Immunity & Ageing最新文献

Decline in immune function with age has been studied extensively, but approaches to immune restoration have been hampered by the lack of simple methods of identifying individuals whose immune system is in decline. Our approach has been to identify individuals whose immune decline has led to a loss of control of common latent viral infections and their consequent reactivation. Viruses excreted in urine were detected and quantified and we believe this approach could provide a 'surrogate marker' for identifying immune compromised individuals. Here we report the detection of human herpes virus (HHV) 5, 6a, 6b and 7 in the urine of healthy individuals over a wide age range and their correlation with T cell receptor excision circle (TREC) data. The results did not show a clear correlation between TREC values and the detection of individual specific viruses or viral load values when measured singly. However, a correlation was found between low TREC values and the detection of several different human herpes viruses in the urine in males. We present evidence suggesting that for males, the detection of three or more different human herpes viruses in the urine could identify individuals with declining immune function as evidenced by their significantly lower TREC levels.

Introduction: Immunotherapy with checkpoint inhibition (ICI) is increasingly prescribed to older patients with cancer. High age, especially in combination with frailty, has been associated to immune senescence, which is the age-related decline in immune function, thereby possibly hindering ICI effectiveness. This cross-sectional study aimed to assess whether blood cell immune senescence markers are associated with age, frailty and response to anti-PD-1 treatment in older patients with metastatic melanoma.

Methods: In a prospective observational study, sixty patients with stage IIIC or IV melanoma undergoing anti-PD1 treatment were categorized into young (< 65 years; n = 22), old (> 65 years) without frailty (n = 19), and old with frailty (n = 19). In-depth immune cell phenotyping was performed in baseline blood samples (prior to treatment) using multispectral flow cytometry and compared between groups and with immunotherapy treatment response. Antigen-presenting cell capacity was evaluated using mixed lymphocyte reaction and T cell proliferative potential was assessed using PHA proliferation assay.

Results: No significant differences in treatment response rates were observed across age groups. Older patients, irrespective of frailty, showed lower levels of naïve CD8 + T cells, with the old and frail group also exhibiting reduced tissue-resident effector memory CD8 + T cells and CD8 + mucosal associated invariant T (MAIT) cells. These differences were not associated with treatment outcomes. T cell proliferation and antigen-presenting cell capacities did not differ across groups.

Conclusion: Several ageing and frailty associated changes were detected among circulating immune cells in blood but were not associated with response to immunotherapy in our study. While these findings suggest that the level of frailty and ageing may not necessarily preclude the efficacy of ICI therapy, further investigation is needed to fully understand the impact of frailty and ageing on immunotherapy.

Background: MicroRNAs (miRNAs) play crucial roles in regulating inflammation and cellular senescence. Among them, miR-146a has emerged as a key modulator of inflammation, but its role in obesity-induced senescence remains unexplored. This study investigates the involvement of miR-146a in high-fat diet (HFD)-induced hypothalamic senescence and in protective effects of elocalcitol (Elo), a non-hypercalcemic, fluorinated vitamin D analog on HFD-induced senescence.

Results: Wild-type (WT) HFD-fed mice exhibited increased body weight, impaired locomotor activity, and cognitive decline compared to low-fat diet (LFD) controls. In the brain, HFD induced senescence markers (p16, p21), β-galactosidase activity (β-gal) of microglia, and increased expression of senescence associated secretory phenotype (SASP) cytokines (Il1b, Il18, Tnf, Il6) in activated hypothalamic microglia. In the liver, increased p21 and SASP cytokines were detected, although p16 and β-gal levels remained unchanged. Importantly, miR-146a expression was significantly downregulated in the hypothalamus following HFD exposure in WT mice, while miR-146a knockout (Mir146a-/-) mice subjected to HFD showed augmented hypothalamic senescence characterized by higher levels of p16, p21, and β-gal + microglial cells as compared to WT mice. The SASP profile remained similar between Mir146a-/- HFD and WT HFD mice. Among miR-146a target genes, smad4 was upregulated the hypothalamus of HFD-fed mice, with a more pronounced increase in the hypothalamus of HFD-fed Mir146a-/- mice. Further, treatment with Elo upregulated miR-146a expression in both the hypothalamus and the liver, lowered body weight and improved cognitive function, while reducing senescence markers and SASP cytokines in WT HFD mice. These effects were absent in Mir146a-/- HFD mice when treated with Elo, indicating the dependence of Elo's therapeutic efficacy on miR-146a.

