Immunity & Ageing最新文献

Aging is a multifactorial biological process driven by oxidative stress, chronic inflammation, genomic instability, and mitochondrial dysfunction. Recent research underscores the potential of naturally derived compounds to modulate these aging hallmarks. Curcumin, epigallocatechin gallate (EGCG), thymoquinone, and resveratrol exhibit antioxidant, anti-inflammatory, and autophagy-enhancing effects that target core pathways involved in cellular senescence and tissue degeneration. These phytochemicals regulate key molecular players such as sirtuins, AMPK, NF-κB, and mTOR, offering promise in delaying age-associated pathologies and promoting longevity. This review discusses the molecular mechanisms underlying their anti-aging actions and highlights their potential as dietary geroprotective interventions.

Background: Aging is linked to various dysfunctions of the immune system, including the decline of its primary developmental source: the hematopoietic stem cell (HSC) niche. This decline leads to chronic inflammation, increased vulnerability to infections, cancer, autoimmune diseases, and reduced vaccine efficacy. As individuals age, the HSC niche undergoes significant changes, including greater adipocyte accumulation and alterations in the molecular microenvironment, which may influence the development and function of immune cells. Among these cells, the impact of the aging HSC niche on dendritic cell (DC) function is less understood. Heterochronic autologous HSC transplantation is a promising intervention to prevent age-related disorders, contributing to the extension of healthspan and longevity, however, several murine experiments failed to produce the expected results, which led us to presume that the problem lies within the old HSC niche. Therefore, we created in vitro models of young and old HSC niches and examined how these microenvironments affect the differentiation and maturation and functionality of BM-derived DCs (BMDCs).

Results: An analysis of the conditioned media from young and aged HSC niches revealed that the environment of aged niches exhibited an increased presence of adiponectin. This media was subsequently utilized in BMDC differentiation and maturation protocols, with their effects closely monitored. Our results indicate that the old HSC niche microenvironment promotes premature BMDC activation, characterized by elevated MHC class II expression and enhanced allostimulatory capacity of BMDCs at their immature stage. Additionally, LPS stimulation of BMDCs, used to induce DC maturation, significantly increased CD86 expression on BMDCs from the aged niche. However, these cells did not show superior allostimulatory capacity compared to their counterparts from the young niche environment. By analyzing the BMDC cytokine profile, we observed that when cultured in aged niche-conditioned media, the BMDCs secreted significantly higher levels of IL-6, indicating a heightened proinflammatory activation state.

Conclusions: Collectively, our findings suggest that aging-related changes within the HSC niche can considerably alter DC functionality by disrupting their normal development from BM precursors. These results emphasize the significance of this phenomenon and its implications for immunosenescence.

Background: Cytomegalovirus (CMV) infection is one of the most common infections in humans, and CMV antigens are the major drivers of repetitive T-cell stimulation as a part of a well-adapted immune response in immunocompetent individuals. With higher age, the recurrent clonal expansion of CMV-specific T cells results in high frequencies of CMV-specific effector T cells. Further on, CMV seropositivity has been linked to an increased risk of developing cardiovascular diseases (CVD). Here we investigated the frequency and phenotype of CMV-specific T cells in the circulation of a population cohort of 650 individuals focusing on the age group over 60 years. Circulating immune cells of individuals carrying the HLA-A*02 allele were investigated (n = 302) applying MHC class I tetramers.

Results: We add to previous knowledge by showing that the frequency of CMVpp65-specific CD8⁺ T cells is associated with the total percentage and absolute counts of CD8⁺ and CD4⁺CD8⁺ double-positive T cells within leukocytes, and further with systolic blood pressure (SBP) and history of CVD. An investigation into the differentiation status of CMV-specific T cells revealed an association of higher age and increased frequencies of both T_EM and CD27-expressing T_EMRA cells. In contrast, higher CMV-IgG titers were found to be associated with T_EM and CD27^- T_EMRA cell frequencies. SBP significantly correlated with CMV-specific effector CD8⁺ T cells, which was mostly reflected by CD27^- T_EMRA cells.

Conclusions: Within the circulating CMV-specific T cell population, different effector T-cell subtypes were associated with age, serostatus and SBP. This suggests that it is not age or infection per se that render CMV-positive individuals susceptible to CVD, but rather the cellular immune response to CMV. Detailed immunophenotyping may identify individuals whose immune systems are strongly influenced by the response to CMV, leading to health consequences and impairing healthy aging.

