Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Hallmarks of T cell aging

Abstract

The aged adaptive immune system is characterized by progressive dysfunction as well as increased autoimmunity. This decline is responsible for elevated susceptibility to infection and cancer, as well as decreased vaccination efficacy. Recent evidence indicates that CD4+ T cell–intrinsic alteratins contribute to chronic inflammation and are sufficient to accelerate an organism-wide aging phenotype, supporting the idea that T cell aging plays a major role in body-wide deterioration. In this Review, we propose ten molecular hallmarks to represent common denominators of T cell aging. These hallmarks are grouped into four primary hallmarks (thymic involution, mitochondrial dysfunction, genetic and epigenetic alterations, and loss of proteostasis) and four secondary hallmarks (reduction of the TCR repertoire, naive–memory imbalance, T cell senescence, and lack of effector plasticity), and together they explain the manifestation of the two integrative hallmarks (immunodeficiency and inflammaging). A major challenge now is weighing the relative impact of these hallmarks on T cell aging and understanding their interconnections, with the final goal of defining molecular targets for interventions in the aging process.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Hallmarks of T cell aging.
Fig. 2: Thymus involution.
Fig. 3: Features and consequences of T cell aging.
Fig. 4: Classification of the hallmarks.
Fig. 5: Interventions that might improve T cell aging.

References

  1. López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  2. Goronzy, J. J. & Weyand, C. M. Mechanisms underlying T cell ageing. Nat. Rev. Immunol. 19, 573–583 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. Hakim, F. T., Flomerfelt, F. A., Boyiadzis, M. & Gress, R. E. Aging, immunity and cancer. Curr. Opin. Immunol. 16, 151–156 (2004).

    CAS  PubMed  Article  Google Scholar 

  4. Minato, N., Hattori, M. & Hamazaki, Y. Physiology and pathology of T-cell aging. Int. Immunol. 32, 223–231 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. Desdín-Micó, G. et al. T cells with dysfunctional mitochondria induce multimorbidity and premature senescence. Science 368, 1371–1376 (2020).

    PubMed  Article  CAS  Google Scholar 

  6. Ovadya, Y. et al. Impaired immune surveillance accelerates accumulation of senescent cells and aging. Nat. Commun. 9, 5435 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. Miller, J. F. A. P. The function of the thymus and its impact on modern medicine. Science 369, eaba2429 (2020).

    CAS  PubMed  Article  Google Scholar 

  8. Elyahu, Y. & Monsonego, A. Thymus involution sets the clock of the aging T-cell landscape: implications for declined immunity and tissue repair. Ageing Res. Rev. 65, 101231 (2021).

    CAS  PubMed  Article  Google Scholar 

  9. Thapa, P. & Farber, D. L. The role of the thymus in the immune response. Thorac. Surg. Clin. 29, 123–131 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  10. Hsu, H.-C., Li, L., Zhang, H.-G. & Mountz, J. D. Genetic regulation of thymic involution. Mech. Ageing Dev. 126, 87–97 (2005).

    CAS  PubMed  Article  Google Scholar 

  11. Hale, J. S., Boursalian, T. E., Turk, G. L. & Fink, P. J. Thymic output in aged mice. Proc. Natl Acad. Sci. USA 103, 8447–8452 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  12. den Braber, I. et al. Maintenance of peripheral naive T cells is sustained by thymus output in mice but not humans. Immunity 36, 288–297 (2012).

    Article  CAS  Google Scholar 

  13. Calder, A. E., Hince, M. N., Dudakov, J. A., Chidgey, A. P. & Boyd, R. L. Thymic involution: where endocrinology meets immunology. Neuroimmunomodulation 18, 281–289 (2011).

    CAS  PubMed  Article  Google Scholar 

  14. Rezzani, R., Nardo, L., Favero, G., Peroni, M. & Rodella, L. F. Thymus and aging: morphological, radiological, and functional overview. Age (Dordr.) 36, 313–351 (2014).

    Article  Google Scholar 

  15. Sempowski, G. D. et al. Leukemia inhibitory factor, oncostatin M, IL-6, and stem cell factor mRNA expression in human thymus increases with age and is associated with thymic atrophy. J. Immunol. 164, 2180–2187 (2000).

