The role of cytochrome P450-derived epoxy-oxylipins and their metabolites in human inflammation and resolution is unknown. We report that epoxy-oxylipins are present in blood of healthy, male volunteers at baseline and following intradermal injection of UV-killed Escherichia coli, an experimental model of acute resolving inflammation. At the site of inflammation, cytochrome P450s and epoxide hydrolase (EH) isoforms, which catabolise oxylipins to corresponding diols, are differentially upregulated throughout the inflammatory response, as is the biosynthesis of epoxy-oxylipins. GSK2256294, a selective sEH inhibitor specifically elevates 12,13-EpOME and 14,15-EET. While inhibition of sEH hastens pain resolution, it has no effect on tissue heat, redness and swelling. GSK2256294, however, significantly reduces numbers of circulating intermediate monocytes that expand during inflammation. We find that 12,13-EpOME blocks the transition of classical to intermediate monocytes in a p38 MAPK-dependent manner, results that are recapitulated when blocking p38 MAPK in vitro and when administering the p38 MAPK inhibitor losmapimod in vivo to healthy volunteers. Furthermore, fewer intermediate monocytes are observed at the site of inflammation, accompanied by reduced tissue CD4 T cells. Hence, we have mapped the expression, activity and function of epoxy-oxylipins in human inflammation revealing new mechanisms of monocyte differentiation and resolution biology. Here they demonstrate a therapeutic intervention elevating levels of CYP450-derived lipids to control the expansion of intermediate monocytes in tissue and peripheral blood, presenting a first in class therapeutic approach for treating chronic inflammatory disease.

Abstract Introduction and aims Skin ageing is associated with visible phenotypical changes such as wrinkling. On a cellular level, the number of senescent cells accumulates with age, which can drive skin ageing phenotype. During ageing, there are also profound changes in cutaneous immunity which render older adults more susceptible to skin cancers and infections. We have previously shown that skin from older adults (≥ 65 years) has impaired antigen-recall response against pathogens. This age-associated impairment is due to recruitment of proinflammatory monocytes by activated senescent fibroblasts, these monocytes secret prostaglandin E2 and blunt antigen-specific immunity. However, the mechanisms of senescent fibroblast activation that induces the recruitment of inflammatory monocytes are currently unknown. Owing to ethical limitations of performing repeated biopsies on humans, a novel ageing skin model needs to be developed. The aim of this project is to build immune responsive ‘young’ and ‘old’ in vitro three-dimensional human skin equivalent (HSE) model to identify the cellular source of this age-associated skin inflammation. Methods We have built ‘young’ (100% proliferating fibroblasts) and ‘old’ (10% senescent; 90% proliferating) HSEs. The dermal fibroblasts were isolated from sun-protected healthy human skin, and N/TERTs were employed for the epidermis. Furthermore, we established immune-responsive HSEs with the addition of monocytes isolated from fresh peripheral blood to the dermal layer. Results The ‘old’ HSEs exhibited epidermal thinning and ECM disorganization. Additionally, the increase of senescent fibroblast percentage within the HSE dermis is associated with further impairment of epidermal development. The monocytes within the HSEs differentiated into dermal macrophages as defined by CD68 expression. Conclusions We have developed HSEs that recapitulate human skin ageing. Research is ongoing to determine the influence of the old skin environment on mononuclear phagocyte differentiation. This project will aid our understanding of age-related cutaneous immune decline, and ultimately, the identification of druggable pathways to help improve skin health in older adults.

