Cited by 1,165T-cell and B-cell ImmunologyGenetics, Aging, and Longevity in Model OrganismsTelomeres, Telomerase, and Senescence

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The Aging Immune System: Primer and Prospectus

Miller, Richard A.·1996·Science

DOI 10.1126/science.273.5271.70

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Abstract

Changes in T lymphocyte populations underlie much of the age-related decline in the protective immune response. Aging leads to the replacement of virgin T cells by memory T cells and to the accumulation of cells with signal transduction defects. Studies of antibody gene assembly, accessory cell function, post-thymic T cell development, skewed selection of T cell receptor repertoire, and the clinical concomitants of immune senescence will shed new light on the causes and consequences of age-dependent immune failure.

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Wolf, N. S., & Pendergrass, W. (1999) · The Journals of Gerontology Series A · doi:10.1093/gerona/54.11.b502 · Cited by 37
AGE AND CALORIC RESTRICTION DIETS ARE CONFOUNDING FACTORS THAT MODIFY THE RESPONSE TO LIPOPOLYSACCHARIDE BY PERITONEAL MACROPHAGES IN C57BL/6 MICE
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The Effect of Influenza Vaccination for the Elderly on Hospitalization and Mortality
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Repeated In Vivo Stimulation of T and B Cell Responses in Old Mice Generates Protective Immunity against Lethal West Nile Virus Encephalitis
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Immune parameters in patients with anxiety or depression during psychotherapy
Atanackovic, D., Kröger, H., Serke, S., & Deter, H. (2003) · Journal of Affective Disorders · doi:10.1016/s0165-0327(03)00165-4 · Cited by 37
Local immune response to respiratory syncytial virus infection is diminished in senescence-accelerated mice
Liu, B., & Kimura, Y. (2007) · Journal of General Virology · doi:10.1099/vir.0.83089-0 · Cited by 35
“Agerelated immune dysregulation (Miller, 1996; Boukhvalova et al., 2007) seems likely to be the most important factor in association with infectious diseases.”
Background
T‐cell development: an extrathymic perspective
Blais, M., Louis, I., & Perreault, C. (2006) · Immunological Reviews · doi:10.1111/j.0105-2896.2006.00341.x · Cited by 38
Senescent BALB/c Mice Are Able To Develop Resistance toLeishmania majorInfection
Ehrchen, J. M., Sindrilaru, A., Grabbe, S., Schönlau, F., Schlesiger, C., Sorg, C., Scharffetter‐Kochanek, K., & Sunderkötter, C. H. (2004) · Infection and Immunity · doi:10.1128/iai.72.9.5106-5114.2004 · Cited by 38
“Thus, resistance remained unharmed in senescent C57BL/6 mice in spite of the various deficiencies which have been reported to take place in the general immune response during aging (12, 23, 26).”
Background
Regulation of transcription factor NF KAPPA B in immune senescence
Ponnappan, U. (1998) · Frontiers in bioscience · doi:10.2741/a271 · Cited by 37
WITHDRAWN: Oxidative stress in aging: Theoretical outcomes and clinical evidences in humans
del Valle, L. G. (2010) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2010.09.010 · Cited by 36
Retracted
Evaluation of lymphocyte levels in a random sample of 218 elderly individuals from São Paulo city
Teixeira, D., Longo‐Maugéri, I. M., Santos, J. L. F., Duarte, Y. A. O., Lebrão, M. L., & Bueno, V. (2011) · Revista Brasileira de Hematologia e Hemoterapia · doi:10.5581/1516-8484.20110100 · Cited by 36
“In addition, the contribution of this system to longevity and healthy aging remains unknown.(6-8) Subclinical pathogenic infections, which are very common in the elderly, cause persistent inflammation and thus contribute to tumor development, heart attacks and strokes.”
Background
The Role of EBV in the Pathogenesis of Diffuse Large B Cell Lymphoma
Healy, J. A., & Davé, S. S. (2015) · Current topics in microbiology and immunology · doi:10.1007/978-3-319-22822-8_13 · Cited by 36
“It is presently unclear whether elderly patients can be truly considered immune competent, and thus distinct from other EBV-positive DLBCL subtypes, or whether the EBV reactivation in these patients is due to age-related T cell dysfunction (Miller 1996).”
Background
Modeling immune response and its effect on infectious disease outbreak dynamics
Silveyra, J., & Mikler, A. R. (2016) · Theoretical Biology and Medical Modelling · doi:10.1186/s12976-016-0033-6 · Cited by 38
“This factor was selected given its importance is highlighted in multiple studies [34–37].”
Background
Thiazolidinedione treatment and constitutive‐PPARγ activation induces ectopic adipogenesis and promotes age‐related thymic involution
Youm, Y., Yang, H., Amin, R., Smith, S. R., Leff, T., & Dixit, V. D. (2010) · Aging Cell · doi:10.1111/j.1474-9726.2010.00574.x · Cited by 37
“…aging thymus to replenish the pool of naı̈ve T cells is linked to restriction of T cell receptor (TCR) diversity in elderly with increased risk of infections, vaccination failures and reduced immune-surveillance (Miller, 1996; Nikolich-Zugich et al., 2004; Naylor et al., 2005; Swain et al., 2005).”
Influential
