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Cited by 275Immune cells in cancerPhagocytosis and Immune RegulationImmune responses and vaccinations

The impact of ageing on monocytes and macrophages

Open access
De Maeyer, Roel P.H., Chambers, Emma S.·2021·Immunology Letters
DOI 10.1016/j.imlet.2020.12.003
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Abstract

Ageing is a global burden. Increasing age is associated with increased incidence of infections and cancer and decreased vaccine efficacy. This increased morbidity observed with age, is believed to be due in part to a decline in adaptive immunity, termed immunosenescence. However not all aspects of immunity decrease with age as ageing presents with systemic low grade chronic inflammation, characterised by elevated concentrations of mediators such as IL-6, TNFα and C Reactive protein (CRP). Inflammation is a strong predictor of morbidity and mortality, and chronic inflammation is known to be detrimental to a functioning immune system. Although the source of the inflammation is much discussed, the key cells which are believed to facilitate the inflammageing phenomenon are the monocytes and macrophages. In this review we detail how macrophages and monocytes phenotype and function change with age. The impact of ageing on macrophages includes decreased phagocytosis and immune resolution, increased in senescent-associated markers, increase inflammatory cytokine production, and reduced autophagy and decrease in TLR expression. With monocytes there is an increase in circulating CD16+ monocytes, decreased type I IFN production, and decreased efferocytosis. In conclusion, we believe that monocytes and macrophages contribute to immunosenescence and inflammageing and as a result have an important role in defective immunity with age.

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Crossref · 10.1016/j.imlet.2020.12.003

Cites

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Claims the paper makes

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  • Findingcitation

    Monocytes and macrophages could not engulf apoptotic immune cells after an inflammatory insult.

    “Mononuclear phagocytes, consisting of monocytes and macrophages, were unable to engulf apoptotic immune cells following an inflammatory insult.”
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    Senescence arises from irreparable cellular damage such as DNA damage, telomere erosion, or oxidative stress.

    “Senescence occurs as a result of irreparable cellular insults, such as excessive DNA damage, telomere erosion, or oxidative stress (13).”
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    Senescence has been observed in several immune cell types, including macrophages and T cells.

    “In the immune system, senescence has been shown in multiple cell types including macrophages and T cells (10)(11)(12).”
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    The SASP can induce senescence in neighbouring cells, maintaining a tissue environment that is increasingly senescent and inflammatory.

    “The SASP can drive paracrine senescence perpetuating an increasingly senescent and inflammatory tissue environment (17).”
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    Systemic accumulation of senescent cells is closely associated with age-related disease and inflammageing.

    “Systemic increases in senescent cells are closely linked to age-related pathology and inflammageing, the chronic low-grade inflammation observed with age in humans (15).”
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    Findingcitation

    This failure led to accumulation of apoptotic cells, debris, and mononuclear phagocytes that did not adopt a proresolution phenotype.

    “This resulted in an accumulation of apoptotic cells, cellular debris, and mononuclear phagocytes that did not switch to a proresolution phenotype.”
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    Excessive inflammation lowers vaccine efficacy and antigen-specific immunity and increases immunoregulatory mechanisms.

    “In addition, excessive inflammation has been shown to reduce vaccine efficacy (24,25), antigen-specific immunity (26) and increased immunoregulatory mechanisms to combat the increased inflammation (27).”
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    Interpretationreasoning

    Age-related immune changes lead to weaker antigen-specific immunity and poorer vaccine responses.

    “All these age-related changes suggest that there are alterations in immunity which result in poorer antigen-specific immunity and worse vaccine efficacy.”
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    Premisecitation

    Lower levels of inflammatory cytokines in peripheral blood are associated with better health, longevity, and lower mortality in older adults.

    “Conversely, lower levels of inflammatory cytokines in the peripheral blood correlate with good health outcomes, longevity, and reduced risk of death of older adults (22).”
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    There is no single definitive marker of senescence.

    “However, there is no one definitive marker of senescence and this subject has been reviewed extensively elsewhere (13).”
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    Senescent stromal cells do not divide and are resistant to apoptosis.

