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Biomarkers of immunosenescence within an evolutionary perspective: the challenge of heterogeneity and the role of antigenic load
Abstract
Under an evolutionary perspective, antigens can be considered nothing else than chronic stressors that constituted the major selective pressure for immune system emergence and evolution. In this review, recent data are discussed under the hypothesis that human immunosenescence is the consequence of the continuous attrition caused by chronic antigenic overload/stress. The advantage of this theoretical approach is that a unifying hypothesis is proposed, which tries to fill in the current gap between the conceptualizations concerning the mechanisms which counteract aging and favor longevity in invertebrates and vertebrates. The hypothesis is that the immune system is, at a higher level of biological organization and complexity, the counterpart of the anti-stress response network identified in invertebrates as the major determinant of survival. We argue that some of the most important characteristics of immunosenescence, i.e. the accumulation and the clonal expansion of memory and effector T cells, the reduction/exhaustion of naive T cells, and the shrinkage of T cell repertoire, are compatible with this assumption. Thus, immunosenescence can be envisaged as a global reduction of the "immunological space." Concomitantly, immunosenescence results in the progressive generation of cellular mosaicism which is the consequence of the heterogeneous replicative histories and telomere shortening of T and B cell subsets, as well as hemopoietic stem cells. Most of the parameters affected by immunosenescence appear to be under genetic control, and future research on biomarkers should address this point. On the whole, immunosenescence can be taken as a proof that the beneficial effects of the immune system, devoted to the neutralization of dangerous/harmful agents early in life and in adulthood, turn to be detrimental late in life, in a period largely not foreseen by evolution. This perspective fits with basic assumptions of evolutionary theories of aging, such as antagonistic pleiotropy.
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Changes in thymic function with age and during the treatment of HIV infection
Douek, D. C., McFarland, R. D., Keiser, P. H., Gage, E. A., Massey, J. M., Haynes, B. F., Polis, M. A., Haase, A. T., Feinberg, M. B., Sullivan#, J. L., et al. (1998) · Nature · doi:10.1038/25374 · Cited by 1,893
Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly
Harris, T. B., Ferrucci, L., Tracy, R. P., Corti, M. C., Wacholder, S., Ettinger, W. H., Heimovitz, H., Cohen, H. J., & Wallace, R. (1999) · The American Journal of Medicine · doi:10.1016/s0002-9343(99)00066-2 · Cited by 1,488
Longevity, Stress Response, and Cancer in Aging Telomerase-Deficient Mice
Rudolph, K. L., Chang, S., Lee, H.-W., Blasco, M., Gottlieb, G. J., Greider, C., & DePinho, R. A. (1999) · Cell · doi:10.1016/s0092-8674(00)80580-2 · Cited by 1,349
Essential role of mouse telomerase in highly proliferative organs
Lee, H.-W., Blasco, M. A., Gottlieb, G. J., Horner, J. W., Greider, C. W., & DePinho, R. A. (1998) · Nature · doi:10.1038/33345 · Cited by 1,270
Evidence for a mitotic clock in human hematopoietic stem cells: loss of telomeric DNA with age.
Vaziri, H., Dragowska, W., Allsopp, R. C., Thomas, T. E., Harley, C. B., & Lansdorp, P. M. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.21.9857 · Cited by 1,132
Serum IL‐6 Level and the Development of Disability in Older Persons
Ferrucci, L., Harris, T. B., Guralnik, J. M., Tracy, R. P., Corti, M., Cohen, H. J., Penninx, B., Pahor, M., Wallace, R., & Havlik, R. J. (1999) · Journal of the American Geriatrics Society · doi:10.1111/j.1532-5415.1999.tb01583.x · Cited by 809
Genetic determination of telomere size in humans: a twin study of three age groups.