    CAS  PubMed  Article  Google Scholar 

  16. Velardi, E., Tsai, J. J. & van den Brink, M. R. M. T cell regeneration after immunological injury. Nat. Rev. Immunol. https://doi.org/10.1038/s41577-020-00457-z (2020).

  17. Kinsella, S. & Dudakov, J. A. When the damage is done: injury and repair in thymus function. Front. Immunol. 11, 1745 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. Youm, Y.-H., Horvath, T. L., Mangelsdorf, D. J., Kliewer, S. A. & Dixit, V. D. Prolongevity hormone FGF21 protects against immune senescence by delaying age-related thymic involution. Proc. Natl Acad. Sci. USA 113, 1026–1031 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  19. Howard, J. K. et al. Leptin protects mice from starvation-induced lymphoid atrophy and increases thymic cellularity in ob/ob mice. J. Clin. Invest. 104, 1051–1059 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. Dixit, V. D. et al. Ghrelin promotes thymopoiesis during aging. J. Clin. Invest. 117, 2778–2790 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. Dudakov, J. A. et al. Interleukin-22 drives endogenous thymic regeneration in mice. Science 336, 91–95 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. Duggal, N. A., Pollock, R. D., Lazarus, N. R., Harridge, S. & Lord, J. M. Major features of immunesenescence, including reduced thymic output, are ameliorated by high levels of physical activity in adulthood. Aging Cell 17, e12750 (2018).

    PubMed Central  Article  CAS  Google Scholar 

  23. Fahy, G. M. et al. Reversal of epigenetic aging and immunosenescent trends in humans. Aging Cell 18, e13028 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. El-Kadiry, A. E.-H. & Rafei, M. Restoring thymic function: then and now. Cytokine 120, 202–209 (2019).

    CAS  PubMed  Article  Google Scholar 

  25. Oh, J., Wang, W., Thomas, R. & Su, D.-M. Thymic rejuvenation via FOXN1-reprogrammed embryonic fibroblasts (FREFs) to counteract age-related inflammation. JCI Insight 5, e140313 (2020).

    PubMed Central  Article  Google Scholar 

  26. Ron-Harel, N. et al. Defective respiration and one-carbon metabolism contribute to impaired naive T cell activation in aged mice. Proc. Natl Acad. Sci. USA 115, 13347–13352 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  27. Bektas, A. et al. Age-associated changes in human CD4+ T cells point to mitochondrial dysfunction consequent to impaired autophagy. Aging 11, 9234–9263 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. Vardhana, S. A. et al. Impaired mitochondrial oxidative phosphorylation limits the self-renewal of T cells exposed to persistent antigen. Nat. Immunol. 21, 1022–1033 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. Desdín-Micó, G., Soto-Heredero, G. & Mittelbrunn, M. Mitochondrial activity in T cells. Mitochondrion 41, 51–57 (2018).

    PubMed  Article  CAS  Google Scholar 

  30. Sena, L. A. et al. Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity 38, 225–236 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. Quinn, K. M., Palchaudhuri, R., Palmer, C. S. & La Gruta, N. L. The clock is ticking: the impact of ageing on T cell metabolism. Clin. Transl. Immunol. 8, e01091 (2019).

    Article  Google Scholar 

  32. Soto-Heredero, G., Gómez de las Heras, M. M., Gabandé-Rodríguez, E., Oller, J. & Mittelbrunn, M. Glycolysis — a key player in the inflammatory response. FEBS J. 287, 3350–3369 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. Xu, K. et al. Glycolysis fuels phosphoinositide 3-kinase signaling to bolster T cell immunity. Science 371, 405–410 (2021).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  34. Callender, L. A. et al. Human CD8+ EMRA T cells display a senescence-associated secretory phenotype regulated by p38 MAPK. Aging Cell 17, e12675 (2018).