    “Senescent stromal cells do not divide and are apoptosis resistant (14).”
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    The number of older people worldwide is rising.

    “Ageing populations are becoming a global trend (1), however increasing lifespan is outstripping health-span.”
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    Macrophages interact with surrounding cells to maintain order and quickly remove potentially hazardous debris.

    “Macrophages interact with the cells around them to maintain order and rapidly remove potentially hazardous debris (39).”
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    Macrophages express many pattern recognition receptors, such as TLRs, that trigger inflammatory signalling when activated.

    “Macrophages express a broad range of PRRs, such as TLRs, that when triggered initiate an inflammatory signalling cascade.”
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    Geriatric mice have greater gut permeability, allowing bacterial LPS to enter the bloodstream and activate mononuclear phagocytes through TLR4.

    “Geriatric mice have been shown to have increased gut permeability which results in bacterial lipopolysaccharide (LPS) leakage into the blood stream and activation of mononuclear phagocytes via binding to Toll-like receptor (TLR)4 (28,29).”
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    Macrophages exposed to interferon-γ and LPS are classically activated M1 cells that release TNFα, IL-1β, and IL-12 and produce more reactive oxygen species.

    “Macrophages (and often monocyte-derived cells) exposed to the pro-inflammatory mediators interferon-γ and LPS are characterised as having the classically activated, pro-inflammatory M1 phenotype based on their release of cytokines such as TNFα, IL-1β, and IL-12 as well as their increased reactive oxygen species (ROS) production (40).”
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    In vivo, macrophages and monocytes show mixed phenotypes and are not fully polarised as the M1/M2 classification suggests.

    “In vivo, however, macrophages (and monocytes) display mixed phenotypes and are not completely polarised as described by the in vitro classification of M1/M2 (42,43).”
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    Premisecitation

    Old mice have more CX3CR1-expressing macrophages and fewer Ly6C+ macrophages than young mice.

    “Further analysis of these macrophages has identified an increased frequency of CX3CR1 expressing macrophages and conversely a reduction of Ly6C + macrophages in old mice compared to young (57).”
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    Premisecitation

    Aged mice have higher levels of damage-associated molecular patterns, suggesting that human ageing may also increase DAMP production.

    “Additionally, aged mice have elevated damage-associated molecular patterns (DAMPs), suggesting that human ageing may also lead to increased DAMP production (31).”
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    Macrophages can ingest diverse targets, including bacteria, apoptotic cells, thorns, tattoo ink, and helminths.

    “They are capable of ingesting a host of targets ranging from bacteria to apoptotic cells, thorns to tattoo ink, and grapple with helminths (37)(38)(39).”
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    The original view was that monocytes enter tissues and then become macrophages.

    “The original dogma proposed that monocytes were recruited to tissues where they subsequently differentiated into macrophages (52).”
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    In mice, embryonic precursors in the intestine proliferate locally and are later replaced by Ly6C+ monocytes that the tissue environment and microbiota instruct to become macrophages.

    “It has been shown in mice that embryonic precursors seeded in the intestine underwent in situ proliferation, during the neonatal period they were subsequently replaced by an influx of Ly6C + monocytes instructed by the local tissue environment and microbiota to differentiate into macrophages (53).”
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    This macrophage activity helps resolve immune responses, restore tissue homeostasis, and create conditions for immune memory.

    “This mechanism is also used to bring about immune resolution and restore tissues to their homeostatic states while providing an environment conducive to immune memory (44,45).”
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    Older adults have more visceral fat, and visceral fat is an inflammatory site where infiltrating immune cells, including mononuclear phagocytes, release inflammatory mediators.

    “Older adults exhibit increased visceral adiposity; visceral fat is an inflammatory site as infiltrating immune cells, including mononuclear phagocytes, secrete a raft of inflammatory mediators (30).”
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    Bifidobacterium and Lactobacillus species become less prevalent with age, while Bacteroides, Clostridia, and Fusobacteria increase in number and diversity.

