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Cited by 510Telomeres, Telomerase, and SenescenceT-cell and B-cell ImmunologyCancer Immunotherapy and Biomarkers

Immunosenescence: a key player in cancer development

Open access
Lian, Jingyao, Yue, Ying, Yu, Weina, Zhang, Yi·2020·Journal of Hematology & Oncology
DOI 10.1186/s13045-020-00986-zPMC PMC7653700
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Abstract

Immunosenescence is a process of immune dysfunction that occurs with age and includes remodeling of lymphoid organs, leading to changes in the immune function of the elderly, which is closely related to the development of infections, autoimmune diseases, and malignant tumors. T cell–output decline is an important feature of immunosenescence as well as the production of senescence-associated secretory phenotype, increased glycolysis, and reactive oxygen species. Senescent T cells exhibit abnormal phenotypes, including downregulation of CD27, CD28, and upregulation of CD57, killer cell lectin-like receptor subfamily G, Tim-3, Tight, and cytotoxic T-lymphocyte-associated protein 4, which are tightly related to malignant tumors. The role of immunosenescence in tumors is sophisticated: the many factors involved include cAMP, glucose competition, and oncogenic stress in the tumor microenvironment, which can induce the senescence of T cells, macrophages, natural killer cells, and dendritic cells. Accordingly, these senescent immune cells could also affect tumor progression. In addition, the effect of immunosenescence on the response to immune checkpoint blocking antibody therapy so far is ambiguous due to the low participation of elderly cancer patients in clinical trials. Furthermore, many other senescence-related interventions could be possible with genetic and pharmacological methods, including mTOR inhibition, interleukin-7 recombination, and NAD + activation. Overall, this review aims to highlight the characteristics of immunosenescence and its impact on malignant tumors and immunotherapy, especially the future directions of tumor treatment through senescence-focused strategies.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review argues that immunosenescence—thymic involution, reduced T cell output, SASP, metabolic changes, and senescent immune-cell phenotypes—contributes to cancer development and complicates immunotherapy in older adults. It highlights conflicting age effects on tumor progression and immune checkpoint blockade, and discusses senescence-targeted interventions such as IL-7, mTOR inhibition, and NAD+ precursors.

Key findings

  • Immunosenescence features thymic degeneration and decreased T cell output, SASP, increased glycolysis and ROS, and senescent T cell phenotypes such as CD27−CD28−CD57+KLRG-1+ with increased Tim-3, TIGIT, and CTLA-4.
  • The tumor microenvironment can induce senescence of T cells, macrophages, NK cells, and dendritic cells via factors including cAMP, glucose competition, and oncogenic stress; senescent immune cells can in turn affect tumor progression.
  • Age effects on cancer and immunotherapy are mixed: Kugel et al. analyzed 538 melanoma patients and found those over 60 responded better to anti-PD-1 than those under 60; a retrospective study of 226 colorectal cancer patients aged 80+ found better prognosis than younger patients; another retrospective analysis of 1869 women with breast cancer found invasive ductal carcinoma incidence increased in patients <39 years.
  • ICB outcomes in the elderly remain ambiguous; patients over 75 represent less than 10% of patients with cancer in clinical studies, and interventions discussed include IL-7, mTOR inhibition, metformin, NAD+ precursors, and senolytic CAR-T cells.

Methods

  • Narrative review; no new primary data are collected.
  • Synthesizes cited preclinical and clinical literature, including mouse tumor models, retrospective patient analyses, meta-analyses, and clinical trials such as NCT00799799, NCT02186860, NCT01109095, and NCT01990157.
  • Main analysis is thematic synthesis of immunosenescence hallmarks, senescence-related immune cell subsets in the TME, tumor immunotherapy, and candidate interventions.

Limitations

  • The authors state that there are relatively few systematic studies on immunosenescence, that existing immunological techniques cannot thoroughly analyze the complexity of the immune system, and that the 6–8-week mouse model most frequently used in tumor studies may not be entirely applicable to humans.
  • The authors state that the human–mouse age correspondence is still under discussion and that a more convincing in vivo aging model is needed.
  • The authors state that elderly patients are underrepresented in clinical studies and that data on ICB safety and toxicity in the elderly are limited, so the effect of ICB antibody therapy in elderly patients has not been fully elucidated; evident from the text, this is a narrative review without a systematic search or meta-analytic synthesis.

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Integrity signals

Registry

Crossref · 10.1186/s13045-020-00986-z

Cites

212 of 212 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 266 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    T cell output decline is an important feature of immunosenescence.

    “T cell–output decline is an important feature of immunosenescence as well as the production of senescence-associated secretory phenotype, increased glycolysis, and reactive oxygen species.”
    • Also stated in: § Concept, process, and hallmarks of immunosenescence · plain
      “Moreover, an important distinguishing feature is that the thymus gradually recedes and degenerates with age, resulting in a decrease in T cell output [24, 25].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [24] Palmer S, Albergante L, Blackburn CC, Newman TJ. Thymic involution and rising disease incidence with age. Proc Natl Acad Sci U S A. 2018;115(8):1883–8. source

      Not checked in the free run.

    • cites [25] Thomas R, Wang W, Su D-M. Contributions of Age-Related Thymic Involution to Immunosenescence and Inflammaging. Immun Ageing. 2020;17:2. source

      Not checked in the free run.

  • Premisereasoning

    The T cell phenotype CD27−CD28−CD57+KLRG-1+ is an indicator of immunosenescence.

    “Therefore, the T cell phenotype of CD27−CD28−CD57+KLRG-1+ is also an indicator of immunosenescence.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Huff WX, Kwon JH, Henriquez M, Fetcko K, Dey M. The evolving role of CD8CD28 Immunosenescent T cells in cancer immunology. Int J Mol Sci. 2019;20(11):2810. source

      Not checked in the free run.

  • Premisecitation

    Many factors in the tumor microenvironment, including cAMP, glucose competition, and oncogenic stress, can induce senescence of T cells, macrophages, natural killer cells, and dendritic cells.

    “The role of immunosenescence in tumors is sophisticated: the many factors involved include cAMP, glucose competition, and oncogenic stress in the tumor microenvironment, which can induce the senescence of T cells, macrophages, natural killer cells, and dendritic cells.”
    • Also stated in: § Immunosenescence and cancer · plain
      “Many factors in the TME can induce the senescence of immune cells and dramatically affect their function.”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [51] Ye J, Huang X, Hsueh EC, Zhang Q, Ma C, Zhang Y, Varvares MA, Hoft DF, Peng G. Human regulatory T cells induce T-lymphocyte senescence. Blood. 2012;120(10):2021–31. source

      Not checked in the free run.

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    • cites [60] Freund A, Patil CK, Campisi J. p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype. EMBO J. 2011;30(8):1536–48. source

      Not checked in the free run.

  • Premisecitation

    Production of senescence-associated secretory phenotype (SASP) is an important feature of immunosenescence.

    “T cell–output decline is an important feature of immunosenescence as well as the production of senescence-associated secretory phenotype, increased glycolysis, and reactive oxygen species.”
    • Also stated in: § Concept, process, and hallmarks of immunosenescence · plain
      “Additionally, inflammation related to advanced age will produce a senescence-associated secretory phenotype (SASP), which also leads to immune system senescence [15, 23, 25].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [15] Accardi G, Caruso C. Immune-inflammatory responses in the elderly: an update. Immun Ageing. 2018;15:11. source

      Not checked in the free run.

    • cites [23] Pinti M, Appay V, Campisi J, Frasca D, Fülöp T, Sauce D, Larbi A, Weinberger B, Cossarizza A. Aging of the immune system: Focus on inflammation and vaccination. Eur J Immunol. 2016;46(10):2286–301. source

      Not checked in the free run.

    • cites [25] Thomas R, Wang W, Su D-M. Contributions of Age-Related Thymic Involution to Immunosenescence and Inflammaging. Immun Ageing. 2020;17:2. source

      Not checked in the free run.

  • Premisecitation

    IL-7 and its receptors play a key role in immunosenescence, affecting the balance of the immune system.

    “Indeed, some potential targets were already investigated: a recent study has reported that interleukin (IL)-7 and its receptors play a key role in immunosenescence, affecting the balance of the immune system [30] (Fig. 2).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Nguyen V, Mendelsohn A, Larrick JW. Interleukin-7 and Immunosenescence. J Immunol Res. 2017;2017:4807853. source

      Not checked in the free run.

  • Classified as probably not a substantial claim. 22
  • May combine two claims. 74

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

    Premisecitation

    Immunosenescence is a process of immune dysfunction that occurs with age and includes remodeling of lymphoid organs, leading to changes in the immune function of the elderly.

