Global analyses revealed age‐related alterations in innate immune responses after stimulation of pathogen recognition receptors
Open accessAbstract
Summary: Aging leads to dysregulation of multiple components of the immune system that results in increased susceptibility to infections and poor response to vaccines in the aging population. The dysfunctions of adaptive B and T cells are well documented, but the effect of aging on innate immunity remains incompletely understood. Using a heterogeneous population of peripheral blood mononuclear cells ( PBMC s), we first undertook transcriptional profiling and found that PBMC s isolated from old individuals (≥ 65 years) exhibited a delayed and altered response to stimulation with TLR 4, TLR 7/8, and RIG ‐I agonists compared to cells obtained from adults (≤ 40 years). This delayed response to innate immune agonists resulted in the reduced production of pro‐inflammatory and antiviral cytokines and chemokines including TNF α, IL ‐6, IL ‐1β, IFN α, IFN γ, CCL 2, and CCL 7. While the major monocyte and dendritic cell subsets did not change numerically with aging, activation of specific cell types was altered. PBMC s from old subjects also had a lower frequency of CD 40+ monocytes, impaired up‐regulation of PD ‐L1 on monocytes and T cells, and increased expression of PD ‐L2 and B7‐H4 on B cells. The defective immune response to innate agonists adversely affected adaptive immunity as TLR ‐stimulated PBMC s (minus CD 3 T cells) from old subjects elicited significantly lower levels of adult T‐cell proliferation than those from adult subjects in an allogeneic mixed lymphocyte reaction ( MLR ). Collectively, these age‐associated changes in cytokine, chemokine and interferon production, as well as co‐stimulatory protein expression could contribute to the blunted memory B‐ and T‐cell immune responses to vaccines and infections.
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Many immune cell subsets become hyporesponsive to acute challenges with age.
“Thus, many immune cell subsets become hyporesponsive to acute challenges as we age17,19-25.”
From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [22]
PBMCs from old individuals have delayed and altered transcriptional responses to TLR4, TLR7/8 and RIG-I agonists, with decreased production of TNF-α, IL-6, IL-1β, IFN-α, IFN-γ, CCL2 and CCL7.
“Peripheral blood mononuclear cells (PBMCs) from old individuals ( 65 years) have been shown to have a delayed and altered transcriptional response to stimulation with TLR4, TLR7/8, and RIG-I agonists; this altered response is accompanied by a decreased production of the pro-inflammatory and antiviral cytokines TNF-α, IL-6, IL-1β, IFN-α, and IFN-γ, and of the chemokines CCL2 and CCL7 [44].”
From Aging of the immune system: Focus on inflammation and vaccination (2016) · cites this paper as [44]
Aging does not significantly change the absolute number or frequency of overall monocytes in humans, but it changes their relative distribution, reducing classical monocytes and increasing intermediate and non-classical monocytes.
“Aging has not been shown to significantly alter the absolute number and the frequency of overall monocytes in humans [44], but does determines significant changes in the relative distribution of their subsets, with a marked reduction of the classical subset and an increase in the number of intermediate and non-classical monocytes [46].”
From Aging of the immune system: Focus on inflammation and vaccination (2016) · cites this paper as [44]
Basal production of pro-inflammatory cytokines without TLR engagement is higher in cells from older compared with young individuals, suggesting dysregulation that may limit further activation by TLR engagement.
“basal production of pro-inflammatory cytokines in the absence of TLR engagement has been found to be higher in cells from older compared with young individuals, suggesting a dysregulation of cytokine production that may limit further activation by TLR engagement [44].”
From Aging of the immune system: Focus on inflammation and vaccination (2016) · cites this paper as [44]
Macrophages show reduced chemotaxis and phagocytosis, and decreased cytokine production.
“Neutrophils show reduced function in bacteria phagocytosis and in the oxidative burst while macrophages show reduced chemotaxis and phagocytosis, and decreased cytokine production.”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [25]
NK cell cytotoxicity is well-preserved in centenarians, and an increase in the actual number of NK cells is observed in healthy aging.
