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The intestinal epithelium serves as a physical and functional barrier against harmful substances, preventing their entry into the circulation and subsequent induction of a systemic immune response. Gut barrier dysfunction has recently emerged as a feature of ageing linked to declining health, and increased intestinal membrane permeability has been shown to promote heightened systemic inflammation in aged hosts. Concurrent with age‐related changes in the gut microbiome, the thymic microenvironment undergoes a series of morphological, phenotypical and architectural alterations with age, including disorganisation of the corticomedullary junction, increased fibrosis, increased thymic adiposity and the accumulation of senescent cells. However, a direct link between gut barrier dysbiosis and thymic involution leading to features of immune ageing has not been explored thus far. Herein, we reveal strong associations between enhanced microbial translocation and the peripheral accumulation of terminally differentiated, senescent and exhausted T cells and the compensatory expansion of regulatory T cells in older adults. Crucially, we demonstrate that aged germ‐free mice are protected from age‐related increases in intestinal permeability, highlighting the direct impact of mucosal permeability on thymic ageing. Together, these findings establish a novel mechanism by which gut barrier dysfunction drives systemic activation of the immune system during ageing through thymic involution. This enhances our understanding of drivers of T cell ageing and opens up the possibility for the use of microbiome‐based interventions to restore immune homeostasis and promote healthy ageing in older adults. [ABSTRACT FROM AUTHOR]

Abstract Background Traumatic injury elicits a hyperinflammatory response and remodelling of the immune system leading to immuneparesis. This study aimed to evaluate whether traumatic injury results in a state of prematurely aged immune phenotype to relate this to clinical outcomes and a greater risk of developing additional morbidities post-injury. Methods and findings Blood samples were collected from 57 critically injured patients with a mean Injury Severity Score (ISS) of 26 (range 15–75 years), mean age of 39.67 years (range 20–84 years), and 80.7% males, at days 3, 14, 28 and 60 post-hospital admission. 55 healthy controls (HC), mean age 40.57 years (range 20–85 years), 89.7% males were also recruited. The phenotype and frequency of adaptive immune cells were used to calculate the IMM-AGE score, an indicator of the degree of phenotypic ageing of the immune system. IMM-AGE was elevated in trauma patients at an early timepoint (day 3) in comparison with healthy controls (p

Background: Older people achieve lower levels of antibody titers than younger populations after Covid-19 vaccination and show a marked waning humoral immunity over time, likely due to the senescence of the immune system. Nevertheless, age-related predictive factors of the waning humoral immune response to the vaccine have been scarcely explored. In a cohort of residents and healthcare workers from a nursing home that had received two doses of the BNT162b2 vaccine, we measured specific anti-S antibodies one (T1), four (T4), and eight (T8) months after receiving the second dose. Thymic-related functional markers, including thymic output, relative telomere length, and plasma thymosin-α1 levels, as well as immune cellular subsets, and biochemical and inflammatory biomarkers, were determined at T1, and tested for their associations with the magnitude of the vaccine response (T1) and the durability of such response both, at the short- (T1-T4) and the long-term (T1-T8). We aimed to identify age-related factors potentially associated with the magnitude and persistence of specific anti-S immunoglobulin G (IgG)-antibodies after COVID-19 vaccination in older people. Results: Participants (100% men, n = 98), were subdivided into three groups: young (< 50 years-old), middle-age (50–65 years-old), and older (≥65 years-old). Older participants achieved lower antibody titers at T1 and experienced higher decreases in both the short- and long-term. In the entire cohort, while the magnitude of the initial response was mainly associated with the levels of homocysteine [β (95% CI); − 0.155 (− 0.241 to − 0.068); p = 0.001], the durability of such response at both, the short-term and the long-term were predicted by the levels of thymosin-α1 [− 0.168 (− 0.305 to − 0.031); p = 0.017, and − 0.123 (− 0.212 to − 0.034); p = 0.008, respectively]. Conclusions: Higher plasma levels of thymosin-α1 were associated with a lower waning of anti-S IgG antibodies along the time. Our results suggest that plasma levels of thymosin-α1 could be used as a biomarker for predicting the durability of the responses after COVID-19 vaccination, possibly allowing to personalize the administration of vaccine boosters. [ABSTRACT FROM AUTHOR]