    “For example, the prevalence of Bifidobacterium and Lactobacillus species decreases with age, whereas the numbers and diversity of Bacteroides, Clostridia and Fusobacteria increased (61).”
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    Premisecitation

    Different macrophage types carry out specific tissue functions: microglia prune synapses, bone marrow macrophages enucleate erythroblasts, and splenic red pulp macrophages clear damaged erythrocytes.

    “Finally, different types of macrophages have very specific tissue functions, for example, microglia help orchestrate neuronal connectivity by pruning synapses (46), bone marrow macrophages enucleate erythroblasts during erythrocyte development (47) and splenic red pulp macrophages phagocytose and clear damaged erythrocytes (48).”
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    Premisecitation

    Each tissue imprints function on macrophages regardless of whether they are embryonic or monocyte-derived, so each tissue has unique macrophage populations.

    “Each tissue imprints function upon the macrophage irrespective of whether it is embryonically derived or monocyte-derived, thus meaning that each tissue has unique macrophage populations (56).”
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    Interpretationcitation

    Some free fatty acids, such as palmitate, promote an inflammatory phenotype and may contribute to atherosclerosis.

    “certain free fatty acids such as palmitate promote an inflammatory phenotype and in turn may contribute to atherosclerosis pathology (143).”
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    Premisecitation

    In a study by Metcalf et al, the three monocyte populations were isolated and examined separately, and baseline monocytes from young and old donors were found to be similar.

    “isolated the three monocyte populations and studied them individually, showing that at baseline, monocytes from young and old people were similar.”
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    Interpretationcitation

    The reduced type I interferon production is proposed as one reason older adults are more vulnerable to respiratory infections, since type I interferon is required for infection clearance.

    “is thought to be one of the reasons that older people are more susceptible to respiratory infections, as type I interferon is necessary to clear infection (138).”
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    Premisecitation

    Germ-free mice do not develop age-dependent inflammation and retain macrophage function.

    “Interestingly mice that were kept in a germ-free environment did not develop age-dependent inflammation and had preserved macrophage function (28).”
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    Premisecitation

    Nyugen et al proposed that the TLR1/2 signalling defect is limited to CD16-expressing monocytes, because classical monocytes showed no difference.

    “Nyugen et al suggest that there the defect in the TLR1/2 signalling is restricted to the monocytes that express CD16, as for the classical monocytes there was no difference (129).”
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    Interpretationreasoning

    RAD001 might also inhibit inflammation originating from aged mononuclear phagocytes.

    “Although the authors note the beneficial effects of this inhibitor on adaptive immunity, there is every potential that it could also inhibit inflammation originating from aged mononuclear phagocytes.”
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    Interpretationcitation

    This leads to prolonged inflammation at the damage site and slower healing, and is suggested to contribute to the development of inflammageing.

    “This led to sustained inflammation at the site of damage and a longer time to heal and is suggested to be a contributor to the aetiology of inflammageing.”
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    Premisecitation

    Blocking monocyte-derived COX2-driven inflammation with the p38 MAP kinase inhibitor Losmapimod significantly reduces monocyte infiltration and downstream inflammatory processes and improves inflammatory resolution.

    “We have shown that blocking monocyte-derived COX2-driven inflammation using the p38 MAP Kinase inhibitor, Losmapimod, could significantly reduce monocyte infiltration and downstream inflammatory processes (26,141), as well as improve inflammatory resolution (33).”
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    Interpretationreasoning

    Targeting inflammation caused by aged monocytes and macrophages could reduce the harmful effects of inflammageing and possibly improve immunity in older adults.

    “We believe that targeting inflammation caused by aged monocytes and macrophages has the potential to limit the detrimental effects of inflammageing and potentially boost immunity in older adults.”
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    Interpretationcitation

    The immunomodulatory effect of monocytes may be a by-product of the inflamed skin environment, because older skin contains more senescent stromal cells such as fibroblasts.

    “However, this immunomodulatory property of monocytes may be a by-product of the increased inflammatory skin environmentas increased senescent stromal cells such as fibroblasts are present in older skin (10).”
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  • The paper relies on this without support.

    There are important aspects of monocyte and macrophage ageing that remain poorly understood.

