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Understanding immunosenescence to improve responses to vaccines
Open accessAbstract
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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“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]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“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]
Experimental — accuracy not yet measuredIn the citing paper
“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
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“The hallmarks of immunosenescence include: (i) a reduced ability to respond to new antigens; (ii) the accumulation of memory T cells; (iii) a lingering level of low-grade inflammation termed “inflamm-aging.””
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [23]
In the citing paper
“T cell clones specific for HCMV dominate the repertoire in the older people and contribute to the contraction in diversity in the memory compartment (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]
In the citing paper
“In contrast, high frequencies of antigen-specific T cells reactive to HCMV persist throughout life.”
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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“dysfunctional; most commonly due to immune senescence associated with aging or immune suppression.(81) Reduced T-cell”
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BackgroundImmune‐suppressive effects of interleukin‐6 on T‐cell‐mediated anti‐tumor immunity
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BackgroundT-cell aging in rheumatoid arthritis
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“The authors explained that this may be due to the different immunological background in older patients, such as modification of T-cell co-stimulatory/co-inhibitory proteins expression or higher concentrations of inflammatory cytokines [68,69].”
BackgroundReduced naïve CD 8 + T ‐cell priming efficacy in elderly adults
Briceño, O., Lissina, A., Wanke, K., Afonso, G., Braun, A., Ragon, K., Miquel, T., Gostick, E., Papagno, L., Stiasny, K., et al. (2016) · Aging Cell · doi:10.1111/acel.12384 · Cited by 151
“In contrast, experimental evidence for compromised na€ıve T-cell responsiveness in old humans is scarce (Goronzy & Weyand, 2013; Appay & Sauce, 2014).”
BackgroundShen-Orr, S. S., Furman, D., Kidd, B. A., Hadad, F., Lovelace, P., Huang, Y.-W., Rosenberg-Hasson, Y., Mackey, S., Grisar, F. A. G., Pickman, Y., et al. (2016) · Cell Systems · doi:10.1016/j.cels.2016.09.009 · Cited by 154
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“More-over, as individuals age, their immune system undergoes alterations that eventually lead to a noticeable and severe decline, resulting in increased rates of mortality from infectious and long-term comorbidity [48].”
BackgroundModeling Influenza Virus Infection: A Roadmap for Influenza Research
Boianelli, A., Nguyễn, V. K., Ebensen, T., Schulze, K., Wilk, E., Sharma, N., Stegemann‐Koniszewski, S., Bruder, D., Toapanta, F. R., Guzmán, C. A., et al. (2015) · Viruses · doi:10.3390/v7102875 · Cited by 158
“, type 2 diabetes), poor responses to vaccination, and increased vulnerability to common infectious diseases [108].”
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Antiviral B cell and T cell immunity in the lungs
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“In addition, vaccines are often less effective in those with immature or senescent immune systems 14, 15 .”
BackgroundToback, S., Galiza, E., Cosgrove, C. A., Galloway, J. B., Goodman, A. L., Swift, P. A., Rajaram, S., Graves-Jones, A., Edelman, J., Burns, F. M., et al. (2021) · The Lancet Respiratory Medicine · doi:10.1016/s2213-2600(21)00409-4 · Cited by 156
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“This process has been called ‘immunosenescence’ (Goronzy and Weyand, 2013).”
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“an increased production of proinflammatory cytokines [14].”
Heterogeneous fibroblasts underlie age-dependent tertiary lymphoid tissues in the kidney
Sato, Y., Mii, A., Hamazaki, Y., Fujita, H., Nakata, H., Masuda, K., Nishiyama, S., Shibuya, S., Haga, H., Ogawa, O., et al. (2016) · JCI Insight · doi:10.1172/jci.insight.87680 · Cited by 148
“Aging is often accompanied by chronic inflammation that leads to a functional decline in various organs (24).”
BackgroundParadoxical changes in innate immunity in aging: recent progress and new directions
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“marrow lymphopoiesis; diminished antigen receptor repertoire diversity, in part, reflecting control of chronic viral infections, such as cytomegalovirus; and developmental and signal transduction alterations, resulting in impaired generation of protective antibodies and CD4 and CD8 T cell responses [2, 3].”
BackgroundImmunosenescence: signaling pathways, diseases and therapeutic targets
Fu, Y., Wang, B., Alu, A., Hong, W., Hong, L., He, X., Shi, H., Cheng, P., & Yang, X. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02371-z · Cited by 168
“257,259 Moreover, JAK3 mutations have been shown to lead to severe immunode fi cien-cies, whereas STAT3 mutations impair IL-17 production, which increases susceptibility to bacterial and fungal infections.”
NADPH oxidase deficiency underlies dysfunction of aged CD8+ Tregs
Wen, Z., Shimojima, Y., Shirai, T., Li, Y., Ju, J., Yang, Z., Tian, L., Goronzy, J. J., & Weyand, C. M. (2016) · Journal of Clinical Investigation · doi:10.1172/jci84181 · Cited by 146
“Functional insufficiency of CD8 Tregs in older individuals, a possible risk factor for the chronic inflammatory syndrome associated with immune aging (65), is associated with age-related loss of NOX2.”
BackgroundSelf-citationShaping Variation in the Human Immune System
Liston, A., Carr, E. J., & Linterman, M. A. (2016) · Trends in Immunology · doi:10.1016/j.it.2016.08.002 · Cited by 149
Effects of Aging on Influenza Virus Infection Dynamics
Hernandez-Vargas, E. A., Wilk, E., Canini, L., Toapanta, F. R., Binder, S. C., Uvarovskii, A., Ross, T. M., Guzmán, C. A., Perelson, A. S., & Meyer‐Hermann, M. (2014) · Journal of Virology · doi:10.1128/jvi.03644-13 · Cited by 141
“In order to enhance vaccine efficacy in the elderly (56, 57), we need to better understand the immune responses to influenza virus infection and influenza vaccines.”
