Abstract
Aging is the decline of physiological capabilities required for life maintenance and reproduction over time. The human immune cells, including T-cells lymphocytes, undergo dramatic aging-related changes, including those related to telomeres and telomerase. It was demonstrated that telomeres and telomerase play crucial roles in T-cell differentiation, aging, and diseases, including a well-documented link between short telomeres and telomerase activation demonstrated in several T-cells malignancies. Herein, we provide a comprehensive review of the literature regarding T-cells’ telomeres and telomerase in health and age related-diseases.
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Akbar AN, Vukmanovic-Stejic M (2007) Telomerase in T lymphocytes: use it and lose it? J Immunol Baltim Md 178:6689–6694. https://doi.org/10.4049/jimmunol.178.11.6689
Akbar AN, Henson SM (2011) Are senescence and exhaustion intertwined or unrelated processes that compromise immunity? Nat Rev Immunol 11:289–295. https://doi.org/10.1038/nri2959
Akbar AN, Beverley PCL, Salmon M (2004) Will telomere erosion lead to a loss of T-cell memory? Nat Rev Immunol 4:737–743. https://doi.org/10.1038/nri1440
Akbar AN, Henson SM, Lanna A (2016) Senescence of T lymphocytes: implications for enhancing human immunity. Trends Immunol 37:866–876. https://doi.org/10.1016/j.it.2016.09.002
Arakawa F, Miyoshi H, Yoshida N et al (2021) Expression of telomerase reverse transcriptase in peripheral T-cell lymphoma. Cancer Med 10:6786–6794. https://doi.org/10.1002/cam4.4200
Bekaert S, De Meyer T, Rietzschel ER et al (2007) Telomere length and cardiovascular risk factors in a middle-aged population free of overt cardiovascular disease. Aging Cell 6:639–647. https://doi.org/10.1111/j.1474-9726.2007.00321.x
Bellon M, Nicot C (2007) Telomerase: a crucial player in HTLV-I-induced human T-cell leukemia. Cancer Genom Proteom 4:21–25
Belver L, Ferrando A (2016) The genetics and mechanisms of T cell acute lymphoblastic leukaemia. Nat Rev Cancer 16:494–507. https://doi.org/10.1038/nrc.2016.63
Bennaceur K, Atwill M, Al Zhrany N et al (2014) Atorvastatin induces T cell proliferation by a telomerase reverse transcriptase (TERT) mediated mechanism. Atherosclerosis 236:312–320. https://doi.org/10.1016/j.atherosclerosis.2014.07.020
Billard P, Poncet DA (2019) Replication stress at telomeric and mitochondrial DNA: common origins and consequences on ageing. Int J Mol Sci 20:4959. https://doi.org/10.3390/ijms20194959
Blasco MA (2005) Telomeres and human disease: ageing, cancer and beyond. Nat Rev Genet 6:611–622. https://doi.org/10.1038/nrg1656
Brunet A, Berger SL (2014) Epigenetics of aging and aging-related disease. J Gerontol A Biol Sci Med Sci 69(Suppl 1):S17-20. https://doi.org/10.1093/gerona/glu042
Buckley MT, Sun ED, George BM et al (2023) Cell-type-specific aging clocks to quantify aging and rejuvenation in neurogenic regions of the brain. Nat Aging 3:121–137. https://doi.org/10.1038/s43587-022-00335-4
Carrasco E, Gómez de Las Heras MM, Gabandé-Rodríguez E et al (2022) The role of T cells in age-related diseases. Nat Rev Immunol 22:97–111. https://doi.org/10.1038/s41577-021-00557-4
Carty CL, Kooperberg C, Liu J et al (2015) Leukocyte telomere length and risks of incident coronary heart disease and mortality in a racially diverse population of postmenopausal women. Arterioscler Thromb Vasc Biol 35:2225–2231. https://doi.org/10.1161/ATVBAHA.115.305838
