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Signal Transduction and Targeted Therapy May 2023Infection susceptibility, poor vaccination efficacy, age-related disease onset, and neoplasms are linked to innate and adaptive immune dysfunction that accompanies aging... (Review)
Review
Infection susceptibility, poor vaccination efficacy, age-related disease onset, and neoplasms are linked to innate and adaptive immune dysfunction that accompanies aging (known as immunosenescence). During aging, organisms tend to develop a characteristic inflammatory state that expresses high levels of pro-inflammatory markers, termed inflammaging. This chronic inflammation is a typical phenomenon linked to immunosenescence and it is considered the major risk factor for age-related diseases. Thymic involution, naïve/memory cell ratio imbalance, dysregulated metabolism, and epigenetic alterations are striking features of immunosenescence. Disturbed T-cell pools and chronic antigen stimulation mediate premature senescence of immune cells, and senescent immune cells develop a proinflammatory senescence-associated secretory phenotype that exacerbates inflammaging. Although the underlying molecular mechanisms remain to be addressed, it is well documented that senescent T cells and inflammaging might be major driving forces in immunosenescence. Potential counteractive measures will be discussed, including intervention of cellular senescence and metabolic-epigenetic axes to mitigate immunosenescence. In recent years, immunosenescence has attracted increasing attention for its role in tumor development. As a result of the limited participation of elderly patients, the impact of immunosenescence on cancer immunotherapy is unclear. Despite some surprising results from clinical trials and drugs, it is necessary to investigate the role of immunosenescence in cancer and other age-related diseases.
Topics: Humans; Immunosenescence; T-Lymphocytes; Cellular Senescence; Neoplasms
PubMed: 37179335
DOI: 10.1038/s41392-023-01451-2 -
Frontiers in Immunology 2022Aging induces a series of immune related changes, which is called immunosenescence, playing important roles in many age-related diseases, especially neurodegenerative... (Review)
Review
Aging induces a series of immune related changes, which is called immunosenescence, playing important roles in many age-related diseases, especially neurodegenerative diseases, tumors, cardiovascular diseases, autoimmune diseases and coronavirus disease 2019(COVID-19). However, the mechanism of immunosenescence, the association with aging and successful aging, and the effects on diseases are not revealed obviously. In order to provide theoretical basis for preventing or controlling diseases effectively and achieve successful aging, we conducted the review and found that changes of aging-related phenotypes, deterioration of immune organ function and alterations of immune cell subsets participated in the process of immunosenescence, which had great effects on the occurrence and development of age-related diseases.
Topics: Autoimmune Diseases; COVID-19; Humans; Immunosenescence; Neurodegenerative Diseases
PubMed: 35983061
DOI: 10.3389/fimmu.2022.942796 -
Nature Jun 2021Ageing of the immune system, or immunosenescence, contributes to the morbidity and mortality of the elderly. To define the contribution of immune system ageing to...
Ageing of the immune system, or immunosenescence, contributes to the morbidity and mortality of the elderly. To define the contribution of immune system ageing to organism ageing, here we selectively deleted Ercc1, which encodes a crucial DNA repair protein, in mouse haematopoietic cells to increase the burden of endogenous DNA damage and thereby senescence in the immune system only. We show that Vav-iCre;Ercc1 mice were healthy into adulthood, then displayed premature onset of immunosenescence characterized by attrition and senescence of specific immune cell populations and impaired immune function, similar to changes that occur during ageing in wild-type mice. Notably, non-lymphoid organs also showed increased senescence and damage, which suggests that senescent, aged immune cells can promote systemic ageing. The transplantation of splenocytes from Vav-iCre;Ercc1 or aged wild-type mice into young mice induced senescence in trans, whereas the transplantation of young immune cells attenuated senescence. The treatment of Vav-iCre;Ercc1 mice with rapamycin reduced markers of senescence in immune cells and improved immune function. These data demonstrate that an aged, senescent immune system has a causal role in driving systemic ageing and therefore represents a key therapeutic target to extend healthy ageing.