Severe Impairment of Primary but Not Memory Responses to Influenza Viral Antigens in Aged Mice: Costimulation in Vivo Partially Reverses Impaired Primary Immune Responses
Sambhara, S. R., Kurichh, A., Miranda, R., James, O., Underdown, B. J., Klein, M. C. A., Tartaglia, J., & Burt, D. S. (2001) · Cellular Immunology · doi:10.1006/cimm.2001.1799 · Cited by 36
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“Several studies, however, have defined age-dependent alterations in immunity, including: (1) deficits in T cell function [7, 8], including defective generation of longlasting memory responses after immunization [9]; (2) reduced generation of high-affinity antibodies [7, 10] in the face of elevated total antibody level…”
BackgroundInfluential
Age increases vulnerability to bacterial endotoxin-induced behavioral decrements
Kohman, R. A., Tarr, A. J., Byler, S. L., & Boehm, G. W. (2007) · Physiology & Behavior · doi:10.1016/j.physbeh.2007.03.032 · Cited by 36
Age-Related Changes in Major Lymphocyte Subsets in Cynomolgus Monkeys.
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Age-associated parallel increase of Foxp3+CD4+ regulatory and CD44+CD4+ memory T cells in SJL/J mice
Han, G.-M., Zhao, B., Jeyaseelan, S., & Feng, J.-M. (2009) · Cellular Immunology · doi:10.1016/j.cellimm.2009.05.003 · Cited by 35
“One of the reasons for this is that aging-related thymic involution would dramatically reduce rather than increase the total output of all new T cells, which has long been considered the most reasonable cause of the age-related decline in T cell function [31-34].”
Contribution of viral and bacterial infections to senescence and immunosenescence
Reyes, A., Ortiz, G., Duarte, L. F., Fernández, C., Hernández‐Armengol, R., Palacios, P. A., Prado, Y., Andrade, C. A., Rodríguez‐Guilarte, L., Kalergis, A. M., et al. (2023) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2023.1229098 · Cited by 38
“T cells in old age have also been identi ﬁ ed in patients with chronic infections, such as with the HIV (Miller, 1996; Akbar and Fletcher, 2005).”
BackgroundInfluential
Growth hormone in T-lymphocyte thymic and postthymic development: A study in HIV-infected children
Viganò, M., Saresella, M., Trabattoni, D., Giacomet, V., di Natale, B., Merlo, M., Venuto, A., Villa, M. L., Vanzulli, S., Ferrante, P., et al. (2004) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2004.06.027 · Cited by 32
Live Attenuated Leishmania donovani Centrin Knock Out Parasites Generate Non-inferior Protective Immune Response in Aged Mice against Visceral Leishmaniasis
Bhattacharya, P., Dey, R., Dagur, P. K., Joshi, A. B., Ismail, N., Gannavaram, S., Debrabant, A., Akue, A. D., KuKuruga, M. A., Selvapandiyan, A., et al. (2016) · PLoS neglected tropical diseases · doi:10.1371/journal.pntd.0004963 · Cited by 34
“Of note, when compared to young mice, the induction of nitrite concentration and IgG2a titer level was significantly lower in aged mice from all the groups which is in agreement with other studies [15, 75] and corroborate with the diminished protection in aged mice.”
BackgroundResultInfluential
Immunotherapy with Listeria reduces metastatic breast cancer in young and old mice through different mechanisms
Jahangir, A., Chandra, D., Quispe‐Tintaya, W., Singh, M., Selvanesan, B. C., & Gravekamp, C. (2017) · OncoImmunology · doi:10.1080/2162402x.2017.1342025 · Cited by 35
Unraveling the Molecular Mechanism of Immunosenescence in Drosophila
Min, K., & Tatar, M. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19092472 · Cited by 33
“Extensive research has been undertaken to elucidate how changes in adaptive immunity contribute to such aging [1,2].”
Background
Interleukin-6 and interleukin-10 are expressed in organs of normal young and old mice.
Hacham, M., White, R. M., Argov, S., Segal, S., & Apte, R. N. (2004) · PubMed · Cited by 35
New Epidemiological and Clinical Signatures of 18 Pathogens from Respiratory Tract Infections Based on a 5-Year Study
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“On a related note, different behavioral habits, environments, and degrees of immunity are experienced at different ages [16].”
Background
A Subset of CD8 Memory T Cells from Old Mice Have High Levels of CD28 and Produce IFN-γ
Ortiz-Suárez, A., & Miller, R. A. (2002) · Clinical Immunology · doi:10.1006/clim.2002.5221 · Cited by 35
Self-citation
Immunosenescence and vaccination of the elderly I. Age-related immune impairment
Ongrádi, J., Stercz, B., Kövesdi, V., & Vértes, L. (2009) · Acta Microbiologica et Immunologica Hungarica · doi:10.1556/amicr.56.2009.3.1 · Cited by 35
“This results in the loss of naive B cells and an increase in memory cells with age [21, 22] dampening an individual’s ability to respond to novel antigens as they age.”
Background
Regulation of Extrathymic T Cell Development and Turnover by Oncostatin M
Boileau, C., Houde, M., Dulude, G., Clegg, C. H., & Perreault, C. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.164.11.5713 · Cited by 35
“Changes in T lymphocyte function underlie much of the age-related decline in protective immune responses (1).”
Background