    Article  CAS  Google Scholar 

  35. Ramstead, A. G. et al. Mitochondrial pyruvate carrier 1 promotes peripheral T cell homeostasis through metabolic regulation of thymic development. Cell Rep. 30, 2889–2899 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. Callender, L. A. et al. Mitochondrial mass governs the extent of human T cell senescence. Aging Cell 19, e13067 (2020).

    CAS  PubMed  Article  Google Scholar 

  37. Baixauli, F. et al. Mitochondrial respiration controls lysosomal function during inflammatory T cell responses. Cell Metab. 22, 485–498 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. Younes, S.-A. et al. Cycling CD4+ T cells in HIV-infected immune nonresponders have mitochondrial dysfunction. J. Clin. Invest. 128, 5083–5094 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  39. Kulkarni, A. S., Gubbi, S. & Barzilai, N. Benefits of metformin in attenuating the hallmarks of Aging. Cell Metab. 32, 15–30 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. Böhme, J. et al. Metformin enhances anti-mycobacterial responses by educating CD8+ T-cell immunometabolic circuits. Nat. Commun. 11, 5225 (2020).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  41. Dumauthioz, N. et al. Enforced PGC-1α expression promotes CD8 T cell fitness, memory formation and antitumor immunity. Cell. Mol. Immunol. https://doi.org/10.1038/s41423-020-0365-3 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Scharping, N. E. et al. Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion. Nat. Immunol. 22, 205–215 (2021).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  43. Yu, Y.-R. et al. Disturbed mitochondrial dynamics in CD8+ TILs reinforce T cell exhaustion. Nat. Immunol. 21, 1540–1551 (2020).

    CAS  Article  PubMed  Google Scholar 

  44. Sanderson, S. L. & Simon, A. K. In aged primary T cells, mitochondrial stress contributes to telomere attrition measured by a novel imaging flow cytometry assay. Aging Cell 16, 1234–1243 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. Moon, J. S. et al. Growth differentiation factor 15 protects against the aging-mediated systemic inflammatory response in humans and mice. Aging Cell 19, e13195 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. Terao, C. et al. Chromosomal alterations among age-related haematopoietic clones in Japan. Nature 584, 130–135 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. Thol, F. et al. Acute myeloid leukemia derived from lympho-myeloid clonal hematopoiesis. Leukemia 31, 1286–1295 (2017).

    CAS  PubMed  Article  Google Scholar 

  48. Li, Y. et al. Deficient activity of the nuclease MRE11A induces T cell aging and promotes arthritogenic effector functions in patients with rheumatoid arthritis. Immunity 45, 903–916 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. Fali, T. et al. New Insights into lymphocyte differentiation and aging from telomere length and telomerase activity measurements. J. Immunol. 202, 1962–1969 (2019).

    CAS  PubMed  Article  Google Scholar 

  50. Jergović, M., Contreras, N. A. & Nikolich-Žugich, J. Impact of CMV upon immune aging: facts and fiction. Med. Microbiol. Immunol. 208, 263–269 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  51. Popescu, I. et al. Impaired cytomegalovirus immunity in idiopathic pulmonary fibrosis lung transplant recipients with short telomeres. Am. J. Respir. Crit. Care Med. 199, 362–376 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. Wagner, C. L. et al. Short telomere syndromes cause a primary T cell immunodeficiency. J. Clin. Invest. 128, 5222–5234 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  53. Tedone, E. et al. Telomere length and telomerase activity in T cells are biomarkers of high-performing centenarians. Aging Cell 18, e12859 (2019).

    PubMed  Article  CAS  Google Scholar 

  54. Chen, B. H. et al. Leukocyte telomere length, T cell composition and DNA methylation age. Aging 9, 1983–1995 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. Márquez, E. J. et al. Sexual-dimorphism in human immune system aging. Nat. Commun. 11, 751 (2020).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  56. Ucar, D. et al. The chromatin accessibility signature of human immune aging stems from CD8+ T cells. J. Exp. Med. 214, 3123–3144 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. Ye, Z. et al. Regulation of miR-181a expression in T cell aging. Nat. Commun. 9, 3060 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  58. Kim, C. et al. Defects in antiviral T cell responses inflicted by aging-associated miR-181a deficiency. Cell Rep. 29, 2202–2216 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. Hu, R. et al. miR-155 promotes T follicular helper cell accumulation during chronic, low-grade inflammation. Immunity 41, 605–619 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. Ekiz, H. A. et al. T cell–expressed microRNA-155 reduces lifespan in a mouse model of age-related chronic inflammation. J. Immunol. 204, 2064–2075 (2020).

