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Cited by 285T-cell and B-cell ImmunologyTelomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model Organisms

Senescence of T Lymphocytes: Implications for Enhancing Human Immunity

Akbar, Arne N., Henson, Sian M., Lanna, Alessio·2016·Trends in Immunology
DOI 10.1016/j.it.2016.09.002
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Abstract

As humans live longer, a central concern is to find ways to maintain their health as they age. Immunity declines during ageing, as shown by the increased susceptibility to infection by both previously encountered and new pathogens and by the decreased efficacy of vaccination. It is therefore crucial to understand the mechanisms responsible for this decrease in immunity and to develop new strategies to enhance immune function in older humans. We discuss here how the induction of senescence alters leukocyte, and specifically T cell, function. An emerging concept is that senescence and nutrient sensing-signalling pathways within T cells converge to regulate functional responses, and the manipulation of these pathways may offer new ways to enhance immunity during ageing.

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Written from the paper’s full text.

TL;DR

This review argues that human T cell senescence is an actively maintained, reversible state driven by telomere/DNA damage and nutrient-sensing signaling, especially AMPK/TAB1/p38 MAPK. It proposes that blocking these pathways may enhance immunity in ageing, vaccination, and cancer, while cautioning about safety and broad effects.

Key findings

  • T cell senescence is defined here as low proliferative activity resulting from excessive telomere erosion or DNA damage, not simply global immunosenescence; senescent CD4+ and CD8+ T cells are CD27−CD28−CD45RA+KLRG1+CD57+, accumulate with ageing and persistent CMV/HIV, and unlike fibroblasts are prone to apoptosis in vitro.
  • Senescence is actively maintained: p38 MAPK is constitutively active, and small-molecule inhibitors or shRNA against p38 reconstitute proliferation and telomerase activity after activation. A third p38 activation pathway in senescent T cells involves AMPK/TAB1/p38, and inhibiting AMPK, TAB1, or p38 also reconstitutes proliferation and telomerase.
  • Senescent CD8+ T cells preferentially use glycolysis, show mitochondrial dysfunction, increased ROS, impaired mitochondrial biogenesis, low autophagy, and lack mTORC1 activity. p38 blockade enhances autophagy, mitochondrial biogenesis, clears dysfunctional mitochondria, and reduces ROS, but cells still preferentially use glycolysis; recycled metabolic precursors fuel proliferation.
  • Senescent T cells show a T-cell-adapted SASP, secreting IFNγ, TNFα, perforin, granzyme B, and MMPs; inflammation is linked to a 2–4 fold rise in acute-phase markers (CRP, VCAM-1, IL-6), and a meta-analysis of 27 studies on 13 different cancers found an inverse correlation between immune-cell telomere length and cancer incidence. p38 inhibitors were safe short term (weeks) in human trials but discontinued after >3 months due to hepatotoxicity and pathway adaptation; PD-1 plus p38 blockade is additive.

Methods

  • Design: narrative review, not primary research; no experimental sample or statistical analysis reported.
  • Data/sample: synthesizes cited human and mouse studies, with emphasis on primary human T cells (CD4+ and CD8+) and senescent fibroblasts.
  • Main analysis: conceptual synthesis linking senescence, nutrient sensing, inflammation, metabolism, and therapeutic targeting of p38/AMPK/TAB1 pathways.

Limitations

  • Paper states ethical constraints preclude most such studies in humans and an appropriate animal model is needed; p38 inhibitor trials were discontinued due to hepatotoxicity after long-term treatment (>3 months) and reduced efficacy from pathway adaptation, and senescent T cell function was not tested before or after treatment.
  • Paper states AMPK inhibition may be too broad, blocking p38 rescues only certain features, TAB1 feasibility requires further study, and the role of T cell senescence in cancer and the metabolic landscape of TILs in humans needs future work.
  • Evident from the text: as a review, it reports no new primary data; many mechanistic claims derive from in vitro human T cell experiments, and epidemiological telomere–disease associations are correlative with no causal information (the paper itself notes this).

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

Integrity signals

Registry

Crossref · 10.1016/j.it.2016.09.002

Cites

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Statistics

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Claims the paper makes

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  • Premisecitation
    § What is senescence?

    Short telomeres are interpreted as DNA damage by cell sensing machinery and initiate a cascade culminating in growth arrest.

    “Short telomeres are interpreted as DNA damage by cell sensing machinery that initiates a cascade of events that culminates in growth arrest (reviewed in Akbar and Henson 2011 [12]).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] 12. Akbar, A.N. and Henson, S.M. (2011) Are senescence and exhaustion intertwined or unrelated processes that compromise immunity? Nat Rev Immunol 11, 289-295 source

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  • Premisecitation
    § What is T cell senescence?

    Within primary human T cells, both CD4+ and CD8+ populations contain a subset of poorly proliferative cells with characteristics very similar to senescent fibroblasts.