    “Immunosenescence is a process of immune dysfunction that occurs with age and includes remodeling of lymphoid organs, leading to changes in the immune function of the elderly, which is closely related to the development of infections, autoimmune diseases, and malignant tumors.”
    • Also stated in: § Concept, process, and hallmarks of immunosenescence · plain
      “As a consequence, immunosenescence is a process of immune dysfunction that occurs with age and includes remodeling of lymphoid organs, leading to changes in the immune function of the elderly.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Walford RL. The Immunologic Theory of Aging. Gerontologist. 1964;4:195–7. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Immunosenescence is closely related to the development of infections, autoimmune diseases, and malignant tumors.

    “Immunosenescence is a process of immune dysfunction that occurs with age and includes remodeling of lymphoid organs, leading to changes in the immune function of the elderly, which is closely related to the development of infections, autoimmune diseases, and malignant tumors.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [10] Pawelec G. Age and immunity: What is “immunosenescence”? Exp Gerontol. 2018;105:4–9. source

      Not checked in the free run.

    • cites [11] Pawelec G. Immunosenescence comes of age. Symposium on Aging Research in Immunology: The Impact of Genomics. EMBO Rep. 2007;8(3):220–3. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Senescent T cells exhibit downregulation of CD27 and CD28 and upregulation of CD57, KLRG-1, Tim-3, TIGIT, and CTLA-4.

    “Senescent T cells exhibit abnormal phenotypes, including downregulation of CD27, CD28, and upregulation of CD57, killer cell lectin-like receptor subfamily G, Tim-3, Tight, and cytotoxic T-lymphocyte-associated protein 4, which are tightly related to malignant tumors.”
    • Also stated in: § Concept, process, and hallmarks of immunosenescence · plain
      “Age-related immune biomarkers, such as the downregulation of the costimulatory molecule CD28 of senescent T cells, have also been employed in several senescence studies [41], which do not express costimulatory molecules such as CD27 and CD28 but express the killer cell lectin-like receptor subfamily G (KLRG-1) and CD57.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [41] Huff WX, Kwon JH, Henriquez M, Fetcko K, Dey M. The evolving role of CD8CD28 Immunosenescent T cells in cancer immunology. Int J Mol Sci. 2019;20(11):2810. source

      Not checked in the free run.

    • cites [42] Mondal AM, Horikawa I, Pine SR, Fujita K, Morgan KM, Vera E, Mazur SJ, Appella E, Vojtesek B, Blasco MA, et al. p53 isoforms regulate aging- and tumor-associated replicative senescence in T lymphocytes. J Clin Invest. 2013;123(12):5247–57. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increased glycolysis and reactive oxygen species (ROS) production are features of immunosenescence.

    “T cell–output decline is an important feature of immunosenescence as well as the production of senescence-associated secretory phenotype, increased glycolysis, and reactive oxygen species.”
    • Also stated in: § Concept, process, and hallmarks of immunosenescence · plain
      “Additionally, as the immune system ages, metabolism also changes, showing increased glycolysis and reactive oxygen species (ROS) production, as well as decreased mitochondrial synthesis [35, 36].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [35] Patsoukis N, Bardhan K, Chatterjee P, Sari D, Liu B, Bell LN, Karoly ED, Freeman GJ, Petkova V, Seth P, et al. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat Commun. 2015;6:6692. source

      Not checked in the free run.

    • cites [36] Henson SM, Lanna A, Riddell NE, Franzese O, Macaulay R, Griffiths SJ, Puleston DJ, Watson AS, Simon AK, Tooze SA, et al. p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8+ T cells. J Clin Invest. 2014;124(9):4004–16. source

      Not checked in the free run.

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

    Premisecitation

    Immunosenescence is characterized by decreased adaptive immunity, decreased infection resistance, and increased autoimmune risk.

    “The concept of immunosenescence was first proposed by Walford in 1964 [9] and is characterized by decreased adaptive immunity, decreased infection resistance, and increased autoimmune risk [10, 11].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [10] Pawelec G. Age and immunity: What is “immunosenescence”? Exp Gerontol. 2018;105:4–9. source

      Not checked in the free run.

    • cites [11] Pawelec G. Immunosenescence comes of age. Symposium on Aging Research in Immunology: The Impact of Genomics. EMBO Rep. 2007;8(3):220–3. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Immunosenescence is a natural process that occurs with age and leads to a decline in immune function, affecting immune functional networks and increasing cancer risk.

    “Moreover, immune system aging, also known as immunosenescence, is a natural process that occurs with age and leads to a decline in immune function, thus affecting various aspects of immune functional networks and increasing cancer risk.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [9] Walford RL. The Immunologic Theory of Aging. Gerontologist. 1964;4:195–7. source

      Not checked in the free run.

    • cites [10] Pawelec G. Age and immunity: What is “immunosenescence”? Exp Gerontol. 2018;105:4–9. source

      Not checked in the free run.

    • cites [11] Pawelec G. Immunosenescence comes of age. Symposium on Aging Research in Immunology: The Impact of Genomics. EMBO Rep. 2007;8(3):220–3. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    With increasing age, expression of CD62L and TLR1/4 on monocytes and macrophages decreases, and expression of CD11b and TLR5 increases.

    “With an increase in age, the expression of CD62L and TLR1/4 on monocytes and macrophages is decreased, and the expression of CD11b and TLR5 is increased [28].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Hazeldine J, Lord JM. Innate immunosenescence: underlying mechanisms and clinical relevance. Biogerontology. 2015;16(2):187–201. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    T cell senescence is irreversible, whereas anergy and exhaustion are considered reversible.

    “T cell senescence is irreversible, as opposed to their anergy and exhaustion, both of which are considered reversible [31, 38–40].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [31] Crespo J, Sun H, Welling TH, Tian Z, Zou W. T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment. Curr Opin Immunol. 2013;25(2):214–21. source

      Not checked in the free run.

    • cites [38] Larbi A, Fulop T. From, “truly naïve” to “exhausted senescent” T cells: when markers predict functionality. Cytometry A. 2014;85(1):25–35. source

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    • cites [39] Zhao Y, Shao Q, Peng G. Exhaustion and senescence: two crucial dysfunctional states of T cells in the tumor microenvironment. Cell Mol Immunol. 2020;17(1):27–35. source

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      Not checked in the free run.

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

    Premisecitation

    New types of immunosenescence biomarkers include circular RNAs (e.g., circular RNA100783) and microRNAs (e.g., MiR-181a, a T cell-specific senescence marker).

    “Recent studies have identified new types of immunosenescence biomarkers, including circular RNAs (e.g.,, circular RNA100783) and microRNAs, e.g., MiR-181a, which is reported to be a T cell-specific senescence marker [47, 48].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [47] Tahir S, Fukushima Y, Sakamoto K, Sato K, Fujita H, Inoue J, Uede T, Hamazaki Y, Hattori M, Minato N. A CD153+CD4+ T follicular cell population with cell-senescence features plays a crucial role in lupus pathogenesis via osteopontin production. J Immunol. 2015;194(12):5725–35. source

      Not checked in the free run.

    • cites [48] Wang Y-H, Yu X-H, Luo S-S, Han H. Comprehensive circular RNA profiling reveals that circular RNA100783 is involved in chronic CD28-associated CD8(+)T cell ageing. Immun Ageing. 2015;12:17. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Thymus degeneration leads to a decrease in the number and proportion of CD8+ naïve T cells, which is one of the main manifestations of immunosenescence.

    “Thymus degeneration leads to a decrease in the number and proportion of CD8+ naïve T cells, which is one of the main manifestations of immunosenescence [24, 25] (Fig. 2).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [24] Palmer S, Albergante L, Blackburn CC, Newman TJ. Thymic involution and rising disease incidence with age. Proc Natl Acad Sci U S A. 2018;115(8):1883–8. source

      Not checked in the free run.

    • cites [25] Thomas R, Wang W, Su D-M. Contributions of Age-Related Thymic Involution to Immunosenescence and Inflammaging. Immun Ageing. 2020;17:2. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In immunosenescence, activating receptor expression of NK cell markers NKP30, NKP46, etc., is reduced, while inhibitory receptor expression of KIR, NKG2C, etc., is increased.

    “It should be noted that, in the process of immunosenescence, the activating receptor expression of natural killer (NK) cell markers NKP30, NKP46, etc., is reduced, while the inhibitory receptor expression of KIR, NKG2C, etc., is increased [45, 46].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [45] Manser AR, Uhrberg M. Age-related changes in natural killer cell repertoires: impact on NK cell function and immune surveillance. Cancer Immunol Immunother. 2016;65(4):417–26. source

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    Premisecitation

    During aging, the cytotoxic activity of immune cells decreases, and the expression of functional molecules associated with cytotoxic activity, such as IFN-γ, granzyme B, and perforin, is reduced.

    “More recent studies have shown that, during aging, the cytotoxic activity of immune cells decreases, and the expression of functional molecules associated with cytotoxic activity, such as interferon gamma (IFN-γ), granzyme B, and perforin, is also reduced [31–34] (Table 1).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [31] Crespo J, Sun H, Welling TH, Tian Z, Zou W. T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment. Curr Opin Immunol. 2013;25(2):214–21. source

      Not checked in the free run.

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  • May combine two claims.