Slagboom, P. E., Droog, S., & Boomsma, D. I. (1994) · PubMed Central · Cited by 734
Rufer, N., Brümmendorf, T. H., Kolvraa, S., Bischoff, C., Christensen, K., Wadsworth, L., Schulzer, M., & Lansdorp, P. M. (1999) · The Journal of Experimental Medicine · doi:10.1084/jem.190.2.157 · Cited by 709
Increased cytokine production in mononuclear cells of healthy elderly people
Fagiolo, U., Cossarizza, A., Scala, E., Fanales‐Belasio, E., Ortolani, C., Cozzi, E., Monti, D., Franceschi, C., & Paganelli, R. (1993) · European Journal of Immunology · doi:10.1002/eji.1830230950 · Cited by 665
Self-citationTersmette, M. (1989) · The Lancet · doi:10.1016/s0140-6736(89)92628-7 · Cited by 576
Research works printed but not linked: 2
- Franceschi, 1978, T and B lymphocyte subpopulations in Down’s syndrome. Study on not-institutionalized subjects, J Ment Defic Res, 22, 179
- Slagboom, 1994, Genetic determination of telomere size in humans, Am J Hum Genet, 55, 876
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BackgroundFranceschi, C., Bonafè, M., & Valensin, S. (2000) · Vaccine · doi:10.1016/s0264-410x(99)00513-7 · Cited by 495
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Giunta, B., Fernandez, F., Nikolic, W. V., Obregon, D., Rrapo, E., Town, T., & Tan, J. (2008) · Journal of Neuroinflammation · doi:10.1186/1742-2094-5-51 · Cited by 327
“This accumulation of a limited repertoire of "megaclones" of effector memory CD8+ T cells results from long-term, chronic exposure to antigens over time frames much longer than during evolution of the human immune system [28,33-39].”
Decreased epigenetic age of PBMCs from Italian semi-supercentenarians and their offspring
Horvath, S., Pirazzini, C., Bacalini, M. G., Gentilini, D., Di Blasio, A. M., Delledonne, M., Mari, D., Arosio, B., Monti, D., Passarino, G., et al. (2015) · Aging · doi:10.18632/aging.100861 · Cited by 316
“A rich literature describes the relationship between blood-based markers and age [8-12] and many genetic studies were devoted to clarify whether exceptional longevity is a highly heritable trait [13-17].”
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“immune function during ageing that involves both the innate and adaptive arms of the immune system, has been termed “immunosenescence” [15].”
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Self-citationOuyang, Q., Wagner, W. M., Wikby, A., Walter, S., Aubert, G., Dodi, A. I., Travers, P. J., & Pawelec, G. (2003) · Journal of Clinical Immunology · doi:10.1023/a:1024580531705 · Cited by 239
“In all these conditions, chronic antigenic stress results in the accumulation of clonal expansions of dysfunctional T cells, characterized by “anergy” and possibly by apoptosis-resistance (28).”
Aging of the immune system: A risk factor for autoimmunity?
Prelog, M. (2005) · Autoimmunity Reviews · doi:10.1016/j.autrev.2005.09.008 · Cited by 223
Naeger, D. M., Martin, J. N., Sinclair, E., Hunt, P. W., Bangsberg, D. R., Hecht, F. M., Hsue, P. Y., McCune, J. M., & Deeks, S. G. (2010) · PLoS ONE · doi:10.1371/journal.pone.0008886 · Cited by 190
“Based on extensive experimental data, a theoretical model has emerged that could provide an mechanistic basis for these observations [39,40,43,44,45,46].”
