D + Q directly eliminates senescent cells in human adipose tissue and skin and significantly improves the physical function of participants with idiopathic pulmonary fibrosis.

    “The first-in-human open-label pilot study indicates that D + Q directly eliminates senescent cells in human adipose tissue and skin [120] and significantly improves the physical function of participants with idiopathic pulmonary fibrosis [45].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [120] Hickson, 2019, Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease, EBioMedicine source

      Not checked in the free run.

    • cites [45] Justice, 2019, Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study, EBioMedicine source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Senescent cells generally demonstrate an enlarged and flattened cell morphology, expanded nucleoli, enhanced SA-β-gal activity, telomere shortening, elevation of p16 or p21, macromolecular damage and metabolism dysfunction.

    “Senescent cells generally demonstrate an enlarged and flattened cell morphology [27] and expanded nucleoli [28,29], enhanced senescence-associated beta-galactosidase (SA-β-gal) activity [30], telomere shortening, elevation of the cyclin-dependent kinase inhibitor p16 [11,31] or p21 [32], macromolecular damage and metabolism dysfunction [1].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [27] Mammoto, 2019, Effects of age-dependent changes in cell size on endothelial cell proliferation and senescence through yap1, Aging source

      Not checked in the free run.

    • cites [28] Buchwalter, 2017, Nucleolar expansion and elevated protein translation in premature aging, Nat. Commun. source

      Not checked in the free run.

    • cites [29] Tiku, 2017, Small nucleoli are a cellular hallmark of longevity, Nat. Commun. source

      Not checked in the free run.

    • cites [30] Matthews, 2006, Vascular smooth muscle cells undergo telomere-based senescence in human atherosclerosis: Effects of telomerase and oxidative stress, Circ. Res. source

      Not checked in the free run.

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

    Premisecitation

    Lipofuscin is an emerging and more sensitive biomarker than SA-β-gal activity for cellular senescence in vitro and in vivo.

    “Lipofuscin is an emerging and more sensitive biomarker than SA-β-gal activity for cellular senescence in vitro and in vivo.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Evangelou, 2017, Robust, universal biomarker assay to detect senescent cells in biological specimens, Aging Cell. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Clearance of p16+ senescent astrocytes and microglia using INKATTAC transgene restrains gliosis, tau hyperphosphorylation, neurofibrillary tangle deposition and degeneration of cortical and hippocampal neurons, thus restoring cognitive function.

    “Bussian et al. reported that clearance of p16+ senescent astrocytes and microglia using INKATTAC transgene restrains gliosis, super-phosphorylation of both soluble and insoluble tau resulting in neurofibrillary tangle deposition and degeneration of cortical and hippocampal neurons, thus restoring cognitive function.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Bussian, 2018, Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline, Nature source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Cellular senescence accumulation usually arises from increased stresses-induced cellular senescence and reduction of senescent cell removal due to apoptosis evasion and/or immune system dysfunction.

    “Cellular senescence accumulation usually arises from increased stresses-induced cellular senescence and reduction of senescent cell removal due to apoptosis evasion and/or immune system dysfunction.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    DRP1-deficient macrophages present impaired efferocytosis in vivo and subsequently increased plaque necrosis in advanced atherosclerotic lesions of Western diet-fed LDLR knockout mice.

    “DRP1-deficient macrophages present impaired efferocytosis in vivo and subsequently increased plaque necrosis in advanced atherosclerotic lesions of Western diet-fed LDLR knockout mice [147].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [147] Wang, 2017, Mitochondrial fission promotes the continued clearance of apoptotic cells by macrophages, Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Both macrophage and apoptotic or senescent cells control macrophage efferocytosis ability.

    “Both macrophage and apoptotic or senescent cells control macrophage efferocytosis ability.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Senescent tumor cells induced by p53 reconstitution recruit innate immune cells such as macrophages, leading to eradication of senescent tumor cells and subsequent tumor regression.

    “These senescent tumor cells recruit innate immune cells, such as macrophages, leading to the eradication of senescent tumor cells and subsequent tumor regression [145].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [145] Xue, 2007, Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Antibodies blocking CD47 reactivate efferocytosis of diseased vascular tissue without altering cellular apoptosis, as well as alleviate atherosclerosis in both aortic sinus and en face of aorta in multiple mouse models.

