Understanding immunosenescence to improve responses to vaccines

Goronzy, Jörg J; Weyand, Cornelia M

doi:10.1038/ni.2588

Cited by 841T-cell and B-cell ImmunologyImmune responses and vaccinationsImmunotherapy and Immune Responses

Understanding immunosenescence to improve responses to vaccines

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Goronzy, Jörg J, Weyand, Cornelia M·2013·Nature Immunology

DOI 10.1038/ni.2588PMC PMC4183346

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Abstract

In the older adult, the benefits of vaccination to prevent infectious disease are limited, mainly because of the adaptive immune system's inability to generate protective immunity. The age-dependent decrease in immunological competence, often referred to as 'immunosenescence', results from the progressive deterioration of innate and adaptive immune responses. Most insights into mechanisms of immunological aging have been derived from studies of mouse models. In this Review, we explore how well such models are applicable to understanding the aging process throughout the 80-100 years of human life and discuss recent advances in identifying and characterizing the mechanisms that underlie age-associated defective adaptive immunity in humans.

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In these models, accelerated aging depends, at least partly, on cellular senescence.
“These and other models, for which it has been shown that accelerated aging depends, at least partly, on cellular senescence, are valuable for studying the impact of senescence on health and lifespan”
From Guidelines for minimal information on cellular senescence experimentation in vivo (2024) · cites this paper as [100]
The Abstract (page not provided) says immune senescence is only partially explained by organismal and cellular senescence. But the paper does not establish that accelerated aging in the models mentioned by the citing sentence depends on cellular senescence; its discussion of models concerns accelerated immune aging, not aging or lifespan generally. (LLM, conf=0.83)
Experimental — accuracy not yet measured
Mouse models of rapid telomere shortening, dysfunctional mitosis, or impaired DNA repair (Terc, BubR1, and Ercc1 mutant mice, respectively) display high levels of cellular senescence and accelerated aging.
“Mouse models of rapid telomere shortening, dysfunctional mitosis or impaired DNA repair (Terc, BubR1, and Ercc1 mutant mice, respectively), display high levels of cellular senescence and accelerated aging86,99,100.”
From Guidelines for minimal information on cellular senescence experimentation in vivo (2024) · cites this paper as [100]
The “Immune Aging Concepts – From Mice to Men” section discusses telomere shortening and DNA repair in immune aging, but does not report outcomes for Terc, BubR1, or Ercc1 mutant mice. Searches for those mutants and for accelerated aging in the models found no passage establishing the claimed high cellular senescence or accelerated aging. (LLM, conf=0.76)
Experimental — accuracy not yet measured
Waning adaptive immunity begins in mid adulthood, around age 50, and becomes clinically more relevant in the 7th-10th decades.
“Evidence of waning adaptive immunity is already apparent in mid adulthood, as early as at the age of 50 years, with increasing clinical relevance in the 7th–10th decade of life”
From Successful and Maladaptive T Cell Aging (2017) · cites this paper as Goronzy and Weyand, 2013
Immunosenescence is only partially explained by organismal and cellular senescence.
“Mechanistically, immunosenescence is only partially explained by organismal and cellular senescence.”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [23]
These hallmarks of immunosenescence would be markedly affected by the history of the individual exposure to pathogens.
“Therefore, these hallmarks of immunosenescence would be markedly affected by the history of the individual exposure to pathogens (6, 23).”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [23]