    “Within primary human T cells, in both CD4 + [23, 28, 29] and CD8 + [25, 30] populations, there is a subset of poorly proliferative cells that exhibit characteristics that are very similar to senescent fibroblasts (Fig. 1).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [23] 23. Di Mitri, D. et al. (2011) Reversible Senescence in Human CD4+CD45RA+CD27Memory T Cells. J Immunol 187, 2093-2100 source

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    • cites [28] 28. Libri, V. et al. (2011) Cytomegalovirus infection induces the accumulation of short-lived, multifunctional CD4+CD45RA+CD27+ T cells: the potential involvement of interleukin-7 in this process. Immunology 132, 326-339 source

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    • cites [29] 29. Lanna, A. et al. (2013) IFN-alpha inhibits telomerase in human CD8(+) T cells by both hTERT downregulation and induction of p38 MAPK signaling. J Immunol 191, 37443752 source

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    • cites [25] 25. Henson, S.M. et al. (2014) p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8+ T cells. J Clin Invest 124, 4004-4016 source

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    • cites [30] 30. Henson, S.M. et al. (2015) Blockade of PD-1 or p38 MAP kinase signaling enhances senescent human CD8(+) T-cell proliferation by distinct pathways. Eur J Immunol 45, 1441-1451 source

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  • Premisecitation
    § What is T cell senescence?

    Senescent-like T cells can be identified by surface marker expression CD27-, CD28-, CD45RA+, KLRG1+, CD57+, which are characteristics of highly differentiated T cells.

    “These cells can be identified by surface marker expression (CD27 - ,CD28 - , CD45RA + , KLRG1 + , CD57 + ) that are all characteristics of highly differentiated T cells [23, 28, 30, 31].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [23] 23. Di Mitri, D. et al. (2011) Reversible Senescence in Human CD4+CD45RA+CD27Memory T Cells. J Immunol 187, 2093-2100 source

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    • cites [28] 28. Libri, V. et al. (2011) Cytomegalovirus infection induces the accumulation of short-lived, multifunctional CD4+CD45RA+CD27+ T cells: the potential involvement of interleukin-7 in this process. Immunology 132, 326-339 source

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    • cites [30] 30. Henson, S.M. et al. (2015) Blockade of PD-1 or p38 MAP kinase signaling enhances senescent human CD8(+) T-cell proliferation by distinct pathways. Eur J Immunol 45, 1441-1451 source

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    • cites [31] 31. Henson, S.M. et al. (2009) KLRG1 signaling induces defective Akt (ser473) phosphorylation and proliferative dysfunction of highly differentiated CD8+ T cells. Blood 113, 6619-6628 source

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  • Interpretationreasoning
    § What is T cell senescence?

    Restriction of proliferation of T cells specific for frequently encountered or persistent antigens may compromise maintenance of specific immunity in older humans.

    “The restriction to the extent of proliferation of T cells, especially those that are specific for frequently encountered or persistent antigens may therefore compromise the maintenance of specific immunity in older humans as they may be driven towards senescence [1, 12].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] 1. Akbar, A.N. et al. (2004) Will telomere erosion lead to a loss of T-cell memory? Nat Rev Immunol 4, 737-743 source

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    • cites [12] 12. Akbar, A.N. and Henson, S.M. (2011) Are senescence and exhaustion intertwined or unrelated processes that compromise immunity? Nat Rev Immunol 11, 289-295 source

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  • Interpretationreasoning
    § Introduction

    Inhibition of senescence and nutrient sensing signalling pathways can enhance T cell function.

    “Furthermore the inhibition of these signalling pathways can enhance T cell function is a reason to be optimistic in the search of ways to enhance immunity during ageing.”
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  • Classified as probably not a substantial claim. 12
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    Premisecitation
    § What is senescence?

    Accumulation of senescent cells is associated with ageing of tissues.

    “While the limit to the extent of proliferation of cells that have damaged DNA is considered to be a natural defense against malignancy, the accumulation of senescent cells is associated with the ageing of tissues [17, 18].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [17] 17. Baker, D.J. et al. (2016) Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature 530, 184-189 source

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    • cites [18] 18. van Deursen, J.M. (2014) The role of senescent cells in ageing. Nature 509, 439-446 source

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    Interpretationnone given
    § Introduction

    Senescence and nutrient sensing signalling pathways within T cells converge to regulate functional responses.

    “An emerging concept is that senescence and nutrient sensing signalling pathways within T cells converge to regulate functional responses.”
    Quote in the paperNot a substantial claim

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

    Premisecitation
    § What is senescence?

    The Hayflick Limit is widely considered to be an anti-cancer mechanism.

    “This constraint on the excessive proliferative activity, i.e. 'growing old' of fibroblasts in tissue culture, is known as the Hayflick Limit, that is widely considered to be an anti-cancer mechanism [8].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] 8. Campisi, J. (2005) Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120, 513-522 source

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

    Premisecitation
    § What is T cell senescence?

    Senescent fibroblasts generated by continuous culture until the Hayflick limit stop proliferating but remain metabolically active and persist as long as supplied with nutrients in vitro.

    “Senescent fibroblasts that are generated by continuous culture until they reach the Hayflick limit stop proliferating but are still metabolically active and perisist as long as they are supplied with nutrients in vitro [7, 26].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [7] 7. Hayflick, L. and Moorhead, P.S. (1961) The serial cultivation of human diploid cell strains. Exp Cell Res 25, 585-621 source

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    • cites [26] 26. Blagosklonny, M.V. (2011) Cell cycle arrest is not senescence. Aging 3, 94-101 source

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    Premisecitation
    § What is senescence?