“Briefly, natural killer (NK) cell cytotoxicity is well-preserved in centenarians, and an increase in the actual number of NK cells is observed in healthy aging.”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [25]
The general picture of innate immunity in older people is down-regulation of some functions and up-regulation of others.
“The general picture of innate immunity in older people, which emerges from several studies, is that of the down-regulation of some functions and the up-regulation of others.”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [25]
Neutrophils show reduced function in bacteria phagocytosis and in the oxidative burst.
“Neutrophils show reduced function in bacteria phagocytosis and in the oxidative burst while macrophages show reduced chemotaxis and phagocytosis, and decreased cytokine production.”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [25]
The addition of PAMPs to a subunit vaccine, triggering their corresponding pattern-recognition receptors (e.g., TLRs), improves vaccine efficacy in older humans and mice.
“On the other hand, the addition of PAMPs to a subunit vaccine, triggering their corresponding pattern-recognition receptors (e.g., TLRs) improves vaccine efficacy in older humans and mice (25, 30–32).”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [25]
Metcalf et al. demonstrated that CD28− costimulation is required for the expansion of PD-1+ CD8 T cells and effectiveness of PD-1 therapy in murine models of chronic viral infection and cancer.
“Concerning this point, Metcalf et al. (25) have demonstrated that CD28− costimulation is required for the expansion of PD-1+ CD8 T cells and effectiveness of PD-1 therapy in murine models of chronic viral infection and cancer.”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [25]
An age-associated reduction or delay in cytokine, chemokine, or interferon production in response to stimulation can negatively impact innate immune responses in the lung.
“An age-associated reduction or delay in cytokine, chemokine, or interferon production in response to stimulation can negatively impact innate immune responses in the lung (110).”
From Aging and Lung Disease (2020) · cites this paper as [110]
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- Authors
- Metcalf, T. U., Cubas, R. A., Ghneim, K., Cartwright, M. J., Grevenynghe, J. V., Richner, J. M., Olagnier, D. P., Wilkinson, P. A., Cameron, M. J., Park, B. S., Hiscott, J. B., Diamond, M. S., Wertheimer, A. M., Nikolich‐Zugich, J., & Haddad, E. K.
- Affiliations
- Vaccine & Gene Therapy Institute of Florida (US)
- Case Western Reserve University (US)
- Jewish General Hospital (CA)
- Washington University in St. Louis (US)
- Oregon Health & Science University (US)
- University of Arizona (US)
- Department of Immunobiology and Medicine University of Arizona College of Medicine Tucson AZ USA
- Corresponding author
- Haddad, Elias K.
- ORCID
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2015-02-27
- Volume
- 14
- Issue
- 3
- Pages
- 421-432
- ISSN
- 1474-9718 (ISSN-L)
- 1474-9726
- PMC
- PMC4406671
- OpenAlex
- W2051020804
- Cited by
- 189
- References
- 48
- Citations by year
- 2026: 5 · 2025: 14 · 2024: 12 · 2023: 18 · 2022: 19 · 2021: 21 · 2020: 28 · 2019: 25 · 2018: 12 · 2017: 19 · 2016: 9 · 2015: 6 · 2013: 1
- FWCI
- 7.54
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Aging Cell (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
- Funders
- National Institutes of Health (HHSN272201100017C)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- immunosenescence, innate immunity, aging, pathogen recognition receptors, TLR4, TLR7/8, RIG-I, peripheral blood mononuclear cells, cytokine and chemokine production, interferon, PD-L1, PD-L2, B7-H4, T cell proliferation, mixed lymphocyte reaction, vaccine response, infection susceptibility
- MeSH terms
- Adult, Aged, Aged, 80 and over, Aging, B-Lymphocytes, Dendritic Cells, Humans, Immunity, Innate, Leukocytes, Mononuclear, Lymphocyte Activation, Monocytes, T-Lymphocytes, Cytokines, Chemokines, Young Adult, Adaptive Immunity
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 ›
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