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Defective proliferative capacity and accelerated telomeric loss of hematopoietic progenitor cells in rheumatoid arthritis.
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B cell repertoire and ageing
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Signal inhibition by the dual-specific phosphatase 4 impairs T cell-dependent B-cell responses with age
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Immune Aging and Rheumatoid Arthritis
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Chronic inflammation and aging: DNA damage tips the balance
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Acquired hematopoietic stem cell defects determine B-cell repertoire changes associated with aging
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Hepatitis-B Vaccination in the Elderly
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Lifelong Persistent Viral Infection Alters the Naive T Cell Pool, Impairing CD8 T Cell Immunity in Late Life
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DNA-dependent protein kinase catalytic subunit mediates T-cell loss in rheumatoid arthritis.
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Impact of immune-metabolic interactions on age-related thymic demise and T cell senescence
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Insufficient recovery of thymopoiesis predicts for opportunistic infections in allogeneic hematopoietic stem cell transplant recipients
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Ageing and immunity
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Immune responses in the skin in old age
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Estimating Influenza Vaccine Effectiveness in Community-Dwelling Elderly Patients Using the Instrumental Variable Analysis Method
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Decline in excision circles requires homeostatic renewal or homeostatic death of naive T cells
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Why does the thymus involute? A selection-based hypothesis
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Decreased STAT 5 phosphorylation and GATA ‐3 expression in NOX 2‐deficient T cells: Role in T helper development
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Translational research in immune senescence: Assessing the relevance of current models
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Age-Dependent Signature of Metallothionein Expression in Primary CD4 T Cell Responses Is Due to Sustained Zinc Signaling
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Functional CD8 T Cell Memory Responding to Persistent Latent Infection Is Maintained for Life
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Report of the ad-hoc consultation on aging and immunization for a future WHO research agenda on life-course immunization
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Immunology Taught by Humans
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Age-related Deficiencies in Antigen-Specific CD4 T cell Responses: Lessons from Mouse Models.
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Tumor suppressor mechanisms in immune aging
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Aging impairs murine B cell differentiation and function in primary and secondary lymphoid tissues.
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Genetic Regulation of Thymocyte Progenitor Aging
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DNA-Damage-Induced Differentiation in Hematopoietic Stem Cells
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T cells from elderly persons respond to neoantigenic stimulation with an unimpaired IL-2 production and an enhanced differentiation into effector cells
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The role of adjuvants in vaccines for seasonal and pandemic influenza
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Finding Balance: T cell Regulatory Receptor Expression during Aging.
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A single-cell transcriptomic atlas characterizes ageing tissues in the mouse
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Hyperprogressive Disease Is a New Pattern of Progression in Cancer Patients Treated by Anti-PD-1/PD-L1
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“This may be explained by a different immunological background in older patients such as modification of T-cell costimulatory/co-inhibitory proteins expression or higher concentrations of inflammatory cytokines (20, 21).”
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Resistance Mechanisms to Immune-Checkpoint Blockade in Cancer: Tumor-Intrinsic and -Extrinsic Factors