    Premisecitation

    Small-scale cellular senescence does not represent systematic senescence; only when the scale of cellular senescence increases and affects the whole system may senescent phenotypes and age-related diseases such as malignant tumors occur.

    “Nevertheless, small-scale cellular senescence does not represent systematic senescence: only when the scale of cellular senescence gradually increases and affects the whole system, senescent phenotypes and age-related diseases, such as malignant tumors, may occur [7].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A variety of factors, including genetics, exercise, nutrition, previous exposure to microorganisms, sex, and human cytomegalovirus infection, can influence immunosenescence.

    “In addition, a variety of factors can dramatically influence this status, such as genetics, exercise, nutrition, previous exposure to microorganisms, sex, and human cytomegalovirus infection [12–16].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [12] Pawelec G. Hallmarks of human “immunosenescence”: adaptation or dysregulation? Immun Ageing. 2012;9(1):15. source

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    • cites [13] Caruso C, Accardi G, Virruso C, Candore G. Sex, gender and immunosenescence: a key to understand the different lifespan between men and women? Immun Ageing. 2013;10(1):20. source

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    • cites [14] Turner JE. Is immunosenescence influenced by our lifetime “dose” of exercise? Biogerontology. 2016;17(3):581–602. source

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    • cites [15] Accardi G, Caruso C. Immune-inflammatory responses in the elderly: an update. Immun Ageing. 2018;15:11. source

      Not checked in the free run.

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    Premisecitation

    SASP mediates the paracrine activity of senescent cells, inducing several senescence-related diseases, including various malignancies.

    “It has been proposed that SASP, a unique characteristic of aging cells, wherein these cells secrete a variety of soluble factors, including growth factors, cytokines, proteases, chemokines, and extracellular matrix (ECM) components, mediates the paracrine activity of senescent cells, thus inducing several senescence-related diseases, including various malignancies [37].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Expression of CD11a and CD11b in neutrophils does not change significantly with age.

    “However, the expression of CD11a and CD11b in neutrophils did not change significantly [28] (Table 1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Hazeldine J, Lord JM. Innate immunosenescence: underlying mechanisms and clinical relevance. Biogerontology. 2015;16(2):187–201. source

      Not checked in the free run.

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    Premisecitation

    T cells are the main effectors of acquired immunity, and their compartment is heavily affected during aging, cumulating defects that can increase immune system damage, disease susceptibility, and occurrence of malignant tumors in the elderly.

    “For example, T cells are the main effectors of acquired immunity, and their compartment is heavily affected during aging, cumulating defects [20] that can increase immune system damage, disease susceptibility, and the occurrence of malignant tumors in the elderly.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Nikolich-Žugich J. Aging of the T cell compartment in mice and humans: from no naive expectations to foggy memories. J Immunol. 2014;193(6):2622–9. source

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    Premisecitation

    The immune system plays an immune surveillance role in the antitumor response but is also closely associated with the initiation and progression of tumors.

    “The immune system has an ambiguous role in cancer, as it plays an important immune surveillance role in the antitumor response but is also closely associated with the initiation and progression of tumors [8].”
    Quote in the paperSubstantial claim0 of 1 sources checked
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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Malignant tumors are generally defined as aging diseases because morbidity and mortality rates of various tumors increase with age.

    “The morbidity and mortality rates of various tumors increase with age, and thus, malignant tumors are generally defined as aging diseases [1, 2].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7–30. source

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    • cites [2] Hsu T. Educational initiatives in geriatric oncology - Who, why, and how? J Geriat Oncol. 2016;7(5):390–6. source

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    Premisecitation

    Glucose competition triggers ATM-related DNA damage, activates ERK1/2 and P38 pathways, and cooperates with STAT1/3, leading to T cell cycle arrest and aging.

    “Similarly, glucose competition triggers ATM-related DNA damage, activates the ERK1/2 and P38 pathways, and cooperates with STAT1/3, leading to T cell cycle arrest and aging.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [64] Lanna A, Gomes DCO, Muller-Durovic B, McDonnell T, Escors D, Gilroy DW, Lee JH, Karin M, Akbar AN. A sestrin-dependent Erk-Jnk-p38 MAPK activation complex inhibits immunity during aging. Nat Immunol. 2017;18(3):354–63. source

      Not checked in the free run.

    • cites [65] Lanna A, Henson SM, Escors D, Akbar AN. The kinase p38 activated by the metabolic regulator AMPK and scaffold TAB1 drives the senescence of human T cells. Nat Immunol. 2014;15(10):965–72. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a preclinical mouse model of pancreatic ductal adenocarcinoma, T/P drugs induced senescence of pancreatic cancer cells and activated SASP-dependent vascular remodeling, which enhances the uptake and efficacy of chemotherapy drugs and promotes the infiltration of T cells into tumor tissues.

    “In a preclinical mouse model of pancreatic ductal adenocarcinoma, T/P drugs induced senescence of pancreatic cancer cells and activated SASP-dependent vascular remodeling, which not only enhances the uptake and efficacy of chemotherapy drugs but also promotes the infiltration of T cells into tumor tissues [78].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [78] Ruscetti M, Morris JP, Mezzadra R, Russell J, Leibold J, Romesser PB, Simon J, Kulick A, Ho Y-J, Fennell M, et al. Senescence-induced vascular remodeling creates therapeutic vulnerabilities in pancreas cancer. Cell. 2020;181(2):424-441.e21. source

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  • May combine two claims.

    Premisecitation

    In elderly group of Engelbreth-Holm-Swarm cancer and B16F10 melanoma mouse models, tumor growth and metastasis sizes were lower and subjects had a higher survival rate.

    “In the elderly group of Engelbreth-Holm-Swarm cancer and B16F10 melanoma mouse models, tumor growth and metastasis sizes were lower and the subjects had a higher survival rate [74, 75].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [74] Ershler WB, Stewart JA, Hacker MP, Moore AL, Tindle BH. B16 murine melanoma and aging: slower growth and longer survival in old mice. J Natl Cancer Inst. 1984;72(1):161–4. source

      Not checked in the free run.

    • cites [75] Pili R, Guo Y, Chang J, Nakanishi H, Martin GR, Passaniti A. Altered angiogenesis underlying age-dependent changes in tumor growth. J Natl Cancer Inst. 1994;86(17):1303–14. source

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  • May combine two claims.

    Premisecitation

    The number of mature NK cells in all lymphoid organs and the expression of T-box protein and eomesodermin were significantly reduced in aged mice.

    “The number of mature NK cells in all lymphoid organs and the expression of T-box protein, expressed in T cells (also called TBX21), and eomesodermin were both significantly reduced in aged mice [81].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [81] Shehata HM, Hoebe K, Chougnet CA. The aged nonhematopoietic environment impairs natural killer cell maturation and function. Aging Cell. 2015;14(2):191–9. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aging T cells preferentially employ anaerobic glycolysis to generate energy, resulting in mitochondrial dysfunction and increased ROS generation.

    “Moreover, aging T cells preferentially employ anaerobic glycolysis to generate energy, which results in mitochondrial dysfunction and increased reactive oxygen species (ROS) generation [36].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Henson SM, Lanna A, Riddell NE, Franzese O, Macaulay R, Griffiths SJ, Puleston DJ, Watson AS, Simon AK, Tooze SA, et al. p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8+ T cells. J Clin Invest. 2014;124(9):4004–16. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Activation of ATM and AMPK pathways induced by glucose can cause DNA damage and T cell senescence, in which AMPK activates P38 by binding to TAB1 protein and downregulating the telomerase reverse transcriptase gene.

    “The activation of ATM and AMPK pathways induced by glucose can also cause DNA damage and T cell senescence, in which AMPK activates P38 by binding to TAB1 protein and downregulating the telomerase reverse transcriptase gene [64, 65].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [64] Lanna A, Gomes DCO, Muller-Durovic B, McDonnell T, Escors D, Gilroy DW, Lee JH, Karin M, Akbar AN. A sestrin-dependent Erk-Jnk-p38 MAPK activation complex inhibits immunity during aging. Nat Immunol. 2017;18(3):354–63. source

      Not checked in the free run.

    • cites [65] Lanna A, Henson SM, Escors D, Akbar AN. The kinase p38 activated by the metabolic regulator AMPK and scaffold TAB1 drives the senescence of human T cells. Nat Immunol. 2014;15(10):965–72. source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Immunosenescence affects the innate immune system (NK cells and macrophages) and reduces the function of the acquired immune system (T cells and B cells).

    “Immunosenescence not only affects the innate immune system, which includes NK cells and macrophages, but also reduces the function of the acquired immune system, including T cells and B cells (Fig. 4).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    An immune system disorder in the elderly may promote tumor growth and induce T cell senescence, such as an increase in the proportion of tumor-associated macrophages and regulatory T cells.