    “Antibodies blocking CD47 reactivate efferocytosis of diseased vascular tissue without altering cellular apoptosis, as well as alleviate atherosclerosis in both the aortic sinus and en face of the aorta in multiple mouse models [148].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [148] Kojima, 2016, Cd47-blocking antibodies restore phagocytosis and prevent atherosclerosis, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Senescent cells recruit and make immune cells senescent and dysfunctional via SASP, leading to persistent and excessive accumulation of senescent cells.

    “Senescent cells recruit and make immune cells senescent and dysfunctional via SASP, leading to persistent and excessive accumulation of senescent cells [122].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [122] Prata, 2018, Senescent cell clearance by the immune system: Emerging therapeutic opportunities, Semin. Immunol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    F4/80+ macrophages are key players in removal of senescent uterine cells after parturition to keep postpartum uterine functionality in wild-type mice and maintain success rate of a second pregnancy in a preterm birth mouse model.

    “F4/80+ macrophages are also key players in the removal of senescent uterine cells after parturition to keep postpartum uterine functionality in wild-type mice and maintain the success rate of a second pregnancy in a preterm birth mouse model [135].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [135] Egashira, 2017, F4/80+ macrophages contribute to clearance of senescent cells in the mouse postpartum uterus, Endocrinology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CD4+ T cells require monocytes/macrophages but not NK cells to remove pre-malignant senescent hepatocytes, subsequently blocking liver tumor development.

    “Kang et al. demonstrated that CD4+ T cells require monocytes/macrophages but not NK cells, to remove pre-malignant senescent hepatocytes, subsequently blocking liver tumor development [130].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [130] Kang, 2011, Senescence surveillance of pre-malignant hepatocytes limits liver cancer development, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Impaired macrophage efferocytosis enhances atherogenesis and atherosclerotic plaque instability.

    “The impaired ability of macrophage efferocytosis would enhance atherogenesis [139,140,141] and atherosclerotic plaque instability [142,143,144].”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [139] Proto, 2018, Regulatory t cells promote macrophage efferocytosis during inflammation resolution, Immunity source

      Not checked in the free run.

    • cites [140] Schrijvers, 2005, Phagocytosis of apoptotic cells by macrophages is impaired in atherosclerosis, Arterioscler. Thromb. Vasc. Biol. source

      Not checked in the free run.

    • cites [141] Kojima, 2017, The role of efferocytosis in atherosclerosis, Circulation source

      Not checked in the free run.

    • cites [142] Seneviratne, 2017, Interferon regulatory factor 5 controls necrotic core formation in atherosclerotic lesions by impairing efferocytosis, Circulation source

      Not checked in the free run.

    • cites [143] Thorp, 2008, Mertk receptor mutation reduces efferocytosis efficiency and promotes apoptotic cell accumulation and plaque necrosis in atherosclerotic lesions of apoe-/- mice, Arterioscler. Thromb. Vasc. Biol. source

      Not checked in the free run.

    • cites [144] Yurdagul, 2017, Mechanisms and consequences of defective efferocytosis in atherosclerosis, Front. Cardiovasc Med. source

      Not checked in the free run.

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

    Interpretationnone given

    Excessive and persistent accumulation of different senescent cells drives unique ageing and chronic disease development.

    “Excessive and persistent accumulation of different senescent cells drives unique ageing and chronic disease development.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    p53-expressing senescent liver tumor cells recruit NK cells by inducing chemokine CCL2 but not CCL3, CCL4 or CCL5, in senescent tumor cells without affecting ligand expression of RAE-1 proteins in tumor cells.

    “p53-expressing senescent liver tumor cells recruit NK cells by inducing the chemokine CCL2 but not CCL3, CCL4 or CCL5, in senescent tumor cells without affecting the ligand expression of RAE-1 proteins in the tumor cells [153].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [153] Iannello, 2013, P53-dependent chemokine production by senescent tumor cells supports nkg2d-dependent tumor elimination by natural killer cells, J. Exp. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Apoptotic cells without CDKN2B impair macrophage efferocytosis and result in development of advanced atherosclerotic plaques with large necrotic cores.

    “Thus, apoptotic cells without CDKN2B impair macrophages efferocytosis and result in the development of advanced atherosclerotic plaques with large necrotic cores.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [149] Kojima, 2014, Cyclin-dependent kinase inhibitor 2b regulates efferocytosis and atherosclerosis, J. Clin. Investig. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Adoptive constitution of engineered specific CAR-CD8+ T cells selectively targeting FAP notably alleviates cardiac fibrosis and reverses both systolic and diastolic cardiac function in angiotensin II and phenylephrine-treated mice.