Chebly A, Chouery E, Ropio J et al (2021) Diagnosis and treatment of lymphomas in the era of epigenetics. Blood Rev 48:100782. https://doi.org/10.1016/j.blre.2020.100782
Chebly A, Ropio J, Peloponese J-M et al (2022) Exploring hTERT promoter methylation in cutaneous T-cell lymphomas. Mol Oncol 16:1931–1946. https://doi.org/10.1002/1878-0261.12946
Cherkas LF, Hunkin JL, Kato BS et al (2008) The association between physical activity in leisure time and leukocyte telomere length. Arch Intern Med 168:154–158. https://doi.org/10.1001/archinternmed.2007.39
Chevret E, Andrique L, Prochazkova-Carlotti M et al (2014) Telomerase functions beyond telomere maintenance in primary cutaneous T-cell lymphoma. Blood 123:1850–1859. https://doi.org/10.1182/blood-2013-05-500686
Chistiakov DA, Sobenin IA, Orekhov AN (2013) Regulatory T cells in atherosclerosis and strategies to induce the endogenous atheroprotective immune response. Immunol Lett 151:10–22. https://doi.org/10.1016/j.imlet.2013.01.014
Chou JP, Effros RB (2013) T cell replicative senescence in human aging. Curr Pharm Des 19:1680–1698. https://doi.org/10.2174/138161213805219711
Codd V, Nelson CP, Albrecht E et al (2013) Identification of seven loci affecting mean telomere length and their association with disease. Nat Genet 45:422–427. https://doi.org/10.1038/ng.2528. (427e1-2)
D’Angelo C, Goldeck D, Pawelec G et al (2020) Exploratory study on immune phenotypes in Alzheimer’s disease and vascular dementia. Eur J Neurol 27:1887–1894. https://doi.org/10.1111/ene.14360
Davison GM (2007) Telomeres and telomerase in leukaemia and lymphoma. Transfus Apher Sci off J World Apher Assoc off J Eur Soc Haemapheresis 37:43–47. https://doi.org/10.1016/j.transci.2007.04.006
De Felice B, Annunziata A, Fiorentino G et al (2014) Telomerase expression in amyotrophic lateral sclerosis (ALS) patients. J Hum Genet 59:555–561. https://doi.org/10.1038/jhg.2014.72
de Lange T (2005) Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev 19:2100–2110. https://doi.org/10.1101/gad.1346005
Demanelis K, Jasmine F, Chen LS et al (2020) Determinants of telomere length across human tissues. Science 369:eaaz6876. https://doi.org/10.1126/science.aaz6876
Deng Y, Li Q, Zhou F et al (2022) Telomere length and the risk of cardiovascular diseases: a mendelian randomization study. Front Cardiovasc Med 9:1012615. https://doi.org/10.3389/fcvm.2022.1012615
Desdín-Micó G, Soto-Heredero G, Aranda JF et al (2020) T cells with dysfunctional mitochondria induce multimorbidity and premature senescence. Science 368:1371–1376. https://doi.org/10.1126/science.aax0860
Elyahu Y, Hekselman I, Eizenberg-Magar I et al (2019) Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes. Sci Adv 5:eaaw8330. https://doi.org/10.1126/sciadv.aaw8330
Fessler J, Angiari S (2021) The role of T cell senescence in neurological diseases and its regulation by cellular metabolism. Front Immunol 12:706434. https://doi.org/10.3389/fimmu.2021.706434
Fooksman DR, Vardhana S, Vasiliver-Shamis G et al (2010) Functional anatomy of T cell activation and synapse formation. Annu Rev Immunol 28:79–105. https://doi.org/10.1146/annurev-immunol-030409-101308
