Immunity & Ageing最新文献

Cellular senescence is a fundamental biological process characterized by stable cell cycle arrest, genomic instability, and the acquisition of a proinflammatory secretory phenotype. While senescence is traditionally associated with aging, growing evidence reveals that chronic infections such as viral, bacterial, and protozoan parasites can serve as powerful inducers of senescence, contributing to premature aging and long-term tissue damage. This review explores the diverse mechanisms by which persistent pathogens trigger or sustain senescence in host cells. We highlight how these chronic infections manipulate host DNA repair, mitochondrial dynamics, telomere maintenance, oxidative stress, and immune function to promote senescence and immunosenescence. Emerging findings also reveal how pathogens hijack the host cellular machinery to induce senescence across various tissue types. In many cases, senescence not only enables pathogen persistence but also drives pathological outcomes such as fibrosis, neurodegeneration, cardiomyopathy, and immune exhaustion. Collectively, this emerging evidence highlights a unifying strategy among diverse pathogens: the exploitation of cellular senescence to support chronic infection and promote disease. Understanding how infectious agents drive senescence offers new insights into age-related pathologies and highlights potential therapeutic targets, such as senolytic and senomorphic agents, to mitigate the long-term impacts of chronic infections.

We have previously demonstrated that proinflammatory T cells in adipose tissue and the liver play a mechanistic role in glucose intolerance in old mice. Further, we and others have demonstrated that early life thymectomy results in a T cell phenotype that shares many features of classical T cell aging in an otherwise young healthy mouse. In this investigation, we sought to test the hypothesis that inducing premature T cell aging via early life thymectomy results in T cell mediated inflammation of the liver and visceral adipose tissue, as well as glucose intolerance in otherwise young mice. Mice were thymectomized at three weeks of age. At 9 months of age, thymectomized mice exhibited glucose intolerance that was independent of body mass along with greater frailty. Thymectomized mice exhibited blunted proportions of naïve and greater proportions of memory cells in the spleen, liver and perigonadal adipose tissue (pgWAT). Bulk RNAseq of the pgWAT revealed that thymectomized mice exhibited an upregulation of genes responsible for immune activation, chemokine signaling, and inflammation along with a downregulation of genes responsible for metabolic function. We also found that T cells in the pgWAT of thymectomized mice exhibited greater chemokine receptor expression as well as increased markers of histopathological inflammation that were independent of greater adipose tissue expansion. These results suggest that early life thymectomy results in T cell mediated pgWAT inflammation, systemic glucose intolerance and frailty in adult mice.

Known as immunosenescence, the major dysregulation of the immune system with age is associated with poor vaccination efficacy, and increased susceptibility to infections, age-related pathologies, and neoplasms, with incidences exacerbated with age. Cellular senescence is a crucial process that puts cells in an irreversible cell-cycle arrest which prevents damaged or stressed cells from uncontrolled propagation and eventually potential malignancy. Paradoxically, senescence also contributes to the occurrence of cancer and increases the risk of metastasis through different secretory mediators. Altogether, the recent use of senotherapy to eliminate senescent cells has been shown to delay tumorigenesis, attenuate age-related deterioration of organs, and promote healthy aging. Interestingly, immune cells have been shown to specifically interact with, and kill senescent cells, thus opening new opportunities for the development of specific therapeutic strategies similar to immunotherapy in cancer. Through its detrimental impact on the immune system, immunosenescence is also leading to the accumulation of senescent cells with age thus further contributing to the occurrence and worsening of multiple age-related pathologies such as cancer. Understanding the molecular and cellular events occurring during the aging process, and triggering immunosenescence as well as the mechanisms by which senescent cells escape immune surveillance would help to improve immune responses to senescent cells and their clearance. In this review, we highlight how senescent cells interact with immune cells, and how immunosenescence-associated phenotypical and functional deregulation hinder the ability of immune cells to clear senescent cells. We further characterize strategies aimed at promoting the clearance of senescent cells by the immune system.

The MetaboHealth score is an indicator of physiological frailty in middle aged and older individuals. The aim of the current study was to explore which molecular pathways co-vary with the MetaboHealth score. Using a Luminex cytokine assay and liquid chromatography-mass spectrometry-based proteomics we explored the plasma proteins associating with the difference in 100 extreme scoring individuals selected from two large population cohorts, the Leiden Longevity Study (LLS) and the Rotterdam Study (RS), and discordant monozygotic twin pairs from the Netherlands Twin Register (NTR). In addition, we estimated the heritability of the score using 726 monozygotic (MZ) and 450 dizygotic (DZ) twin pairs. In the contrasting extreme scoring individuals from LLS and RS, we uncovered significant differences in 3 (out of 15) cytokines (GDF15, IL6, and MIG), and 106 (out of 289) plasma proteins. The high, poor health related, score associated with 42 increased inflammatory and immune related protein levels (CRP, LBP, HPT) and lowered levels of 71 HDL remodeling and cholesterol transport related proteins (e.g. APOA1, APOA2, APOA4, and TETN). Using the NTR twins, we subsequently showed that the MetaboHealth score is moderately heritable (h² = 0.4). In MZ twins selected for maximal discordance within a pair we found 68 serum proteins associated with the MetaboHealth score indicating that only a minor part of the associations observed in LLS and RS is likely explained by genetic influences. Taken together, our study sheds light on the intricate interplay between the MetaboHealth score, plasma proteins, cytokines, and genetic influences, paving the way for future investigations aimed at optimizing this mortality risk indicator.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder and the most common cause of dementia. While the amyloid cascade hypothesis has long dominated AD research, emerging evidence suggests that neuroinflammation may play a more central role in disease onset and progression. Increasingly, AD is recognized as a multifactorial disorder influenced by systemic inflammation and immune dysregulation, shifting focus toward peripheral immune mechanisms as potential contributors to neurodegeneration. This review explores the hypothesis that inflammaging, the age-related increase in pro-inflammatory mediators, combined with lifelong exposure to infections, injuries, metabolic changes, and chronic diseases, among others, may prime the immune system, amplifying neuroinflammation and influencing the progression and exacerbation of AD pathology. To this end, we examined how systemic immune disturbances, including chronic pain, post-operative cognitive dysfunction, viral and bacterial infections, gut microbiome dysregulation, and cardiovascular disease, may act as risk factors for AD. Overall, evidence suggests that modulating peripheral inflammation, accompanied by early diagnosis, could significantly reduce the risk of developing AD. Furthermore, we highlight key immune signaling pathways involved in both central and peripheral immune responses, such as the NLRP3 inflammasome and TREM2, which represent promising therapeutic targets for modulating inflammation while preserving protective immune functions. Strategies aimed at reducing systemic inflammation, identifying early biomarkers, and intervening before significant neurodegeneration occurs may provide novel approaches to delay or prevent AD onset. In conclusion, this review underscores the crucial role of systemic inflammation in AD pathogenesis and progression. By targeting peripheral immune dysfunction, we may advance our understanding of AD mechanisms and develop more effective therapeutic interventions to mitigate disease risk and progression.

Elderly individuals were disproportionally affected during the COVID-19 pandemic, and more than 80% of the global COVID-19-related deaths between 2020 and 2021 occurred among people aged 60 years or older. Several cellular modifications in aged cells may lead to systemic inflammation and fibrotic responses. Age or exogenous insults induce cellular senescence, further increasing the release of pro-inflammatory mediators, leading to the condition known as inflammaging, that can contribute to disease severity. Older individuals presented signs of systemic hyperinflammation in severe COVID-19, but few studies analyzed the influence of age on lung tissue responses in cases of severe COVID-19. We hypothesized that age related alterations regarding innate/acquired immunity and cellular senescence in lung tissue of individuals without lung diseases could predispose to viral infection. We also aimed to identify how the aged lung responded to severe COVID-19 infection. We studied lung tissues from 19 individuals that died from non-pulmonary causes and 28 adult individuals who died from COVID-19 between March and May of 2020, divided according to their age (> or < 60 years). Tissue sections were stained, via immunohistochemistry, and 19 markers among immune cells, COVID-19 receptors, cytokines and senescence were analyzed in the lung parenchyma of both groups. In the COVID-19 group, the Luminex multiplex assay technique was used to detect a panel of 25 cytokines/chemokines. In control lungs, aged individuals had a lower TLR7 expression, without differences in other markers. Older patients had a shorter time between onset of symptoms and death, with a significant negative correlation with age. Unlike the adult younger group, older COVID - 19 patients presented significant differences in relation to their age matched controls in the expression of CD8 + T cells, IFN-α2, TLR7, pSTAT-3, p21 and p53. They also presented higher protein expression that IFN-α2 and TGF-beta than the adult COVID-19 group, with a trend to decreased CD20 + cell density in the lungs. Taken together, our data show age adversely affects the lung expression of key proteins related to COVID-19 susceptibility and severity, by perpetuating inflammation and increasing pro-fibrotic responses.

Background: The chemokine CCL11 is negatively correlated with cognitive function and is able to cause dysfunctions of synaptic plasticity. This research investigate whether CCL11 induce microglia senescence to damage synaptic plasticity and the protective role of Qifuyin.

Method: This study involved the intraperitoneal injection of CCL11 in C57BL/6 mice to create an ageing mouse model. Behavioral tests were conducted to evaluate the changes in cognitive function after Qifuyin treatment. LTP and Golgi staining were used to evaluate synaptic structure and function. Cellular senescence was assessed using SA-β-Gal staining, co-localization of p21 or p16 with Iba-1 was identified using multiplex immunofluorescence, and senescence-associated secretory phenotype (SASP) was evaluated via the Luminex. CCR3 knockout/overexpression HMC3 cells were treated with five brain-entering components of Qifuyin to observe protective effects of Qifuyin.

Results: Here we found that Qifuyin improved the ability of object recognition and memory, spatial learning and memory and conditional fear memory in CCL11-induced cognitive dysfunction of C57BL/6 mice. Qifuyin can improve synaptic plasticity, increase the expression of GAP-43, PSD-95 and SYN in the hippocampus of CCL11-induced mice. Cellular senescence of microglia and the amounts of SASP in the hippocampus were also reduced after Qifuyin treatment. Through the study of HMC3 cells with CCR3 gene knockout/overexpression, it was found that the brain components of Qifuyin could unlock the cell cycle arrest induced by CCL11/CCR3 pathway, reduce the proportion of G0 and G1 cells, reduce the expressions of p16, p21 and SASP, and enhance the synaptic connection of HT-22 cells damaged by HMC3 cells.

Conclusion: This study discovered that CCL11 precipitates microglia senescence in brain, resulting in synaptic structural damage and impaired neuronal functional plasticity, hence causing disruptions in learning and memory functions. Qifuyin can mitigate microglial senescence, safeguard synaptic plasticity, and enhance cognitive function.

Background: In several diseases, senescent T lymphocytes increase in number and release a senescence-associated secretory phenotype (SASP) with inflammatory and osteoclastogenic potential, favoring inflammation and bone loss. It is well known that the activation of p38 mitogen-activated protein kinase (p38 MAPK) orchestrates senescence in CD8⁺ T lymphocytes. However, p38 MAPK contribution to CD4⁺ T lymphocyte senescence remains less comprehensively characterized and warrants further investigation. This study investigates the contribution of p38 MAPK to senescence in CD4⁺ T lymphocytes, focusing on mitochondrial dysfunction and SASP production to elucidate their pathological potential.

Results: Splenic CD4⁺ T lymphocytes isolated from wild-type C57BL/6 mice were subjected to subcytotoxic oxidative stress by H₂O₂ exposure to generate stress-induced premature senescence. H₂O₂-exposed CD4⁺ T lymphocytes exhibited hallmark features of senescence, including increased cell size, reduced cell proliferation, and upregulation of the cell cycle regulators p16^Ink4a and p21^Cip1. Additionally, these cells displayed defective mitophagy, accumulation of dysfunctional mitochondria, and a SASP enriched in Th17-associated cytokines. In senescence-induced CD4⁺ T lymphocytes, an increase in the expression of phospho-p38 MAPK was also detected. The senescence changes were reversed when p38 MAPK was blocked using the specific inhibitor BIRB-796. In particular, neutralizing p38 MAPK reduced mitochondrial dysfunction and Th17-type SASP production, demonstrating its critical role in driving these senescent traits in CD4⁺ T lymphocytes. These findings ratify the involvement of p38 MAPK as a central regulator of CD4⁺ T lymphocyte senescence, particularly concerning the accumulation of dysfunctional mitochondria and pro-inflammatory SASP production.

Conclusions: This study provides critical insights into immune aging mechanisms in CD4⁺ T lymphocytes and underscores the therapeutic potential of targeting p38 MAPK to mitigate senescence-driven inflammatory diseases.

Background: Immunosenescence describes the gradual remodeling of immune responses, leading to disturbed immune homeostasis and increased susceptibility of older adults for infections, neoplasia and autoimmunity. Decline in cellular immunity is associated with intrinsic changes in the T cell compartment, but can be further pushed by age-related changes in cells regulating T cell immunity. Myeloid-derived suppressor cells (MDSCs) are potent inhibitors of T cell activation and function, whose induction requires chronic inflammation. Since aging is associated with low grade inflammation (inflammaging) and increased myelopoiesis, age-induced changes in MDSC induction and function in relation to T cell immunity were analyzed.

Results: MDSC numbers and functions were compared between "healthy" young and old adults, who were negatively diagnosed for severe acute and chronic diseases known to induce MDSC accumulation. MDSCs were either isolated from peripheral blood or generated in vitro from blood-derived CD14 cells. Aging was associated with significantly increased MDSC numbers in the monocytic- (M-) and polymorphonuclear (PMN-) MDSC subpopulations. MDSCs could be induced more efficiently from CD14 cells of old donors and these MDSCs inhibited CD3/28-induced T cell proliferation significantly better than MDSCs induced from young donors. Serum factors of old donors supported MDSC induction comparable to serum factors from young donors, but increased immunosuppressive activity of MDSCs was only achieved by serum from old donors. Elevated immunosuppressive activity of MDSCs from old donors was associated with major metabolic changes and increased intracellular levels of neutral and oxidized lipids known to promote immunosuppressive functions. Independent of age, MDSC-mediated suppression of T cell proliferation required direct MDSC- T cell contact. Besides their increased ability to inhibit activation-induced T cell proliferation, MDSCs from old donors strongly shift the immune response towards Th2 immunity and might thereby further contribute to impaired cell-mediated immunity during aging.

Conclusions: These results indicate that immunosenescence of innate immunity comprises accumulation and functional changes in the MDSC compartment, which directly impacts T cell functions and contribute to age-associated impaired T cell immunity. Targeting MDSCs during aging might help to maintain functional T cell responses and increase the chance of healthy aging.