    “there are clearly facets of ageing in this context that are poorly understood”

  • The paper relies on this without support.

    Most aged mouse studies have focused on macrophages, so information about monocytes is limited.

    “The focus of many aged mouse studies has been on macrophages so the information on monocytes is rather limited.”

  • The paper relies on this without support.

    Many senescence markers are commonly expressed by mononuclear phagocytes because of their normal role in inflammation.

    “many of the markers of senescence are commonly expressed by mononuclear phagocytes, given their physiological role in inflammation”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In response to fracture, macrophages are recruited to the injury site and raise an inflammatory response that is critical for robust healing and that is followed by an anti-inflammatory response.

    “In response to fracture, macrophages are recruited to the injury site and raise an inflammatory response that is critical for robust healing and that is followed by an anti-inflammatory response [12, 13].”

    From Osteoimmunology of Fracture Healing. (2024) · cites this paper as [12]

    The Macrophage phenotype and function section describes macrophages initiating inflammatory signalling and, under other stimuli, releasing anti-inflammatory and tissue-repair molecules. The Function section describes mononuclear phagocytes recruited to tissue damage and links failed inflammatory resolution to slower healing. Neither section establishes this sequence specifically after fracture or shows that the inflammatory response is critical for robust fracture healing (page numbers unavailable in our copy). (LLM, conf=0.85)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Figure 1 is assigned to both monocytes and macrophages

    Minor

    One caption identifies Figure 1 as showing age-related changes in human monocytes, while another identifies Figure 1 as showing changes in macrophages. The monocyte section also refers to its summary as Figure 2.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 6

  1. van Furth, 1972, The mononuclear phagocyte system: a new classification of macrophages, monocytes, and their precursor cells, Bull. World Health Organ., 46, 845
  2. Njie, 2012, Ex vivo cultures of microglia from young and aged rodent brain reveal age-related changes in microglial function, Neurobiol. Aging, 33, 195 e1, 10.1016/j.neurobiolaging.2010.05.008 · DOI · Paper page
  3. Weyand, 2014, Clinical practice. Giant-cell arteritis and polymyalgia rheumatica, N. Engl. J. Med., 371, 50, 10.1056/NEJMcp1214825 · DOI
  4. Chuang, 1982, Polymyalgia rheumatica: a 10-year epidemiologic and clinical study, Ann. Intern. Med., 97, 672, 10.7326/0003-4819-97-5-672 · DOI
  5. Weiner, 1994, Phase I trial of recombinant macrophage colony-stimulating factor and recombinant gamma-interferon: toxicity, monocytosis, and clinical effects, Cancer Res., 54, 4084
  6. Chambers, 2020, Monocyte-derived Prostaglandin E2 inhibits antigen-specific cutaneous immunity during ageing, bioRxiv

Cited by

Sorted by citations

Authors
De Maeyer, R. P. H., & Chambers, E. S.
Affiliations
Queen Mary University of London (GB)
Corresponding author
Chambers, Emma S.
ORCID
Venue
Immunology Letters
Publisher
Elsevier BV
Published
2021-02
Volume
230
Pages
1-10
ISSN
0165-2478 (ISSN-L)
DOI
10.1016/j.imlet.2020.12.003
OpenAlex
W3113258554
Semantic Scholar
ee69c163d7cc613730bdc97543aa95c098e61c42
Cited by
275
References
142
Citations by year
2026: 36 · 2025: 54 · 2024: 60 · 2023: 54 · 2022: 47 · 2021: 24
FWCI
3.06
Type
journal article
Language
en
Open access
Licence
Locations
  • Immunology Letters (publishedVersion)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Queen Mary Research Online (Queen Mary University of London) (submittedVersion)
Funders
Barts Charity
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
  • Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
Keywords
aging, monocytes, macrophages, immunosenescence, inflammaging, low-grade inflammation, CD16+ monocytes, type I interferon, efferocytosis, phagocytosis, immune resolution, autophagy, TLR expression, inflammatory cytokines, vaccine efficacy
MeSH terms
Immunosenescence, Aging, Animals, Humans, Inflammation, Macrophages, Monocytes

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