Abstract Introduction and aims Junctional epidermolysis bullosa (JEB) is an inherited, rare blistering disorder caused by loss of laminin-332, a mediator of epidermis–dermis adhesion, causing cutaneous fragility, impaired healing and exacerbating pruritus. Chronic inflammation is prominent, with elevated levels of the inflammatory cytokines tumour necrosis factor (TNF) and interleukin (IL)-1β relative to matched controls, yet in-depth immunological study of JEB is absent. We propose the underlying molecular pathology induces a distinct inflammatory niche, and repurposing TNF and IL-1β signalling inhibitors will improve inflammation and clinical symptoms. Accordingly, we aim to characterize cutaneous leucocyte composition and investigate effects of TNF and IL-1β inhibition on itch, inflammation and cutaneous phenotype. Methods Our inducible Lama3 knockout C57BL/6 murine model of severe, progressive JEB replicates symptoms of the human condition and is employed to investigate cutaneous leucocytes alongside evaluating TNF (adalimumab) and IL-1β (Anakinra) signalling inhibitor treatments on JEB pathology. We developed a murine leucocyte staining panel for spectral flow cytometry alongside a recording system to quantify pruritus during disease progression, a first in JEB research. In preliminary experiments, JEB mice received 2-week courses of adalimumab or anakinra with weekly recordings performed, and cutaneous tissues were harvested for downstream immunohistochemical and flow analyses. Results Blistered JEB skin was dominated by mononuclear phagocytes (prominently Ccr2+ macrophages, F4/80+Ly6clo macrophages, and monocytes), granulocytes, with few lymphocytes. Preliminary experimentation indicates adalimumab treatment arrested exacerbation of pruritus, reduced recruitment of monocytes, eosinophils, basophils and neutrophils, and elevated F4/80+Ly6clo and Ccr2+ macrophages alongside impeding angiogenesis. Conversely, anakinra treatment saw no improvements in pruritus, with mixed effects observed upon inflammatory leucocyte makeup, reducing neutrophil and monocyte infiltration simultaneously with F4/80+Ly6clo and Ccr2+ macrophage populations, while populations of T lymphocytes and eosinophils rose. Conclusions Our data illuminate underlying JEB wound inflammation, indicating repurposing established anti-TNF therapeutics presents a putative opportunity to improve patient quality of life, and that anti-IL-1β treatments may not relieve inflammation during JEB.

Accumulation of damaged biomolecules in body tissues is the primary cause of aging and age-related chronic diseases. Since this damage often occurs spontaneously, it has traditionally been regarded as untreatable, with typical therapeutic strategies targeting genes or enzymes being ineffective in this domain. In this report, we demonstrate that an antibody targeting the isoDGR damage motif in lung tissue can guide immune clearance of harmful damaged proteins in vivo, effectively reducing age-linked lung inflammation. We observed age-dependent accumulation of the isoDGR motif in human lung tissues, as well as an 8-fold increase in isoDGR-damaged proteins in lung fibrotic tissues compared with healthy tissue. This increase was accompanied by marked infiltration of CD68+/CD11b + macrophages, consistent with a role for isoDGR in promoting chronic inflammation. We therefore assessed isoDGR function in mice that were either naturally aged or lacked the isoDGR repair enzyme. IsoDGR-protein accumulation in mouse lung tissue was strongly correlated with chronic inflammation, pulmonary edema, and hypoxemia. This accumulation also induced mitochondrial and ribosomal dysfunction, in addition to features of cellular senescence, thereby contributing to progressive lung damage over time. Importantly, treatment with anti-isoDGR antibody was able to reduce these molecular features of disease and significantly reduced lung pathology in vivo.

To enable in vitro investigation of human skin immunology, this study develops a microfluidic human skin equivalent (HSE) that supports the delivery of circulating immune cells via a vascular microchannel embedded within the dermis of a full-thickness construct. Within this platform, activation of keratinocyte inflammation promotes monocyte migration out of the vascular channel and into the dermal and epidermal compartments. Single-cell transcriptomic analysis reveals dynamic and cell-specific patterns of gene expression that are characteristic of acute activation and resolution of an inflammatory immune response, and the gene signatures of the monocyte-derived cells closely matches the differentiation trajectory of the monocytes into mature dermal macrophages. The microfluidic HSE is also applied to modeling age-associated immune dysfunction and accurately replicates elevated monocyte recruitment in aged skin. Thus, the microfluidic HSE presented here replicates key aspects of dynamic inflammatory immune responses and represents a tractable experimental tool for interrogating mechanisms of human skin immunology.

