The DOI matches its Crossref record; 55 of the 56 references it cites were found in a registry or an index.
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.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Citations
Cites
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
The immunology of exceptional individuals: the lesson of centenarians
Franceschi, C., Monti, D., Sansoni, P., & Cossarizza, A. (1995) · Immunology Today · doi:10.1016/0167-5699(95)80064-6 · Cited by 535
Self-citationInterleukin‐6: A Cytokine for Gerontolgists
Ershler, W. B. (1993) · Journal of the American Geriatrics Society · doi:10.1111/j.1532-5415.1993.tb02054.x · Cited by 475
Disease states associated with telomerase deficiency appear earlier in mice with short telomeres
Herrera, E., Samper, E., Martín‐Caballero, J., Flores, J. M., Lee, H., & Blasco, M. A. (1999) · The EMBO Journal · doi:10.1093/emboj/18.11.2950 · Cited by 471
Genetic control of the CD4/CD8 T-cell ratio in humans
Amadori, A., Zamarchi, R., Silvestro, G. D., Forza, G., Cavatton, G., Danieli, G. A., Clementi, M., & Chieco‐Bianchi, L. (1995) · Nature Medicine · doi:10.1038/nm1295-1279 · Cited by 440
Mitochondrial DNA inherited variants are associated with successful aging and longevity in humans
BENEDICTIS, G. D., Rose, G., Carrieri, G., Luca, M. D., Falcone, E., Passarino, G., Bonafè, M., Monti, D., Baggio, G., Bertolini, S., et al. (1999) · The FASEB Journal · doi:10.1096/fasebj.13.12.1532 · Cited by 390
Self-citationWikby, A., Maxson, P., Olsson, J., Johansson, B. E. A., & Ferguson, F. G. (1998) · Mechanisms of Ageing and Development · doi:10.1016/s0047-6374(97)00151-6 · Cited by 381
Ferguson, F. G., Wikby, A., Maxson, P., Olsson, J., & Johansson, B. (1995) · The Journals of Gerontology Series A · doi:10.1093/gerona/50a.6.b378 · Cited by 378
Expansion of cytotoxic CD8 + CD28 − T cells in healthy ageing people, including centenarians
FAGNONI, F. F., VESCOVINI, R., MAZZOLA, M., BOLOGNA, G., NIGRO, E., LAVAGETTO, G., FRANCESCHI, C., PASSERI, M., & SANSONI, P. (1996) · Immunology · doi:10.1046/j.1365-2567.1996.d01-689.x · Cited by 362
Self-citationPawelec, G. (1998) · Frontiers in bioscience · doi:10.2741/a266 · Cited by 357
Positive correlation between mammalian life span and cellular resistance to stress
Kapahi, P., Boulton, M. E., & Kirkwood, T. B. L. (1999) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(98)00323-2 · Cited by 326
The neuroimmunology of stress from invertebrates to man
Ottaviani, E., & Franceschi, C. (1996) · Progress in Neurobiology · doi:10.1016/0301-0082(95)00049-6 · Cited by 306
Self-citationTelomere lengthening and telomerase activation during human B cell differentiation
Weng, N., Granger, L., & Hodes, R. J. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.20.10827 · Cited by 272
Dynamic Changes in Mouse Hematopoietic Stem Cell Numbers During Aging
de Haan, G., & Van Zant, G. (1999) · Blood · doi:10.1182/blood.v93.10.3294.410k07_3294_3301 · Cited by 208
Posnett, D. N., Edinger, J. W., Manavalan, J. S., Irwin, C., & Marodon, G. (1999) · International Immunology · doi:10.1093/intimm/11.2.229 · Cited by 202
Baggio, G., Donazzan, S., Monti, D., Mari, D., Martini, S., Gabelli, C., Vestra, M. D., Previato, L., Guido, M., Pigozzo, S., et al. (1998) · The FASEB Journal · doi:10.1096/fasebj.12.6.433 · Cited by 178
Self-citationWack, A. (1998) · International Immunology · doi:10.1093/intimm/10.9.1281 · Cited by 173
Ottaviani, E., & Franceschi, C. (1997) · Immunology Today · doi:10.1016/s0167-5699(97)84663-4 · Cited by 169