Conclusion: Elocalcitol prevents development of senescence in microglia via modulation of miR-146a expression, while miR-146a provides protection against HFD-induced cellular senescence in the hypothalamus most probably via inhibition of TGF/Smad4 pathway. These findings highlight Elo and miR-146a as promising therapeutic candidates for ameliorating obesity-related neuroinflammation and senescence.

Ageing is a major risk factor that contributes to increased mortality and morbidity rates during influenza A virus (IAV) infections. Macrophages are crucial players in the defense against viral infections and display impaired function during ageing. However, the impact of ageing on macrophage function in response to an IAV infection remains unclear and offers potential insight for underlying mechanisms. In this study, we investigated the immune response of young and aged human monocyte-derived macrophages to two different H1N1 IAV strains. Interestingly, macrophages of aged individuals showed a lower interferon response to IAV infection, resulting in increased viral load. Transcriptomic data revealed a reduced expression of stimulator of interferon genes (STING) in aged macrophages albeit the cGAS-STING pathway was upregulated. Our data clearly indicate the importance of STING signaling for interferon production by applying a THP-1 STING knockout model. Evaluation of mitochondrial function during IAV infection revealed the release of mitochondrial DNA to be the activator of cGAS-STING pathway. The subsequent induction of apoptosis was attenuated in aged macrophages due to decreased STING signaling. Our study provides new insights into molecular mechanisms underlying age-related immune impairment. To our best knowledge, we are the first to discover an age-dependent difference in gene expression of STING on a transcriptional level in human monocyte-derived macrophages possibly leading to a diminished interferon production.

Cognitive decline is a critical hallmark of brain aging. Although aging is a natural process, there is significant heterogeneity in cognition levels among individuals; however, the underlying mechanisms remain uncertain. In our study, we classified aged male Sprague‒Dawley rats into aged cognition-unimpaired (AU) group and aged cognition-impaired (AI) group by using an attentional set-shifting task. The transcriptome sequencing results of medial prefrontal cortex (mPFC) demonstrated significant differences in microglial activation and inflammatory response pathways between the two groups. Specifically, compared to AU rats, AI rats exhibited a greater presence of CD86-positive microglia and major histocompatibility complex class II (MHC-II)-positive microglia, along with elevated inflammatory molecules, in mPFC. Conversely, AI rats exhibited a reduction in the percentage of microglia expressing CD200R and the anti-inflammatory molecules Arg-1 and TGF-β. Additionally, peripheral blood analysis of AI rats demonstrated elevated levels of Th17 and Th1 cells, along with proinflammatory molecules; however, decreased levels of Treg cells, along with anti-inflammatory molecules, were observed in AI rats. Our research suggested that peripheral Th17/Treg cells and central microglial activation were associated with cognitive heterogeneity in aged rats. These findings may provide a new target for healthy aging.

Background: Preventing metabolic syndrome (MetS) and frailty in older adults is crucial for healthy aging. The association between MetS and physical frailty is well-documented, with low-grade inflammation as potential explanation. However, the association between MetS and frailty as a multidimensional concept, and the association of low-grade inflammation with presence of MetS and frailty, is yet unclear. Therefore, we examined these associations low-grade inflammation in a large cohort of community-dwelling older adults.

Methods: This cross-sectional study was performed among adults aged ≥ 65 years enrolled in the Dutch Lifelines population cohort. MetS was defined according to the Joint Interim Statement of 2009. Frailty was measured by the Groningen Frailty Indicator (GFI), which consists of 15 self-reported items on both physical and psychosocial functioning, with a score ≥ 4 indicating presence of frailty. The association between MetS and its five components and frailty was assessed using logistic regression models. Low-grade inflammation was represented by high-sensitivity C-reactive protein (hsCRP) level. The association of hsCRP level with presence of MetS and frailty was assessed using multinomial logistic regression in a sub-cohort with available hsCRP measurements.

Results: Of 11,552 adults (52.1% women) included, the prevalences of MetS and frailty were 28% and 15%, respectively. MetS was positively associated with frailty after adjusting for relevant covariates (OR: 1.37; 95% CI: 1.22-1.53). MetS components elevated blood pressure was most strongly associated with frailty. In the sub-cohort of 3896 participants, high hsCRP was associated with presence of MetS and frailty (OR: 1.31; 95% CI: 1.15-1.51), and MetS alone (OR: 1.44; 95% CI: 1.33-1.56), but not to frailty alone. A higher hsCRP level was associated with a higher score on the physical domain of frailty (b: 0.06; 95% CI: 0.03-0.08).

Conclusions: Presence of MetS is associated with presence of frailty indicated by a multidimensional index in a large group of Dutch older adults. Low-grade inflammation, indicated by plasma hsCRP level, was found to be associated with both presence of MetS and frailty and presence of MetS alone. Increased hsCRP levels were associated with the physical component of frailty, but not with frailty as a multidimensional concept.