Background: Traumatic injury elicits a hyperinflammatory response and remodelling of the immune system leading to immuneparesis. This study aimed to evaluate whether traumatic injury results in a state of prematurely aged immune phenotype to relate this to clinical outcomes and a greater risk of developing additional morbidities post-injury. Methods and findings: Blood samples were collected from 57 critically injured patients with a mean Injury Severity Score (ISS) of 26 (range 15–75 years), mean age of 39.67 years (range 20–84 years), and 80.7% males, at days 3, 14, 28 and 60 post-hospital admission. 55 healthy controls (HC), mean age 40.57 years (range 20–85 years), 89.7% males were also recruited. The phenotype and frequency of adaptive immune cells were used to calculate the IMM-AGE score, an indicator of the degree of phenotypic ageing of the immune system. IMM-AGE was elevated in trauma patients at an early timepoint (day 3) in comparison with healthy controls (p < 0.001), driven by an increase in senescent CD8 T cells (p < 0.0001), memory CD8 T cells (p < 0.0001) and regulatory T cells (p < 0.0001) and a reduction in naïve CD8 T cells (p < 0.001) and overall T cell lymphopenia (p < 0.0001). These changes persisted to day 60. Furthermore, the IMM-AGE scores were significantly higher in trauma patients (mean score 0.72) that developed sepsis (p = 0.05) in comparison with those (mean score 0.61) that did not. Conclusions: The profoundly altered peripheral adaptive immune compartment after critical injury can be used as a potential biomarker to identify individuals at a high risk of developing sepsis and this state of prematurely aged immune phenotype in biologically young individuals persists for up to two months post-hospitalisation, compromising the host immune response to infections. Reversing this aged immune system is likely to have a beneficial impact on short- and longer-term outcomes of trauma survivors. [ABSTRACT FROM AUTHOR]

Advancing age is accompanied by significant remodelling of the immune system, termed immune senescence, and increased systemic inflammation, termed inflammageing, both of which contribute towards an increased risk of developing chronic diseases in old age. Age‐associated alterations in metabolic homeostasis have been linked with changes in a range of physiological functions, but their effects on immune senescence remains poorly understood. In this article, we review the recent literature to formulate hypotheses as to how an age‐associated dysfunctional metabolism, driven by an accumulation of key host metabolites (saturated fatty acids, cholesterol, ceramides and lactate) and loss of other metabolites (glutamine, tryptophan and short‐chain fatty acids), might play a role in driving immune senescence and inflammageing, ultimately leading to diseases of old age. We also highlight the potential use of metabolic immunotherapeutic strategies targeting these processes in counteracting immune senescence and restoring immune homeostasis in older adults. LINKED ARTICLES: This article is part of a themed issue on Inflammation, Repair and Ageing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.9/issuetoc [ABSTRACT FROM AUTHOR]

Abstract Background Reduced response to hepatitis B vaccines is associated with aging, confounding and comorbid conditions, as well as inadvertent subcutaneous (SC) inoculation. We hypothesized that the antibody and T cell-mediated immune responses (T-CMI) of elderly adults to a vaccine intended for intramuscular (IM) administration would be attenuated when deposited into SC fat, independent of confounding conditions. Results Fifty-two healthy, community dwelling elderly adults (65–82 years), seronegative for HBV, were enrolled in the SENIEUR protocol as a strictly healthy population. These seniors were randomized to receive a licensed alum-adjuvanted recombinant HBV vaccine either SC or IM, with the inoculum site verified by imaging. The response rates, defined as hepatitis B surface antibodies (HBsAb) ≥10 IU/L, were significantly lower in the elderly than in young adults, a group of 12, healthy, 21–34-year-old volunteers. Moreover, elderly participants who received the vaccine IM were significantly more likely to be responders than those immunized SC (54% versus 16%, p = 0.008). The low seroconversion rate in the IM group progressively declined with increasing age, and responders had significantly lower HBsAb titers and limited isotype responses. Moreover, T-CMI (proliferation and cytokine production) were significantly reduced in both percentage of responders and intensity of the response for both Th1 and Th2 subsets in the elderly. Conclusions Our data demonstrate the blunted immunogenicity of SC inoculation as measured by peak titers and response rates. Further, the qualitative and quantitative deficits in B- and T-CMI responses to primary alum adjuvanted protein antigens persisted even in strictly healthy elderly populations with verified IM placement compared to younger populations. Clinical trial registration ClinicalTrials.gov , NCT04162223 . Registered 14 November 2019. Retrospectively registered.

Bearing a strong resemblance to the phenotypic and functional remodeling of the immune system that occurs during aging (termed immunesenescence), the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus disease 2019 (COVID-19), is characterized by an expansion of inflammatory monocytes, functional exhaustion of lymphocytes, dysregulated myeloid responses and the presence of highly activated senescent T cells. Alongside advanced age, male gender and pre-existing co-morbidities [e.g., obesity and type 2 diabetes (T2D)] are emerging as significant risk factors for COVID-19. Interestingly, immunesenescence is more profound in males when compared to females, whilst accelerated aging of the immune system, termed premature immunesenescence, has been described in obese subjects and T2D patients. Thus, as three distinct demographic groups with an increased susceptibility to COVID-19 share a common immune profile, could immunesenescence be a generic contributory factor in the development of severe COVID-19? Here, by focussing on three key aspects of an immune response, namely pathogen recognition, elimination and resolution, we address this question by discussing how immunesenescence may weaken or exacerbate the immune response to SARS-CoV-2. We also highlight how aspects of immunesenescence could render potential COVID-19 treatments less effective in older adults and draw attention to certain therapeutic options, which by reversing or circumventing certain features of immunesenescence may prove to be beneficial for the treatment of groups at high risk of severe COVID-19.

Bearing a strong resemblance to the phenotypic and functional remodeling of the immune system that occurs during aging (termed immunesenescence), the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus disease 2019 (COVID-19), is characterized by an expansion of inflammatory monocytes, functional exhaustion of lymphocytes, dysregulated myeloid responses and the presence of highly activated senescent T cells. Alongside advanced age, male gender and pre-existing co-morbidities [e.g., obesity and type 2 diabetes (T2D)] are emerging as significant risk factors for COVID-19. Interestingly, immunesenescence is more profound in males when compared to females, whilst accelerated aging of the immune system, termed premature immunesenescence, has been described in obese subjects and T2D patients. Thus, as three distinct demographic groups with an increased susceptibility to COVID-19 share a common immune profile, could immunesenescence be a generic contributory factor in the development of severe COVID-19? Here, by focussing on three key aspects of an immune response, namely pathogen recognition, elimination and resolution, we address this question by discussing how immunesenescence may weaken or exacerbate the immune response to SARS-CoV-2. We also highlight how aspects of immunesenescence could render potential COVID-19 treatments less effective in older adults and draw attention to certain therapeutic options, which by reversing or circumventing certain features of immunesenescence may prove to be beneficial for the treatment of groups at high risk of severe COVID-19. [ABSTRACT FROM AUTHOR]

Background: Reduced response to hepatitis B vaccines is associated with aging, confounding and comorbid conditions, as well as inadvertent subcutaneous (SC) inoculation. We hypothesized that the antibody and T cell-mediated immune responses (T-CMI) of elderly adults to a vaccine intended for intramuscular (IM) administration would be attenuated when deposited into SC fat, independent of confounding conditions. Results: Fifty-two healthy, community dwelling elderly adults (65–82 years), seronegative for HBV, were enrolled in the SENIEUR protocol as a strictly healthy population. These seniors were randomized to receive a licensed alum-adjuvanted recombinant HBV vaccine either SC or IM, with the inoculum site verified by imaging. The response rates, defined as hepatitis B surface antibodies (HBsAb) ≥10 IU/L, were significantly lower in the elderly than in young adults, a group of 12, healthy, 21–34-year-old volunteers. Moreover, elderly participants who received the vaccine IM were significantly more likely to be responders than those immunized SC (54% versus 16%, p = 0.008). The low seroconversion rate in the IM group progressively declined with increasing age, and responders had significantly lower HBsAb titers and limited isotype responses. Moreover, T-CMI (proliferation and cytokine production) were significantly reduced in both percentage of responders and intensity of the response for both Th1 and Th2 subsets in the elderly. Conclusions: Our data demonstrate the blunted immunogenicity of SC inoculation as measured by peak titers and response rates. Further, the qualitative and quantitative deficits in B- and T-CMI responses to primary alum adjuvanted protein antigens persisted even in strictly healthy elderly populations with verified IM placement compared to younger populations. Clinical trial registration: ClinicalTrials.gov, NCT04162223. Registered 14 November 2019. Retrospectively registered. [ABSTRACT FROM AUTHOR]

Summary: It is widely accepted that aging is accompanied by remodelling of the immune system including thymic atrophy and increased frequency of senescent T cells, leading to immune compromise. However, physical activity, which influences immunity but declines dramatically with age, is not considered in this literature. We assessed immune profiles in 125 adults (55–79 years) who had maintained a high level of physical activity (cycling) for much of their adult lives, 75 age‐matched older adults and 55 young adults not involved in regular exercise. The frequency of naïve T cells and recent thymic emigrants (RTE) were both higher in cyclists compared with inactive elders, and RTE frequency in cyclists was no different to young adults. Compared with their less active counterparts, the cyclists had significantly higher serum levels of the thymoprotective cytokine IL‐7 and lower IL‐6, which promotes thymic atrophy. Cyclists also showed additional evidence of reduced immunesenescence, namely lower Th17 polarization and higher B regulatory cell frequency than inactive elders. Physical activity did not protect against all aspects of immunesenescence: CD28−veCD57+ve senescent CD8 T‐cell frequency did not differ between cyclists and inactive elders. We conclude that many features of immunesenescence may be driven by reduced physical activity with age. [ABSTRACT FROM AUTHOR]