    “Multiple studies have shown that an immune system disorder in the elderly may promote tumor growth and induce T cell senescence, such as an increase in the proportion of tumor-associated macrophages and regulatory T cells (Tregs) [51–55].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [51] Ye J, Huang X, Hsueh EC, Zhang Q, Ma C, Zhang Y, Varvares MA, Hoft DF, Peng G. Human regulatory T cells induce T-lymphocyte senescence. Blood. 2012;120(10):2021–31. source

      Not checked in the free run.

    • cites [52] Ye J, Ma C, Hsueh EC, Eickhoff CS, Zhang Y, Varvares MA, Hoft DF, Peng G. Tumor-derived γδ regulatory T cells suppress innate and adaptive immunity through the induction of immunosenescence. J Immunol. 2013;190(5):2403–14. source

      Not checked in the free run.

    • cites [53] Liu X, Mo W, Ye J, Li L, Zhang Y, Hsueh EC, Hoft DF, Peng G. Regulatory T cells trigger effector T cell DNA damage and senescence caused by metabolic competition. Nat Commun. 2018;9(1):249. source

      Not checked in the free run.

    • cites [54] Wang D, Yang L, Yue D, Cao L, Li L, Wang D, Ping Y, Shen Z, Zheng Y, Wang L, et al. Macrophage-derived CCL22 promotes an immunosuppressive tumor microenvironment via IL-8 in malignant pleural effusion. Cancer Lett. 2019;452:244–53. source

      Not checked in the free run.

    • cites [55] Yang L, Zhang Y. Tumor-associated macrophages: from basic research to clinical application. J Hematol Oncol. 2017;10(1):58. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NK cells are a key component of innate immunity and promote the antitumor immune response.

    “NK cells are a key component of innate immunity and, to a large extent, promote the antitumor immune response [79, 80].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [79] Naumova E, Pawelec G, Mihaylova A. Natural killer cells, ageing and cancer. Cancer Immunol Immunother. 2016;65(4):367–70. source

      Not checked in the free run.

    • cites [80] Habif G, Crinier A, André P, Vivier E, Narni-Mancinelli E. Targeting natural killer cells in solid tumors. Cell Mol Immunol. 2019;16(5):415–22. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Two subpopulations of NK cells, immature CD14+CD56dim and mature CD14+CD56bright, are associated with aging and remodeling of mature NK cell subsets, and reduced expression of activated receptors may promote the escape of NK cells in the elderly.

    “Two subpopulations of NK cells, immature CD14+CD56dim and mature CD14+CD56bright, are associated with aging and remodeling of mature NK cell subsets, and the reduced expression of activated receptors may promote the escape of NK cells in the elderly [45].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [45] Manser AR, Uhrberg M. Age-related changes in natural killer cell repertoires: impact on NK cell function and immune surveillance. Cancer Immunol Immunother. 2016;65(4):417–26. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Upregulated methylmalonic acid in the serum of the elderly induces the expression of SOX4 and triggers transcriptional reprogramming, making cancer cells more aggressive.

    “Recent research has highlighted that the upregulated methylmalonic acid in the serum of the elderly induces the expression of SOX4 and thus triggers the ability of transcriptional reprogramming, which can make cancer cells more aggressive [77].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [77] Gomes AP, Ilter D, Low V, Endress JE, Fernández-García J, Rosenzweig A, Schild T, Broekaert D, Ahmed A, Planque M, et al. Age-induced accumulation of methylmalonic acid promotes tumour progression. Nature. 2020;585(7824):283–7. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Patient-derived glioblastoma stem cells were killed by CD133-specific CAR-T cells, but at the same time induced the expression of CD57, thereby inducing CAR-T senescence.

    “Moreover, they also found that patient-derived glioblastoma stem cells were killed by CD133-specific CAR-T cells, but at the same time induced the expression of CD57, thereby inducing CAR-T senescence [125].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [125] Zhu X, Prasad S, Gaedicke S, Hettich M, Firat E, Niedermann G. Patient-derived glioblastoma stem cells are killed by CD133-specific CAR T cells but induce the T cell aging marker CD57. Oncotarget. 2015;6(1):171–84. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The accumulation of PD-1+ memory phenotype CD4+ T cell subsets gradually increases with age and is the predominant subset in the aging phase of normal mice; this process is strongly accelerated during leukemia.

    “The accumulation of the programmed cell death protein 1 (PD-1)+ memory phenotype CD4+ T cell subsets gradually increases with age and is the predominant subset in the aging phase of normal mice; this process is strongly accelerated during leukemia [129].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [129] Shimatani K, Nakashima Y, Hattori M, Hamazaki Y, Minato N. PD-1+ memory phenotype CD4+ T cells expressing C/EBPalpha underlie T cell immunodepression in senescence and leukemia. Proc Natl Acad Sci USA. 2009;106(37):15807–12. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Naïve T cells are a very relevant factor in immunosenescence research; their generation is completely dependent on thymus function.

    “Naïve T cells are a very relevant factor in immunosenescence research [90]: their generation is completely dependent on the thymus function, so the degeneration of the thymus is of great significance to the study of human immunosenescence [91, 92].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [90] Goronzy JJ, Fang F, Cavanagh MM, Qi Q, Weyand CM. Naive T cell maintenance and function in human aging. J Immunol. 2015;194(9):4073–80. source

      Not checked in the free run.

    • cites [91] Qi Q, Zhang DW, Weyand CM, Goronzy JJ. Mechanisms shaping the naïve T cell repertoire in the elderly - thymic involution or peripheral homeostatic proliferation? Exp Gerontol. 2014;54:71–4. source

      Not checked in the free run.

    • cites [92] Drabkin MJ, Meyer JI, Kanth N, Lobel S, Fogel J, Grossman J, Krumenacker JH. Age-stratified patterns of thymic involution on multidetector CT. J Thorac Imaging. 2018;33(6):409–16. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    uPAR-specific CAR-T cells can effectively eliminate senescent cells in vitro and in vivo and prolong the survival of lung adenocarcinoma mice.

    “Moreover, recent studies have shown that uPAR-specific CAR-T cells can effectively eliminate senescent cells in vitro and in vivo and prolong the survival of lung adenocarcinoma mice [127].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [127] Amor C, Feucht J, Leibold J, Ho Y-J, Zhu C, Alonso-Curbelo D, Mansilla-Soto J, Boyer JA, Li X, Giavridis T, et al. Senolytic CAR T cells reverse senescence-associated pathologies. Nature. 2020;583(7814):127–32. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The frequency of CD4+ and CD8+ TSCM is relatively stable at different ages, and the absolute number of CD8+ TSCM decreases with age.

    “However, a study has shown that the frequency of CD4+ and CD8+ TSCM is relatively stable at different ages, and the absolute number of CD8+ TSCM decreases with age [108].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [108] Li M, Yao D, Zeng X, Kasakovski D, Zhang Y, Chen S, Zha X, Li Y, Xu L. Age related human T cell subset evolution and senescence. Immun Ageing. 2019;16:24. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The NK cell compartments in elderly patients with acute myeloid leukemia are remodeled, evidenced by reduced output of immature CD56bright cells and accumulation of highly differentiated CD56dim NK cells, which is associated with disease progression and survival.

    “The NK cell compartments in elderly patients with acute myeloid leukemia (AML) are also remodeled, as evidenced by the reduced output of immature CD56bright cells and the accumulation of highly differentiated CD56dim NK cells, which is associated with disease progression and survival [81, 87, 88].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [81] Shehata HM, Hoebe K, Chougnet CA. The aged nonhematopoietic environment impairs natural killer cell maturation and function. Aging Cell. 2015;14(2):191–9. source

      Not checked in the free run.

    • cites [87] Sanchez-Correa B, Campos C, Pera A, Bergua JM, Arcos MJ, Bañas H, Casado JG, Morgado S, Duran E, Solana R, et al. Natural killer cell immunosenescence in acute myeloid leukaemia patients: new targets for immunotherapeutic strategies? Cancer Immunol Immunother. 2016;65(4):453–63. source

      Not checked in the free run.

    • cites [88] Tarazona R, Sanchez-Correa B, Casas-Avilés I, Campos C, Pera A, Morgado S, López-Sejas N, Hassouneh F, Bergua JM, Arcos MJ, et al. Immunosenescence: limitations of natural killer cell-based cancer immunotherapy. Cancer Immunol Immunother. 2017;66(2):233–45. source

      Not checked in the free run.

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

    Premisecitation

    CAR-T cell therapy is being developed as a potential treatment for patients with advanced hematological malignancies.

    “Chimeric antigen receptor T (CAR-T) cell therapy is being developed as a potential treatment for patients with advanced hematological malignancies [110–116].”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [110] Im A, Pavletic SZ. Immunotherapy in hematologic malignancies: past, present, and future. J Hematol Oncol. 2017;10(1):94. source

      Not checked in the free run.

    • cites [111] Yu S, Li A, Liu Q, Li T, Yuan X, Han X, Wu K. Chimeric antigen receptor T cells: a novel therapy for solid tumors. J Hematol Oncol. 2017;10(1):78. source

      Not checked in the free run.