    Fibroblasts have a finite capacity to replicate when cultured in vitro, after which they stop dividing but remain metabolically active for extended periods.

    “Cellular senescence was first described in fibroblasts by Leonard Hayflick who with co-workers showed that fibroblasts have a finite capacity to replicate when cultured in vitro , after which they stop dividing but remain metabolically active for extended periods [7].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] 7. Hayflick, L. and Moorhead, P.S. (1961) The serial cultivation of human diploid cell strains. Exp Cell Res 25, 585-621 source

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    Premisecitation
    § Introduction

    Immunity declines during ageing, manifest as increased susceptibility to infection by previously encountered and new emerging pathogens and decreased ability to respond to vaccination.

    “Immunity declines during ageing and this is highlighted by the increased susceptibility to infection induced by previously encountered [1, 2] as well as new emerging pathogens [3-5] and also decreased ability to respond to vaccination [6].”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [1] 1. Akbar, A.N. et al. (2004) Will telomere erosion lead to a loss of T-cell memory? Nat Rev Immunol 4, 737-743 source

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    • cites [2] 2. Nikolich-Zugich, J. and Rudd, B.D. (2010) Immune memory and aging: an infinite or finite resource? Curr Opin Immunol 22, 535-540 source

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    • cites [3] 3. Brien, J.D. et al. (2009) Key role of T cell defects in age-related vulnerability to West Nile virus. J Exp Med 206, 2735-2745 source

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    • cites [4] 4. Whitehorn, J. and Simmons, C.P. (2011) The pathogenesis of dengue. Vaccine 29, 7221-7228 source

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    • cites [5] 5. Gupta, M. et al. (2004) Persistent infection with ebola virus under conditions of partial immunity. J Virol 78, 958-967 source

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    • cites [6] 6. Grubeck-Loebenstein, B. et al. (2009) Immunosenescence and vaccine failure in the elderly. Aging Clin Exp Res 21, 201-209 source

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    Premisecitation
    § What is T cell senescence?

    Senescent fibroblasts have short telomeres, high activity of the enzyme beta-galactosidase, high expression of gamma-H2Ax, constitutive activation of p53 and p38 MAPK, and the cyclin inhibitor p16.

    “These cells have short telomeres, high activity of the enzyme  galactosidase, show high expression of the DNA repair complex associated protein  H2Ax and constitutive activation of p53 and p38 map kinase (p38 MAPK), as well the cyclin inhibitor p16 [9, 27] (Table 1).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] 9. von Zglinicki, T. et al. (2005) Human cell senescence as a DNA damage response. Mech Ageing Dev 126, 111-117 source

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    • cites [27] 27. Freund, A. et al. (2010) Inflammatory networks during cellular senescence: causes and consequences. Trends in Molecular Medicine 16, 238-246 source

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    Interpretationcitation
    § What is T cell senescence?

    Decreased proliferative activity of T cells after vaccination reduces vaccine efficacy, which is known to be suboptimal in older subjects.

    “Furthermore, decreased proliferative activity of T cells after vaccination will reduce vaccine efficacy that is known to be suboptimal in older subjects [6].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] 6. Grubeck-Loebenstein, B. et al. (2009) Immunosenescence and vaccine failure in the elderly. Aging Clin Exp Res 21, 201-209 source

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    Premisecitation
    § What is senescence?

    The molecular basis for the Hayflick Limit is erosion of telomeres that occurs each time a cell divides.

    “It was subsequently shown that the molecular basis for the Hayflick Limit is the erosion of telomeres, repeating hexameric DNA sequences at the ends of chromosomes, that occurs each time a cell divides and has been described extensively elsewhere [9-11].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [9] 9. von Zglinicki, T. et al. (2005) Human cell senescence as a DNA damage response. Mech Ageing Dev 126, 111-117 source

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    • cites [10] 10. Blasco, M.A. (2002) Telomerase beyond telomeres. Nat Rev Cancer 2, 627-633 source

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    • cites [11] 11. Weng, N.P. (2008) Telomere and adaptive immunity. Mech Ageing Dev 129, 60-66 source

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    Premisecitation
    § T cell senescence is maintained by active signalling and is reversible

    Senescent fibroblasts have constitutively activated p38 MAP kinase and inhibition of this enzyme revives the proliferative activity of these cells.

    “It was shown that senescent fibroblasts have constitutively activated p38 MAPkinase and the inhibition of this enzyme revives the proliferative activity of these cells [57, 58].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [57] 57. Passos, J.F. et al. (2010) Feedback between p21 and reactive oxygen production is necessary for cell senescence. Mol Syst Biol 6, 347 source

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    • cites [58] 58. Davis, T. et al. (2010) Evaluating the role of p38 MAP kinase in growth of Werner syndrome fibroblasts. Ann N Y Acad Sci 1197, 45-48 source

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    Premisecitation
    § T cell senescence is maintained by active signalling and is reversible

    Two separate pathways for p38 MAPK activation in T cells had been previously described.