BackgroundExpression of CD39 on activated T cells impairs their survival in older individuals
Fang, F., Yu, M., Cavanagh, M. M., Hutter Saunders, J., Qi, Q., Ye, Z., Le Saux, S., Sultan, W., Turgano, E., Dekker, C. L., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.01.002 · Cited by 138
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“Furthermore, vaccination of the elderly provides inadequate protection against most infectious diseases, leaving these individuals vulnerable to a number of diseases (Goronzy and Weyand, 2013; Sasaki et al., 2011).”
BackgroundSARS-CoV-2 and COVID-19: A genetic, epidemiological, and evolutionary perspective
Sironi, M., Hasnain, S. E., Rosenthal, B. M., Phan, T. G., Luciani, F., Shaw, M., Sallum, M. A. M., Mirhashemi, M. E., Morand, S., & Gónzález‐Candelas, F. (2020) · Infection Genetics and Evolution · doi:10.1016/j.meegid.2020.104384 · Cited by 145
Li, Y., Shen, Y., Hohensinner, P. J., Ju, J., Wen, Z., Goodman, S. B., Zhang, H., Goronzy, J. J., & Weyand, C. M. (2016) · Immunity · doi:10.1016/j.immuni.2016.09.013 · Cited by 138
“…45, 1–14, October 18, 2016 immune cells follow a ‘‘universal’’ aging program is insufficiently understood, but RA T cells and T cells from aged humans lack the irreversible cell-cycle arrest that is considered a cardinal feature of senescence (Goronzy and Weyand, 2013; Sharpless and Sherr, 2015).”
Self-citationSex differences in Sjögren’s syndrome: a comprehensive review of immune mechanisms
Brandt, J. E., Priori, R., Valesini, G., & Fairweather, D. (2015) · Biology of Sex Differences · doi:10.1186/s13293-015-0037-7 · Cited by 146
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“Given that decline in T-cell diversity is one of the major mechanisms that contributes to immune senescence and reduced immune surveillance in aging (33, 34), we next investigated the impact of FGF21 on peripheral T-cell diversity in middle-aged mice.”
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“This process is characterized by decreases in naïve T cells and increases in memory T cells (1, 5, 6).”
Nosrati, A., Tsai, K. K., Goldinger, S. M., Tumeh, P. C., Grimes, B. A., Loo, K. L., Algazi, A. P., Nguyen‐Kim, T. D. L., Levesque, M. P., Dummer, R., et al. (2017) · British Journal of Cancer · doi:10.1038/bjc.2017.70 · Cited by 126
“…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…”
BackgroundThe Immune Landscape of Visceral Adipose Tissue During Obesity and Aging
Khan, S. M., Chan, Y. T., Revelo, X. S., & Winer, D. A. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00267 · Cited by 140
“The changes in the immune system associated with aging are characterized by an imbalance between inflammatory and anti-inflammatory pathways, leading to low-grade inflammation and a greater susceptibility to chronic disease (11).”
BackgroundImmunology of the ageing kidney
Sato, Y., & Yanagita, M. (2019) · Nature Reviews Nephrology · doi:10.1038/s41581-019-0185-9 · Cited by 126
Short telomere syndromes cause a primary T cell immunodeficiency
Wagner, C. L., Hanumanthu, V. S., Talbot, C. C., Abraham, R. S., Hamm, D. E., Gable, D. L., Kanakry, C. G., Applegate, C. D., Siliciano, J. D., Jackson, J. B., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci120216 · Cited by 127
“While these age-associated changes are well described, the genetic and molecular programs that drive T cell aging remain poorly understood (1, 2).”
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Chlíbek, R., Pauksens, K., Rombo, L., van Rijckevorsel, G. G. C., Richardus, J. H., Plassmann, G., Schwarz, T. F., Catteau, G., Lal, H., & Heineman, T. C. (2015) · Vaccine · doi:10.1016/j.vaccine.2015.09.073 · Cited by 125
The impact of senescence-associated T cells on immunosenescence and age-related disorders
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“Age-associated changes in immune functions, collectively called immunosenescence, are characterized by diminished adaptive immune competence leading to reduced infection resistance, pro-inflammatory traits that may underlie chronic inflammatory disorders, and increased risk of autoimmunity in the elderly [1, 2].”
BackgroundNaive T cells: The crux of cellular immune aging?
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“Thus, it is imperative to identify predictors of HPD, some of which include the following: (1) HPD significantly correlates with older age, especially an age ≥65 years [106], which may be due to the different immune background of elderly patients [108, 109].”
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“The replenishment of T cell frequency is achieved through export by the thymus and the self-renewal of peripheral naïveTcells 41 .”
BackgroundSchulz, A. R., Mälzer, J. N., Domingo, C., Jürchott, K., Grützkau, A., Babel, N., Nienen, M., Jelinek, T., Niedrig, M., & Thiel, A. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1500598 · Cited by 112
“tancy and individual systemic immune properties (6, 7).”
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“development, thymic involution at puberty drastically reduces the output of na€ ve T cells and during aging, after long-term residence in the host, the remaining na€ ve T cells exhibit impaired functionality, such as differentiation into effector cells after antigen stimulation, reduced production of cytokines, and a…”
Background
Metadata
- Authors
- Goronzy, J. J., & Weyand, C. M.
- Affiliations
- Stanford Medicine (US)
- VA Palo Alto Health Care System (US)
- Corresponding author
- Goronzy, Jörg J
- Venue
- Nature Immunology
- Published
- 2013-04-18
- Volume
- 14
- Issue
- 5
- Pages
- 428-436
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- 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
- 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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