Biological sex is a crucial, but poorly understood variable in age-related susceptibility to infection. Monocytes are important immune cells responsible for initiating and resolving inflammatory responses to infection. While changes in monocyte populations result in increased susceptibility to infection, there is limited research on the impact of age and sex on human monocyte phenotype and function. The aim of this work was to dissect the impact of increasing age and biological sex on human monocyte phenotype and function. Here, we show that older females have increased inflammatory intermediate and non-classical monocytes compared to young. These monocyte subsets were the most inflammatory ex vivo, and their frequency correlated with markers of inflammageing. Proteomic analysis of sorted monocyte populations demonstrated that the three human monocyte subsets have largely distinct phenotypes. Key age-associated protein pathways were identified, including complement cascade and phagocytosis. We confirmed the proteomics findings, showing that circulating C3 concentrations were reduced with age in females but not males. This decrease in complement in older females resulted in reduced monocyte phagocytosis. Crucially, we demonstrate that in peri/menopausal females, hormone replacement therapy (HRT) reversed this expansion in intermediate monocytes and decreased circulating CRP as compared to age-matched controls. Importantly, peri/menopausal females on HRT had increased C3 serum concentrations and significant improvement in monocyte phagocytosis. The data presented here indicate the importance of menopause in aging monocyte phenotype and function. These data highlight the potential use of HRT in restoring monocyte function in females during aging and potentially improving anti-pathogen immunity.

Sex differences in immunity are well-documented, though mechanisms underpinning these differences remain ill-defined. Here, in a human-only ex vivo study, we demonstrate that postpubertal cisgender females have higher levels of CD19+CD27+IgD- class-switched memory B cells compared with age-matched cisgender males. This increase is only observed after puberty and before menopause, suggesting a strong influence for sex hormones. Accordingly, B cells express high levels of estrogen receptor 2 (ESR2), and class-switch-regulating genes are enriched for ESR2-binding sites. In a gender-diverse cohort, blockade of natal estrogen in transgender males (XX karyotype) reduced class-switched memory B cell frequency, while gender-affirming estradiol treatment in transgender females (XY karyotype) did not increase these levels. In postmenopausal cis-females, class-switched memory B cells were increased in those taking hormone replacement therapy (HRT) compared with those who were not. These data demonstrate that sex hormones and chromosomes work in tandem to impact immune responses, with estrogen only influencing the frequency of class-switched memory B cells in individuals with an XX chromosomal background.

The integrated behaviour of multiple senescent cell types within a single human tissue leading to the development of malignancy is unclear. Patients with Familial Melanoma Syndrome (FMS) have heterozygous germline defects in the CDKN2A gene coding for the cyclin inhibitor p16 INK4a . Melanocytes within skin biopsies from FMS patients express significantly less p16 INK4a but express higher levels of the DNA-damage protein 𝛾H2AX a than fibroblastic cells. However, patient fibroblasts also exhibit defects since senescent cells do not increase in the skin during ageing and fibroblasts isolated from the skin of patients have increased replicative capacity compared to control fibroblasts in vitro, culminating in abnormal nuclear morphology. Patient derived fibroblasts also secreted less SASP than control cells. Predisposition of FMS patients to melanoma may therefore result from integrated dysregulation of senescence in multiple cell types in vivo. The inherently greater levels of DNA damage and the overdependence of melanocytes on p16 for cell cycle inhibition after DNA damage makes them exquisitely susceptible to malignant transformation. This may be accentuated by senescence-related defects in fibroblasts, in particular reduced SASP secretion that hinders recruitment of T cells in the steady state and thus reduces cutaneous immunosurveillance in vivo.

Vitamin D 3 replacement in older insufficient adults significantly improves their antigen-specific varicella zoster virus (VZV) cutaneous immunity. However, the mechanisms involved in this enhancement of cutaneous immunity are not known. Here, we show for the first time that vitamin D 3 blocks the senescence-associated secretory phenotype (SASP) production by senescent fibroblasts by partially inhibiting the p38 MAPK pathway. Furthermore, transcriptomic analysis of skin biopsies from older subjects after vitamin D 3 supplementation shows that vitamin D 3 inhibits the same inflammatory pathways in response to saline as the specific p38 inhibitor, losmapimod, which also enhances immunity in the skin of older subjects. Vitamin D 3 supplementation therefore may enhance immunity during ageing in part by blocking p38 MAPK signalling and in turn inhibit SASP production from senescent cells in vivo.