Self-citationPaganelli, R., Quinti, I., Fagiolo, U., Cossarizza, A., ORTOLANI, C., GUERRA, E., Sansoni, P., Pucillo, L. P., Scala, E., Cozzi, E., et al. (1992) · Clinical & Experimental Immunology · doi:10.1111/j.1365-2249.1992.tb07954.x · Cited by 156
Self-citationFabris, Ν., Amadio, L., Licastro, F., Mocchegiani, E., Zannotti, M., & Franceschi, C. (1984) · The Lancet · doi:10.1016/s0140-6736(84)92325-0 · Cited by 156
Self-citationNociari, M., Telford, W. G., & Russo, C. (1999) · The Journal of Immunology · doi:10.4049/jimmunol.162.6.3327 · Cited by 154
Cytometric analysis of immunosenescence
Cossarizza, A., Ortolani, C., Monti, D., & Franceschi, C. (1997) · Cytometry · doi:10.1002/(sici)1097-0320(19970401)27:4 · Cited by 142
Self-citationT cells and aging (update February 1999)
Pawelec, G. (1999) · Frontiers in bioscience · doi:10.2741/pawelec · Cited by 140
T-cell clonality in immune responses
Maini, M. K., Casorati, G., Dellabona, P., Wack, A., & Beverley, P. C. L. (1999) · Immunology Today · doi:10.1016/s0167-5699(99)01472-3 · Cited by 121
Cossarizza, A., Ortolani, C., Forti, E., Montagnani, G., Paganelli, R., Zannotti, M., Marini, M., Monti, D., & Franceschi, C. (1991) · Blood · doi:10.1182/blood.v77.6.1263.1263 · Cited by 114
Self-citationTelomere Length in Fibroblasts and Blood Cells from Healthy Centenarians
Mondello, C., Petropoulou, C., Monti, D., GONOS, E., Franceschi, C., & Nuzzo, F. (1999) · Experimental Cell Research · doi:10.1006/excr.1999.4398 · Cited by 109
Self-citationTelomere Length, Aging, and Somatic Cell Turnover
Hodes, R. J. (1999) · The Journal of Experimental Medicine · doi:10.1084/jem.190.2.153 · Cited by 108
Bagnara, G. P., Bonsi, L., Strippoli, P., Bonifazi, F., Tonelli, R., D’Addato, S., Paganelli, R., Scala, E., Fagiolo, U., Monti, D., et al. (2000) · The Journals of Gerontology Series A · doi:10.1093/gerona/55.2.b61 · Cited by 100
Self-citationLong-term immunologic effects of thymectomy in patients with myasthenia gravis
Gerli, R., Paganelli, R., Cossarizza, A., Muscat, C., Piccolo, G., Barbieri, D., Mariotti, S., Monti, D., Bistoni, O., Raiola, E., et al. (1999) · Journal of Allergy and Clinical Immunology · doi:10.1016/s0091-6749(99)70431-8 · Cited by 99
Self-citationMolecular mechanisms of yeast longevity
Jazwinski, S. M. (1999) · Trends in Microbiology · doi:10.1016/s0966-842x(99)01509-7 · Cited by 80
Immunosenescence in Humans: Deterioration or Remodelling?
Franceschi, C., Monti, D., Barbieri, D., Grassilli, E., Troiano, L., Salvioli, S., Negro, P., Capri, M., Guido, M., Azzi, R., et al. (1995) · International Reviews of Immunology · doi:10.3109/08830189509056702 · Cited by 74
Self-citationHarley, C. B. (2007) · Novartis Foundation symposium · doi:10.1002/9780470515433.ch9 · Cited by 67
Sansoni, P., Fagnoni, F. F., Vescovini, R., Mazzola, M., Brianti, V., Bologna, G., Nigro, E., Lavagetto, G., Cossarizza, A., Monti, D., et al. (1997) · Mechanisms of Ageing and Development · doi:10.1016/s0047-6374(97)01887-3 · Cited by 59
Self-citationT AND B LYPMHOCYTE SUBPOPULATIONS IN DOWN'S SYNDROME. A STUDY ON NON‐INSTITUTIONALISED SUBJECTS
Franceschi, C., Licastro, F., Paolucci, P., Masi, M., Cavicchi, S., & Zannotti, M. (1978) · Journal of Intellectual Disability Research · doi:10.1111/j.1365-2788.1978.tb00975.x · Cited by 53
Self-citationThe thymus in the age of retirement
Rodewald, H.-R. (1998) · Nature · doi:10.1038/25251 · Cited by 46
Human lymphocyte telomerase is genetically regulated
Kosciolek, B. A., & Rowley, P. T. (1998) · Genes Chromosomes and Cancer · doi:10.1002/(sici)1098-2264(199802)21:2 · Cited by 42
p53 Variants Predisposing to Cancer Are Present in Healthy Centenarians
Bonafè, M., Olivieri, F., Mari, D., Baggio, G., Mattace, R., Sansoni, P., Benedictis, G. D., Luca, M. D., Bertolini, S., Barbi, C., et al. (1999) · The American Journal of Human Genetics · doi:10.1086/302196 · Cited by 42