BackgroundImmunosenescence: Role and measurement in influenza vaccine response among the elderly
Targonski, P. V., Jacobson, R. M., & Poland, G. A. (2007) · Vaccine · doi:10.1016/j.vaccine.2007.01.025 · Cited by 186
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Agelli, M., Clegg, L. X., Becker, J. C., & Rollison, D. E. M. (2010) · Current Problems in Cancer · doi:10.1016/j.currproblcancer.2010.01.001 · Cited by 176
Vescovini, R., Biasini, C., Fagnoni, F. F., Telera, A. R., Zanlari, L., Pedrazzoni, M., Bucci, L., Monti, D., Medici, M. C., Chezzi, C., et al. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.6.4283 · Cited by 173
Self-citationCevenini, E., Caruso, C., Candore, G., Capri, M., Nuzzo, D., Duro, G., Rizzo, C., Colonna‐Romano, G., Lio, D., Carlo, D., et al. (2010) · Current Pharmaceutical Design · doi:10.2174/138161210790883840 · Cited by 168
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“org Clin Cancer Res; 27(2) January 15, 2021 495”
BackgroundInfluentialGoto, M. (2008) · PubMed · Cited by 154
DelaRosa, O., Pawelec, G., Peralbo, E., Wikby, A., Mariani, E., Mocchegiani, E., Tarazona, R., & Solana, R. (2006) · Biogerontology · doi:10.1007/s10522-006-9062-6 · Cited by 150
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Self-citationMonti, D., Salvioli, S., Capri, M., Malorni, W., Straface, E., Cossarizza, A., Botti, B., Piacentini, M., Baggio, G., Barbi, C., et al. (2001) · Mechanisms of Ageing and Development · doi:10.1016/s0047-6374(00)00220-7 · Cited by 86
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Self-citationMaintenance of a healthy trajectory of the intestinal microbiome during aging: A dietary approach
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“…as a icrobial organ’’ of the human body (O’Hara and Shanahan, 06), the IM must be added in the mosaic model of human aging evenini et al., 2008; Franceschi et al., 1999), which describes ing of the human body as a non-homogeneous process where fferent tissues and organs age at different…”
BackgroundComplexity of Anti‐immunosenescence Strategies in Humans
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Self-citationAge as an independent risk factor for severity of experimental choroidal neovascularization.
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Hanson, M. A., Cooper, C. C., Sayer, A. A., Eendebak, R. J. A. H., Clough, G. F., & Beard, J. (2015) · The Journal of Physiology · doi:10.1113/jp270579 · Cited by 85
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Epigenetic regulation of the immune system in health and disease
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“B cell subsets, and thus the antibody repertoire, are altered in specificity, isotype, and idiotype (113, 114).”
Mocchegiani, E., Giacconi, R., Cipriano, C., Muzzioli, M., Gasparini, N., Moresi, R., Stecconi, R., Suzuki, H., Cavalieri, E., & Mariani, E. (2002) · Experimental Gerontology · doi:10.1016/s0531-5565(01)00202-9 · Cited by 76
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Fagnoni, F. F., Lozza, L., Zibera, C., Zambelli, A., Ponchio, L., Gibelli, N., Oliviero, B., Pavesi, L., Gennari, R., Vescovini, R., et al. (2002) · Immunology · doi:10.1046/j.1365-2567.2002.01400.x · Cited by 67
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Heath, J., & Grant, M. D. (2020) · Cells · doi:10.3390/cells9030766 · Cited by 57
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Self-citationIncidental lymphopenia and mortality: a prospective cohort study
Warny, M., Helby, J., Nordestgaard, B. G., Birgens, H., & Bojesen, S. E. (2020) · Canadian Medical Association Journal · doi:10.1503/cmaj.191024 · Cited by 52
“Male sex 1465 (55) 46 145 (45) 986 (38)”
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Xu, K., Chen, J., Kong, X., Qian, W., Mu, F., Lu, T., & Lu, Y. (2020) · Medical Gas Research · doi:10.4103/2045-9912.304221 · Cited by 41
Chmielewski, P. P., Borysławski, K., Chmielowiec, K., Chmielowiec, J., & Strzelec, B. (2015) · Annals of Anatomy - Anatomischer Anzeiger · doi:10.1016/j.aanat.2015.09.002 · Cited by 35
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“[40] Franceschi C, Valensin S, Fagnoni F, Barbi C, Bonafe M.”
BackgroundSelf-citationInflammation, aging, and cancer vaccines
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“T cells, have been proposed as ‘‘hallmarks of immunosenescence’’ in humans (Franceschi et al. 1999).”
