Kipling, D. Telomeres, replicative senescence and human ageing. Maturitas 38, 25–37 (2001).

CAS  PubMed  Article  Google Scholar 

Hayflick, L. & Moorhead, P. S. The serial cultivation of human diploid cell strains. Exp. Cell. Res. 25, 585–621 (1961).

CAS  PubMed  Article  Google Scholar 

Blasco, M. A. Telomeres and human disease: ageing, cancer and beyond. Nat. Rev. Genet. 6, 611–622 (2005).

CAS  PubMed  Article  Google Scholar 

Collins, K. Mammalian telomeres and telomerase. Curr. Opin. Cell Biol. 12, 378–383 (2000).

CAS  PubMed  Article  Google Scholar 

Cesare, A. J. & Reddel, R. R. Alternative lengthening of telomeres: models, mechanisms and implications. Nat. Rev. Genet. 11, 319–330 (2010).

CAS  PubMed  Article  Google Scholar 

Fooksman, D. R. et al. Functional anatomy of T cell activation and synapse formation. Annu. Rev. Immunol. 28, 79–105 (2010).

CAS  PubMed  PubMed Central  Article  Google Scholar 

Akbar, A. N., Beverley, P. C. L. & Salmon, M. Will telomere erosion lead to a loss of T-cell memory? Nat. Rev. Immunol. 4, 737–743 (2004).

CAS  PubMed  Article  Google Scholar 

Weng, N.-P., Akbar, A. N. & Goronzy, J. CD28− T cells: their role in the age-associated decline of immune function. Trends Immunol. 30, 306–312 (2009).

CAS  PubMed  PubMed Central  Article  Google Scholar 

Plunkett, F. J. et al. 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 (2007).

CAS  PubMed  Article  Google Scholar 

Boraschi, D. et al. The gracefully aging immune system. Sci. Transl. Med. 5, 185ps8 (2013).

PubMed  Article  CAS  Google Scholar 

Goronzy, J. J. & Weyand, C. M. Understanding immunosenescence to improve responses to vaccines. Nat. Immunol. 14, 428–436 (2013).

CAS  PubMed  PubMed Central  Article  Google Scholar 

Lanna, A. et al. A sestrin-dependent Erk-Jnk-p38 MAPK activation complex inhibits immunity during aging. Nat. Immunol. 18, 354–362 (2017).

CAS  PubMed  PubMed Central  Article  Google Scholar 

Akbar, A. N. et al. Senescence of T lymphocytes: implications for enhancing human immunity. Trends Immunol. 37, 866–876 (2016).

CAS  PubMed  Article  Google Scholar 

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 

Akbar, A. N. & Vukmanovic-Stejic, M. Telomerase in T lymphocytes: use it and lose it? J. Immunol. 178, 6689–6694 (2007).

CAS  PubMed  Article  Google Scholar 

Hodes, R. J., Hathcock, K. S. & Weng, N. Telomeres in T and B cells. Nat. Rev. Immunol. 2, 699–706 (2002).

CAS  PubMed  Article  Google Scholar 

Dustin, M. L. & Groves, J. T. Receptor signaling clusters in the immune synapse. Annu. Rev. Biophys. 41, 543–556 (2012).

CAS  PubMed  PubMed Central  Article  Google Scholar 

Chakraborty, A. K. & Weiss, A. Insights into the initiation of TCR signaling. Nat. Immunol. 15, 798–807 (2014).

CAS  PubMed  PubMed Central  Article  Google Scholar 

Choudhuri, K. et al. Polarized release of T-cell-receptor-enriched microvesicles at the immunological synapse. Nature 507, 118–123 (2014).

CAS  PubMed  PubMed Central  Article  Google Scholar 

Molenaar, C. et al. Visualizing telomere dynamics in living mammalian cells using PNA probes. EMBO J. 22, 6631–6641 (2003).

CAS  PubMed  PubMed Central  Article  Google Scholar 

Messenger, S. W., Woo, S. S., Sun, Z. & Martin, T. F. J. A Ca2+-stimulated exosome release pathway in cancer cells is regulated by Munc13-4. J. Cell Biol. 217, 2877–2890 (2018).