    CAS  PubMed  Article  Google Scholar 

  61. Witkowski, J. M., Mikosik, A., Bryl, E. & Fulop, T. Proteodynamics in aging human T cells — the need for its comprehensive study to understand the fine regulation of T lymphocyte functions. Exp. Gerontol. 107, 161–168 (2018).

    CAS  PubMed  Article  Google Scholar 

  62. Stepensky, P. et al. Early-onset Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency. Blood 125, 753–761 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. Arata, Y. et al. Defective induction of the proteasome associated with T-cell receptor signaling underlies T-cell senescence. Genes Cells 24, 801–813 (2019).

    CAS  PubMed  Article  Google Scholar 

  64. Wang, Z. et al. Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade. Nat. Med. 25, 141–151 (2019).

    CAS  PubMed  Article  Google Scholar 

  65. Katsyuba, E., Romani, M., Hofer, D. & Auwerx, J. NAD+ homeostasis in health and disease. Nat. Metab. 2, 9–31 (2020).

    CAS  PubMed  Article  Google Scholar 

  66. Madeo, F., Eisenberg, T., Pietrocola, F. & Kroemer, G. Spermidine in health and disease. Science 359, eaan2788 (2018).

    PubMed  Article  CAS  Google Scholar 

  67. Zhang, H. & Simon, A. K. Polyamines reverse immune senescence via the translational control of autophagy. Autophagy 16, 181–182 (2020).

    PubMed  Article  CAS  Google Scholar 

  68. Jin, J. et al. FOXO1 deficiency impairs proteostasis in aged T cells. Sci. Adv. 6, eaba1808 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. Buono, R. & Longo, V. D. When fasting gets tough, the tough immune cells get going — or die. Cell 178, 1038–1040 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. Fang, E. F. et al. NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome. Nat. Commun. 10, 5284 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  71. Clarke, A. J. & Simon, A. K. Autophagy in the renewal, differentiation and homeostasis of immune cells. Nat. Rev. Immunol. 19, 170–183 (2019).

    CAS  PubMed  Article  Google Scholar 

  72. Macian, F. Autophagy in T cell function and aging. Front. Cell Dev. Biol. 7, 213 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  73. Swadling, L. et al. Human liver memory CD8+ T cells use autophagy for tissue residence. Cell Rep. 30, 687–698.e6 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. DiToro, D. et al. Insulin-like growth factors are key regulators of T helper 17 regulatory T cell balance in autoimmunity. Immunity 52, 650–667 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. Kabat, A. M. et al. The autophagy gene Atg16l1 differentially regulates Treg and TH2 cells to control intestinal inflammation. Elife 5, e12444 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  76. Parekh, V. V. et al. Impaired autophagy, defective T cell homeostasis, and a wasting syndrome in mice with a T cell–specific deletion of Vps34. J. Immunol. 190, 5086–5101 (2013).

    CAS  PubMed  Article  Google Scholar 

  77. Le Texier, L. et al. Autophagy-dependent regulatory T cells are critical for the control of graft-versus-host disease. JCI Insight 1, e86850 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  78. Wei, J. et al. Autophagy enforces functional integrity of regulatory T cells by coupling environmental cues and metabolic homeostasis. Nat. Immunol. 17, 277–285 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. Carriche, G. M. et al. Regulating T-cell differentiation through the polyamine spermidine. J. Allergy Clin. Immunol. https://doi.org/10.1016/j.jaci.2020.04.037 (2020).

  80. Araki, K. et al. mTOR regulates memory CD8 T-cell differentiation. Nature 460, 108–112 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. Mannick, J. B. et al. mTOR inhibition improves immune function in the elderly. Sci. Transl. Med. 6, 268ra179 (2014).