    “Two separate pathways for p38 MAPK activation in T cells had been previously described [24, 60].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [24] 24. Lanna, A. et al. (2014) The kinase p38 activated by the metabolic regulator AMPK and scaffold TAB1 drives the senescence of human T cells. Nat Immunol 15, 965-972 source

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    • cites [60] 60. Salvador, J.M. et al. (2005) Alternative p38 activation pathway mediated by T cell receptor-proximal tyrosine kinases. Nat Immunol 6, 390-395 source

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    Premisecitation
    § The secretory nature of senescent cells

    Senescent T cells within both CD4+ and CD8+ subsets express high levels of intracellular granules containing perforin and granzyme B and can mediate spontaneous antigen-specific cytotoxicity against infected target cells.

    “Senescent T cells within both CD4 + and CD8 + subsets express high levels of intracellular granules containing the cytotoxic proteins perforin and granzyme B and can mediate spontaneous antigen-specific cytotoxicity against infected target cells [47-49].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [47] 47. Hislop, A.D. et al. (2007) Cellular responses to viral infection in humans: lessons from Epstein-Barr virus. Annu Rev Immunol 25, 587-617 source

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    • cites [48] 48. Dunne, P.J. et al. (2005) Quiescence and functional reprogramming of Epstein-Barr virus (EBV)-specific CD8+ T cells during persistent infection. Blood 106, 558-565 source

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    • cites [49] 49. Long, H.M. et al. (2011) Cytotoxic CD4+ T Cell Responses to EBV Contrast with CD8 Responses in Breadth of Lytic Cycle Antigen Choice and in Lytic Cycle Recognition. The Journal of Immunology 187, 92-101 source

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    Premisecitation
    § How can we detect senescent T cells?

    Undifferentiated T cells with relatively long telomeres are CD27+CD28+, while senescent T cells with the shortest telomeres are found within the CD27-CD28- population.

    “While undifferentiated T cells that have relatively long telomeres are CD27 + CD28 + , senescent T cells with the shortest telomeres are found within the CD27 - CD28 - population [22, 28, 34, 54].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [22] 22. Plunkett, F.J. et al. (2007) The loss of telomerase activity in highly differentiated CD8+CD28-CD27- T cells is associated with decreased Akt (Ser473) phosphorylation. J Immunol 178, 7710-7719 source

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    • cites [28] 28. Libri, V. et al. (2011) Cytomegalovirus infection induces the accumulation of short-lived, multifunctional CD4+CD45RA+CD27+ T cells: the potential involvement of interleukin-7 in this process. Immunology 132, 326-339 source

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    • cites [34] 34. Fletcher, J.M. et al. (2005) Cytomegalovirus-specific CD4+ T cells in healthy carriers are continuously driven to replicative exhaustion. J Immunol 175, 8218-8225 source

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    • cites [54] 54. Riddell, N.E. et al. (2015) Multifunctional cytomegalovirus (CMV)-specific CD8(+) T cells are not restricted by telomere-related senescence in young or old adults. Immunology 144, 549-560 source

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    Premisecitation
    § How can we detect senescent T cells?

    Common markers used to identify senescent cells in histological sections are senescence associated beta-galactosidase expression, the cyclin inhibitor p16/INK or the DNA damage response protein gamma-H2AX, but these techniques are rarely combined.

    “To identify senescent cells in histological section by immunocytochemistry or immunofluorescence, the most common markers used are senescence associated  galactosidase (SA  gal) expression, the cyclin inhibitor p16/INK or the DNA damage response protein  H2AX however these techniques are rarely combined [55].”
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    • cites [55] 55. de Jesus, B.B. and Blasco, M.A. (2012) Assessing Cell and Organ Senescence Biomarkers. Circulation research 111, 97-109 source

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    Interpretationcitation
    § How can we detect senescent T cells?

    CD45RA re-expressing senescent T cells do not have critically short telomeres, suggesting that senescence in these cells may be induced by other mechanisms including DNA damage by increased ROS production.

    “Intriguingly, the CD45RA re-expressing senesecent T cells do not have critically short telomeres suggesting that senescence in these cell may be induced by other mechanisms including DNA damage by increased ROS production [25, 30].”
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    • cites [25] 25. Henson, S.M. et al. (2014) p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8+ T cells. J Clin Invest 124, 4004-4016 source

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    • cites [30] 30. Henson, S.M. et al. (2015) Blockade of PD-1 or p38 MAP kinase signaling enhances senescent human CD8(+) T-cell proliferation by distinct pathways. Eur J Immunol 45, 1441-1451 source

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    Premisecitation
    § T cell senescence is maintained by active signalling and is reversible

    Inflammatory cytokines such as IFN-alpha can activate p38 in non-senescent T cells and inhibit proliferation and telomerase activity.

    “In this context, inflammatory cytokines such as IFN- , can activate p38 in non-senescent T cells and this can inhibit proliferation and telomerase activity [29, 34, 61].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [29] 29. Lanna, A. et al. (2013) IFN-alpha inhibits telomerase in human CD8(+) T cells by both hTERT downregulation and induction of p38 MAPK signaling. J Immunol 191, 37443752 source

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    • cites [34] 34. Fletcher, J.M. et al. (2005) Cytomegalovirus-specific CD4+ T cells in healthy carriers are continuously driven to replicative exhaustion. J Immunol 175, 8218-8225 source

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    • cites [61] 61. Reed, J.R. et al. (2004) Telomere erosion in memory T cells induced by telomerase inhibition at the site of antigenic challenge in vivo. J Exp Med 199, 1433-1443 source

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    Interpretationreasoning
    § The secretory nature of senescent cells

    The secretory characteristics of senescent T cells are involved with immune effector functions, whereas fibroblast SASP may be involved with tissue remodelling.