OBJECTIVE:Asthma is a major global disease affecting adults and children, which can lead to hospitalization and death due to breathing difficulties. Although targeted monoclonal antibody therapies have revolutionized treatment of severe asthma, some patients still fail to respond. Here we critically evaluate the literature on biologic therapy failure in asthma patients with particular reference to anti-drug antibody production, and subsequent loss of response, as the potential primary cause of drug failure in asthma patients. RECENT FINDINGS:Encouragingly, asthma in most cases responds to treatment, including the use of an increasing number of biologic drugs in moderate to severe disease. This includes monoclonal antibody inhibitors of immunoglobulin E and cytokines, including interleukin 4, 5, or 13 and thymic stromal lymphopoietin. These limit mast cell and eosinophil activity that cause the symptomatic small airways obstruction and exacerbations. SUMMARY:Despite humanization of the antibodies, it is evident that benralizumab; dupilumab; mepolizumab; omalizumab; reslizumab and tezepelumab all induce anti-drug antibodies to some extent. These can contribute to adverse events including infusion reactions, serum sickness, anaphylaxis and potentially disease activity due to loss of therapeutic function. Monitoring anti-drug antibodies (ADA) may allow prediction of future treatment-failure in some individuals allowing treatment cessation and switching therefore potentially limiting disease breakthrough.

The intricate immunological functions of human skin involve the interplay between multiple different cell types as well as dynamic trafficking of leukocytes in and out the tissue, both of which are extremely challenging to replicate in vitro. To enable in vitro investigation of human skin immunology, we developed a microfluidic human skin equivalent (HSE) that supports the delivery of circulating immune cells via a vascular microchannel embedded within the dermis of a full-thickness construct. We demonstrated that stimulation of keratinocyte inflammation with lipopolysaccharide and nigericin promoted rapid monocyte recruitment out of the vascular channel and into the epidermal layer within 24 hours, followed by a second wave of monocyte migration into the dermis over a period of six days. Single-cell transcriptomic analysis of the tissue-resident and recruited cell populations revealed dynamic and cell-specific patterns of gene expression that were characteristic of acute activation and resolution of an inflammatory immune response. Moreover, comparison of the gene signatures of the monocyte-derived cells to in vivo populations provided molecular level validation of the model and indicated a differentiation trajectory of the monocytes through to mature dermal macrophages. To extend the microfluidic platform to additional applications, we also modelled age-associated immune dysfunction by the inclusion of senescent fibroblasts, which promoted increased monocyte recruitment into the HSE, replicating previous in vivo human studies. Thus, the microfluidic HSE presented here replicates key aspects of dynamic inflammatory immune responses within the skin and represents a tractable experimental tool for interrogating mechanisms of human skin immunology. ### Competing Interest Statement The authors have declared no competing interest.

Vaccine development targeting SARS-CoV-2 in 2020 was of critical importance in reducing COVID-19 severity and mortality. In the U.K. during the initial roll-out most individuals either received two doses of Pfizer COVID-19 vaccine (BNT162b2) or the adenovirus-based vaccine from Oxford/AstraZeneca (ChAdOx1-nCoV-19). There are conflicting data as to the impact of age, sex and body habitus on cellular and humoral responses to vaccination, and most studies in this area have focused on determinants of mRNA vaccine immunogenicity. Here, we studied a cohort of participants in a population-based longitudinal study (COVIDENCE UK) to determine the influence of age, sex, body mass index (BMI) and pre-vaccination anti-Spike (anti-S) antibody status on vaccine-induced humoral and cellular immune responses to two doses of BNT162b2 or ChAdOx-n-CoV-19 vaccination. Younger age and pre-vaccination anti-S seropositivity were both associated with stronger antibody responses to vaccination. BNT162b2 generated higher neutralising and anti-S antibody titres to vaccination than ChAdOx1-nCoV-19, but cellular responses to the two vaccines were no different. Irrespective of vaccine type, increasing age was also associated with decreased frequency of cytokine double-positive CD4+T cells. Increasing BMI was associated with reduced frequency of SARS-CoV-2-specific TNF+CD8% T cells for both vaccines. Together, our findings demonstrate that increasing age and BMI are associated with attenuated cellular and humoral responses to SARS-CoV-2 vaccination. Whilst both vaccines induced T cell responses, BNT162b2 induced significantly elevated humoral immune response as compared to ChAdOx-n-CoV-19.