    PubMed  Article  CAS  Google Scholar 

  82. Mannick, J. B. et al. TORC1 inhibition enhances immune function and reduces infections in the elderly. Sci. Transl. Med. 10, eaaq1564 (2018).

    PubMed  Article  CAS  Google Scholar 

  83. Raz, Y. et al. Activation-induced autophagy is preserved in CD4+ T-cells in familial longevity. J. Gerontol. A. Biol. Sci. Med. Sci. 72, 1201–1206 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. Akbar, A. N., Henson, S. M. & Lanna, A. Senescence of T lymphocytes: implications for enhancing human immunity. Trends Immunol. 37, 866–876 (2016).

    CAS  PubMed  Article  Google Scholar 

  85. Huang, H. et al. Select sequencing of clonally expanded CD8+ T cells reveals limits to clonal expansion. Proc. Natl Acad. Sci. USA 116, 8995–9001 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  86. Schober, K. et al. Reverse TCR repertoire evolution toward dominant low-affinity clones during chronic CMV infection. Nat. Immunol. 21, 434–441 (2020).

    CAS  PubMed  Article  Google Scholar 

  87. Kared, H. et al. Immunological history governs human stem cell memory CD4 heterogeneity via the Wnt signaling pathway. Nat. Commun. 11, 821 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. Lanfermeijer, J., Borghans, J. A. M. & van Baarle, D. How age and infection history shape the antigen-specific CD8+ T-cell repertoire: implications for vaccination strategies in older adults. Aging Cell 19, e13262 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. Egorov, E. S. et al. The changing landscape of naive T cell receptor repertoire with human aging. Front. Immunol. 9, 1618 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  90. Kallemeijn, M. J. et al. Next-generation sequencing analysis of the human TCRγδ+ T-cell repertoire reveals shifts in Vγ- and Vδ-usage in memory populations upon aging. Front. Immunol. 9, 448 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  91. Xu, W. et al. Mapping of γ/δ T cells reveals Vδ2+ T cells resistance to senescence. EBioMedicine 39, 44–58 (2019).

    PubMed  Article  Google Scholar 

  92. Sportès, C. et al. Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets. J. Exp. Med. 205, 1701–1714 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  93. Mold, J. E. et al. Cell generation dynamics underlying naive T-cell homeostasis in adult humans. PLoS Biol. 17, e3000383 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. Thome, J. J. C. et al. Longterm maintenance of human naive T cells through in situ homeostasis in lymphoid tissue sites. Sci. Immunol. 1, eaah6506 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  95. Senda, T. et al. Microanatomical dissection of human intestinal T-cell immunity reveals site-specific changes in gut-associated lymphoid tissues over life. Mucosal Immunol. 12, 378–389 (2019).

    CAS  PubMed  Article  Google Scholar 

  96. Goronzy, J. J., Fang, F., Cavanagh, M. M., Qi, Q. & Weyand, C. M. Naive T cell maintenance and function in human aging. J. Immunol. 194, 4073–4080 (2015).

    CAS  PubMed  Article  Google Scholar 

  97. Link, A. et al. Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells. Nat. Immunol. 8, 1255–1265 (2007).

    CAS  PubMed  Article  Google Scholar 

  98. Chiu, B.-C., Martin, B. E., Stolberg, V. R. & Chensue, S. W. Cutting edge: central memory CD8 T cells in aged mice are virtual memory cells. J. Immunol. 191, 5793–5796 (2013).

    CAS  PubMed  Article  Google Scholar 

  99. Renkema, K. R., Li, G., Wu, A., Smithey, M. J. & Nikolich-Žugich, J. Two separate defects affecting true naive or virtual memory T cell precursors combine to reduce naive T cell responses with aging. J. Immunol. 192, 151–159 (2014).

    CAS  PubMed  Article  Google Scholar 

  100. White, J. T. et al. Virtual memory T cells develop and mediate bystander protective immunity in an IL-15-dependent manner. Nat. Commun. 7, 11291 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. Quinn, K. M. et al. Age-related decline in primary CD8+ T cell responses is associated with the development of senescence in virtual memory CD8+ T cells. Cell Rep. 23, 3512–3524 (2018).