Franceschi C, Garagnani P, Parini P et al (2018) Inflammaging: a new immune–metabolic viewpoint for age-related diseases. Nat Rev Endocrinol 14:576–590. https://doi.org/10.1038/s41574-018-0059-4
Fumagalli M, Rossiello F, Clerici M et al (2012) Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat Cell Biol 14:355–365. https://doi.org/10.1038/ncb2466
Furman D, Campisi J, Verdin E et al (2019) Chronic inflammation in the etiology of disease across the life span. Nat Med 25:1822–1832. https://doi.org/10.1038/s41591-019-0675-0
Gao X, Yu X, Zhang C et al (2022) Telomeres and mitochondrial metabolism: implications for cellular senescence and age-related diseases. Stem Cell Rev Rep 18:2315–2327. https://doi.org/10.1007/s12015-022-10370-8
Goronzy JJ, Weyand CM (2013) Understanding immunosenescence to improve responses to vaccines. Nat Immunol 14:428–436. https://doi.org/10.1038/ni.2588
Goronzy JJ, Weyand CM (2019) Mechanisms underlying T cell ageing. Nat Rev Immunol 19:573–583. https://doi.org/10.1038/s41577-019-0180-1
Goronzy JJ, Fang F, Cavanagh MM et al (2015) Naive T cell maintenance and function in human aging. J Immunol Baltim Md 1950 194:4073–4080. https://doi.org/10.4049/jimmunol.1500046
Greenman C, Stephens P, Smith R et al (2007) Patterns of somatic mutation in human cancer genomes. Nature 446:153–158. https://doi.org/10.1038/nature05610
Greider CW (1991) Telomeres. Curr Opin Cell Biol 3:444–451. https://doi.org/10.1016/0955-0674(91)90072-7
Gruber H-J, Semeraro MD, Renner W, Herrmann M (2021) Telomeres and age-related diseases. Biomedicines 9:1335. https://doi.org/10.3390/biomedicines9101335
Guo N, Parry EM, Li L-S et al (2011) Short telomeres compromise β-cell signaling and survival. PLoS One 6:e17858. https://doi.org/10.1371/journal.pone.0017858
Hashimoto K, Kouno T, Ikawa T et al (2019) Single-cell transcriptomics reveals expansion of cytotoxic CD4 T cells in supercentenarians. Proc Natl Acad Sci USA 116:24242–24251. https://doi.org/10.1073/pnas.1907883116
Haycock PC, Heydon EE, Kaptoge S et al (2014) Leucocyte telomere length and risk of cardiovascular disease: systematic review and meta-analysis. BMJ 349:g4227. https://doi.org/10.1136/bmj.g4227
Hayflick L, Moorhead PS (1961) The serial cultivation of human diploid cell strains. Exp Cell Res 25:585–621. https://doi.org/10.1016/0014-4827(61)90192-6
Henson SM, Macaulay R, Riddell NE 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. https://doi.org/10.1002/eji.201445312
Hodes RJ, Hathcock KS, Weng N (2002) Telomeres in T and B cells. Nat Rev Immunol 2:699–706. https://doi.org/10.1038/nri890
Hoffmann J, Richardson G, Haendeler J et al (2021) Telomerase as a therapeutic target in cardiovascular disease. Arterioscler Thromb Vasc Biol 41:1047–1061. https://doi.org/10.1161/ATVBAHA.120.315695
Kahrizi MS, Patra I, Jalil AT et al (2022) Leukocyte telomere length and obesity in children and adolescents: a systematic review and meta-analysis. Front Genet 13:861101. https://doi.org/10.3389/fgene.2022.861101
Klenerman P (2018) The (gradual) rise of memory inflation. Immunol Rev 283:99–112. https://doi.org/10.1111/imr.12653
Kogure Y, Kataoka K (2017) Genetic alterations in adult T-cell leukemia/lymphoma. Cancer Sci 108:1719–1725. https://doi.org/10.1111/cas.13303
Kroupa M, Rachakonda S, Vymetalkova V et al (2020) Telomere length in peripheral blood lymphocytes related to genetic variation in telomerase, prognosis and clinicopathological features in breast cancer patients. Mutagenesis 35:491–497. https://doi.org/10.1093/mutage/geaa030