    “the adoptive constitution of engineered specific CAR-CD8+ T cells selectively targeting FAP notably alleviates cardiac fibrosis and reverses both systolic and diastolic cardiac function in angiotensin II and phenylephrine-treated mice [134].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [134] Aghajanian, 2019, Targeting cardiac fibrosis with engineered t cells, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice with defects in granule exocytosis accumulate senescent stellate cells and display stronger liver fibrosis in response to a fibrogenic agent.

    “mice with defects in granule exocytosis accumulate senescent stellate cells and display stronger liver fibrosis in response to a fibrogenic agent [131].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [131] Sagiv, 2013, Granule exocytosis mediates immune surveillance of senescent cells, Oncogene source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ligands or antigens to activate receptors NKG2D and DNAM-1 or ligands HLA-E for inhibitory receptor NKG2A have demonstrated expression in senescent cells.

    “Notably, ligands or antigens to activate the receptors NKG2D and DNAM-1 or ligands HLA-E for the inhibitory receptor NKG2A, have demonstrated expression in senescent cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    NK cell activation by polyinosinic-polycytidylic acid decreases senescent cell number in liver in vivo, leading to reduced liver fibrosis.

    “NK cell activation by polyinosinic-polycytidylic acid [152] decreases the senescent cell number in the liver in vivo, leading to reduced liver fibrosis [20].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [152] Radaeva, 2006, Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in nkg2d-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent manners, Gastroenterology source

      Not checked in the free run.

    • cites [20] Krizhanovsky, 2008, Senescence of activated stellate cells limits liver fibrosis, Cell source

      Not checked in the free run.

28 of 28

  • The paper relies on this without support.

    Findings from animal models and preclinical studies of senescent cell clearance will translate to human ageing and chronic diseases.

    “Mounting evidence indicates that immunotherapy targeting senescent cells combats ageing and chronic diseases and subsequently extends the healthy lifespan.”

  • The paper relies on this without support.

    Targeting or clearing senescent cells can be done safely without eliminating beneficial functions of acute or transient senescence.

    “Usually, sudden or acute senescence will exert beneficial functions such as anti-fibrosis [20] and wound healing [21].”

  • The paper relies on this without support.

    Maintaining immune system function is sufficient to prevent or reduce pathological accumulation of senescent cells.

    “A study investigating human ageing at the individual level by frequent sampling and prolonged deep molecular profiling indicates that immune pathways are one of the significant pathways that alter with age [38].”

  • The paper relies on this without support.

    Selectivity and efficiency of cytotoxic T cells decline with age.

    “However, the selectivity and efficiency of cytotoxic T cells decline with age.”

  • The paper relies on this without support.

    Senescent cells are beneficial in the short term.

    “Because senescent cells are also beneficial in the short term, the homeostasis of senescent cells is critical for healthy ageing.”
5 of 5

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?

  • Immune cell-mediated clearance of senescent cells is emerging as a promising strategy to fight multiple chronic diseases and aging.

    “On the other hand, immune cell-mediated clearance of senescent cells is emerging as a promising strategy to fight multiple chronic diseases and aging.349”

    From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [349]

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Related

Authors
Song, P., An, J., & Zou, M.-H.
Affiliations
Georgia State University (US)
Corresponding author
Song, Ping
ORCID
Venue
Cells
Publisher
MDPI AG
Published
2020-03-10
Volume
9
Issue
3
Pages
671
ISSN
2073-4409 (ISSN-L)
DOI
10.3390/cells9030671
PMC
PMC7140645
OpenAlex
W3011483812
Semantic Scholar
533bd613fedce791195cd41b29206c4ed982619d
Cited by
198
References
164
Citations by year
2026: 22 · 2025: 37 · 2024: 40 · 2023: 23 · 2022: 38 · 2021: 24 · 2020: 12 · 2019: 2
FWCI
3.09
Type
journal article
Language
en
Open access
Licence
Locations
  • Cells (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Foundation for the National Institutes of Health (AG047776, HL089920, HL110488, HL128014, HL132500, HL137371, HL140954, CA213022)
Topics
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
Keywords
senescent cells, immune clearance, immunosenescence, senolytics, aging, chronic disease, tissue aging, immune cells, apoptosis, healthspan, small molecule drugs
MeSH terms
Aging, Chronic Disease, Humans, Immunotherapy, Cellular Senescence

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 2026-10-10.

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

Statistics and arithmetic are recomputed, not judged.

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

What counts as a claim ›How we measure confidence ›How we check this ›

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