    CAS  PubMed  Article  Google Scholar 

  102. Akbar, A. N. & Henson, S. M. Are senescence and exhaustion intertwined or unrelated processes that compromise immunity? Nat. Rev. Immunol. 11, 289–295 (2011).

    CAS  PubMed  Article  Google Scholar 

  103. Ahmed, R. et al. CD57+ memory T cells proliferate in vivo. Cell Rep. 33, 108501 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  104. Czesnikiewicz-Guzik, M. et al. T cell subset-specific susceptibility to aging. Clin. Immunol. 127, 107–118 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. Suzuki, J. et al. The tumor suppressor menin prevents effector CD8 T-cell dysfunction by targeting mTORC1-dependent metabolic activation. Nat. Commun. 9, 3296 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  106. Lanna, A. et al. A sestrin-dependent Erk–Jnk–p38 MAPK activation complex inhibits immunity during aging. Nat. Immunol. 18, 354–363 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  107. Pereira, B. I. et al. Sestrins induce natural killer function in senescent-like CD8+ T cells. Nat. Immunol. 21, 684–694 (2020).

    CAS  PubMed  Article  Google Scholar 

  108. Hashimoto, K. et al. Single-cell transcriptomics reveals expansion of cytotoxic CD4 T cells in supercentenarians. Proc. Natl Acad. Sci. USA 116, 24242–24251 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  109. Elyahu, Y. et al. Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes. Sci. Adv. 5, eaaw8330 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  110. Guo, Z. et al. DCAF1 regulates Treg senescence via the ROS axis during immunological aging. J. Clin. Invest. 130, 5893–5908 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  111. Chou, J. P. & Effros, R. B. T cell replicative senescence in human aging. Curr. Pharm. Des. 19, 1680–1698 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Derhovanessian, E., Larbi, A. & Pawelec, G. Biomarkers of human immunosenescence: impact of cytomegalovirus infection. Curr. Opin. Immunol. 21, 440–445 (2009).

    CAS  PubMed  Article  Google Scholar 

  113. Pan, X.-X. et al. T-cell senescence accelerates angiotensin II-induced target organ damage. Cardiovasc. Res. 117, 271–283 (2021).

    CAS  PubMed  Article  Google Scholar 

  114. Shirakawa, K. et al. Obesity accelerates T cell senescence in murine visceral adipose tissue. J. Clin. Invest. 126, 4626–4639 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  115. Yoshida, S. et al. The CD153 vaccine is a senotherapeutic option for preventing the accumulation of senescent T cells in mice. Nat. Commun. 11, 2482 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  116. Gate, D. et al. Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease. Nature 577, 399–404 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  117. Preite, S., Gomez-Rodriguez, J., Cannons, J. L. & Schwartzberg, P. L. T and B-cell signaling in activated PI3K delta syndrome: from immunodeficiency to autoimmunity. Immunol. Rev. 291, 154–173 (2019).

    CAS  PubMed  Article  Google Scholar 

  118. Di Mitri, D. et al. Reversible senescence in human CD4+CD45RA+CD27 memory T cells. J. Immunol. 187, 2093–2100 (2011).

    PubMed  Article  Google Scholar 

  119. Henson, S. M. et al. p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8+ T cells. J. Clin. Invest. 124, 4004–4016 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. Lanna, A., Henson, S. M., Escors, D. & Akbar, A. N. The kinase p38 activated by the metabolic regulator AMPK and scaffold TAB1 drives the senescence of human T cells. Nat. Immunol. 15, 965–972 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  121. Henson, S. M. et al. KLRG1 signaling induces defective Akt (ser473) phosphorylation and proliferative dysfunction of highly differentiated CD8+ T cells. Blood 113, 6619–6628 (2009).

    CAS  PubMed  Article  Google Scholar 

  122. Ji, Y. et al. miR-155 harnesses Phf19 to potentiate cancer immunotherapy through epigenetic reprogramming of CD8+ T cell fate. Nat. Commun. 10, 2157 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  123. Sharma, R. & Padwad, Y. Nutraceuticals-based immunotherapeutic concepts and opportunities for the mitigation of cellular senescence and aging: a narrative review. Ageing Res. Rev. 63, 101141 (2020).