BackgroundGarcia-Just, A., Miró, L., Pérez‐Bosque, A., Amat, C., Polo, J., Pallàs, M., Griñán‐Ferré, C., & Moretó, M. (2019) · Journal of Nutrition · doi:10.1093/jn/nxz239 · Cited by 28
Luciani, F., Valensin, S., Vescovini, R., Sansoni, P., Fagnoni, F. F., Franceschi, C., Bonafè, M., & Turchetti, G. (2001) · Journal of Theoretical Biology · doi:10.1006/jtbi.2001.2433 · Cited by 26
“A profound reshaping of all the above mentioned T cell subsets, and consequently of the adaptive clonotypic immunity, is the major characteristic of immunosenescence in humans (Franceschi et al., 1995; Wack et al., 1998; Nociari et al., 1999; Franceschi et al., 1999; Franceschi et al., 2000a).”
BackgroundInfluentialSelf-citationNon-melanoma skin cancers in elderly patients
Perrotta, R. E., Giordano, M., & Malaguarnera, M. (2011) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2011.04.011 · Cited by 25
Geographical Segregation and IL-6: a Marker of Chronic Inflammation in Older Adults
Purser, J. L., Kuchibhatla, M. N., Miranda, M. L., Blazer, D. G., Cohen, H. J., & Fillenbaum, G. G. (2008) · Biomarkers in Medicine · doi:10.2217/17520363.2.4.335 · Cited by 23
“Evolving evidence supports the idea that proinflammatory genetic predisposition plays a role in aging [20], and may also vary by race [23–26].”
BackgroundTranscriptomic biomarkers of human ageing in peripheral blood mononuclear cell total RNA
Vo, T. K. D., Godard, P., de Saint‐Hubert, M., Morrhaye, G., Bauwens, É., Debacq‐Chainiaux, F., Glupczynski, Y., Swine, C., Geenen, V. G., & Martens, H. (2009) · Experimental Gerontology · doi:10.1016/j.exger.2009.12.001 · Cited by 21
Research Progress on Frailty in Elderly People
Liu, X., & Yang, X. (2024) · Clinical Interventions in Aging · doi:10.2147/cia.s474547 · Cited by 23
Satapathy, T., & Kumar, D. (2024) · Pharmacological Research - Modern Chinese Medicine · doi:10.1016/j.prmcm.2024.100499 · Cited by 20
Rodríguez, P. C., Gonzalez, I., Gonzalez, A., Avellanet, J., López, A., Pérez, R., Lage, A., & Montero, E. (2008) · Vaccine · doi:10.1016/j.vaccine.2008.07.003 · Cited by 20
Epstein–Barr virus-positive diffuse large B-cell lymphoma of the elderly
Hong, J. Y., Ko, Y. H., Kim, S. J., & Kim, W. S. (2015) · Current Opinion in Oncology · doi:10.1097/cco.0000000000000210 · Cited by 19
Thymectomy in Early Childhood: A Model for Premature T Cell Immunosenscence?
Zlamy, M., & Prelog, M. (2009) · Rejuvenation Research · doi:10.1089/rej.2009.0864 · Cited by 20
“11,35,36 43 In the elderly, CD4 (cid:2) CD28 (cid”
Alberro, A., Osorio-Querejeta, I., Sepúlveda, L., Fernández‐Eulate, G., Mateo‐Abad, M., Muñoz‐Culla, M., Carregal‐Romero, S., Matheu, A., Vergara, I., de Munaín, A. L., et al. (2019) · Aging · doi:10.18632/aging.102517 · Cited by 21
Proliferation and apoptosis of human T cells during replicative senescence--a critical approach.
Jaruga, E., Skierski, J., Radziszewska, E., & Sikora, E. (2000) · Acta Biochimica Polonica · doi:10.18388/abp.2000_4009 · Cited by 16
“It is also believed that, to a certain extent in vitro senescing reflects the processes in vivo [4].”