    • cites [112] Sun W. Recent advances in cancer immunotherapy. J Hematol Oncol. 2017;10(1):96. source

      Not checked in the free run.

    • cites [113] Lichtenegger FS, Krupka C, Haubner S, Köhnke T, Subklewe M. Recent developments in immunotherapy of acute myeloid leukemia. J Hematol Oncol. 2017;10(1):142. source

      Not checked in the free run.

    • cites [114] Wei G, Ding L, Wang J, Hu Y, Huang H. Advances of CD19-directed chimeric antigen receptor-modified T cells in refractory/relapsed acute lymphoblastic leukemia. Exp Hematol Oncol. 2017;6:10. source

      Not checked in the free run.

    • cites [115] Zhang C, Liu J, Zhong JF, Zhang X. Engineering CAR-T cells. Biomark Res. 2017;5:22. source

      Not checked in the free run.

    • cites [116] Qin L, Zhao R, Li P. Incorporation of functional elements enhances the antitumor capacity of CAR T cells. Exp Hematol Oncol. 2017;6:28. source

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  • May combine two claims.

    Premisecitation

    TSCM represent a small group of memory T cells with enhanced proliferation and differentiation characteristics, and they can produce more terminally differentiated daughter cells expressing effector molecules, which is significant for cancer immunotherapy.

    “TSCM represent a small group of memory T cells with enhanced proliferation and differentiation characteristics, and they can produce more terminally differentiated daughter cells expressing effector molecules, which is of great significance for cancer immunotherapy [103, 104].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [103] Jansen CS, Prokhnevska N, Master VA, Sanda MG, Carlisle JW, Bilen MA, Cardenas M, Wilkinson S, Lake R, Sowalsky AG, et al. An intra-tumoral niche maintains and differentiates stem-like CD8 T cells. Nature. 2019;576(7787):465–70. source

      Not checked in the free run.

    • cites [104] Held W, Siddiqui I, Schaeuble K, Speiser DE. Intratumoral CD8 T cells with stem cell-like properties: implications for cancer immunotherapy. Sci Transl Med. 2019;11(515):eaay6863. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Memory T cells with a naïve phenotype also accumulate with age, and the number and ratio of memory CD8+ T cells in the elderly are usually higher, affecting their immune function.

    “Memory T cells with a naïve phenotype also accumulate with age [100], and the number and ratio of memory CD8+ T cells in the elderly are usually higher, affecting their immune function.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [100] Pulko V, Davies JS, Martinez C, Lanteri MC, Busch MP, Diamond MS, Knox K, Bush EC, Sims PA, Sinari S, et al. Human memory T cells with a naive phenotype accumulate with aging and respond to persistent viruses. Nat Immunol. 2016;17(8):966–75. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aging is related to the loss of Wnt/β-catenin signaling in CD4+ TSCM and the increase of Dickkopf-related protein 1.

    “Anis et al. found that aging is related to the loss of Wnt/β-catenin signaling in CD4+ TSCM and the increase of Dickkopf-related protein 1 (an inhibitor of the Wnt/β-catenin pathway).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [109] Kared H, Tan SW, Lau MC, Chevrier M, Tan C, How W, Wong G, Strickland M, Malleret B, Amoah A, et al. Immunological history governs human stem cell memory CD4 heterogeneity via the Wnt signaling pathway. Nat Commun. 2020;11(1):821. source

      Not checked in the free run.

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

    Premisecitation

    A global study on CAR-T cells showed that this therapy is very effective on young patients with recurrent B-ALL but did not discuss the impact on elderly patients, possibly due to the negative effect of the aging microenvironment.

    “However, a global study on CAR-T cells showed that this therapy is very effective on young patients with recurrent B-ALL [120], but did not discuss the impact on elderly patients, maybe due to the negative effect of the aging microenvironment.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [120] Stirrups R. CAR T-cells for relapsed B-cell ALL in children and young adults. Lancet Oncol. 2018;19(3):e144. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Age significantly affects the distribution of other T cell subsets but does not affect the frequency of TSCM.

    “Graham et al. also found that age significantly affected the distribution of other T cell subsets, but does not affect the frequency of TSCM [106].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [106] Di Benedetto S, Derhovanessian E, Steinhagen-Thiessen E, Goldeck D, Müller L, Pawelec G. Impact of age, sex and CMV-infection on peripheral T cell phenotypes: results from the Berlin BASE-II Study. Biogerontology. 2015;16(5):631–43. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TSCM in young and elderly subjects are maintained through continuous proliferation and show limited telomere length erosion and high expression of telomerase and Ki67.

    “Similarly, a study has shown that TSCM in young and elderly subjects is maintained through continuous proliferation and shows limited telomere length erosion and high expression of telomerase and Ki67 [107].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [107] Ahmed R, Roger L, Costa Del Amo P, Miners KL, Jones RE, Boelen L, Fali T, Elemans M, Zhang Y, Appay V, et al. Human stem cell-like memory T cells are maintained in a state of dynamic flux. Cell reports. 2016;17(11):2811–8. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Degeneration of the thymus leads to structural changes and declines in function, ultimately leading to a significant reduction in thymus output of naïve T cells, thereby reducing T cell antigen receptor diversity pool and leading to destruction of T cell homeostasis.

    “Degeneration of the thymus leads to structural changes and declines in function, which ultimately leads to a significant reduction in the thymus output of naïve T cells [93–95], thereby reducing the T cell antigen receptor diversity pool and ultimately leading to the destruction of T cell homeostasis.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [93] Hale JS, Boursalian TE, Turk GL, Fink PJ. Thymic output in aged mice. Proc Natl Acad Sci USA. 2006;103(22):8447–52. source

      Not checked in the free run.

    • cites [94] Rezzani R, Nardo L, Favero G, Peroni M, Rodella LF. Thymus and aging: morphological, radiological, and functional overview. Age (Dordr). 2014;36(1):313–51. source

      Not checked in the free run.

    • cites [95] Palmer DB. The effect of age on thymic function. Frontiers in immunology. 2013;4:316. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The aging process leads to changes in the distribution of mature B cell subsets and impaired activation after stimulation.

    “The aging process leads to changes in the distribution of mature B cell subsets and impaired activation after stimulation [23, 140].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [23] Pinti M, Appay V, Campisi J, Frasca D, Fülöp T, Sauce D, Larbi A, Weinberger B, Cossarizza A. Aging of the immune system: Focus on inflammation and vaccination. Eur J Immunol. 2016;46(10):2286–301. source

      Not checked in the free run.

    • cites [140] Bulati M, Caruso C, Colonna-Romano G. From lymphopoiesis to plasma cells differentiation, the age-related modifications of B cell compartment are influenced by “inflamm-ageing.” Ageing Res Rev. 2017;36:125–36. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Age may have a significant effect on different tumor types and various physiological states.

    “indicating that age may have a significant effect on different tumor types and various physiological states [153].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [153] Padron A, Hurez V, Gupta HB, Clark CA, Pandeswara SL, Yuan B, Svatek RS, Turk MJ, Drerup JM, Li R, et al. Age effects of distinct immune checkpoint blockade treatments in a mouse melanoma model. Exp Gerontol. 2018;105:146–54. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SASP-expressing senescent cells secrete chemokines and cytokines, which recruit MDSCs to local regions and result in immune escape and tumor cell metastasis.

    “SASP-expressing senescent cells secrete several kinds of chemokines and cytokines, which recruit MDSCs to local regions and result in immune escape and tumor cell metastasis [58].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [58] Salminen A, Kauppinen A, Kaarniranta K. Myeloid-derived suppressor cells (MDSC): an important partner in cellular/tissue senescence. Biogerontology. 2018;19(5):325–39. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The expansion of MDSCs may not only promote immunosenescence but may also induce harmful age-related bystander effects in host tissues by secreting TGF-β and IL-10.

    “The expansion of MDSCs may not only promote immunosenescence but may also induce harmful age-related bystander effects in host tissues by secreting TGF-β and IL-10 [149].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [149] Salminen A, Kauppinen A, Kaarniranta K. AMPK activation inhibits the functions of myeloid-derived suppressor cells (MDSC): impact on cancer and aging. J Mol Med (Berl). 2019;97(8):1049–64. source

      Not checked in the free run.

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

    Premisecitation

    In the first few weeks of mice and human development, MDSCs can suppress T cells, and thus the accumulation of MDSCs is considered to result from a pathological process or pregnancy.

    “He et al. [148] found that in the first few weeks of mice and humans’ development, MDSCs can suppress T cells, and thus the accumulation of MDSCs is considered to result from a pathological process or pregnancy.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [148] He Y-M, Li X, Perego M, Nefedova Y, Kossenkov AV, Jensen EA, Kagan V, Liu Y-F, Fu S-Y, Ye Q-J, et al. Transitory presence of myeloid-derived suppressor cells in neonates is critical for control of inflammation. Nat Med. 2018;24(2):224–31. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tregs gradually accumulate with age, and the percentage of CD4+CD25+ Tregs in the peripheral blood of elderly mice significantly increased.