    CAS  PubMed  Article  Google Scholar 

  124. van Beek, J. J. P., Rescigno, M. & Lugli, E. A fresh look at the T helper subset dogma. Nat. Immunol. 22, 104–105 (2021).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  125. Hu, B. et al. Transcription factor networks in aged naïve CD4 T cells bias lineage differentiation. Aging Cell 18, e12957 (2019).

    PubMed  PubMed Central  Google Scholar 

  126. Mogilenko, D. A. et al. Comprehensive profiling of an aging immune system reveals clonal GZMK+ CD8+ T cells as conserved hallmark of inflammaging. Immunity 54, 99–115 (2021).

    CAS  PubMed  Article  Google Scholar 

  127. Lefebvre, J. S., Masters, A. R., Hopkins, J. W. & Haynes, L. Age-related impairment of humoral response to influenza is associated with changes in antigen specific T follicular helper cell responses. Sci. Rep. 6, 25051 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  128. Goronzy, J. J., Li, G., Yu, M. & Weyand, C. M. Signaling pathways in aged T cells — a reflection of T cell differentiation, cell senescence and host environment. Semin. Immunol. 24, 365–372 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  129. Maeda, T. et al. Regeneration of CD8αβ T cells from T-cell-derived iPSC imparts potent tumor antigen-specific cytotoxicity. Cancer Res. 76, 6839–6850 (2016).

    CAS  PubMed  Article  Google Scholar 

  130. Palmer, S., Albergante, L., Blackburn, C. C. & Newman, T. J. Thymic involution and rising disease incidence with age. Proc. Natl Acad. Sci. USA 115, 1883–1888 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  131. Buqué, A. et al. Immunoprophylactic and immunotherapeutic control of hormone receptor-positive breast cancer. Nat. Commun. 11, 3819 (2020).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  132. Betjes, M. G. H., Langerak, A. W., Klepper, M. & Litjens, N. H. R. A very low thymus function identifies patients with substantial increased risk for long-term mortality after kidney transplantation. Immun. Ageing A 17, 4 (2020).

    Article  Google Scholar 

  133. Betjes, M. G. Uremia-associated ageing of the thymus and adaptive immune responses. Toxins 12, 224 (2020).

    CAS  PubMed Central  Article  Google Scholar 

  134. Crépin, T. et al. Uraemia-induced immune senescence and clinical outcomes in chronic kidney disease patients. Nephrol. Dial. Transplant. 35, 624–632 (2020).

    PubMed  Article  Google Scholar 

  135. Huang, S. et al. Reduced T-cell thymic export reflected by sj-TREC in patients with coronary artery disease. J. Atheroscler. Thromb. 23, 632–643 (2016).

    CAS  PubMed  Article  Google Scholar 

  136. Pereira, B. I. et al. Senescent cells evade immune clearance via HLA-E-mediated NK and CD8+ T cell inhibition. Nat. Commun. 10, 2387 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  137. Franceschi, C., Garagnani, P., Vitale, G., Capri, M. & Salvioli, S. Inflammaging and ‘Garb-aging’. Trends Endocrinol. Metab. 28, 199–212 (2017).

    CAS  PubMed  Article  Google Scholar 

  138. Ferrucci, L. & Fabbri, E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat. Rev. Cardiol. 15, 505–522 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  139. Furman, D. et al. Chronic inflammation in the etiology of disease across the life span. Nat. Med. 25, 1822–1832 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  140. Chambers, E. S. & Akbar, A. N. Can blocking inflammation enhance immunity during aging? J. Allergy Clin. Immunol. 145, 1323–1331 (2020).

    CAS  PubMed  Article  Google Scholar 

  141. Vukmanovic-Stejic, M. et al. Enhancement of cutaneous immunity during aging by blocking p38 mitogen-activated protein (MAP) kinase-induced inflammation. J. Allergy Clin. Immunol. 142, 844–856 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  142. Chambers, E. S. et al. Recruitment of inflammatory monocytes by senescent fibroblasts inhibits antigen-specific tissue immunity during human aging. Nat. Aging 1, 101–113 (2021).