Kubuki Y, Suzuki M, Sasaki H et al (2005) Telomerase activity and telomere length as prognostic factors of adult T-cell leukemia. Leuk Lymphoma 46:393–399. https://doi.org/10.1080/10428190400018349
Lai T-P, Wright WE, Shay JW (2018) Comparison of telomere length measurement methods. Philos Trans R Soc B Biol Sci 373:20160451. https://doi.org/10.1098/rstb.2016.0451
Lanna A, Vaz B, D’Ambra C et al (2022) An intercellular transfer of telomeres rescues T cells from senescence and promotes long-term immunological memory. Nat Cell Biol 24:1461–1474. https://doi.org/10.1038/s41556-022-00991-z
Li Y, Shen Y, Hohensinner P et al (2016) Deficient activity of the nuclease MRE11A induces T cell aging and promotes arthritogenic effector functions in patients with rheumatoid arthritis. Immunity 45:903–916. https://doi.org/10.1016/j.immuni.2016.09.013
Li C, Wei G-J, Xu L et al (2017) The involvement of senescence induced by the telomere shortness in the decline of osteogenic differentiation in BMSCs. Eur Rev Med Pharmacol Sci 21:1117–1124
López-Otín C, Blasco MA, Partridge L et al (2013) The hallmarks of aging. Cell 153:1194–1217. https://doi.org/10.1016/j.cell.2013.05.039
Martincorena I, Campbell PJ (2015) Somatic mutation in cancer and normal cells. Science 349:1483–1489. https://doi.org/10.1126/science.aab4082
Martincorena I, Fowler JC, Wabik A et al (2018) Somatic mutant clones colonize the human esophagus with age. Science 362:911–917. https://doi.org/10.1126/science.aau3879
Martínez-Zamudio RI, Dewald HK, Vasilopoulos T et al (2021) Senescence-associated β-galactosidase reveals the abundance of senescent CD8 + T cells in aging humans. Aging Cell 20:e13344. https://doi.org/10.1111/acel.13344
Meyer DH, Schumacher B (2021) BiT age: a transcriptome-based aging clock near the theoretical limit of accuracy. Aging Cell 20:e13320. https://doi.org/10.1111/acel.13320
Minato N, Hattori M, Hamazaki Y (2020) Physiology and pathology of T-cell aging. Int Immunol 32:223–231. https://doi.org/10.1093/intimm/dxaa006
Mittelbrunn M, Kroemer G (2021) Hallmarks of T cell aging. Nat Immunol 22:687–698. https://doi.org/10.1038/s41590-021-00927-z
Mogilenko DA, Shpynov O, Andhey PS et al (2021) Comprehensive Profiling of an aging immune system reveals clonal GZMK + CD8 + T cells as conserved hallmark of inflammaging. Immunity 54:99-115e12. https://doi.org/10.1016/j.immuni.2020.11.005
Montpetit AJ, Alhareeri AA, Montpetit M et al (2014) Telomere length: a review of methods for measurement. Nurs Res 63:289–299. https://doi.org/10.1097/NNR.0000000000000037
Mozaffarian D, Benjamin EJ, Go AS et al (2015) Heart disease and stroke statistics–2015 update: a report from the American Heart Association. Circulation 131:e29-322. https://doi.org/10.1161/CIR.0000000000000152
Nikolouzakis TK, Vakonaki E, Stivaktakis PD et al (2021) Novel prognostic biomarkers in metastatic and locally advanced colorectal cancer: micronuclei frequency and telomerase activity in peripheral blood lymphocytes. Front Oncol 11:683605
Olovnikov AM (1971) Principle of marginotomy in template synthesis of polynucleotides. Dokl Akad Nauk SSSR 201:1496–1499
Olovnikov AM (1973) A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon. J Theor Biol 41:181–190. https://doi.org/10.1016/0022-5193(73)90198-7