BackgroundCD57 T cells associated with immunosenescence in adults living with HIV or AIDS
Júnior, E. E., Gubert, V. T., Jacob, C. M. B., Puga, M. A. M., Gouveia, C. G., Sichinel, Â. H., & Tozetti, I. A. (2023) · Immunology · doi:10.1111/imm.13707 · Cited by 15
“This theory suggests that the beneficial effects of the immune system — which neutralizes potentially harmful agents during early life or adulthood — may become limited in terms of antigen discrimination and recognition capacity at an advanced age [3].”
BackgroundAge-related dynamics of constitutive cytokine transcription levels of feline monocytes
Kipar, A., Baptiste, K. E., Meli, M. L., BARTH, A., Knietsch, M., Reinacher, M., & Lutz, H. (2005) · Experimental Gerontology · doi:10.1016/j.exger.2004.12.007 · Cited by 14
“Since this progressive inflammatory status appears to occur in both ill and healthy older individuals, then it can be regarded as a characteristic of both successful and unsuccessful aging (Franceschi et al., 1999; 2000).”
BackgroundRole of Lipid Rafts in Activation-Induced Cell Death : The Fas Pathway in Aging
Larbi, A., Muti, E., Giacconi, R., Mocchegiani, E., & Fülöp, T. (2007) · Springer eBooks · doi:10.1007/0-387-34132-3_11 · Cited by 14
Kerlikowsky, F., Krüger, K., Hahn, A., & Schuchardt, J. P. (2025) · Nutrition Research · doi:10.1016/j.nutres.2025.06.005 · Cited by 14
Schäefer, A. S., Nibali, L., Zoheir, N., Moutsopoulos, N. M., & Loos, B. G. (2025) · Periodontology 2000 · doi:10.1111/prd.12622 · Cited by 19
Role of the immune system in aging
la Fuente, M. D. (2008) · Inmunología · doi:10.1016/s0213-9626(08)70066-0 · Cited by 12
“In the case of the members of the human species living in developed countries that show considerable increases in their mean life span, they usually suffer the consequences of a very activated immune system during a long period of time (35,70,71,79) .”
IL-1 and senescence: Friends and foe of EGFR neutralization and immunotherapy
Romaniello, D., Gelfo, V., Pagano, F., Sgarzi, M., Morselli, A., Girone, C., Filippini, D. M., D’Uva, G., & Lauriola, M. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.1083743 · Cited by 13
“Firstly introduced by Walford in 1994, immunosenescence, regarding both adaptive and innate immunity, is characterized by a readjustment of the microenvironment composition, including the complex cytokines landscape (Franceschi et al., 1999).”
BackgroundThe Role of Immunotherapy in the First-Line Treatment of Elderly Advanced Non-Small Cell Lung Cancer
Spagnuolo, A., & Gridelli, C. (2023) · Cancers · doi:10.3390/cancers15082319 · Cited by 13
Mariani, L., Turchetti, G., & Franceschi, C. (2003) · Mechanisms of Ageing and Development · doi:10.1016/s0047-6374(03)00022-8 · Cited by 11
“…accompanied by a decrease of virgin antigennon experienced (ANE) T cells (Fagnoni et al., 2000), it is reasonable to hypothesize that such parameters can be assumed bonafide as candidate biomarkers of immunosenescence (Franceschi et al., 1999; Franceschi et al., 2000a; Pawelec et al., 2002a).”
BackgroundSelf-citationAGE, AUTOIMMUNITY, AND INFLAMMATION: THE CURIOUS CASE OF IMMUNOSENESCENCE AND INFLAMM-AGING
Sundaram, T. G., & Ahmed, S. (2022) · Anti-Aging Eastern Europe · doi:10.56543/aaeeu.2022.1.1.04 · Cited by 10
“Studies have shown that there exists a direct relationship between ageing and macrophage inflammation [10].”