    “While the SASP in fibroblasts that may be involved with tissue re-modelling, the secretory characteristics of senescent T cells are involved with immune effector functions (Table 1).”
    Quote in the paperSubstantial claim

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    Premisecitation
    § The secretory nature of senescent cells

    The senescence associated secretory phenotype is considered important for remodelling of ageing tissues.

    “This is known as the senescence associated secretory phenotype or SASP and is considered to be important for remodelling of ageing tissues [41, 42].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [41] 41. Coppe, J.P. et al. (2010) The senescence-associated secretory phenotype: the dark side of tumor suppression. Annual review of pathology 5, 99-118 source

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    • cites [42] 42. Tchkonia, T. et al. (2013) Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J Clin Invest 123, 966-972 source

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    Interpretationreasoning
    § Implications of blocking senescence by targeting p38 to enhance immunity

    Senescence in T cells is actively regulated, and by blocking cell signalling pathways, the inhibition of proliferation and telomerase activity in these cells can be reversed.

    “The emerging picture is that senescence in T cell is actively regulated and that by blocking cell signalling pathways, the inhibition of proliferation and also telomerase activity in these cells can be reversed.”
    Quote in the paperSubstantial claim

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    Premisecitation
    § T cell senescence is maintained by active signalling and is reversible

    Senescent T cells do not express several kinases and scaffold molecules involved in the alternative p38 activation pathway and are unlikely to engage this second pathway for p38 activation.

    “However, it was found that senescent T cells do not express several kinases and scaffold molecules that are involved in this alternative p38 activation pathway and are thus unlikely to engage this second pathway for p38 activation [24, 60].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [24] 24. Lanna, A. et al. (2014) The kinase p38 activated by the metabolic regulator AMPK and scaffold TAB1 drives the senescence of human T cells. Nat Immunol 15, 965-972 source

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    • cites [60] 60. Salvador, J.M. et al. (2005) Alternative p38 activation pathway mediated by T cell receptor-proximal tyrosine kinases. Nat Immunol 6, 390-395 source

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    Interpretationcitation
    § Implications of blocking senescence by targeting p38 to enhance immunity

    Because cellular senescence is considered a safeguard against malignancy by preventing excessive proliferation of cells with short telomeres or damaged DNA, inhibition of senescence may promote cancer.

    “However since the process of cellular senescence is considered to be a mechanism to safeguard against malignancy by preventing the excessive proliferation of cells with either short telomeres or damaged DNA [8], the possible danger is that the inhibition of senescence may promote cancer.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] 8. Campisi, J. (2005) Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120, 513-522 source

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    Interpretationcitation
    § Inflammation and senescence

    Healthy individuals carrying the HLA-DR4 haplotype share with rheumatoid patients age-inappropriate telomere loss, implying that there is a genetic mechanism in the premature deterioration of chromosomal ends.

    “Furthermore healthy individuals carrying the HLA-DR4 haplotype share with rheumatoid patients the age-inappropriate telomere loss, implying that there is a genetic mechanisms in the premature deterioration of chromosomal ends [70].”
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    • cites [70] 70. Schönland, S.O. et al. (2003) Premature telomeric loss in rheumatoid arthritis is genetically determined and involves both myeloid and lymphoid cell lineages. Proc Natl Acad Sci U S A 100, 13471-13476 source

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    Premisecitation
    § Inflammation and senescence

    Cellular senescence can cause chronic inflammation through the SASP, and this chronic non-microbial sterile inflammation is thought to be the prime cause of many age-related disorders such as atherosclerosis, autoimmunity, cancers and dementias.

    “Cellular senescence can cause chronic inflammation through the SASP and this chronic nonmicrobial (sterile) inflammation is thought to be the prime cause of many age-related disorders such as atherosclerosis, autoimmunity, cancers and dementias [42].”
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    • cites [42] 42. Tchkonia, T. et al. (2013) Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J Clin Invest 123, 966-972 source

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    Premisecitation
    § Metabolism of senescent human T cells

    mTOR regulates multiple processes, including autophagy, a degradation pathway that removes damaged or unwanted organelles as well as providing metabolites during periods of starvation.

    “mTOR regulates multiple processes, including autophagy, a degradation pathway that removes damaged or unwanted organelles as well as providing metabolites during periods of starvation [64].”
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    • cites [64] 64. Terman, A. and Brunk, U.T. (2005) The aging myocardium: roles of mitochondrial damage and lysosomal degradation. Heart, lung & circulation 14, 107-114 source

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    Interpretationcitation
    § Metabolism of senescent human T cells

    Senescent CD8+ T cells exhibit mitochondrial dysfunction, increased production of reactive oxygen species and impaired mitochondrial biogenesis, which may explain their dependence on glycolysis for energy.

    “Senescent CD8 + T cells exhibit mitochondrial dysfunction, increased production of reactive oxygen species (ROS) and impaired mitochondrial biogenesis, which may explain their dependence on glycolysis for energy [25].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] 25. Henson, S.M. et al. (2014) p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8+ T cells. J Clin Invest 124, 4004-4016 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § T cell senescence is maintained by active signalling and is reversible

    AMPK is activated not only by sensing low intracellular glucose but also by endogenous DNA damage (senescence) signalling in T cells.