Current concept in periodontal diseases (PDs) states that it is the host's response toward the periodontal pathogens which leads to tissue destruction and attachment loss. Hence the role of immune response in the progression and resolution of PD must be considered vital. Any alteration in the immune system disturbs the homeostasis of the periodontium. Decline in immune system is the hallmark of aging, leading to increased susceptibility of elderly individuals to bacterial infections. The periodontal apparatus which is being constantly exposed to plaque biofilm is more vulnerable to destruction in aged individuals. Ageing related alterations in immune system has been discussed elsewhere as a contributor to various chronic inflammatory diseases like atherosclerosis, preterm, and low birth weight, etc. This paper reviews on the possible role of aging in periodontal destruction through altered immunity. Aging has long been associated with altered systemic inflammation. It has been discussed whether (1) this systemic inflammation is a consequence of increased occurrence of chronic inflammatory diseases upon aging or (2) aging associated systemic inflammation leads to such diseases. The immune responses which are protective at the first stages of life might result detrimental in the elderly. Hence it might be very difficult to individuate genetic profiles that might allow to identify individuals with a major risk for one or more age related diseases. Taking this into consideration, the cause of PDs in elderly is addressed with a systemic approach in order to understand the complex interplay between the aging immunity and PDs. [ABSTRACT FROM AUTHOR]

Clostridium difficile infection (CDI) is the leading cause of nosocomial diarrhoea in older people, causing substantial morbidity and mortality. The fact that CDI is almost exclusively a disease of older people and the debilitated indicates that patient susceptibility is a major determinant of who gets CDI. It would help efforts to combat this disease if we better understood and could reduce patient susceptibility. In this regard, several strategies are currently under investigation. The use of probiotics for CDI has received particular attention in the medical and lay media. Patients and their carers often ask doctors about them. In this review article, we describe the pathogenesis of CDI before looking at the ageing host in more detail. We discuss how probiotics may work and review the current evidence for their use in CDI. [ABSTRACT FROM AUTHOR]

Aging is accompanied by immune responsiveness alterations, which lead to an increase in susceptibility to infectious diseases, a decrease in response to immunizations, and an increase in autoimmune diseases incidence (1). In this study we have evaluated the immune response of the elderly and the aging associated-inflammation status and we correlate the results with other hematological parameters, clinical status and the existing chronic diseases. We have lead a prospective study on 49 elderly patients without clinical signs of acute infections or inflammation at the beginning of the study, which have been monitored at 1 month, 3 months and 6 months. [ABSTRACT FROM AUTHOR]

Background: A reduced number of naïve T cells along with an accumulation of differentiated cell types in aging have been described but little is known about the polyfunctionality of the T cell responses. In this study we compared the individual and polyfunctional expression of IFN-γ, MIP-1α, TNF-α, perforin, and IL-2 by T cell subsets, including the newly described stem cell like memory T cells (TSCM), in response to stimulation with superantigen staphylococcal enterotoxin B (SEB) in older (median age 80, n = 23) versus younger (median age 27; n = 23) adults., Results: Older age was associated with a markedly lower frequency of CD8+ naïve T cells (11% vs. 47%; p < 0.0001) and an expansion in memory T cell subsets including central memory (p < 0.05), effector memory and effector T cells (p < 0.001 for both). There was also a decline in CD4+ naïve T cells in older subjects (33% vs. 45%; p = 0.02). There were no differences in frequencies or polyfunctional profiles of TSCM between groups. CD8+ naïve cells in the older group had increased expression of all functional parameters measured compared to the younger subjects and exhibited greater polyfunctionality (p = 0.04). CD4+ naïve T cells in the older group also showed greater polyfunctionality with a TNF-α and IL-2 predominance (p = 0.005). CD8+ effector memory and effector T cells exhibited increased polyfunctionality in the older group compared with younger (p = 0.01 and p = 0.003)., Conclusions: These data suggest that aging does not have a negative effect on polyfunctionality and therefore this is likely not a major contributor to the immunesenescence described with aging.

With a falling birth rate and increasing life expectancy we are experiencing dramatic demographic changes that result in an ever ageing population. Ageing is accompanied by increased susceptibility to bacterial and viral infections indicative of a decline in immunity, termed immunesenescence. Immunesenescence also has implications for vaccination programmes and there is clear evidence that the decline in adaptive immunity results in dramatically reduced vaccine responses and vaccine longevity in older adults. This review summarises some of the key changes in the adaptive immune response that change with age and suggests approaches that could be used to try and improve vaccine responses in older adults.