    “Moreover, Tregs gradually accumulate with age [131–133] and the percentage of CD4+CD25+ Tregs in the peripheral blood of elderly mice significantly increased [134].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [131] Elyahu Y, Hekselman I, Eizenberg-Magar I, Berner O, Strominger I, Schiller M, Mittal K, Nemirovsky A, Eremenko E, Vital A, et al. Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes. Sci Adv. 2019;5(8):eaaw8330. source

      Not checked in the free run.

    • cites [132] Kozlowska E, Biernacka M, Ciechomska M, Drela N. Age-related changes in the occurrence and characteristics of thymic CD4(+) CD25(+) T cells in mice. Immunology. 2007;122(3):445–53. source

      Not checked in the free run.

    • cites [133] Thomas DC, Mellanby RJ, Phillips JM, Cooke A. An early age-related increase in the frequency of CD4+ Foxp3+ cells in BDC2.5NOD mice. Immunology. 2007;121(4):565–76. source

      Not checked in the free run.

    • cites [134] Zhao L, Sun L, Wang H, Ma H, Liu G, Zhao Y. Changes of CD4+CD25+Foxp3+ regulatory T cells in aged Balb/c mice. J Leukoc Biol. 2007;81(6):1386–94. source

      Not checked in the free run.

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

    Premisecitation

    After differentiation into plasma cells, B cells are the sole producer of antibodies and play a unique role in immunity.

    “After differentiation into plasma cells, B cells are the sole producer of antibodies and play a unique role in immunity [137].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [137] Wang S-S, Liu W, Ly D, Xu H, Qu L, Zhang L. Tumor-infiltrating B cells: their role and application in anti-tumor immunity in lung cancer. Cell Mol Immunol. 2019;16(1):6–18. source

      Not checked in the free run.

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

    Premisecitation

    Patients over 75 years of age represent less than 10% of patients with cancer.

    “patients over 75 years of age represent less than 10% of patients with cancer [150, 151]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [150] Scher KS, Hurria A. Under-representation of older adults in cancer registration trials: known problem, little progress. J Clin Oncol. 2012;30(17):2036–8. source

      Not checked in the free run.

    • cites [151] Mohile SG, Dale W, Somerfield MR, Hurria A. Practical assessment and management of vulnerabilities in older patients receiving chemotherapy: ASCO guideline for geriatric oncology summary. J Oncol Pract. 2018;14(7):442–6. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Age-modified tissue-specific macrophages and neutrophils may cause chronic low-grade inflammation, which is related to macrophage-mediated immunosuppressive disorders, together leading to the development of many diseases, including cancer.

    “Age-modified tissue-specific macrophages and neutrophils may cause chronic low-grade inflammation, which is related to macrophage-mediated immunosuppressive disorders, together leading to the development of many diseases, including cancer [147].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [147] Jackaman C, Tomay F, Duong L, Abdol Razak NB, Pixley FJ, Metharom P, Nelson DJ. Aging and cancer: the role of macrophages and neutrophils. Ageing Res Rev. 2017;36:105–16. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    With increasing age, the proportion and number of CD19+ B cells in peripheral blood decrease and the function of B cells is impaired, reflected in decreased expression of the autoimmune regulator AIRE and autoantigen genes in thymic B cells.

    “With increasing age, the proportion and number of CD19+ B cells in peripheral blood decrease and the function of B cells is impaired, which is reflected in the decreased expression of the autoimmune regulator AIRE and autoantigen genes in thymic B cells [141, 142].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [141] Kogut I, Scholz JL, Cancro MP, Cambier JC. B cell maintenance and function in aging. Semin Immunol. 2012;24(5):342–9. source

      Not checked in the free run.

    • cites [142] Cepeda S, Cantu C, Orozco S, Xiao Y, Brown Z, Semwal MK, Venables T, Anderson MS, Griffith AV. Age-associated decline in thymic B cell expression of aire and aire-dependent self-antigens. Cell Rep. 2018;22(5):1276–87. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Elderly patients safely tolerate anti-PD-1/PD-L1 antibody treatment, with efficacy and toxicity effects similar to those observed in younger patients.

    “Elderly patients have also been observed to safely tolerate anti-PD-1/programmed cell death 1 ligand 1 (PD-L1) antibody treatment, with efficacy and toxicity effects similar to those observed in younger patients.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [155] Elias R, Giobbie-Hurder A, McCleary NJ, Ott P, Hodi FS, Rahma O. Efficacy of PD-1 & PD-L1 inhibitors in older adults: a meta-analysis. J Immunother Cancer. 2018;6(1):26. source

      Not checked in the free run.

    • cites [156] Li P, Yang X, Feng Y, Wu L, Ma W, Ding G, Wei Y, Sun L. The impact of immunosenescence on the efficacy of immune checkpoint inhibitors in melanoma patients: a meta-analysis. Onco Targets Ther. 2018;11:7521–7. source

      Not checked in the free run.

    • cites [157] Marur S, Singh H, Mishra-Kalyani P, Larkins E, Keegan P, Sridhara R, Blumenthal GM, Pazdur R. FDA analyses of survival in older adults with metastatic non-small cell lung cancer in controlled trials of PD-1/PD-L1 blocking antibodies. Semin Oncol. 2018;45(4):220–5. source

      Not checked in the free run.

    • cites [158] Nishijima TF, Muss HB, Shachar SS, Moschos SJ. Comparison of efficacy of immune checkpoint inhibitors (ICIs) between younger and older patients: a systematic review and meta-analysis. Cancer Treat Rev. 2016;45:30–7. source

      Not checked in the free run.

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

    Premisecitation

    The phagocytosis and antigen presentation ability of macrophages change with age is not clear.

    “The phagocytosis and antigen presentation ability of macrophages change with age is not clear [147].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [147] Jackaman C, Tomay F, Duong L, Abdol Razak NB, Pixley FJ, Metharom P, Nelson DJ. Aging and cancer: the role of macrophages and neutrophils. Ageing Res Rev. 2017;36:105–16. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increased levels of myeloid-derived suppressor cells are observed in the bone marrow, blood, and spleen of tumor-bearing aged mice; this accumulation plays a detrimental role because MDSC-induced immunosuppression impairs senescence and tumor cell clearance and interferes with energy metabolism and maintenance of tissue protein homeostasis.

    “Furthermore, increased levels of myeloid-derived suppressor cells (MDSCs) are observed in the bone marrow, blood, and spleen of tumor-bearing aged mice; this accumulation plays a detrimental role because MDSC-induced immunosuppression impairs senescence and tumor cell clearance and interferes with energy metabolism and maintenance of tissue protein homeostasis [58].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [58] Salminen A, Kauppinen A, Kaarniranta K. Myeloid-derived suppressor cells (MDSC): an important partner in cellular/tissue senescence. Biogerontology. 2018;19(5):325–39. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In aged melanoma mice, anti-PD-L1 treatment had no effect, whereas anti-CTLA-4 and anti-PD-1 treatment showed a positive effect.

    “However, in the aged group, anti-PD-L1 treatment had no effect, whereas anti-CTLA-4 and anti-PD-1 treatment showed a positive effect.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [153] Padron A, Hurez V, Gupta HB, Clark CA, Pandeswara SL, Yuan B, Svatek RS, Turk MJ, Drerup JM, Li R, et al. Age effects of distinct immune checkpoint blockade treatments in a mouse melanoma model. Exp Gerontol. 2018;105:146–54. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Positive effects on aging were observed in mice, but these studies were carried out in short-lived mouse models that were prone to develop cancer in some cases.

    “Positive effects on aging were also observed in mice, but these studies were carried out in short-lived mouse models that were prone to develop cancer in some cases [178].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [178] Anisimov VN. Metformin: do we finally have an anti-aging drug? Cell Cycle. 2013;12(22):3483–9. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Anti-PD1 antibodies appear more effective and well tolerated in elderly (≥ 75 years old) patients with advanced melanoma than in younger patients.

    “Another retrospective study indicated that anti-PD1 antibodies appear more effective and well tolerated in elderly (≥ 75 years old) patients with advanced melanoma than in younger patients [160]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [160] Ridolfi L, De Rosa F, Petracci E, Tanda ET, Marra E, Pigozzo J, Marconcini R, Guida M, Cappellini GCA, Gallizzi G, et al. Anti-PD1 antibodies in patients aged >/= 75 years with metastatic melanoma: a retrospective multicentre study. J Geriatr Oncol. 2020;11(3):515–22. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    By activating telomerase to avoid telomere shortening, mice were seen to have longer telomeres, less DNA damage and aging, and extended lifespan.

    “By activating telomerase to avoid telomere shortening, mice were seen to have longer telomeres, less DNA damage and aging, and extended lifespan [175].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [175] Muñoz-Lorente MA, Cano-Martin AC, Blasco MA. Mice with hyper-long telomeres show less metabolic aging and longer lifespans. Nat Commun. 2019;10(1):4723. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Replenishing young transplantable thymic epithelial cells to middle-aged or defective thymuses can lead to increased thymus growth and T cell production, which directly drives the growth of degenerated thymus.