The purpose of this study was to determine the relationship between the serum levels of kappa (κ) and lambda (λ) total light chain (TLC), the κ/λ ratio, and the combined serum TLCκ and TLCλ (ΣTLC) levels in Chinese centenarians and all-cause mortality. The association between serum TLC and all-cause mortality was investigated using restricted cubic spline (RCS) analysis, Cox proportional hazards models, and Kaplan‒Meier curves. The study included 906 centenarians (18.8% male), 838 (92.5%) of whom died during a median follow-up of 30 months. The proportions of centenarians with abnormal TLCκ and TLCλ levels were 68.1% and 49.0%, respectively. RCS analysis indicated that the levels of TLCκ, TLCλ, and ΣTLC were associated with all-cause mortality (P < 0.05), whereas the κ/λ ratio was not (P > 0.05). Cox proportional hazards analysis demonstrated that the highest quartiles of TLCκ, TLCλ, and ΣTLC were associated with an increased risk of death, with hazard ratios of 1.434 (95% confidence interval [CI], 1.061-1.939; P = 0.019), 1.351 (95% CI, 1.013-1.802; P = 0.041), and 1.891 (95% CI, 1.347-2.654; P < 0.001), respectively. Kaplan-Meier analysis illustrated that centenarians with higher levels of TLCκ, TLCλ, and ΣTLC had significantly shorter median survival times (26 months versus 35 months, P < 0.001; 26 months versus 32 months, P = 0.003; and 26 months versus 36 months, P < 0.001, respectively). Our findings suggest that serum levels of TLCκ, TLCλ, and ΣTLC are significantly associated with all-cause mortality in centenarians. Trial registration Not applicable.

Neurodegenerative dementias including Alzheimer disease severely impair cognitive and social abilities and are a major cause of mortality with no causal treatment yet. Autoimmune mechanisms have been increasingly considered to contribute to disease progression, e.g. by enhancing protein misfolding or pro-inflammatory immune responses. Understanding this contribution may lead to novel treatment options beyond removing neurodegeneration-associated proteins. We hypothesized that CD4⁺ T_H cells against synaptic proteins may play a role in dementia, given the profound changes of synaptic proteins in the disease. We investigated T_H cell frequencies and phenotypes after antigen-reactive T cell enrichment (ARTE) using three important synaptic antigens known to play a role in cognitive function, N-Methyl-D-Aspartate receptor (NMDAR), Leucine-rich, glioma inactivated 1 (LGI1) and metabotropic glutamate receptor 5 (mGluR5). Our data revealed that synaptic autoantigen-specific T_H cells occurred in all cohorts and were similarly frequent in patients with dementia and sex- and age-matched controls. However, they were significantly reduced compared to young healthy subjects, indicating strong age-related effects ('immune senescence'). Compared to the ubiquitously available Candida albicans antigen, synaptic autoantigen-specific T_H cell responses were strongly driven by IFNγ-producing T cells, expression of which markedly decreased with age. Patients with dementia had significantly less IL-17-producing synaptic autoantigen-specific T_H cells than aged healthy controls. This first direct ex vivo quantitative and qualitative analysis of circulating T cells autoreactive to three synaptic autoantigens in dementia shows no correlation with cognitive impairment. It suggests that synaptic autoantigen-specific T_H cells decline with age and are not a major driver of dementia development.

Aging is a complex and multifaceted biological process that results in the gradual decline of physiological functions over time. It is associated with reduced performance across multiple systems, affecting metabolic, reproductive, musculoskeletal, and immune functions. While immune aging has been extensively studied in endothermic animals, and in particular mammals such as laboratory rodents, comparatively little is known about how aging manifests in ectothermic vertebrates like reptiles. This study explored the lymphoid tissue (spleen and thymus) of Boa constrictor, a boid snake indigenous to South and Central America and Mexico, but widely kept in captivity all over the world, for potential age-related changes. We observed a significant decrease in cellularity in the spleen, coupled with an increase in organ size correlated with age. In both spleen and thymus the connective tissue of capsule and trabeculae increased significantly with age, indicative of progressive fibrosis. In addition, several changes were observed with increasing frequency in older animals, epithelial hyperplasia in the thymic medulla as well stromal fibrosis and an increasing infiltration by so-called granular cells in both organs. Granular cells likely represent a leukocyte subtype; their presence indicates a progressive chronic low-grade inflammatory state in the lymphoid organs, a feature known as inflammaging in other animal classes. They may also play a role in the progressive fibrosis of the connective tissue. The results firstly describe morphological evidence of aging in B. constrictor and indicate similarities in the aging across animal classes.