    “The critical point is that AMPK is not only activated by sensing low intracellular glucose but also by endogenous DNA damage (senescence) signalling in T cells but also by [24].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] 24. Lanna, A. et al. (2014) The kinase p38 activated by the metabolic regulator AMPK and scaffold TAB1 drives the senescence of human T cells. Nat Immunol 15, 965-972 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Metabolism of senescent human T cells

    Blocking p38 enhanced autophagy, increased mitochondrial biogenesis, cleared dysfunctional mitochondria and reduced ROS production in senescent CD8+ T cells, indicating an overall improvement of mitochondrial fitness.

    “Blocking p38 enhanced autophagy, increased mitochondrial biogenesis, cleared dysfunctional mitochondria and reduced ROS production in senescent CD8 + T cells [25] indicating an overall improvement of mitochondrial fitness.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] 25. Henson, S.M. et al. (2014) p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8+ T cells. J Clin Invest 124, 4004-4016 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation
    § T cell senescence is maintained by active signalling and is reversible

    Senescent T cells lose expression of costimulatory receptors CD27 and CD28 that activate the canonical pathway and do not express upstream kinases associated with the canonical pathway, suggesting that p38 may be activated by an alternative mechanism in these cells.

    “However senescent T cells lose expression of costimulatory receptors such as CD27 and CD28 that activate the canonical pathway nor do they express the upstream kinases associated with the canonical pathway suggesting that p38 may be activated an alternative mechanism in these cells [24, 60].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [24] 24. Lanna, A. et al. (2014) The kinase p38 activated by the metabolic regulator AMPK and scaffold TAB1 drives the senescence of human T cells. Nat Immunol 15, 965-972 source

      Not checked in the free run.

    • cites [60] 60. Salvador, J.M. et al. (2005) Alternative p38 activation pathway mediated by T cell receptor-proximal tyrosine kinases. Nat Immunol 6, 390-395 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation
    § Inflammation and senescence

    Inflammatory cytokines such as IFN-alpha can inhibit telomerase in T cells and induce telomere erosion, which lends support to the possibility that short telomeres are a secondary consequence of chronic systemic inflammation.

    “The fact that inflammatory cytokines such as IFN  can inhibit telomerase in T cells and induce telomere erosion in these cells [29, 34, 61] lends support to the latter possibility.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [29] 29. Lanna, A. et al. (2013) IFN-alpha inhibits telomerase in human CD8(+) T cells by both hTERT downregulation and induction of p38 MAPK signaling. J Immunol 191, 37443752 source

      Not checked in the free run.

    • cites [34] 34. Fletcher, J.M. et al. (2005) Cytomegalovirus-specific CD4+ T cells in healthy carriers are continuously driven to replicative exhaustion. J Immunol 175, 8218-8225 source

      Not checked in the free run.

    • cites [61] 61. Reed, J.R. et al. (2004) Telomere erosion in memory T cells induced by telomerase inhibition at the site of antigenic challenge in vivo. J Exp Med 199, 1433-1443 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Implications of blocking senescence by targeting p38 to enhance immunity

    These trials of p38 inhibitors have thus far been unsuccessful and were discontinued because of hepatotoxicity after long-term treatment (>3 months) and adaptation of cell signalling pathways leading to reduced drug efficacy.

    “These trials have thus far been unsuccessful and were discontinued because of hepatotoxicity after long term treatment (>3 months) and also adaptation of cell signalling pathways leading to reduced drug efficacy [72].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [72] 72. Sweeney, S.E. (2009) The as-yet unfulfilled promise of p38 MAPK inhibitors. Nature reviews. Rheumatology 5, 475-477 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Metabolism of senescent human T cells

    Senescent CD8+ T cells display both low autophagic activity and lack mTORC1 activity.

    “However senescent CD8 + T cells displayed both low autophagic activity [25, 65] and also lack mTORC1 activity [25].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [25] 25. Henson, S.M. et al. (2014) p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8+ T cells. J Clin Invest 124, 4004-4016 source

      Not checked in the free run.

    • cites [65] 65. Phadwal, K. et al. (2012) A novel method for autophagy detection in primary cells: impaired levels of macroautophagy in immunosenescent T cells. Autophagy 8, 677-689 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § Metabolism of senescent human T cells

    Senescence and nutrient sensing pathways are inextricably linked and control the function of T cells.

    “These results reinforce the observations that senescence and nutrient sensing pathways are inextricably linked and control the function of T cells.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Interpretationcitation
    § T cell senescence is maintained by active signalling and is reversible

    Inhibition of AMPK, TAB1 or p38 provides points for intervention to enhance the function of senescent T cells.

    “This provides points for intervention, in addition to targeting p38 itself, to enhance the function of senescent T cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] 24. Lanna, A. et al. (2014) The kinase p38 activated by the metabolic regulator AMPK and scaffold TAB1 drives the senescence of human T cells. Nat Immunol 15, 965-972 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Inflammation and senescence

    These studies are correlative with no information as to whether telomere shortening increases disease risk or whether short telomeres are a secondary consequence of chronic systemic inflammation associated with these diseases.