Self-citationGrowth Properties and Growth Factor Responsiveness in Skin Fibroblasts from Centenarians
Tesco, G., Vergelli, M., Grassilli, E., Salomoni, P., Bellesia, E., Sikora, E., Radziszewska, E., Barbieri, D., Latorraca, S., Fagiolo, U., et al. (1998) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1998.8322 · Cited by 38
Self-citationHeterogeneity of changes in lymphoproliferative ability with increasing age
Murasko, D. M., Nelson, B. J., Matour, D., Goonewardene, I. M., & Kaye, D. (1991) · Experimental Gerontology · doi:10.1016/0531-5565(91)90020-m · Cited by 34
C-Fos/C-Jun Expression and AP-1 Activation in Skin Fibroblasts from Centenarians
Grassilli, E., Bellesia, E., Salomoni, P., Croce, M. A., Sikora, E., Radziszewska, E., Tesco, G., Vergelli, M., Latorraca, S., Barbieri, D., et al. (1996) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1996.1387 · Cited by 30
Self-citationCell Proliferation and Cell Death in Immunosenescencea
Monti, D., Troiano, L., Grassilli, E., AGNESINI, C., Tropea, F., Barbieri, D., Capri, M., Cristofalo, E. A., Salvioli, S., Ronchetti, I. P., et al. (1992) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1992.tb38668.x · Cited by 29
Self-citationAge-related changes in the absolute number of CD95 positive cells in T cell subsets in the blood
Aspinall, R., Carroll, J., & Jiang, S. (1998) · Experimental Gerontology · doi:10.1016/s0531-5565(98)00035-7 · Cited by 28
Stress, inflammation and natural immunity in the aging process: a new theory
Franceschi, C., & Ottaviani, E. (1997) · Aging Clinical and Experimental Research · doi:10.1007/bf03339694 · Cited by 20
Self-citationReff, M. E., & Schneider, E. L. (1981) · Molecular and Cellular Biochemistry · doi:10.1007/bf02357034 · Cited by 15
Franceschi, C., Mondello, C., Bonafè, M., Valensin, S., Sansoni, P., & Sorbi, S. (1999) · Aging Clinical and Experimental Research · doi:10.1007/bf03399643 · Cited by 15
Self-citationCell culture aging: Insights for cell aging in vivo?
Cristofalo, V. J. (1999) · Aging Clinical and Experimental Research · doi:10.1007/bf03399629 · Cited by 13
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
Cited by
Sorted by citations
Inflamm‐aging: An Evolutionary Perspective on Immunosenescence
FRANCESCHI, C., BONAFÈ, M., VALENSIN, S., OLIVIERI, F., DE LUCA, M., OTTAVIANI, E., & DE BENEDICTIS, G. (2000) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2000.tb06651.x · Cited by 5,358
Self-citationInflammation and immune dysfunction in Parkinson disease
Tansey, M. G., Wallings, R. L., Houser, M. C., Herrick, M. K., Keating, C. E., & Joers, V. (2022) · Nature Reviews Immunology · doi:10.1038/s41577-022-00684-6 · Cited by 1,382
Immune activation and inflammation in HIV‐1 infection: causes and consequences
Appay, V., & Sauce, D. (2007) · The Journal of Pathology · doi:10.1002/path.2276 · Cited by 780
“Paradoxically, it represents the main determinant of the most common age-related diseases and a major determinant of the ageing rate [126].”
BackgroundFranceschi, C., Bonafè, M., & Valensin, S. (2000) · Vaccine · doi:10.1016/s0264-410x(99)00513-7 · Cited by 495
Self-citationInflamm‐ageing and lifelong antigenic load as major determinants of ageing rate and longevity
Martinis, M. D., Franceschi, C., Monti, D., & Ginaldi, L. (2005) · FEBS Letters · doi:10.1016/j.febslet.2005.02.055 · Cited by 495
“An exhaustion of naive T cells occurs in centenarians [32].”
BackgroundSelf-citation
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
About these checks
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review