Topics: Aging; Animals; DNA Damage; DNA Repair; DNA-Binding Proteins; Endonucleases; Female; Healthy Aging; Homeostasis; Immune System; Immunosenescence; Male; Mice; Organ Specificity; Rejuvenation; Sirolimus; Spleen
PubMed: 33981041
DOI: 10.1038/s41586-021-03547-7 -
Cells Jan 2022Acute inflammation is a physiological response to injury or infection, with a cascade of steps that ultimately lead to the recruitment of immune cells to clear invading... (Review)
Review
Acute inflammation is a physiological response to injury or infection, with a cascade of steps that ultimately lead to the recruitment of immune cells to clear invading pathogens and heal wounds. However, chronic inflammation arising from the continued presence of the initial trigger, or the dysfunction of signalling and/or effector pathways, is harmful to health. While successful ageing in older adults, including centenarians, is associated with low levels of inflammation, elevated inflammation increases the risk of poor health and death. Hence inflammation has been described as one of seven pillars of ageing. Age-associated sterile, chronic, and low-grade inflammation is commonly termed inflammageing-it is not simply a consequence of increasing chronological age, but is also a marker of biological ageing, multimorbidity, and mortality risk. While inflammageing was initially thought to be caused by "continuous antigenic load and stress", reports from the last two decades describe a much more complex phenomenon also involving cellular senescence and the ageing of the immune system. In this review, we explore some of the main sources and consequences of inflammageing in the context of immunosenescence and highlight potential interventions. In particular, we assess the contribution of cellular senescence to age-associated inflammation, identify patterns of pro- and anti-inflammatory markers characteristic of inflammageing, describe alterations in the ageing immune system that lead to elevated inflammation, and finally assess the ways that diet, exercise, and pharmacological interventions can reduce inflammageing and thus, improve later life health.
Topics: Aged; Aged, 80 and over; Aging; Biomarkers; Cellular Senescence; Humans; Immunosenescence; Inflammation
PubMed: 35159168
DOI: 10.3390/cells11030359 -
Seminars in Immunopathology Oct 2020The aging immune system (immunosenescence) has been implicated with increased morbidity and mortality in the elderly. Of note, T cell aging and low-grade inflammation... (Review)
Review
The aging immune system (immunosenescence) has been implicated with increased morbidity and mortality in the elderly. Of note, T cell aging and low-grade inflammation (inflammaging) are implicated with several age-related conditions. The expansion of late-differentiated T cells (CD28), regulatory T cells, increased serum levels of autoantibodies, and pro-inflammatory cytokines were implicated with morbidities during aging. Features of accelerated immunosenescence can be identified in adults with chronic inflammatory conditions, such as rheumatoid arthritis, and are predictive of poor clinical outcomes. Therefore, there is an interplay between immunosenescence and age-related diseases. In this review, we discuss how the aging immune system may contribute to the development and clinical course of age-related diseases such as neurodegenerative diseases, rheumatoid arthritis, cancer, cardiovascular, and metabolic diseases.
Topics: Aged; Aging; Cellular Senescence; Cytokines; Humans; Immunosenescence; Inflammation
PubMed: 32747977
DOI: 10.1007/s00281-020-00806-z -
Journal of Hematology & Oncology Nov 2020Immunosenescence is a process of immune dysfunction that occurs with age and includes remodeling of lymphoid organs, leading to changes in the immune function of the... (Review)
Review
Immunosenescence is a process of immune dysfunction that occurs with age and includes remodeling of lymphoid organs, leading to changes in the immune function of the elderly, which is closely related to the development of infections, autoimmune diseases, and malignant tumors. T cell-output decline is an important feature of immunosenescence as well as the production of senescence-associated secretory phenotype, increased glycolysis, and reactive oxygen species. Senescent T cells exhibit abnormal phenotypes, including downregulation of CD27, CD28, and upregulation of CD57, killer cell lectin-like receptor subfamily G, Tim-3, Tight, and cytotoxic T-lymphocyte-associated protein 4, which are tightly related to malignant tumors. The role of immunosenescence in tumors is sophisticated: the many factors involved include cAMP, glucose competition, and oncogenic stress in the tumor microenvironment, which can induce the senescence of T cells, macrophages, natural killer cells, and dendritic cells. Accordingly, these senescent immune cells could also affect tumor progression. In addition, the effect of immunosenescence on the response to immune checkpoint blocking antibody therapy so far is ambiguous due to the low participation of elderly cancer patients in clinical trials. Furthermore, many other senescence-related interventions could be possible with genetic and pharmacological methods, including mTOR inhibition, interleukin-7 recombination, and NAD activation. Overall, this review aims to highlight the characteristics of immunosenescence and its impact on malignant tumors and immunotherapy, especially the future directions of tumor treatment through senescence-focused strategies.
Topics: Aging; Animals; Disease Progression; Humans; Immunosenescence; Immunotherapy; Neoplasms; T-Lymphocytes; Tumor Microenvironment
PubMed: 33168037
DOI: 10.1186/s13045-020-00986-z -
The Journal of Investigative Dermatology Apr 2021As global life expectancy continues to rise, we are challenged with maintaining health into old age. One strategy is to target the chronic low-level inflammation... (Review)
Review
As global life expectancy continues to rise, we are challenged with maintaining health into old age. One strategy is to target the chronic low-level inflammation associated with aging, termed inflammaging. This is characterized by increased levels of circulating proinflammatory cytokines and a shift toward cellular senescence, changes that are believed to drive many age-associated conditions, including dementia, arthritis, and type 2 diabetes. As with other organs, the skin undergoes functional decline during aging, becoming more fragile and susceptible to infection; however, the contribution of inflammaging is not well-understood. This review article describes the evidence for inflammaging in the skin, its relationship with senescence, and how this relates to declining skin structure and function.
Topics: Cellular Senescence; Cytokines; Fibroblasts; Healthy Aging; Humans; Immunosenescence; Inflammation; Keratinocytes; Langerhans Cells; Skin; Skin Aging; T-Lymphocytes
PubMed: 33358020
DOI: 10.1016/j.jid.2020.11.006 -
Ageing Research Reviews Dec 2020Single-cell gene expression (transcriptomics) data are becoming robust and abundant, and are increasingly used to track organisms along their life-course. This allows... (Review)
Review
Single-cell gene expression (transcriptomics) data are becoming robust and abundant, and are increasingly used to track organisms along their life-course. This allows investigation into how aging affects cellular transcriptomes, and how changes in transcriptomes may underlie aging, including chronic inflammation (inflammaging), immunosenescence and cellular senescence. We compiled and tabulated aging-related single-cell datasets published to date, collected and discussed relevant findings, and inspected some of these datasets ourselves. We specifically note insights that cannot (or not easily) be based on bulk data. For example, in some datasets, the fraction of cells expressing p16 (CDKN2A), one of the most prominent markers of cellular senescence, was reported to increase, in addition to its upregulated mean expression over all cells. Moreover, we found evidence for inflammatory processes in most datasets, some of these driven by specific cells of the immune system. Further, single-cell data are specifically useful to investigate whether transcriptional heterogeneity (also called noise or variability) increases with age, and many (but not all) studies in our review report an increase in such heterogeneity. Finally, we demonstrate some stability of marker gene expression patterns across closely similar studies and suggest that single-cell experiments may hold the key to provide detailed insights whenever interventions (countering aging, inflammation, senescence, disease, etc.) are affecting cells depending on cell type.
Topics: Aging; Cellular Senescence; Humans; Immunosenescence; Inflammation; Single-Cell Analysis
PubMed: 32949770
DOI: 10.1016/j.arr.2020.101156 -
Annual Review of Cell and Developmental... Oct 2020Innate and adaptive immune responses decline with age, leading to greater susceptibility to infectious diseases and reduced responses to vaccines. Diseases are more... (Review)
Review
Innate and adaptive immune responses decline with age, leading to greater susceptibility to infectious diseases and reduced responses to vaccines. Diseases are more severe in old than in young individuals and have a greater impact on health outcomes such as morbidity, disability, and mortality. Aging is characterized by increased low-grade chronic inflammation, so-called inflammaging, that represents a link between changes in immune cells and a number of diseases and syndromes typical of old age. In this review we summarize current knowledge on age-associated changes in immune cells with special emphasis on B cells, which are more inflammatory and less responsive to infections and vaccines in the elderly. We highlight recent findings on factors and pathways contributing to inflammaging and how these lead to dysfunctional immune responses. We summarize recent published studies showing that adipose tissue, which increases in size with aging, contributes to inflammaging and dysregulated B cell function.
Topics: Animals; Antibody Formation; B-Lymphocytes; Gastrointestinal Microbiome; Humans; Immunosenescence; Inflammation; Polymorphism, Single Nucleotide
PubMed: 33021823
DOI: 10.1146/annurev-cellbio-011620-034148 -
Cytokine & Growth Factor Reviews Jun 2021Aging is a natural physiological process that features various and variable challenges, associated with loss of homeostasis within the organism, often leading to... (Review)
Review
Aging is a natural physiological process that features various and variable challenges, associated with loss of homeostasis within the organism, often leading to negative consequences for health. Cellular senescence occurs when cells exhaust the capacity to renew themselves and their tissue environment as the cell cycle comes to a halt. This process is influenced by genetics, metabolism and extrinsic factors. Immunosenescence, the aging of the immune system, is a result of the aging process, but can also in turn act as a secondary inducer of senescence within other tissues. This review aims to summarize the current state of knowledge regarding hallmarks of aging in relation to immunosenescence, with a focus on aging-related imbalances in the medullary environment, as well as the components of the innate and adaptive immune responses. Aging within the immune system alters its functionality, and has consequences for the person's ability to fight infections, as well as for susceptibility to chronic diseases such as cancer and cardiovascular disease. The senescence-associated secretory phenotype is described, as well as the involvement of this phenomenon in the paracrine induction of senescence in otherwise healthy cells. Inflammaging is discussed in detail, along with the comorbidities associated with this process. A knowledge of these processes is required in order to consider possible targets for the application of senotherapeutic agents - interventions with the potential to modulate the senescence process, thus prolonging the healthy lifespan of the immune system and minimizing the secondary effects of immunosenescence.
Topics: Aging; Cellular Senescence; Chronic Disease; Humans; Immune System; Immunosenescence; Inflammation
PubMed: 33551332
DOI: 10.1016/j.cytogfr.2021.01.006