    “These studies are correlative with no information as to whether telomere shortening increases the disease risk or whether short telomeres are a secondary consequence of chronic systemic inflammation associated with all these diseases [69].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] 69. Chou, J.P. and Effros, R.B. (2013) T cell replicative senescence in human aging. Current pharmaceutical design 19, 1680-1698 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Metabolism of senescent human T cells

    Human senescent CD8+ T cells preferentially utilise glycolysis to generate ATP, as opposed to the effector memory subset which is more metabolically flexible and can use either glycolysis or oxidative phosphorylation.

    “It was shown that human senescent CD8 + T cells preferentially utilise glycolysis to generate ATP, as opposed to the effector memory subset which are much more metabolically flexible and can either glycolysis or oxidative phosphorylation (OXPHOS) for functional activities (Fig. 3).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] 25. Henson, S.M. et al. (2014) p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8+ T cells. J Clin Invest 124, 4004-4016 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § Implications of blocking senescence by targeting p38 to enhance immunity

    Certain drugs that may target T cell senescence may have already been developed for clinical use, and it may be feasible to treat older humans safely, at least in the short term, to boost immunity.

    “Therefore certain drugs that may target T cell senescence may have already been developed for clinical use and it may be feasible to treat older humans safely, at least in the short term, to boost immunity.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Senescent T cell function was not tested before or after treatment with p38 inhibitors.

  • Classified as probably not a substantial claim.

    Interpretationreasoning
    § Possible situations where inhibiting senescence could enhance immunity

    It may be possible to perform nutrient manipulation as well as anti-senescence therapy to promote antitumour activity by T cells.

    “it may be possible to perform nutrient manipulation as well as anti-senescence therapy to promote antitumour activity by T cells.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Immune activation is an energy-demanding process.

  • May combine two claims.

    Premisecitation
    § Possible situations where inhibiting senescence could enhance immunity

    T regulatory cells (Tregs) are an inhibitory T cell population highly represented at the tumour site and characterized by AMPK-dependent metabolic requirements.

    “the induction of T regulatory cells (Tregs), an inhibitory T cell population, highly represented at the tumour site and characterized by AMPK-dependent metabolic requirements [80].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [80] 80. Ho, P.-C. et al. (2015) Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses. Cell 162, 1217-1228 source

      Not checked in the free run.

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

    Interpretationreasoning
    § Future perspectives

    The reduced proliferative function of senescent primary human T cells that accumulate during ageing is globally controlled by divergent interacting pathways that may be reversible.

    “the reduced proliferative function of senescent primary human T cells that accumulate during ageing is globally controlled by divergent interacting pathways that may be reversible.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Telomere erosion in leukocytes correlates with the severity of a vast array of disease states associated with many different cell types/organs.

  • May combine two claims.

    Premisecitation
    § Possible situations where inhibiting senescence could enhance immunity

    The pathway involved in PD1 engagement in senescent human T cells is different from that induced by p38 MAP signalling, as there is additive enhancement of proliferation when both PD1 and p38 pathways are blocked simultaneously.

    “The pathway involved in PD1 engagement in senescent human T cells is different for that induced by p38 MAP signalling as there is an additive enhancement of proliferation when both PD1 and p38 pathways are blocked simultaneously [30].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] 30. Henson, S.M. et al. (2015) Blockade of PD-1 or p38 MAP kinase signaling enhances senescent human CD8(+) T-cell proliferation by distinct pathways. Eur J Immunol 45, 1441-1451 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Table 1. Characteristics of fibroblast vs T cell senescence.

    The key features of the senescence phenotype are common to fibroblasts and T cells, such as lack of proliferation, short telomeres, and inability to upregulate telomerase.

    “The key features of the senescence phenotype are common to fibroblast and T cells, such as the lack of proliferation, short telomeres and the inability to upregulate telomerase.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] 1. Akbar, A.N. et al. (2004) Will telomere erosion lead to a loss of T-cell memory? Nat Rev Immunol 4, 737-743 source

      Not checked in the free run.

    • cites [15] 15. d'Adda di Fagagna, F. (2008) Living on a break: cellular senescence as a DNA-damage response. Nat Rev Cancer 8, 512-522 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Implications of blocking senescence by targeting p38 to enhance immunity

    AMPK is a central regulator of cell function, and many different cell types including T cells may be affected by its inhibition.

    “However AMPK is also a central regulator of cell function and many different cell types including T cells may be affected [73].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [73] 73. Ho, P.-C. and Liu, P.-S. (2016) Metabolic communication in tumors: a new layer of immunoregulation for immune evasion. Journal for Immunotherapy of Cancer 4, 4 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § Possible situations where inhibiting senescence could enhance immunity

    Short-term blockade of p38 may open a therapeutic window for enhancement of antigen-specific T cell proliferation, increasing the number of antigen-specific cells.

    “the short-term blockade of p38 may open a therapeutic window for enhancement of antigen-specific T cell proliferation, that would increase the number of antigen specific cells.”
    Quote in the paperSubstantial claim

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

    Premisecitation
    § Figure 1. Differences in the manifestation of senescence in T cells and fibroblasts.

    The majority of data on cellular senescence has been performed on fibroblasts.