CAS  PubMed  PubMed Central  Article  Google Scholar 

van der Vlist, E. J., Nolte-’t Hoen, E. N. M., Stoorvogel, W., Arkesteijn, G. J. A. & Wauben, M. H. M. Fluorescent labeling of nano-sized vesicles released by cells and subsequent quantitative and qualitative analysis by high-resolution flow cytometry. Nat. Protoc. 7, 1311–1326 (2012).

PubMed  Article  CAS  Google Scholar 

Hadden, J. M., Déclais, A.-C., Carr, S. B., Lilley, D. M. J. & Phillips, S. E. V. The structural basis of Holliday junction resolution by T7 endonuclease I. Nature 449, 621–624 (2007).

CAS  PubMed  Article  Google Scholar 

Li, J. S. Z. et al. TZAP: a telomere-associated protein involved in telomere length control. Science 355, 638–641 (2017).

CAS  PubMed  PubMed Central  Article  Google Scholar 

Denchi, E. L. & de Lange, T. Protection of telomeres through independent control of ATM and ATR by TRF2 and POT1. Nature 448, 1068–1071 (2007).

CAS  PubMed  Article  Google Scholar 

Sfeir, A. & de Lange, T. Removal of shelterin reveals the telomere end-protection problem. Science 336, 593–597 (2012).

CAS  PubMed  PubMed Central  Article  Google Scholar 

Park, J. Y., Jang, S. Y., Shin, Y. K., Suh, D. J. & Park, H. T. Calcium-dependent proteasome activation is required for axonal neurofilament degradation. Neural Regen. Res. 8, 3401–3409 (2013).

CAS  PubMed  PubMed Central  Google Scholar 

Tarsounas, M. et al. Telomere maintenance requires the RAD51D recombination/repair protein. Cell 117, 337–347 (2004).

CAS  PubMed  Article  Google Scholar 

Vallejo, A. N., Brandes, J. C., Weyand, C. M. & Goronzy, J. J. Modulation of CD28 expression: distinct regulatory pathways during activation and replicative senescence. J. Immunol. 162, 6572–6579 (1999).

CAS  PubMed  Google Scholar 

Warrington, K. J., Vallejo, A. N., Weyand, C. M. & Goronzy, J. J. CD28 loss in senescent CD4+ T cells: reversal by interleukin-12 stimulation. Blood 101, 3543–3549 (2003).

CAS  PubMed  Article  Google Scholar 

Larbi, A. & Fulop, T. From “truly naïve” to “exhausted senescent” T cells: when markers predict functionality. Cytom. Part A 85, 25–35 (2014).

Article  CAS  Google Scholar 

Akbar, A. N. & Fletcher, J. M. Memory T cell homeostasis and senescence during aging. Curr. Opin. Immunol. 17, 480–485 (2005).

CAS  PubMed  Article  Google Scholar 

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

CAS  PubMed  Article  Google Scholar 

Gattinoni, L. et al. A human memory T cell subset with stem cell-like properties. Nat. Med. 17, 1290–1297 (2011).

CAS  PubMed  PubMed Central  Article  Google Scholar 

Shimatani, K., Nakashima, Y., Hattori, M., Hamazaki, Y. & Minato, N. PD-1+ memory phenotype CD4+ T cells expressing C/EBPα underlie T cell immunodepression in senescence and leukemia. Proc. Natl Acad. Sci. USA 106, 15807–15812 (2009).

CAS  PubMed  PubMed Central  Article  Google Scholar 

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 

Pearce, E. L., Poffenberger, M. C., Chang, C.-H. & Jones, R. G. Fueling immunity: insights into metabolism and lymphocyte function. Science 342, 1242454 (2013).

PubMed  PubMed Central  Article  CAS  Google Scholar 

Chang, J. T. et al. Asymmetric T lymphocyte division in the initiation of adaptive immune responses. Science 315, 1687–1691 (2007).

CAS  PubMed  Article