    “Typically, a study has found that replenishing young transplantable thymic epithelial cells to middle-aged or defective thymuses can lead to increased thymus growth and T cell production, which directly drives the growth of degenerated thymus [171].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [171] Kim M-J, Miller CM, Shadrach JL, Wagers AJ, Serwold T. Young, proliferative thymic epithelial cells engraft and function in aging thymuses. J Immunol. 2015;194(10):4784–95. source

      Not checked in the free run.

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

    Premisecitation

    Limiting the caloric intake of mice and rats can prolong lifespan.

    “In 1939, a study found that limiting the caloric intake of mice and rats could prolong lifespan, which proved for the first time that the aging process is plastic [167].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [167] McCay CM, Maynard LA, Sperling G, Barnes LL. The Journal of Nutrition. Volume 18 July--December, 1939. Pages 1--13. Retarded growth, life span, ultimate body size and age changes in the albino rat after feeding diets restricted in calories. Nutrit Rev. 1975;33(8):241–43. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Individuals who maintained physical exercise showed a slowdown in thymic output decline and changes in inflammatory markers, such as a decrease of IL-6 and an increase of IL-7 and IL-15 in serum.

    “individuals who maintained physical exercise showed a slowdown in thymic output decline and changes in inflammatory markers, such as a decrease of IL-6 and an increase of IL-7 and IL-15 in serum, which may promote thymus function [174].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [174] Duggal NA, Pollock RD, Lazarus NR, Harridge S, Lord JM. Major features of immunosenescence, including reduced thymic output, are ameliorated by high levels of physical activity in adulthood. Aging Cell. 2018;17(2):e12750. source

      Not checked in the free run.

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

    Premisecitation

    The same phenomenon of caloric restriction prolonging lifespan was found in primates.

    “Some follow-up studies also found the same phenomenon in primates [168, 169].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [168] Mattison JA, Colman RJ, Beasley TM, Allison DB, Kemnitz JW, Roth GS, Ingram DK, Weindruch R, de Cabo R, Anderson RM. Caloric restriction improves health and survival of rhesus monkeys. Nat Commun. 2017;8:14063. source

      Not checked in the free run.

    • cites [169] Pifferi F, Terrien J, Marchal J, Dal-Pan A, Djelti F, Hardy I, Chahory S, Cordonnier N, Desquilbet L, Hurion M, et al. Caloric restriction increases lifespan but affects brain integrity in grey mouse lemur primates. Commun Biol. 2018;1:30. source

      Not checked in the free run.

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

    Interpretationreasoning

    Life extension is related to aging and increased healthy lifespan.

    “These findings further support the notion that life extension is related to aging and increased healthy lifespan.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Dietary restrictions not only increase lifespan but also inhibit the development of age-related diseases.

    “It is worth noting that dietary restrictions not only increase lifespan but also inhibit the development of age-related diseases [170].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [170] Omodei D, Fontana L. Calorie restriction and prevention of age-associated chronic disease. FEBS Lett. 2011;585(11):1537–42. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In most studies, the number of elderly patients in the ICB antibody therapy group is small and data on the safety and toxicity of ICB antibody treatment are limited.

    “In most studies, the number of elderly patients in the ICB antibody therapy group is small and data on the safety and toxicity of ICB antibody treatment are limited; therefore, the effect of ICB antibody therapy on elderly patients has not been fully elucidated [162].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [162] Belgioia L, Desideri I, Errico A, Franzese C, Daidone A, Marino L, Fiore M, Borghetti P, Greto D, Fiorentino A, et al. Safety and efficacy of combined radiotherapy, immunotherapy and targeted agents in elderly patients: a literature review. Crit Rev Oncol Hematol. 2019;133:163–70. source

      Not checked in the free run.

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

    Premisecitation

    The definition of the corresponding age between humans and mice is still under discussion.

    “Furthermore, the definition of the corresponding age between humans and mice is still under discussion [210, 211]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [210] Dutta S, Sengupta P. Men and mice: relating their ages. Life Sci. 2016;152:244–8. source

      Not checked in the free run.

    • cites [211] Alpert A, Pickman Y, Leipold M, Rosenberg-Hasson Y, Ji X, Gaujoux R, Rabani H, Starosvetsky E, Kveler K, Schaffert S, et al. A clinically meaningful metric of immune age derived from high-dimensional longitudinal monitoring. Nat Med. 2019;25(3):487–95. source

      Not checked in the free run.

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

    Premisenone given

    These pathways are conserved over a wide range of evolutionary distances, and targeting these pathways in model organisms prolongs lifespan.

    “These pathways are conserved over a wide range of evolutionary distances, and targeting these pathways in model organisms prolongs lifespan.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Both NR and NMN increase the lifespan of worms.

    “both NR and NMN increase the lifespan of worms [201]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [201] Mouchiroud L, Houtkooper RH, Moullan N, Katsyuba E, Ryu D, Cantó C, Mottis A, Jo Y-S, Viswanathan M, Schoonjans K, et al. The NAD(+)/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. Cell. 2013;154(2):430–41. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The SASP induced by chemotherapy increases the sensitivity of PD-1 and chemotherapy, thereby reducing tumor progression and metastasis.

    “For example, the SASP induced by chemotherapy increases the sensitivity of PD-1 and chemotherapy, thereby reducing tumor progression and metastasis [78].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [78] Ruscetti M, Morris JP, Mezzadra R, Russell J, Leibold J, Romesser PB, Simon J, Kulick A, Ho Y-J, Fennell M, et al. Senescence-induced vascular remodeling creates therapeutic vulnerabilities in pancreas cancer. Cell. 2020;181(2):424-441.e21. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The 6-8-week mouse model is the most frequent model employed in tumor studies; thus, the model may not be entirely applicable to humans.

    “For example, the 6–8-week mouse model is the most frequent model employed in tumor studies; thus, the model may not be entirely applicable to humans [209, 210].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [209] Davis MM. A prescription for human immunology. Immunity. 2008;29(6):835–8. source

      Not checked in the free run.

    • cites [210] Dutta S, Sengupta P. Men and mice: relating their ages. Life Sci. 2016;152:244–8. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Immunosenescence is a complicated and inevitable process that seems to affect tumor progression and the efficiency of antitumor immune responses in elderly individuals.

    “As indicated above, immunosenescence is a complicated and inevitable process that seems to affect tumor progression and the efficiency of antitumor immune responses in the elderly individuals.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In mice, NR causes a wide range of beneficial effects, including a moderate lifespan extension.

    “In mice, NR causes a wide range of beneficial effects, including a moderate lifespan extension [202].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [202] Zhang H, Ryu D, Wu Y, Gariani K, Wang X, Luan P, D’Amico D, Ropelle ER, Lutolf MP, Aebersold R, et al. NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science (New York, NY). 2016;352(6292):1436–43. source

      Not checked in the free run.

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

    Interpretationnone given

    Immune parameters are different between the young and the elderly.

    “Overall, immune parameters are different between the young and the elderly.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Through slc12a8, 26-month-old mice that took NMN increased their NAD+ levels to close to 3 months old, increasing cell energy in aged mice.

    “through a transporter called slc12a8, 26-month-old mice (equivalent to 70 human years) that took NMN increased their NAD+ levels to close to 3 months old (equivalent to 12 human months). The content level in young mice increased the cell energy in aged mice [208].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [208] Grozio A, Mills KF, Yoshino J, Bruzzone S, Sociali G, Tokizane K, Lei HC, Cunningham R, Sasaki Y, Migaud ME, et al. Slc12a8 is a nicotinamide mononucleotide transporter. Nat Metab. 2019;1(1):47–57. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Emerging evidence suggests the aging microenvironment largely contributes to age-related decline in immune function and may also provide potential targets for rejuvenating the immune system.

    “Finally, emerging evidence suggests that the aging microenvironment largely contributes to age-related decline in immune function and may also provide potential targets for rejuvenating the immune system [18].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Fane M, Weeraratna AT. How the ageing microenvironment influences tumour progression. Nat Rev Cancer. 2020;20(2):89–106. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    The mechanisms that interfere with aging may have great implications.

    “Together, these evidences indicate that the mechanisms that interfere with aging may have great implications.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The aging process particularly affects the immune response, and this imbalance of the immune system may be involved in the development of tumors.

    “Indeed, the aging process particularly affects the immune response: this imbalance of the immune system may be involved in the development of tumors.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    NMN has a significant effect on improving disease conditions and reducing age-related physiological decline.

    “These studies also documented that NMN has a significant effect on improving disease conditions and reducing age-related physiological decline [203–206].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [203] de Picciotto NE, Gano LB, Johnson LC, Martens CR, Sindler AL, Mills KF, Imai S-I, Seals DR. Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice. Aging Cell. 2016;15(3):522–30. source

      Not checked in the free run.