    Article  Google Scholar 

  143. Almanan, M. et al. IL-10-producing TFH cells accumulate with age and link inflammation with age-related immune suppression. Sci. Adv. 6, eabb0806 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  144. Luan, H. H. et al. GDF15 is an inflammation-induced central mediator of tissue tolerance. Cell 178, 1231–1244.e11 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  145. Day, E. A. et al. Metformin-induced increases in GDF15 are important for suppressing appetite and promoting weight loss. Nat. Metab. 1, 1202–1208 (2019).

    CAS  PubMed  Article  Google Scholar 

  146. Bharath, L. P. et al. Metformin enhances autophagy and normalizes mitochondrial function to alleviate aging-associated inflammation. Cell Metab. 32, 44–55 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  147. Wong, Y. T., Gruber, J., Jenner, A. M., Tay, F. E. H. & Ruan, R. Chronic resveratrol intake reverses pro-inflammatory cytokine profile and oxidative DNA damage in ageing hybrid mice. Age (Dordr.) 33, 229–246 (2011).

    CAS  Article  Google Scholar 

  148. Fan, K.-Q. et al. Stress-induced metabolic disorder in peripheral CD4+ T cells leads to anxiety-like behavior. Cell 179, 864–879 (2019).

    CAS  PubMed  Article  Google Scholar 

  149. Sato, K., Kato, A., Sekai, M., Hamazaki, Y. & Minato, N. Physiologic thymic involution underlies age-dependent accumulation of senescence-associated CD4+ T cells. J. Immunol. 199, 138–148 (2017).

    CAS  PubMed  Article  Google Scholar 

  150. Thomas, R., Wang, W. & Su, D.-M. Contributions of age-related thymic involution to immunosenescence and inflammaging. Immun. Ageing 17, 2 (2020).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  151. Nikolich-Žugich, J. The twilight of immunity: emerging concepts in aging of the immune system. Nat. Immunol. 19, 10–19 (2018).

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgements

M.M. is supported by the Miguel Servet Program (CP 19/014, Fundación de Investigación del Hospital 12 de Octubre; the Fondo de Investigación Sanitaria del Instituto de Salud Carlos III (PI19/855), the European Regional Development Fund (ERDF), and the European Commission through H2020-EU.1.1 and European Research Council grant ERC-2016-StG 715322-EndoMitTalk. G.K. is supported by the Ligue contre le Cancer (équipe labellisée); Agence National de la Recherche (ANR) — Projets blancs; AMMICa US23/CNRS UMS3655; Association pour la recherche sur le cancer (ARC); Association ‘Ruban Rose’; Cancéropôle Ile-de-France; Chancelerie des universités de Paris (Legs Poix), Fondation pour la Recherche Médicale (FRM); a donation by Elior; European Research Area Network on Cardiovascular Diseases (ERA-CVD, MINOTAUR); Gustave Roussy Odyssea, the European Union Horizon 2020 Project Oncobiome; Fondation Carrefour; High-end Foreign Expert Program in China (GDW20171100085), Institut National du Cancer (INCa); Inserm (HTE); Institut Universitaire de France; LeDucq Foundation; the LabEx Immuno-Oncology (ANR-18-IDEX-0001); the RHU Torino Lumière; the Seerave Foundation; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); and the SIRIC Cancer Research and Personalized Medicine (CARPEM). This study contributes to the IdEx Université de Paris ANR-18-IDEX-0001.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Maria Mittelbrunn or Guido Kroemer.

Ethics declarations

Competing interests

G.K. is the scientific cofounder of three biotech companies dealing with age-related diseases: everImmune, Samsara Therapeutics, and Therast Bio.

Additional information

Peer review information Nature Immunology thanks Rene van Lier and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Jamie D. K. Wilson was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Mittelbrunn, M., Kroemer, G. Hallmarks of T cell aging. Nat Immunol 22, 687–698 (2021). https://doi.org/10.1038/s41590-021-00927-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41590-021-00927-z

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing