Aging Of Immune System Research Articles

Fever and the Ageing Immune system, A Review

Whether to treat fever in the elderly, is a question that has not yet been answered. This review examines the available evidence so far, to arrive at a comprehensive picture about this question. Aged population are a special category due to their lower basal body temperature, blunted fever response and existing co morbidities. The aging immune system undergoes many changes in all its faculties, which alters its ability to mount an efficient acute inflammatory response. In such a scenario, fever is mostly absent and there is a need to revise the fever criteria in the elderly. Having said that, the most successfully aging, centenarians, mount efficient febrile response during infections, indicating that aging itself may not be the reason for the reduced febrile response. Holistic medicine, such as homeopathy, views the fever scenario differently and advocates interference only when the immune system is helpless. The ‘levels of health theory’ explains that the healthiest benefit from fever while those with reduced immunity suffer from it. This theory may prove to be an invaluable clinical tool to arrive at definite clinical guidelines concerning the treatment of fever, especially in the elderly. However, it requires scientific investigation before it can be used as a clinical tool. 
 There is no conclusive evidence on whether fever must be treated or not in the elderly and whether holistic medicine may have a solution to this dilemma. This is a research gap that needs to be filled with quality studies in the current health scenario.

From Cells to Environment: Exploring the Interplay between Factors Shaping Bone Health and Disease.

The skeletal system is an extraordinary structure that serves multiple purposes within the body, including providing support, facilitating movement, and safeguarding vital organs. Moreover, it acts as a reservoir for essential minerals crucial for overall bodily function. The intricate interplay of bone cells plays a critical role in maintaining bone homeostasis, ensuring a delicate balance. However, various factors, both intrinsic and extrinsic, can disrupt this vital physiological process. These factors encompass genetics, aging, dietary and lifestyle choices, the gut microbiome, environmental toxins, and more. They can interfere with bone health through several mechanisms, such as hormonal imbalances, disruptions in bone turnover, direct toxicity to osteoblasts, increased osteoclast activity, immune system aging, impaired inflammatory responses, and disturbances in the gut-bone axis. As a consequence, these disturbances can give rise to a range of bone disorders. The regulation of bone's physiological functions involves an intricate network of continuous processes known as bone remodeling, which is influenced by various intrinsic and extrinsic factors within the organism. However, our understanding of the precise cellular and molecular mechanisms governing the complex interactions between environmental factors and the host elements that affect bone health is still in its nascent stages. In light of this, this comprehensive review aims to explore emerging evidence surrounding bone homeostasis, potential risk factors influencing it, and prospective therapeutic interventions for future management of bone-related disorders.

Platelet factors attenuate inflammation and rescue cognition in ageing

Identifying therapeutics to delay, and potentially reverse, age-related cognitive decline is critical in light of the increased incidence of dementia-related disorders forecasted in the growing older population1. Here we show that platelet factors transfer the benefits of young blood to the ageing brain. Systemic exposure of aged male mice to a fraction of blood plasma from young mice containing platelets decreased neuroinflammation in the hippocampus at the transcriptional and cellular level and ameliorated hippocampal-dependent cognitive impairments. Circulating levels of the platelet-derived chemokine platelet factor 4 (PF4) (also known as CXCL4) were elevated in blood plasma preparations of young mice and humans relative to older individuals. Systemic administration of exogenous PF4 attenuated age-related hippocampal neuroinflammation, elicited synaptic-plasticity-related molecular changes and improved cognition in aged mice. We implicate decreased levels of circulating pro-ageing immune factors and restoration of the ageing peripheral immune system in the beneficial effects of systemic PF4 on the aged brain. Mechanistically, we identified CXCR3 as a chemokine receptor that, in part, mediates the cellular, molecular and cognitive benefits of systemic PF4 on the aged brain. Together, our data identify platelet-derived factors as potential therapeutic targets to abate inflammation and rescue cognition in old age.

Hypoxic State of Cells and Immunosenescence: A Focus on the Role of the HIF Signaling Pathway.

Hypoxia activates hypoxia-related signaling pathways controlled by hypoxia-inducible factors (HIFs). HIFs represent a quick and effective detection system involved in the cellular response to insufficient oxygen concentration. Activation of HIF signaling pathways is involved in improving the oxygen supply, promoting cell survival through anaerobic ATP generation, and adapting energy metabolism to meet cell demands. Hypoxia can also contribute to the development of the aging process, leading to aging-related degenerative diseases; among these, the aging of the immune system under hypoxic conditions can play a role in many different immune-mediated diseases. Thus, in this review we aim to discuss the role of HIF signaling pathways following cellular hypoxia and their effects on the mechanisms driving immune system senescence.

Lowering maintenance immune suppression in elderly kidney transplant recipients; connecting the immunological and clinical dots.

The management of long-term immune suppressive medication in kidney transplant recipients is a poorly explored field in the area of transplant medicine. In particular, older recipients are at an increased risk for side effects and have an exponentially increased risk of infection-related death. In contrast, an aged immune system decreases the risk of acute T-cell-mediated rejection in older recipients. Recent advances in alloimmunity research have shown a rapid and substantial decline in polyfunctional, high-risk CD4+ T cells post-transplantation. This lowers the direct alloreactivity responsible for T-cell-mediated rejection, also known as donor-specific hyporesponsiveness. Chronic antibody-mediated rejection (c-aABMR) is the most frequent cause of kidney graft loss in the long term. However, in older adults, c-aABMR as a cause of graft loss is outnumbered by death with a functioning graft. In addition, DSA development and a diagnosis of c-aABMR plateau ~10 years after transplantation, resulting in a very low risk for rejection thereafter. The intensity of immune suppression regimes could likely be reduced accordingly, but trials in this area are scarce. Tacrolimus monotherapy for 1 year after transplantation seems feasible in older kidney transplant recipients with standard immunological risk, showing the expected benefits of fewer infections and better vaccination responses.

Effects of an aged tissue niche on the immune potency of dendritic cells using simulated microgravity

Microgravity accelerates the aging of various physiological systems, and it is well acknowledged that aged individuals and astronauts both have increased susceptibility to infections and poor response to vaccination. Immunologically, dendritic cells (DCs) are the key players in linking innate and adaptive immune responses. Their distinct and optimized differentiation and maturation phases play a critical role in presenting antigens and mounting effective lymphocyte responses for long-term immunity. Despite their importance, no studies to date have effectively investigated the effects of microgravity on DCs in their native microenvironment, which is primarily located within tissues. Here, we address a significantly outstanding research gap by examining the effects of simulated microgravity via a random positioning machine on both immature and mature DCs cultured in biomimetic collagen hydrogels, a surrogate for tissue matrices. Furthermore, we explored the effects of loose and dense tissues via differences in collagen concentration. Under these various environmental conditions, the DC phenotype was characterized using surface markers, cytokines, function, and transcriptomic profiles. Our data indicate that aged or loose tissue and exposure to RPM-induced simulated microgravity both independently alter the immunogenicity of immature and mature DCs. Interestingly, cells cultured in denser matrices experience fewer effects of simulated microgravity at the transcriptome level. Our findings are a step forward to better facilitate healthier future space travel and enhance our understanding of the aging immune system on Earth.

COVID-19 and Brain Aging: What are the Implications of Immunosenescence?

The human lifespan is increasing, and mankind is aging. It is estimated that, until the year 2050, this population worldwide will reach 22% of the total world population. Along with aging, the human immunologic system changes, a process called immunosenescence or even inflammaging. The aging immune system increases mortality and morbidity in the elderly mainly because it loses its capacity to react against internal and external aggressions. There is a decrease in B and T lymphocytes and CD4+ lymphocytes lose the CD28 protein expression that is needed for costimulation, leading to reduced response to viral infections. This could be responsible for more deleterious consequences of coronavirus disease infection in the elderly. Besides that, the human brain ages, being more susceptible to damage and viral infections, such as COVID-19 infection. There are several pathways that could explain the susceptibility to the COVID-19 infection in the elderly brain, one of them is binding to ACE 2 receptors in cerebral cells through the spike protein. It has been reported that glial cells and neurons, in addition to endothelial and arterial smooth muscle cells in the brain, express the ACE 2 receptor, which would justify the neurological symptoms and consequences of the disease. This infection can have several clinical manifestations such as hemorrhagic stroke, delirium and long-term cognitive complaints, such as brain fog, polyneuropathies, short time memory complaints and insomnia. Although none of the studies could prove that there is a long-term neuronal damage, there are clinical sequelae that should be taken into account and more studies are necessary to know the consequences of the infection in the elderly brain.

Single-cell profiling reveals age-associated immunity in atherosclerosis.

Aging is a dominant driver of atherosclerosis and induces a series of immunological alterations, called immunosenescence. Given the demographic shift towards elderly, elucidating the unknown impact of aging on the immunological landscape in atherosclerosis is highly relevant. While the young Western diet-fed Ldlr-deficient (Ldlr-/-) mouse is a widely used model to study atherosclerosis, it does not reflect the gradual plaque progression in the context of an aging immune system as occurs in humans. Here, we show that aging promotes advanced atherosclerosis in chow diet-fed Ldlr-/- mice, with increased incidence of calcification and cholesterol crystals. We observed systemic immunosenescence, including myeloid skewing and T-cells with more extreme effector phenotypes. Using a combination of single-cell RNA-sequencing and flow cytometry on aortic leucocytes of young vs. aged Ldlr-/- mice, we show age-related shifts in expression of genes involved in atherogenic processes, such as cellular activation and cytokine production. We identified age-associated cells with pro-inflammatory features, including GzmK+CD8+ T-cells and previously in atherosclerosis undefined CD11b+CD11c+T-bet+ age-associated B-cells (ABCs). ABCs of Ldlr-/- mice showed high expression of genes involved in plasma cell differentiation, co-stimulation, and antigen presentation. In vitro studies supported that ABCs are highly potent antigen-presenting cells. In cardiovascular disease patients, we confirmed the presence of these age-associated T- and B-cells in atherosclerotic plaques and blood. Collectively, we are the first to provide comprehensive profiling of aged immunity in atherosclerotic mice and reveal the emergence of age-associated T- and B-cells in the atherosclerotic aorta. Further research into age-associated immunity may contribute to novel diagnostic and therapeutic tools to combat cardiovascular disease.

Early life adversity: programming inflammation and immunosenescence through immunometabolic pathways?

Whatever form early life adversity (ELA) takes it has long-term health consequences, increasing the risk of many non-communicable diseases that share a significant immune component. In our EpiPath institutionalisation-adoption cohort there was no clear increase in circulating inflammatory markers, however, there was a clear increase in peripheral pro-inflammatory T-cells. Both Th and Tc cells were skewed towards a more activated and senescent state, with differences increasing as the differentiation state advanced from naïve through to terminally differentiated cells. NK cells were also more senescent and lost their cytotoxic capacity after ELA exposure. Overall, these data demonstrate a long-term shift in differentiation state and activation level toward a pro-inflammatory senescent phenotype that shares many aspects with the aged immune system. Concurrently, studies from the ALSPAC cohort have identified long-term changes in DNA methylation induced by ELA. Preliminary analysis suggests that epigenetic age, as measured by epigenetic clocks, is not associated with the immunophenotype, however, specific physiological processes identified through EWAS and gene ontology analyses explain the associations between ELA, the immunophenotype and the long-term health consequences. Several independent early life stressors converge on metabolic pathways in EWAS studies, particularly mitochondrial energy processes such as oxidative phosphorylation. As our knowledge of immunemetabolism grows, it is becoming clear that there is a natural progression of mitochondrial dysfunction with aging leading to this characteristic immunephenotype. It would appear that ELA acts as an accelerator for non-communicable diseases through inflammageing and immunosenescence, and this is most probably mediated through the epigenetic regulation of metabolic pathways.

Immunosenescence and inflammaging: Conspiracies against alveolar bone turnover.

Inflammaging and immunosenescence are characteristics of senescent immune system alterations. This review provides insights into inflammaging and immunosenescence in periodontitis and focuses on the innerlink of inflammaging and immunosenescence in alveolar bone turnover from a perspective of cell-cell interaction. This review is conducted by a narrative approach to discuss the effect of inflammaging and immunosenescence in aging-related alveolar bone loss. A comprehensive literature research in PubMed and Google was applied to identify reports in English. Inflammaging is concerned with abnormal M1 polarization and increasing circulating inflammatory cytokines, while immunosenescence involves reduced infection and vaccine responses, depressed antimicrobial function, and infiltration of aged B cells and memory T cells. TLR-mediated inflammaging and altered adaptive immunity significantly affect alveolar bone turnover and aggravate aging-related alveolar bone loss. Besides, energy consumption also plays a vital role in aged immune and skeletal system of periodontitis. Senescent immune system exerts a significant function in aging-related alveolar bone loss. Inflammaging and immunosenescence interact functionally and mechanistically, which affects alveolar bone turnover. Therefore, further clinical treatment strategies targeting alveolar bone loss could be based on the specific molecular mechanism connecting inflammaging, immunosenescence, and alveolar bone turnover.

GM-CSF and IL-7 fusion cytokine engineered tumor vaccine generates long-term Th-17 memory cells and increases overall survival in aged syngeneic mouse models of glioblastoma.

Age-related immune dysfunctions, such as decreased T-cell output, are closely related to pathologies like cancers and lack of vaccine efficacy among the elderly. Engineered fusokine, GIFT-7, a fusion of interleukin 7 (IL-7) and GM-CSF, can reverse aging-related lymphoid organ atrophy. We generated a GIFT-7 fusokine tumor vaccine and employed it in aged syngeneic mouse models of glioblastoma and found that peripheral vaccination with GIFT-7TVax resulted in thymic regeneration and generated durable long-term antitumor immunity specifically in aged mice. Global cytokine analysis showed increased pro-inflammatory cytokines including IL-1β in the vaccinated group that resulted in hyperactivation of dendritic cells. In addition, GIFT-7 vaccination resulted in increased T-cell trafficking to the brain and robust Th-17 long-term effector memory T-cell formation. TCR-seq analysis showed increased productive frequency among detected rearrangements within the vaccinated group. Overall, our data demonstrate that aging immune system can be therapeutically augmented to generate lasting antitumor immunity.

Aging is associated with accumulated T follicular helper cells with decreased metabolic function

Abstract The aging immune system responds poorly to infection and vaccination, producing reduced numbers of germinal centers, low affinity antibody titers, and reduced B cell memory. Prolonged contacts between activated B cells and CD4+ T cells are crucial to germinal center formation and T follicular helper cell (Tfh) differentiation, but it is unclear how aging impacts the quality of this interaction. Peptide immunization confirmed that aged mice have less expansion of antigen-specific germinal center B cells and reduced antibody titers. Furthermore, aging was associated with decreased CD4+ T conventional cells and accumulated Tfh cells and regulatory T cells, even in naïve mice. Despite increased numbers, our results indicate that aged Tfh have decreased metabolic function, which may have repercussions on germinal center responses. To determine the contribution of cell-extrinsic influences on antigen-specific Tfh induction, we adoptively transferred young, antigen-specific B and CD4+ naïve T cells into aged hosts prior to peptide immunization, which resulted in reduced antigen-specific germinal center B cell and Tfh expansion and reduced antibody titers when compared to young hosts. The results from these experiments emphasize the importance of the lymphoid microenvironment in germinal center initiation and maintenance. We hypothesize that age-associated Tfh accumulation may impair antigen-specific Tfh induction and subsequent germinal center responses. Current studies use live-cell 2-photon microscopy to track the impact of age on lymphocyte motility and Tfh:B interactions, in order to determine the relative contributions of aged APCs, non-specific aged Tfh, and aged regulatory T cells to germinal center deficiency. Research supported by the Mayo Clinic Robert and Arlene Kogod Center on Aging Innovation Award UL1R002377

Conserved epigenetic hallmarks of T-cell age

Abstract As the immune system ages, the protective capacity from established immunological memory wanes over time and is often referred to as immune senescence. Yet the molecular hallmarks of lymphocyte age and replicative senescence remain largely undefined. Here we report our use of a multi-lifetime murine model of repeat vaccination to define a core epigenetic signature coupled to memory T cells that evade replicative senescence. Through adoptive transfer and boosting over a period of approximately four mouse lifetimes, memory T cells became enriched for repressive DNA methylation programs at cell cycle regulators including the canonical senescence gene P19 Arf(CDKN2A/2B locus – human P14 ARF). The senescence-resistance program was progressively acquired throughout phycological and non-physiological aging of murine T cells, leading to the development of a lymphocyte epigenetic clock that can be used to accurately measure a T cell’s age. Application of this clock in physiologically aged human polyclonal and CMV-specific T cells correlated with age-estimates using established epigenetic chronologic clocks. Moreover, T-cell clock-associated senescence-resistance programs were highly enriched in human malignancies of lymphoid origin, specifically delineating known T-cell acute lymphoblastic leukemia (T-ALL) subtypes and revealing non-physiological aging of HOXA9 and MLL pediatric leukemias (estimated to be ~100 years old). Discovery of the senescence-resistance epigenetic clock provides a novel molecular hallmark for describing physiological and non-physiological lymphocyte age.

Single-cell analysis of the aged ovarian immune system reveals a shift towards adaptive immunity and attenuated cell function.

The immune system plays a major role in maintaining many physiological processes in the reproductive system. However, a complete characterization of the immune milieu in the ovary, and particularly how it is affected by female aging, is still lacking. Here, we utilize single-cell RNA sequencing and flow cytometry to construct the complete description of the murine ovarian immune system. We show that the composition of the immune cells undergoes an extensive shift with age towards adaptive immunity. We analyze the effect of aging on gene expression and chemokine and cytokine networks and show an overall decreased expression of inflammatory mediators together with an increased expression of senescent cells recognition receptors. Our results suggest that the fertile female's ovarian immune aging differs from the suggested female post-menopause inflammaging as it copes with the inflammatory stimulations during repeated cycles and the increasing need for clearance of accumulating atretic follicles.

EPIGENETIC ALTERATIONS IN GENE EXPRESSION IN THE AGING IMMUNE SYSTEM

Immunosenescence or aging of the immune system is characterized by dysregulation of the innate and adaptive immune system mechanisms, associated with a systemic low-grade inflammation (i.e., «inflammaging»), non-effective protective humoral and cellular immune responses to a microorgamis or vaccine, autoimmunity, and cancer. In addition, genetic dysregulation and alterations across the immune system drive the cellular manifestations of immunosenescence. In this narrative review, we provide an overview of the recent advancements in immunosenescence research concerning epigenetics alterations in gene regulation and disturbances in gene expression in the aging immune system, focusing on DNA methylation, histone modifications, and microRNAs.

CISH impairs lysosomal function in activated T cells resulting in mitochondrial DNA release and inflammaging.

Chronic systemic inflammation is one of the hallmarks of the aging immune system. Here we show that activated T cells from older adults contribute to inflammaging by releasing mitochondrial DNA (mtDNA) into their environment due to an increased expression of the cytokine-inducible SH2-containing protein (CISH). CISH targets ATP6V1A, an essential component of the proton pump V-ATPase, for proteasomal degradation, thereby impairing lysosomal function. Impaired lysosomal activity caused intracellular accumulation of multivesicular bodies and amphisomes and the export of their cargos, including mtDNA. CISH silencing in T cells from older adults restored lysosomal activity and prevented amphisomal release. In antigen-specific responses in vivo, CISH-deficient CD4+ T cells released less mtDNA and induced fewer inflammatory cytokines. Attenuating CISH expression may present a promising strategy to reduce inflammation in an immune response of older individuals.

Mitochondrial DNA as inflammatory DAMP: a warning of an aging immune system?

Senescence of the immune system is characterized by a state of chronic, subclinical, low-grade inflammation termed 'inflammaging', with increased levels of proinflammatory cytokines, both at the tissue and systemic levels. Age-related inflammation can be mainly driven by self-molecules with immunostimulant properties, named Damage/death Associated Molecular Patterns (DAMPs), released by dead, dying, injured cells or aged cells. Mitochondria are an important source of DAMPs, including mitochondrial DNA - the small, circular, double-stranded DNA molecule found in multiple copies in the organelle. mtDNA can be sensed by at least three molecules: the Toll-like receptor 9, the NLRP3 inflammasomes, and the cyclic GMP-AMP synthase (cGAS). All these sensors can lead to the release of proinflammatory cytokines when engaged. The release of mtDNA by damaged or necrotic cells has been observed in several pathological conditions, often aggravating the course of the disease. Several lines of evidence indicate that the impairment of mtDNA quality control and of the organelle homeostasis associated with aging determines an increase in the leakage of mtDNA from the organelle to the cytosol, from the cell to the extracellular space, and into plasma. This phenomenon, mirrored by an increase in mtDNA circulating levels in elderly people, can lead to the activation of different innate immune cell types, sustaining the chronic inflammatory status that is characteristic of aging.

Pancreatic Ductal Adenocarcinoma and Immune Checkpoint Inhibitors: The Gray Curtain of Immunotherapy and Spikes of Lights

Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with a poor 5-year overall survival rate (~10%). The revolution of immunotherapy in clinical oncology has not substantially changed clinical outcome for patients with PDAC. Despite outstanding efforts, neither immune checkpoint inhibitors (ICIs) alone, nor in combination with chemotherapy or targeted therapies have shown encouraging results. This failure mirrors the lack of knowledge about the real key players of immune system senescence and the complexity of the tumor microenvironment in PDAC. However, some hope can be derived from PARP-inhibitor combinations, vaccines, and CAR-T-cells therapy. In this review, we comprehensively summarize the latest updates about the use of ICIs in PDAC, focusing on clinical evidence and ongoing studies highlighting explanations for the failure of immunotherapy and possible solutions.

Primary tuberculosis with miliary hematogenous generalization in old age

Currently, the problems of the mechanisms of immune and inflammatory response aging, which determine the mechanisms of the development of the inflammatory process in the elderly, are being actively studied. A sectional observation of senile tuberculosis in a patient K., 78 years old, who had been treated for 4 months in the University Clinical Hospital No. 4 of the First Sechenov Moscow State Medical University in 2018 is presented. After autopsy, histological, histochemical and PCR examination, the following pathoanatomical diagnosis was made: primary (senile) tuberculosis with hematogenous and lympho-vascular generalization, with a focus of caseous pneumonia in the III segment of the right lung; caseous lymphadenitis of bifurcation, thoracic and abdominal paraaortic lymph nodes; miliary and large-focal generalization in the lungs, parietal and visceral pleura on the left, spleen and liver (acid fast stain; PCR study No. 18-5935 dated 08/13/2018 (Central Research Institute of Tuberculosis) detected DNA of mycobacterium tuberculosis complex). A feature of senile tuberculosis is the course of primary tuberculosis with hematogenic generalization and predominantly exudative-necrotic tissue reaction. Its pathogenesis is mainly due to the phenomenon of "aging immune system" (immunosenescence), as well as inflammaging — features of the inflammatory response in old age. Their main characteristics are the preactivated status of the immune system even before the recognition of the antigen, characterized by a basal level of circulating cytokines, as well as a sharp weakening of the adaptive immune response in the presence of an antigen associated with impaired functioning of the immune system with a large number of memory T cells lacking naive T-cells.

The aging immune system

The aging immune system