Advancing age is the primary risk factor for pulmonary diseases. Our investigation revealed an 8-fold increase in aging induced isoDGR-damaged proteins in lung tissue from human pulmonary fibrosis patients compared to healthy tissues, accompanied by elevated frequencies of CD68+/CD11b+ macrophages, indicating lung tissue is susceptible to time-dependent accumulation of isoDGR-proteins. To elucidate the mechanisms through which isoDGR-proteins may exacerbate aging lung disorders for potential therapeutic targeting, we assessed the functional role of this isoDGR-motif in naturally-aged mice and mice lacking the corresponding isoDGR repair enzyme (Pcmt1-/-). IsoDGR-protein accumulation in mouse lung tissue and blood vessels correlated with chronic low-grade inflammation, pulmonary edema, and hypoxemia. IsoDGR accretion induced mitochondrial and ribosomal dysfunctions, cellular senescence, and apoptosis, contributing to progressive lung damage over time. Treatment with anti-isoDGR antibodies suppressed TLR pathway activity, mitigated cytokine-driven inflammation, restored mtDNA expression, and significantly reduced lung pathology in-vivo. Similarly, exposure of lung endothelial cells to isoDGR-modified fibronectin impaired oxygen consumption, increased reactive oxygen species levels, and disrupted acidification, but these effects were efficiently reversed by target-specific antibody therapy. Collectively, our findings underscore the significant contribution of isoDGR-damaged proteins to age-linked lung pathology. IsoDGR-specific therapy emerges as a promising treatment approach for pulmonary disorders in older patients.### Competing Interest StatementThe authors have declared no competing interest.

Vaccine development targeting SARS-CoV-2 in 2020 was of critical importance in reducing COVID-19 severity and mortality. In the U.K. during the initial roll-out most individuals either received two doses of Pfizer COVID-19 vaccine (BNT162b2) or the adenovirus-based vaccine from Oxford/AstraZeneca (ChAdOx1-nCoV-19). There are conflicting data as to the impact of age, sex and body habitus on cellular and humoral responses to vaccination, and most studies in this area have focused on determinants of mRNA vaccine immunogenicity. Here we studied a cohort of participants in a population-based longitudinal study (COVIDENCE UK) to determine the influence of age, sex, body mass index (BMI) and pre- vaccination anti-Spike (anti-S) antibody status on vaccine-induced humoral and cellular immune responses to two doses of BNT162b2 or ChAdOx-n-CoV-19 vaccination. Younger age and pre-vaccination anti-S seropositivity were both associated with stronger antibody responses to vaccination. BNT162b2 generated higher neutralising and anti-S antibody titres to vaccination than ChAdOx1-nCoV-19, but cellular responses to the two vaccines were no different. Irrespective of vaccine type, increasing age was also associated with decreased frequency of cytokine double-positive CD4+ T cells. Increasing BMI was associated with reduced frequency of SARS-CoV-2-specific TNF+ CD8% T cells for both vaccines. Together, our findings demonstrate that increasing age and BMI associate with attenuated cellular and humoral responses to SARS-CoV-2 vaccination. Whilst both vaccines induced T cell responses, BNT162b2 induced significantly elevated humoral immune response as compared to ChAdOx-n-CoV-19.

SUMMARYBackground & AimsVitamin D deficiency has been reported to associate with impaired development of antigen-specific responses following vaccination. We aimed to determine whether vitamin D supplements might boost immunogenicity and efficacy of SARS-CoV-2 vaccination.MethodsWe conducted three sub-studies nested within the CORONAVIT randomised controlled trial, which investigated effects of offering vitamin D supplements at a dose of 800 IU/day or 3200 IU/day vs. no offer on risk of acute respiratory infections, including COVID-19, in UK adults with circulating 25-hydroxyvitamin D concentrations <75 nmol/L. Sub-study 1 (n=2808) investigated effects of vitamin D supplementation on risk of breakthrough SARS-CoV-2 infection following two doses of SARS-CoV-2 vaccine. Sub-study 2 (n=1853) investigated effects of vitamin D supplementation on titres of combined IgG, IgA and IgM (IgGAM) anti-Spike antibodies in eluates of dried blood spots collected after SARS-CoV-2 vaccination. Sub-study 3 (n=100) investigated effects of vitamin D supplementation on neutralising antibody and cellular responses in venous blood samples collected after SARS-CoV-2 vaccination.Results1945/2808 (69.3%) sub-study 1 participants received two doses of ChAdOx1 nCoV-19 (Oxford–AstraZeneca); the remainder received two doses of BNT162b2 (Pfizer). Vitamin D supplementation did not influence risk of breakthrough SARS-CoV-2 infection (800 IU/day vs. no offer: adjusted hazard ratio 1.28, 95% CI 0.89 to 1.84; 3200 IU/day vs. no offer: 1.17, 0.81 to 1.70). Neither did it influence IgGAM anti-Spike titres, neutralising antibody titres or IFN-γ concentrations in supernatants of S peptide-stimulated whole blood.ConclusionsAmong adults with sub-optimal baseline vitamin D status, vitamin D replacement at a dose of 800 or 3200 IU/day did not influence protective efficacy or immunogenicity of SARS-CoV-2 vaccination.Clinical Trial RegistrationClinicalTrials.govNCT04579640.

Vitamin D deficiency has been reported to associate with the impaired development of antigen-specific responses following vaccination. We aimed to determine whether vitamin D supplements might boost the immunogenicity and efficacy of SARS-CoV-2 vaccination by conducting three sub-studies nested within the CORONAVIT randomised controlled trial, which investigated the effects of offering vitamin D supplements at a dose of 800 IU/day or 3200 IU/day vs. no offer on risk of acute respiratory infections in UK adults with circulating 25-hydroxyvitamin D concentrations <75 nmol/L. Sub-study 1 (n = 2808) investigated the effects of vitamin D supplementation on the risk of breakthrough SARS-CoV-2 infection following two doses of SARS-CoV-2 vaccine. Sub-study 2 (n = 1853) investigated the effects of vitamin D supplementation on titres of combined IgG, IgA and IgM (IgGAM) anti-Spike antibodies in eluates of dried blood spots collected after SARS-CoV-2 vaccination. Sub-study 3 (n = 100) investigated the effects of vitamin D supplementation on neutralising antibody and cellular responses in venous blood samples collected after SARS-CoV-2 vaccination. In total, 1945/2808 (69.3%) sub-study 1 participants received two doses of ChAdOx1 nCoV-19 (Oxford–AstraZeneca); the remainder received two doses of BNT162b2 (Pfizer). Mean follow-up 25(OH)D concentrations were significantly elevated in the 800 IU/day vs. no-offer group (82.5 vs. 53.6 nmol/L; mean difference 28.8 nmol/L, 95% CI 22.8–34.8) and in the 3200 IU/day vs. no offer group (105.4 vs. 53.6 nmol/L; mean difference 51.7 nmol/L, 45.1–58.4). Vitamin D supplementation did not influence the risk of breakthrough SARS-CoV-2 infection in vaccinated participants (800 IU/day vs. no offer: adjusted hazard ratio 1.28, 95% CI 0.89 to 1.84; 3200 IU/day vs. no offer: 1.17, 0.81 to 1.70). Neither did it influence IgGAM anti-Spike titres, neutralising antibody titres or IFN-γ concentrations in the supernatants of S peptide-stimulated whole blood. In conclusion, vitamin D replacement at a dose of 800 or 3200 IU/day effectively elevated 25(OH)D concentrations, but it did not influence the protective efficacy or immunogenicity of SARS-CoV-2 vaccination when given to adults who had a sub-optimal vitamin D status at baseline.

In this population-based cohort of 7538 adults, combined immunoglobulin (Ig) G, IgA, and IgM (IgG/A/M) anti-spike titers measured after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination were predictive of protection against breakthrough SARS-CoV-2 infection. Discrimination was significantly improved by adjustment for factors influencing risk of SARS-CoV-2 exposure, including household overcrowding, public transport use, and visits to indoor public places. Anti-spike IgG/A/M titers showed positive correlation with neutralizing antibody titers (rs = 0.80 [95% confidence interval, .72-.86]; P < .001) and S peptide-stimulated interferon-γ concentrations (rs = 0.31 [.13-.47]; P < .001).

In this population-based cohort of 7530 adults, combined IgG/A/M anti-Spike titres measured after SARS-CoV-2 vaccination were predictive of protection against breakthrough SARS-CoV-2 infection. Discrimination was significantly improved by adjustment for factors influencing risk of SARS-CoV-2 exposure including household overcrowding, public transport use, and visits to indoor public places.

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 macrophage and monocyte phenotype and function change with age. The impact of ageing on macrophages includes decreased phagocytosis and immune resolution, increased senescent-associated markers, increased inflammatory cytokine production, reduced autophagy, and a 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.