Olovnikov AM (1996) Telomeres, telomerase, and aging: origin of the theory. Exp Gerontol 31:443–448. https://doi.org/10.1016/0531-5565(96)00005-8
Ovadya Y, Landsberger T, Leins H et al (2018) Impaired immune surveillance accelerates accumulation of senescent cells and aging. Nat Commun 9:5435. https://doi.org/10.1038/s41467-018-07825-3
Palmer S, Albergante L, Blackburn CC, Newman TJ (2018) Thymic involution and rising disease incidence with age. Proc Natl Acad Sci USA 115:1883–1888. https://doi.org/10.1073/pnas.1714478115
Panossian LA, Porter VR, Valenzuela HF et al (2003) Telomere shortening in T cells correlates with Alzheimer’s disease status. Neurobiol Aging 24:77–84. https://doi.org/10.1016/s0197-4580(02)00043-x
Passos JF, Saretzki G, von Zglinicki T (2007) DNA damage in telomeres and mitochondria during cellular senescence: is there a connection? Nucleic Acids Res 35:7505–7513. https://doi.org/10.1093/nar/gkm893
Peters MJ, Joehanes R, Pilling LC et al (2015) The transcriptional landscape of age in human peripheral blood. Nat Commun 6:8570. https://doi.org/10.1038/ncomms9570
Petersen C, Bell R, Klag KA et al (2019) T cell-mediated regulation of the microbiota protects against obesity. Science 365:eaat9351. https://doi.org/10.1126/science.aat9351
Plunkett FJ, Franzese O, Finney HM 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 Baltim Md 178:7710–7719. https://doi.org/10.4049/jimmunol.178.12.7710
Ropio J, Chebly A, Ferrer J et al (2020) Reliable blood cancer cells’ telomere length evaluation by qPCR. Cancer Med 9:3153–3162. https://doi.org/10.1002/cam4.2816
Ropio J, Prochazkova-Carlotti M, Batista R et al (2023) Spotlight on hTERT complex regulation in cutaneous T-cell lymphomas. Genes 14:439. https://doi.org/10.3390/genes14020439
Rufer N, Brümmendorf TH, Kolvraa S et al (1999) Telomere fluorescence measurements in granulocytes and T lymphocyte subsets point to a high turnover of hematopoietic stem cells and memory T cells in early childhood. J Exp Med 190:157–167. https://doi.org/10.1084/jem.190.2.157
Sampson MJ, Winterbone MS, Hughes JC et al (2006) Monocyte telomere shortening and oxidative DNA damage in type 2 diabetes. Diabetes Care 29:283–289. https://doi.org/10.2337/diacare.29.02.06.dc05-1715
Sanchez-Espiridion B, Chen M, Chang JY et al (2014) Telomere length in peripheral blood leukocytes and lung cancer risk: a large case-control study in caucasians. Cancer Res 74:2476–2486. https://doi.org/10.1158/0008-5472.CAN-13-2968
Sanderson SL, Simon AK (2017) In aged primary T cells, mitochondrial stress contributes to telomere attrition measured by a novel imaging flow cytometry assay. Aging Cell 16:1234–1243. https://doi.org/10.1111/acel.12640
Schönland SO, Lopez C, Widmann T et al (2003) Premature telomeric loss in rheumatoid arthritis is genetically determined and involves both myeloid and lymphoid cell lineages. Proc Natl Acad Sci USA 100:13471–13476. https://doi.org/10.1073/pnas.2233561100
Shankaran V, Ikeda H, Bruce AT et al (2001) IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410:1107–1111. https://doi.org/10.1038/35074122
Shao L, Wood CG, Zhang D et al (2007) Telomere dysfunction in peripheral lymphocytes as a potential predisposition factor for renal cancer. J Urol 178:1492–1496. https://doi.org/10.1016/j.juro.2007.05.112