Pitt, J. M., Vétizou, M., Daillère, R., Roberti, M. P., Yamazaki, T., Routy, B., Lepage, P., Boneca, I. G., Chamaillard, M., Kroemer, G., et al. (2016) · Immunity · doi:10.1016/j.immuni.2016.06.001 · Cited by 1,040 · see citing works
“For example, segmented filamentous bacteria (SFB) are potent inducers of Th17 and Th1 cells in the small intestine (Goto et al., 2014; Ivanov et al., 2009).”
An aged immune system drives senescence and ageing of solid organs
Yousefzadeh, M. J., Flores, R. R., Zhu, Y., Schmiechen, Z. C., Brooks, R. W., Trussoni, C. E., Cui, Y., Angelini, L., Lee, K.-A., McGowan, S. J., et al. (2021) · Nature · doi:10.1038/s41586-021-03547-7 · Cited by 972 · see citing works
Immunosenescence: molecular mechanisms and diseases
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Human memory T cells: generation, compartmentalization and homeostasis
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Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention
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“Therefore, these hallmarks of immunosenescence would be markedly affected by the history of the individual exposure to pathogens (6, 23).”
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Frailty and sarcopenia: The potential role of an aged immune system
Wilson, D., Jackson, T., Sapey, E., & Lord, J. M. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2017.01.006 · Cited by 573 · see citing works
Sexual-dimorphism in human immune system aging
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A clinically meaningful metric of immune age derived from high-dimensional longitudinal monitoring
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Aging of the Immune System. Mechanisms and Therapeutic Targets
Weyand, C. M., & Goronzy, J. J. (2016) · Annals of the American Thoracic Society · doi:10.1513/annalsats.201602-095aw · Cited by 554 · see citing works
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Immunosenescence: a key player in cancer development
Lian, J., Yue, Y., Yu, W., & Zhang, Y. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00986-z · Cited by 510 · see citing works
Merkel cell carcinoma: Current US incidence and projected increases based on changing demographics
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The Effect of Age on Thymic Function
Palmer, D. B. (2013) · Frontiers in Immunology · doi:10.3389/fimmu.2013.00316 · Cited by 494 · see citing works
“Moreover, it is these age-related changes in peripheral T cells that are believed to contribute significantly toward the features of immunosenescence (12, 13), suggesting that the altered thymic activity is a key trigger toward the decline of immune function in the aged (14).”
Background
Nonlinear dynamics of multi-omics profiles during human aging
Shen, X., Wang, C., Zhou, X., Zhou, W., Hornburg, D., Wu, S., & Snyder, M. P. (2024) · Nature Aging · doi:10.1038/s43587-024-00692-2 · Cited by 500 · see citing works
Vaccination in the elderly: The challenge of immune changes with aging
Ciabattini, A., Nardini, C., Santoro, F., Garagnani, P., Franceschi, C., & Medaglini, D. (2018) · Seminars in Immunology · doi:10.1016/j.smim.2018.10.010 · Cited by 411 · see citing works
The aging gut microbiome and its impact on host immunity
Bosco, N., & Noti, M. (2021) · Genes and Immunity · doi:10.1038/s41435-021-00126-8 · Cited by 418 · see citing works
Successful and Maladaptive T Cell Aging
Goronzy, J. J., & Weyand, C. M. (2017) · Immunity · doi:10.1016/j.immuni.2017.03.010 · Cited by 362 · see citing works
“Evidence of waning adaptive immunity is already apparent in mid adulthood, as early as at the age of 50 years, with increasing clinical relevance in the 7th–10th decade of life (Goronzy and Weyand, 2013; Montecino-Rodriguez et al., 2013; Pinti et al., 2016).”
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Aging and the immune system: An overview
Akha, A. A. S. (2018) · Journal of Immunological Methods · doi:10.1016/j.jim.2018.08.005 · Cited by 389 · see citing works
Aging increases cell-to-cell transcriptional variability upon immune stimulation
Martinez-Jimenez, C. P., Eling, N., Chen, H.-C., Vallejos, C. A., Kolodziejczyk, A. A., Connor, F., Stojic, L., Rayner, T. F., Stubbington, M. J. T., Teichmann, S. A., et al. (2017) · Science · doi:10.1126/science.aah4115 · Cited by 339 · see citing works
“The discovery that CD4+ T cells from aged mice are less able to robustly up-regulate a core activation program may in part explain the aging associated decrease of immune function observed across mammals (21).”
Background
Immunosenescence: Implications for response to infection and vaccination in older people
Pera, A., Campos, C., López, N., Hassouneh, F., Alonso, C., Tarazona, R., & Solana, R. (2015) · Maturitas · doi:10.1016/j.maturitas.2015.05.004 · Cited by 373 · see citing works