    “The majority of data on cellular senescence has been performed on fibroblasts”
    • Also stated in: § Table 1. Characteristics of fibroblast vs T cell senescence. · plain
      “The majority of data on cellular senescence has been performed on fibroblasts”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] 9. von Zglinicki, T. et al. (2005) Human cell senescence as a DNA damage response. Mech Ageing Dev 126, 111-117 source

      Not checked in the free run.

    • cites [15] 15. d'Adda di Fagagna, F. (2008) Living on a break: cellular senescence as a DNA-damage response. Nat Rev Cancer 8, 512-522 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § Implications of blocking senescence by targeting p38 to enhance immunity

    AMPK seems to boost memory T cell generation but may impede effector T cell responses needed for primary immunisation.

    “Thus, AMPK seems to boost memory T cell generation but may impede effector T cell responses needed for primary immunisation”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Figure 1. Differences in the manifestation of senescence in T cells and fibroblasts.

    T cells are susceptible to apoptosis and die before reaching deep irreversible senescence, whereas fibroblasts can remain for long periods in a non-proliferative state.

    “T cells however are susceptible to apoptosis and die before they reach this stage whereas fibroblasts can remain for long periods in a non-proliferative state.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] 9. von Zglinicki, T. et al. (2005) Human cell senescence as a DNA damage response. Mech Ageing Dev 126, 111-117 source

      Not checked in the free run.

    • cites [15] 15. d'Adda di Fagagna, F. (2008) Living on a break: cellular senescence as a DNA-damage response. Nat Rev Cancer 8, 512-522 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Possible situations where inhibiting senescence could enhance immunity

    PD1 blockade in patients enhances tumour eradication by T cells and improves survival of these patients, especially in melanoma.

    “PD1 blockade in patients enhances tumour eradication by T cells and improves the survival of these patients [78].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [78] 78. Mahoney, K.M. et al. (2015) Combination cancer immunotherapy and new immunomodulatory targets. Nat Rev Drug Discov 14, 561-584 source

      Not checked in the free run.

47 of 47

  • The paper relies on this without support.

    The effects of p38 inhibition on senescent T cells observed in vitro will translate to enhanced T cell function in vivo.

    “based on data that has been obtained in vitro , blocking agents to p38 could be used in vivo to enhance certain T cell functions [23-25, 30]”

  • The paper relies on this without support.

    p38 inhibitors that are safe in short-term trials for inflammatory diseases will have the same safety profile when used to target senescent T cells.

    “However senescent T cell function was not tested before or after treatment with these drugs.”

  • The paper relies on this without support.

    Senescent T cell function was not tested before or after treatment with p38 inhibitors.

    “However senescent T cell function was not tested before or after treatment with these drugs.”

  • The paper relies on this without support.

    Tumours grow even when there are large numbers of T cells surrounding or infiltrating them, indicating impaired T-cell killing activity in situ.

    “It is well recognized that tumours grow even when there are large numbers of T cells surrounding or infiltrating them, indicating impaired T-cell killing activity in situ .”

  • The paper relies on this without support.

    Immune activation is an energy-demanding process.

    “Immune-activation is an energy-demanding process”

  • The paper relies on this without support.

    Telomere erosion in leukocytes correlates with the severity of a vast array of disease states associated with many different cell types/organs.

    “The fact that telomere erosion in leukocytes correlates with the severity of a vast array of disease states that are associated with many different cell types/organs”
6 of 6

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?

  • With aging, the naïve subset shrinks and highly differentiated memory cells accumulate, often showing dysregulated properties.

    “With aging, the naïve subset shrinks along with the accumulation of highly differentiated memory cells, which often show dysregulated properties (5, 6).”

    From Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes (2019) · cites this paper as [5]

  • Akbar et al. proposed a senescence model for TEMRAs centered on disproportionate activation of the p38 MAPK pathway.

    “Akbar et al. (2016) have proposed a senescence model for TEMRAs that centers on the disproportionate activation of the p38 MAPK pathway”

    From Successful and Maladaptive T Cell Aging (2017) · cites this paper as Akbar et al., 2016

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Authors
Akbar, A. N., Henson, S. M., & Lanna, A.
Affiliations
  • University College London (GB)
  • University of Oxford (GB)
Corresponding author
Akbar, Arne N.
ORCID
Venue
Trends in Immunology
Publisher
Elsevier BV
Published
2016-12
Volume
37
Issue
12
Pages
866-876
ISSN
1471-4906 (ISSN-L)
DOI
10.1016/j.it.2016.09.002
OpenAlex
W2529494470
Semantic Scholar
05150a9b7d2d81cf2687bcb6fd16409fc096ee24
Cited by
285
References
81
Citations by year
2026: 18 · 2025: 26 · 2024: 37 · 2023: 34 · 2022: 36 · 2021: 45 · 2020: 33 · 2019: 19 · 2018: 20 · 2017: 15 · 2016: 1
FWCI
1.74
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Trends in Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Queen Mary Research Online (Queen Mary University of London) (submittedVersion)
Funders
  • Biotechnology and Biological Science Research Council
  • Medical Research Council
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords
T cell senescence, immunosenescence, aging, immune function, nutrient sensing, senescence-associated secretory phenotype, vaccination efficacy, infection susceptibility, immune enhancement, T cell function
MeSH terms
Aging, Animals, Humans, Immunity, Immunization, T-Lymphocytes, Signal Transduction, Cellular Senescence

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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.

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