Background: Immunosenescence is characterized by a decline in naive T cells, a reduced T cell receptor repertoire, and the accumulation of terminally-differentiated and unspecifically-activated proinflammatory cells, a process called inflammageing. Premature immunosenescence is thought to be pathogenetically relevant in rheumatoid arthritis (RA), either by posing a risk factor for its development, or by advancing the rheumatic disease as a result of excess antigenic and inflammatory stimulation. We investigated parameters of immunosenescence in RA patients treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) only compared to patients treated additionally or exclusively with a tumor necrosis factor inhibitor (TNFi) and age-matched healthy controls to investigate the effect of RA treatment on age-associated T cell phenotypes and functions.

Results: The csDMARD-only treated patients, compared to the TNFi-treated patients and healthy controls, displayed an enhanced age-dependent decline in CD31⁺ recent thymic emigrants (RTE) and Interleukin-7 (IL-7)-receptor α-chain (CD127)-expressing CD4⁺ T cells participating in IL-7-associated homeostatic proliferation, a diminished proliferation of RTE and CD127⁺ T cells, as well as reduced T cell receptor excision circle (TREC) counts. However, whereas the RA patients exhibited reduced proportions of unspecifically activated IFNγ- and IL-17-producing T cells, TNFi initiation induced an increase in these proinflammatory cells.

Conclusions: Whereas a TNFi treatment seems to counteract the non-inflammatory aspects of immunosenescence, it induces increasing proportions of terminally-differentiated, cytokine-producing effector memory T cells, requiring awareness as possibly contributing to secondary autoimmune phenomena in RA.

Background: Immunosenescence is the loss and change of immunological organs, as well as innate and adaptive immune dysfunction with ageing, which can lead to increased sensitivity to infections, age-related diseases, and cancer. Emerging evidence highlights the role of gut-vitamin D axis in the regulation of immune ageing, influencing chronic inflammation and systemic health. This review aims to explore the interplay between the gut microbiota and vitamin D in mitigating immunosenescence and preventing against chronic inflammation and age-related diseases.

Main text: Gut microbiota dysbiosis and vitamin D insufficiency accelerate immunosenescence and risk of chronic diseases. Literature data reveal that vitamin D modulates gut microbiota diversity and composition, enhances immune resilience, and reduce systemic inflammation. Conversely, gut microbiota influences vitamin D metabolism to promote the synthesis of active vitamin D metabolites with implications for immune health.

Conclusions: These findings underscore the potential of targeting gut-vitamin D axis to modulate immune responses, delay the immune ageing, and mitigate age-related diseases. Further research is needed to integrate vitamin D supplementation and microbiome modulation into strategies aimed at promoting healthy ageing.

As global life expectancy increases, research reveals a critical challenge in aging: the progressive deterioration of immune function, termed immunosenescence. This age-related immune decline is characterized by a complex dysregulation of immune responses, which leaves older adults increasingly vulnerable to infections, chronic inflammatory states, and various degenerative diseases. Without intervention, immunosenescence significantly contributes to morbidity and mortality among the elderly, intensifying healthcare burdens and diminishing quality of life on both individual and societal levels. This review explores the essential role of zinc, a trace element critical for immune health, in mitigating the impact of immunosenescence and slowing the cascade of immunological dysfunctions associated with aging. By modulating the activity of key immune cells and pathways, zinc supplementation emerges as a promising approach to strengthen immunity, reduce oxidative stress, and counteract "inflammaging," a state of chronic, low-grade inflammation that accelerates tissue damage and drives disease progression. Zinc's involvement in cellular defense and repair mechanisms across the immune system highlights its ability to enhance immune cell functionality, resilience, and adaptability, strengthening the body's resistance to infection and its ability to manage stressors that contribute to diseases of aging. Indeed, zinc has demonstrated potential to improve immune responses, decrease inflammation, and mitigate the risk of age-related conditions including diabetes, depression, cardiovascular disease, and vision loss. Given the prevalent barriers to adequate zinc intake among older adults, including dietary limitations, decreased absorption, and interactions with medications, this review underscores the urgent need to address zinc deficiency in aging populations. Recent findings on zinc's cellular and molecular effects on immune health present zinc supplementation as a practical, accessible intervention for supporting healthier aging and improving quality of life. By integrating zinc into targeted strategies, public health efforts may not only sustain immunity in the elderly but also extend healthy longevity, reduce healthcare costs, and potentially mitigate the incidence and impact of chronic diseases that strain healthcare systems worldwide.