Background: Mast cells (MCs) are tissue resident cells of the immune system, mainly known for their role in allergy. However, mounting evidence indicates their involvement in the pathology of age-related diseases, such as Alzheimer's disease, Parkinson's disease, and cancer. MC numbers increase in aged tissues, but how ageing affects MCs is poorly understood.

Results: We show that MC ageing is associated with the increased expression of the cell cycle inhibitor p16 ^Ink4a, a marker and inducer of cellular senescence. Relying on this observation and the tight association of ageing with senescence, we developed a model of inducible senescence based on doxycycline-induced expression of p16^Ink4a in cultured bone marrow derived MCs (BMMCs). Using this model, we show that senescent MCs upregulate IL-1β, TNF-α and VEGF-A. We also demonstrate that senescence causes marked morphological changes that impact MC function. Senescent MCs are larger, contain a larger number of secretory granules (SGs) and have less membrane protrusions. Particularly striking are the changes in their SGs, reflected in a significant reduction in the number of electron dense SGs with a concomitant increase in lucent SGs containing intraluminal vesicles. The changes in SG morphology are accompanied by changes in MC degranulation, including a significant increase in receptor-triggered release of CD63-positive extracellular vesicles (EVs) and the exteriorisation of proteoglycans, as opposed to a gradual inhibition of the release of β-hexosaminidase.

Conclusions: The inducible expression of p16^Ink4a imposes MC senescence, providing a model for tracking the autonomous changes that occur in MCs during ageing. These changes include both morphological and functional alterations. In particular, the increased release of small EVs by senescent MCs suggests an enhanced ability to modulate neighbouring cells.

In the last forty years, the number of people over 60 years of age has increased significantly owing to better nutrition and lower rates of infectious diseases in developing countries. Aging significantly impacts adipose tissue, which plays crucial role in hormone regulation and energy storage. This can lead to imbalances in glucose, and overall energy homeostasis within the body. Aging is irreversible phenomena and potentially causing lipid infiltration in other organs, leading to systemic inflammation, metabolic disorders. This review investigates various pathways contributing to aging-related defects in adipogenesis, such as changes in adipose tissue function and distribution. Polyphenols, a diverse group of natural compounds, can mitigate aging effects via free radicals, oxidative stress, inflammation, senescence, and age-related diseases. Polyphenols like resveratrol, quercetin and EGCG exhibit distinct mechanisms and regulate crucial pathways, such as the TGF-β, AMPK, Wnt, PPAR-γ, and C/EBP transcription factors, and influence epigenetic modifications, such as DNA methylation and histone modification. This review highlights the critical importance of understanding the intricate relationship between aging and adipogenesis for optimizing well-being with increasing age. These findings highlight the therapeutic potential of polyphenols like quercetin and resveratrol in enhancing adipose tissue function and promoting healthy aging.

Background: The circulatory peripheral immune system is the most convenient approach for determining an individual's immune status. Due to various reasons, while previous studies have addressed the critical impact of age, most individual studies did not analyze immunosenescence in a systemic manner, which complicates the possibility of building a reference range for age-dependent immune profiles for effective immune monitoring. To address this gap, this study analyzed a group of healthy individuals to establish age-specific reference ranges of the healthy circulatory immune profile, and a systematic review and meta-analysis were conducted to validate the findings and create generalizable immune cell reference ranges.

Results: Our study recruited a total of 363 healthy Taiwanese adults (median age 42 years [IQR 30, 62], age range 21 to 87 years, 43.3% male), including 158 under 40 years old, 127 between 40-64 years old, and 78 over 64 years old. Significant age-related alterations were observed in both adaptive and innate immune cell subsets. CD8 + T cells decreased and CD4/CD8 ratio increased, with notable increases in NK cells. CD4 + T cells were less impacted by aging, while CD8 + T cells significantly lost CD28 and increased CD31 expression with age. A clear reverse trend in naïve and memory subsets of CD4 + and CD8 + T cells was observed. Detailed reference ranges for immune cell subsets in healthy Taiwanese adults were established. A systematic review included 7,425 adults and a meta-analysis of 12 eligible studies confirmed our findings in Taiwan, enhancing generalizability.

Conclusions: Combined with previous studies and original data through a systematic review and meta-analysis, we highlighted and quantified significant immune profile differences between older and younger individuals. The sex and age-specific reference ranges for peripheral immune cell subsets can serve as a basis for effective immune monitoring of various aging-related illnesses.