Shay JW, Bacchetti S (1997) A survey of telomerase activity in human cancer. Eur J Cancer Oxf Engl 33:787–791. https://doi.org/10.1016/S0959-8049(97)00062-2
Shay JW, Wright WE (2019) Telomeres and telomerase: three decades of progress. Nat Rev Genet 20:299–309. https://doi.org/10.1038/s41576-019-0099-1
Strandberg TE, Saijonmaa O, Fyhrquist F et al (2011) Telomere length in old age and cholesterol across the life course. J Am Geriatr Soc 59:1979–1981. https://doi.org/10.1111/j.1532-5415.2011.03610_13.x
Strandberg TE, Strandberg AY, Saijonmaa O et al (2012) Association between alcohol consumption in healthy midlife and telomere length in older men. The Helsinki businessmen study. Eur J Epidemiol 27:815–822. https://doi.org/10.1007/s10654-012-9728-0
Strazhesko ID, Tkacheva ON, Akasheva DU et al (2016) Atorvastatin therapy modulates telomerase activity in patients free of atherosclerotic cardiovascular diseases. Front Pharmacol 7:347. https://doi.org/10.3389/fphar.2016.00347
Victorelli S, Lagnado A, Halim J et al (2019) Senescent human melanocytes drive skin ageing via paracrine telomere dysfunction. EMBO J 38:e101982. https://doi.org/10.15252/embj.2019101982
Vida C, Kobayashi H, Garrido A et al (2019) Lymphoproliferation impairment and oxidative stress in blood cells from early Parkinson’s disease patients. Int J Mol Sci 20:771. https://doi.org/10.3390/ijms20030771
von Zglinicki T (2002) Oxidative stress shortens telomeres. Trends Biochem Sci 27:339–344. https://doi.org/10.1016/s0968-0004(02)02110-2
Wan T, Weir EJ, Johnson M et al (2021) Increased telomerase improves motor function and alpha-synuclein pathology in a transgenic mouse model of Parkinson’s disease associated with enhanced autophagy. Prog Neurobiol 199:101953. https://doi.org/10.1016/j.pneurobio.2020.101953
Weng NP, Levine BL, June CH, Hodes RJ (1995) Human naive and memory T lymphocytes differ in telomeric length and replicative potential. Proc Natl Acad Sci USA 92:11091–11094. https://doi.org/10.1073/pnas.92.24.11091
Weng N-P, Akbar AN, Goronzy J (2009) CD28– T cells: their role in the age-associated decline of immune function. Trends Immunol 30:306–312. https://doi.org/10.1016/j.it.2009.03.013
Wu KD, Hansen ER (2001) Shortened telomere length is demonstrated in T-cell subsets together with a pronounced increased telomerase activity in CD4 positive T cells from blood of patients with mycosis fungoides and parapsoriasis. Exp Dermatol 10:329–336. https://doi.org/10.1034/j.1600-0625.2001.100505.x
Yeh J-K, Wang C-Y (2016) Telomeres and telomerase in cardiovascular diseases. Genes 7:58. https://doi.org/10.3390/genes7090058
Zhang W, Chen Y, Wang Y et al (2013) Short telomere length in blood leucocytes contributes to the presence of atherothrombotic stroke and haemorrhagic stroke and risk of post-stroke death. Clin Sci Lond Engl 1979 125:27–36. https://doi.org/10.1042/CS20120691
Zheng K, Zheng X, Yang W (2022) The role of metabolic dysfunction in T-cell exhaustion during chronic viral Infection. Front Immunol 13:843242. https://doi.org/10.3389/fimmu.2022.843242
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Chebly, A., Khalil, C., Kuzyk, A. et al. T-cell lymphocytes’ aging clock: telomeres, telomerase and aging. Biogerontology 25, 279–288 (2024). https://doi.org/10.1007/s10522-023-10075-6
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DOI: https://doi.org/10.1007/s10522-023-10075-6