Acquired immunity: immunosenescence and physical activity
Malaguarnera, L., Cristaldi, E., Lipari, H. M. A., & Malaguarnera, M. (2008) · European Review of Aging and Physical Activity · doi:10.1007/s11556-008-0039-0 · Cited by 10
“Qualitative changes include shift in the number and activity of B-cell subsets as well as shift in the antibody repertoire with respect to the specificity, isotype, and idiotype [19].”
BackgroundYang, M., Lo, L., Chen, Y., Shiea, J., Wu, P., Tyan, Y., & Jong, Y. (2009) · Rapid Communications in Mass Spectrometry · doi:10.1002/rcm.4241 · Cited by 9
Cellular Stress and Senescence Induction during Trypanosoma cruzi Infection
Pinto, K. G., Ferreira, J. R. M., da Costa, A. L. A., Morrot, A., Freire‐de‐Lima, L., Decotè-Ricardo, D., Freire-de-Lima, C. G., & Filardy, A. A. (2022) · Tropical Medicine and Infectious Disease · doi:10.3390/tropicalmed7070129 · Cited by 9
“Aging also compromises the immune system by reducing its effectiveness, a process called immunosenescence, which causes mild hyperactivity of innate immunity and the decline in adaptive immunity [48,49].”
BackgroundMemory and Selectivity in Evolving Scale-Free Immune Networks
Tieri, P., Valensin, S., Franceschi, C., Morandi, C., & Castellani, G. (2003) · Lecture notes in computer science · doi:10.1007/978-3-540-45192-1_9 · Cited by 9
Self-citationMocchegiani, E., Giacconi, R., Muti, E., Muzzioli, M., & Cipriano, C. (2004) · Neuroimmune biology · doi:10.1016/s1567-7443(04)80004-8 · Cited by 8
Chandrashekharan, S., Chakrabarty, S., Tanwar, M., Madhuvarasu, B., Uduman, M. S., & Ramakrishnan, R. (2022) · Indian Journal of Ophthalmology · doi:10.4103/ijo.ijo_2371_21 · Cited by 7
“Research has shown that there is a direct relationship between advancing age and increased macrophage/lymphocyte activation, which results in a preexisting subclinical inflammatory state.[26,27] This pro‐inflammatory state is further promoted by higher levels of coagulation factors, homocysteine, reactive oxygen speci…”
BackgroundSeasonality as a risk factor for deaths in Parkinson's disease
Fonseca, M. C. M., Sansone, D., Farah, D., FIORINI, A. C., Scorza, C. A., & Scorza, F. A. (2024) · Clinics · doi:10.1016/j.clinsp.2024.100506 · Cited by 7
Metadata
- Authors
- Franceschi, C., Valensin, S., Fagnoni, F., Barbi, C., & Bonafè, M.
- Affiliations
- Istituto Nazionale di Riposo e Cura per Anziani (IT)
- University of Bologna (IT)
- University of Parma (IT)
- Corresponding author
- Franceschi, Claudio
- Venue
- Experimental Gerontology
- Publisher
- Elsevier BV
- Published
- 1999-12
- Volume
- 34
- Issue
- 8
- Pages
- 911-921
- ISSN
- 0531-5565 (ISSN-L)
- OpenAlex
- W1991422276
- Cited by
- 154
- References
- 56
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 6 · 2023: 6 · 2022: 7 · 2021: 5 · 2020: 8 · 2019: 5 · 2018: 6 · 2017: 2 · 2016: 2 · 2015: 8 · 2014: 3 · 2013: 3 · 2012: 6
- FWCI
- 0.60
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Experimental Gerontology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Keywords
- immunosenescence, biomarkers, chronic stress, immune system evolution, T cell exhaustion, T cell receptor repertoire, cellular mosaicism, telomere shortening, hematopoietic stem cells, antagonistic pleiotropy, evolutionary theory of aging, longevity
- MeSH terms
- Aging, Antigens, Biological Evolution, Humans, Immune System, Genetic Variation, Biomarkers
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