    • cites [204] Gomes AP, Price NL, Ling AJY, Moslehi JJ, Montgomery MK, Rajman L, White JP, Teodoro JS, Wrann CD, Hubbard BP, et al. Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell. 2013;155(7):1624–38. source

      Not checked in the free run.

    • cites [205] Mills KF, Yoshida S, Stein LR, Grozio A, Kubota S, Sasaki Y, Redpath P, Migaud ME, Apte RS, Uchida K, et al. Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metab. 2016;24(6):795–806. source

      Not checked in the free run.

    • cites [206] Stein LR, Imai S-i. Specific ablation of Nampt in adult neural stem cells recapitulates their functional defects during aging. EMBO J. 2014;33(12):1321–40. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    NMN and NR are key endogenous compounds in NAD+ biosynthesis and can be used as effective treatments to prevent many age-related diseases.

    “In general, these findings strongly indicate that NMN and NR are key endogenous compounds in NAD+ biosynthesis and can be used as effective treatments to prevent many age-related diseases.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Rapamycin only prolongs lifespan through antitumor mechanisms, thereby inhibiting the main pathological changes in mice.

    “Studies have provided evidence that rapamycin only prolongs lifespan through antitumor mechanisms, thereby inhibiting the main pathological changes in mice [190, 191].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [190] Neff F, Flores-Dominguez D, Ryan DP, Horsch M, Schröder S, Adler T, Afonso LC, Aguilar-Pimentel JA, Becker L, Garrett L, et al. Rapamycin extends murine lifespan but has limited effects on aging. J Clin Invest. 2013;123(8):3272–91. source

      Not checked in the free run.

    • cites [191] Wilkinson JE, Burmeister L, Brooks SV, Chan C-C, Friedline S, Harrison DE, Hejtmancik JF, Nadon N, Strong R, Wood LK, et al. Rapamycin slows aging in mice. Aging Cell. 2012;11(4):675–82. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    The number of genes that can extend lifespan is much higher than expected, indicating that the level of plasticity during aging is highly.

    “First, the number of genes that can extend lifespan is much higher than expected, which indicates that the level of plasticity during aging is highly.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    NR increases the lifespan of yeast replication.

    “NR also increases the lifespan of yeast replication [200]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [200] Belenky P, Racette FG, Bogan KL, McClure JM, Smith JS, Brenner C. Nicotinamide riboside promotes Sir2 silencing and extends lifespan via Nrk and Urh1/Pnp1/Meu1 pathways to NAD+. Cell. 2007;129(3):473–84. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Research on the mTORC1 pathway has the strongest clinical evidence, proving that it can be used as a feasible strategy to prevent aging.

    “At present, research on the mTORC1 pathway has the strongest clinical evidence, proving that it can be used as a feasible strategy to prevent aging.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationnone given

    Existing immunological techniques cannot thoroughly analyze the complexity of the immune system.

    “Moreover, although basic and clinical research on aging has made great progress, the existing immunological techniques cannot thoroughly analyze the complexity of the immune system.”
    Quote in the paperSubstantial claim
87 of 87

  • The paper relies on this without support.

    The interactions between senescence-related changes and different components of the immune system remain unclear.

    “Although our understanding of immunosenescence has steadily progressed over the past few decades and many studies on age-related immune decline have laid the foundation for identifying intervention methods [10, 21–23], the interactions between senescence-related changes and different components of the immune system remain unclear.”

  • The paper relies on this without support.

    The effect of immunosenescence on the response to immune checkpoint blocking antibody therapy is ambiguous due to the low participation of elderly cancer patients in clinical trials.

    “In addition, the effect of immunosenescence on the response to immune checkpoint blocking antibody therapy so far is ambiguous due to the low participation of elderly cancer patients in clinical trials.”

  • The paper relies on this without support.

    The tumor response of innate and adaptive immune systems differs between young and elderly individuals.

    “Many studies have shown that the tumor response of innate and adaptive immune systems is different between young and elderly individuals, but its clinical impact and underlying mechanisms are still mostly not understood.”

  • The paper relies on this without support.

    Aging is a paramount risk factor for most cancers.

    “Aging is a paramount risk factor for most cancers.”

  • The paper relies on this without support.

    The results of immunotherapy in elderly and young patients are inconsistent, likely due to different types, different stages of tumor development, and concomitant diseases.

    “However, the results of immunotherapy in elderly and young patients are inconsistent, which is likely due to different types, different stages of tumor development, and concomitant diseases.”

  • The paper relies on this without support.

    The association between immune-related adverse events and age is controversial.

    “Moreover, the association between immune-related adverse events and age is controversial, and thus analyzing the latest data on the efficacy of immunotherapy in elderly patients with cancer is paramount.”

  • The paper relies on this without support.

    Studies and clinical trials on the effects of host age on the outcome of ICB are limited and the influence of the microenvironment of the elderly on the response to immunotherapy is largely ignored.

    “Although age is one of the greatest risk factors for tumorigenesis, studies and clinical trials on the effects of host age on the outcome of ICB are limited and the influence of the microenvironment of the elderly on the response to immunotherapy is largely ignored.”

  • The paper relies on this without support.

    Little is known about ICB general tolerance and effect in the elderly.

    “Little is known about ICB general tolerance and effect in the elderly.”

  • The paper relies on this without support.

    One of the main characteristics of aging is the involution of the thymus, which leads to a decrease in the production of T cells, leading to immunosenescence.

    “One of the main characteristics of aging is the involution of the thymus, which leads to a decrease in the production of T cells, leading to immunosenescence.”

  • The paper relies on this without support.

    Short telomeres can trigger age-related diseases and shorten the lifespan of mice and humans.

    “Short telomeres can also trigger age-related diseases and shorten the lifespan of mice and humans.”

  • The paper relies on this without support.

    NAD+ is not absorbed by cells, making direct supplementation impossible.

    “However, NAD+ is not absorbed by cells, making direct supplementation impossible.”

  • The paper relies on this without support.

    NAD+ supplements have a protective effect during aging, and nicotinamide is the main precursor in NAD+ biosynthesis.

    “Nonetheless, NAD+ supplements have a protective effect during aging, and nicotinamide is the main precursor in NAD+ biosynthesis.”
12 of 12

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?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Opposite directions reported for SA-β-gal activity

    Minor

    Table 1 marks SA-β-gal activity as increasing, but the Fig. 2 caption says senescent T cells have reduced activity.

  • Opposite directions reported for IFN-γ expression

    Minor

    Table 1 marks IFN-γ as increasing in T cells, while the text says its expression is reduced during aging.

  • Opposite directions reported for P16 and P21

    Minor

    Table 1 marks P16 and P21 as decreasing in T cells, whereas the text says their expression increases with the loss of CD27 and CD28.

  • Telomere length increases in Table 1 but decreases in the text

    Minor

    Table 1 marks telomere length as increasing during immunosenescence, while the text identifies telomere shortening as a hallmark of senescent T cells.

4 of 4

Cites

1 retracted

Flagged first, then by citations

Research works printed but not linked: 1

  1. Sanchez-Correa B, Campos C, Pera A, Bergua JM, Arcos MJ, Bañas H, Casado JG, Morgado S, Duran E, Solana R, et al. Natural killer cell immunosenescence in acute myeloid leukaemia patients: new targets for immunotherapeutic strategies? Cancer Immunol Immunother. 2016;65(4):453–63. · DOI

Cited by

Sorted by citations

Authors
Lian, J., Yue, Y., Yu, W., & Zhang, Y.
Affiliations
First Affiliated Hospital of Zhengzhou University (CN)
Corresponding author
Zhang, Yi
ORCID
Venue
Journal of Hematology & Oncology
Publisher
Springer Science and Business Media LLC
Published
2020-11-10
Volume
13
Issue
1
Pages
151-151
ISSN
1756-8722 (ISSN-L)
DOI
10.1186/s13045-020-00986-z
PMC
PMC7653700
OpenAlex
W3100093629
Semantic Scholar
6e8959d73664f958967a50000448af2b3c44f8af
Cited by
510
References
212
Citations by year
2026: 71 · 2025: 122 · 2024: 112 · 2023: 93 · 2022: 82 · 2021: 30
FWCI
6.57
Type
journal article
Language
en
Update notices
correction (2025-03-05)
Open access
Licence
Locations
  • Journal of Hematology & Oncology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • the National Natural Science Foundation of China (9194230059, 81771781, 81602024)
  • the State’s Key Project of Research and Development Plan (2016YFC1303500)
Topics
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords
immunosenescence, carcinogenesis, T cell senescence, senescence-associated secretory phenotype, tumor microenvironment, immune checkpoint blockade, cancer immunotherapy, macrophage senescence, glycolysis, reactive oxygen species, CD57, TIM-3, mTOR inhibition, IL-7, aging
MeSH terms
Immunosenescence, Aging, Animals, Humans, Immunotherapy, Neoplasms, T-Lymphocytes, Disease Progression, Tumor Microenvironment

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.

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

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