Guidelines for minimal information on cellular senescence experimentation in vivo
Ogrodnik, M., Carlos Acosta, J., Adams, P. D., d’Adda di Fagagna, F., Baker, D. J., Bishop, C. L., Chandra, T., Collado, M., Gil, J., Gorgoulis, V., et al. (2024) · Cell · doi:10.1016/j.cell.2024.05.059 · Cited by 376 · see citing works
Naive T Cell Maintenance and Function in Human Aging
Goronzy, J. J., Fang, F., Cavanagh, M., Qi, Q., & Weyand, C. M. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1500046 · Cited by 348 · see citing works
Self-citation
Phosphofructokinase deficiency impairs ATP generation, autophagy, and redox balance in rheumatoid arthritis T cells
Yang, Z., Fujii, H., Mohan, S. V., Goronzy, J. J., & Weyand, C. M. (2013) · Journal of Experimental Medicine · doi:10.1084/jem.20130252 · Cited by 334 · see citing works
“In con trast, lymphopenia has been implicated in triggering auto immunity, possibly through the selection of autoreactive T cell clones in a host that favors autoproliferation to fill an empty space (King et al., 2004; Goronzy and Weyand, 2012, 2013).”
BackgroundSelf-citation
Regulatory T Cells and the Immune Aging Process: A Mini-Review
Jagger, A., Shimojima, Y., Goronzy, J. J., & Weyand, C. M. (2014) · Gerontology · doi:10.1159/000355303 · Cited by 301 · see citing works
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The state of complement in COVID-19
Afzali, B., Noris, M., Lambrecht, B. N., & Kemper, C. (2021) · Nature reviews. Immunology · doi:10.1038/s41577-021-00665-1 · Cited by 290 · see citing works
Immunometabolism in early and late stages of rheumatoid arthritis
Weyand, C. M., & Goronzy, J. J. (2017) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2017.49 · Cited by 296 · see citing works
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Back to the Future: Lessons Learned From the 1918 Influenza Pandemic
Short, K. R., Kedzierska, K., & van de Sandt, C. E. (2018) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2018.00343 · Cited by 279 · see citing works
Immune cells and inflammation in AKI to CKD progression
Sato, Y., & Yanagita, M. (2018) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00195.2018 · Cited by 273 · see citing works
“The former low-grade systemic chronic inflammation with aging has been termed “inflammaging” (41), while the decline in immune function that occurs in the elderly, which leads to several immunological impairment, has been globally termed “immunosenescence” (49), both of which are tightly interconnected and are postula…”
Background
Human T cell immunosenescence and inflammation in aging
Bektas, A., Schurman, S. H., Sen, R., & Ferrucci, L. (2017) · Journal of Leukocyte Biology · doi:10.1189/jlb.3ri0716-335r · Cited by 270 · see citing works
“mortality from infections increase [61], and response to immunologic challenges, such as flu vaccination, is lessened [59, 61, 62].”
Background
Effects of sex and aging on the immune cell landscape as assessed by single-cell transcriptomic analysis
Huang, Z., Chen, B., Liu, X., Li, H., Xie, L., Gao, Y., Duan, R., Li, Z., Zhang, J., Zheng, Y., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2023216118 · Cited by 247 · see citing works
Epigenomics of human CD8 T cell differentiation and aging
Moskowitz, D. M., Zhang, D. W., Hu, B., Le Saux, S., Yanes, R. E., Ye, Z., Buenrostro, J. D., Weyand, C. M., Greenleaf, W. J., & Goronzy, J. J. (2017) · Science Immunology · doi:10.1126/sciimmunol.aag0192 · Cited by 252 · see citing works
“Much of this decline has been attributed to a breakdown in T cell homeostasis, degrading the competence of the central mediator of adaptive immunity (3, 4).”
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Macrophages in age-related chronic inflammatory diseases
Oishi, Y., & Manabe, I. (2016) · npj Aging and Mechanisms of Disease · doi:10.1038/npjamd.2016.18 · Cited by 262 · see citing works
“Elderly HSCs exhibit less potential to produce lymphocytes and an increase in myeloid potential.(6) Distinct HSC subsets having lymphoid- or myeloid-biased potential have been identified,(12) and while the number of lymphoid-biased HSCs declines with age, myeloid-biased HSCs are increased.”
Background
Aging and the Immune System: the Impact of Immunosenescence on Viral Infection, Immunity and Vaccine Immunogenicity
Oh, S. J., Lee, J. K., & Shin, O. S. (2019) · Immune Network · doi:10.4110/in.2019.19.e37 · Cited by 261 · see citing works
“The efficacy and effectiveness of influenza vaccines decrease with age due to the detrimental impact of aging on the immune system's ability to function (6).”
BackgroundInfluential
Jasmonate response decay and defense metabolite accumulation contributes to age-regulated dynamics of plant insect resistance