Authors: Miller, R. A.
Affiliations: University of Michigan (US)
Corresponding author: Miller, Richard A.
ORCID: Miller, Richard A.
Venue: Science
Publisher: American Association for the Advancement of Science (AAAS)
Published: 1996-07-05
Volume: 273
Issue: 5271
Pages: 70-74
ISSN: 0036-8075 (ISSN-L)
1095-9203
DOI: 10.1126/science.273.5271.70
OpenAlex: W2043464691
Cited by: 1,165
References: 71
Citations by year: 2026: 7 · 2025: 7 · 2024: 15 · 2023: 19 · 2022: 9 · 2021: 22 · 2020: 34 · 2019: 25 · 2018: 33 · 2017: 32 · 2016: 24 · 2015: 31 · 2014: 26 · 2013: 40 · 2012: 35
FWCI: 5.20
Type: journal article
Language: en
Open access: closed
Locations: Science (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, aging, T cells, memory T cells, T cell receptor repertoire, signal transduction defects, accessory cell function, age-related immune decline
MeSH terms: Aged, Aged, 80 and over, Aging, Animals, Antibody Formation, Antigen-Presenting Cells, B-Lymphocytes, Cytotoxicity, Immunologic, Disease Susceptibility, Humans, Immune System, Immunologic Memory, Killer Cells, Natural, Longevity, Receptors, Antigen, T-Cell, T-Lymphocytes

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