Mao, Y., Liu, Y.-Q., Chen, D.-Y., Chen, F., Fang, X., Hong, G., Wang, L.-J., Wang, J., & Chen, X. (2017) · Nature Communications · doi:10.1038/ncomms13925 · Cited by 256 · see citing works
Soluble Urokinase Plasminogen Activator Receptor (suPAR) as a Biomarker of Systemic Chronic Inflammation
Rasmussen, L. J. H., Petersen, J. E. V., & Eugen‐Olsen, J. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.780641 · Cited by 256 · see citing works
Chaperone-mediated autophagy regulates T cell responses through targeted degradation of negative regulators of T cell activation
Valdor, R., Mocholi, E., Botbol, Y., Guerrero-Ros, I., Chandra, D., Koga, H., Gravekamp, C., Cuervo, A. M., & Macian, F. (2014) · Nature Immunology · doi:10.1038/ni.3003 · Cited by 244 · see citing works
Senescent cells: SASPected drivers of age-related pathologies
Ovadya, Y., & Krizhanovsky, V. (2014) · Biogerontology · doi:10.1007/s10522-014-9529-9 · Cited by 232 · see citing works
“Impaired surveillance of senescent cells in advanced age A growing bulk of evidence indicates that the immune system is highly susceptible to age (Goronzy and Weyand 2013; Hazeldine and Lord 2013; Herndler- Biogerontology (2014) 15:627–642 631 Brandstetter et al. 2011; Shaw et al. 2013).”
Background
A time-resolved proteomic and prognostic map of COVID-19
Demichev, V., Tober-Lau, P., Lemke, O., Nazarenko, T., Thibeault, C., Whitwell, H., Röhl, A., Freiwald, A., Szyrwiel, L., Ludwig, D., et al. (2021) · Cell Systems · doi:10.1016/j.cels.2021.05.005 · Cited by 200 · see citing works
Immunosenescence Study of T Cells: A Systematic Review
Rodríguez, I. J., Lalinde-Ruiz, N., León, M. L., Martínez-Enriquez, L. C., Velásquez, M. D. P. M., Aguirre, J. P. O., Bohórquez, O. M. R., Vargas, E. A. V., Hernández-Álvarez, E. D., & Parra-López, C. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.604591 · Cited by 224 · see citing works
“To classify the data, four categories were defined: (1) memory subsets, (2) senescence and exhaustion-associated markers, (3) cytokines, and (4) telomere length.”
BackgroundMethod
From discovery to licensure, the Adjuvant System story
Garçon, N., & Pasquale, A. D. (2016) · Human Vaccines & Immunotherapeutics · doi:10.1080/21645515.2016.1225635 · Cited by 217 · see citing works
“dysfunctional; most commonly due to immune senescence associated with aging or immune suppression.(81) Reduced T-cell”
Background
Progress and prospects of mRNA-based drugs in pre-clinical and clinical applications
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Immunosenescence: signaling pathways, diseases and therapeutic targets
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SARS-CoV-2 and COVID-19: A genetic, epidemiological, and evolutionary perspective
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“…to experience many alterations, including an increase in suppressive immune cell populations, such as MDSCs and Treg cells (Pawelec et al, 2010; Goronzy and Weyand, 2013), and MDSCs have been reported as potential predictors of resistance to ipilimumab therapy (Meyer et al, 2014; Martens et…”
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Authors: Goronzy, J. J., & Weyand, C. M.
Affiliations: Stanford Medicine (US)
VA Palo Alto Health Care System (US)
Corresponding author: Goronzy, Jörg J
ORCID: Goronzy, Jörg J
Weyand, Cornelia M
Venue: Nature Immunology
Publisher: Springer Science and Business Media LLC
Published: 2013-04-18
Volume: 14
Issue: 5
Pages: 428-436
ISSN: 1529-2908 (ISSN-L)
1529-2916
DOI: 10.1038/ni.2588
PMC: PMC4183346
OpenAlex: W1992431343
Cited by: 827
References: 115
Citations by year: 2026: 66 · 2025: 62 · 2024: 89 · 2023: 76 · 2022: 61 · 2021: 83 · 2020: 58 · 2019: 68 · 2018: 46 · 2017: 59 · 2016: 53 · 2015: 53 · 2014: 38 · 2013: 15
FWCI: 4.65
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
Locations: Nature Immunology (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health
National Heart, Lung, and Blood Institute (P01HL058000, R01HL117913)
National Eye Institute (R01EY011916)
National Institute of Allergy and Infectious Diseases (R01AI044142, U01AI089859, R01AI44142, R01AI108906, U19AI090019, R01AI108891, U19AI057266)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR042527)
Topics: Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords: immunosenescence, immunological aging, older adults, vaccine response, innate immune dysregulation, mouse models of aging
MeSH terms: Aged, Aged, 80 and over, Aging, Animals, Communicable Disease Control, Humans, Immunocompetence, Vaccination, Vaccines, Cellular Senescence, Mice, Adaptive Immunity

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Understanding immunosenescence to improve responses to vaccines

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