scholarly journals Hallmarks and detection techniques of cellular senescence and cellular ageing in immune cells

Aging Cell ◽  
2021 ◽  
Vol 20 (2) ◽  
Author(s):  
Dingxi Zhou ◽  
Mariana Borsa ◽  
Anna Katharina Simon
Keyword(s):  
Cellular Senescence ◽  
Immune Cells ◽  
Detection Techniques ◽  
Cellular Ageing

scholarly journals oxLDL-mediated cellular senescence is associated with increased NADPH oxidase p47phox recruitment to caveolae

2018 ◽  
Vol 38 (3) ◽  
Author(s):  
Jing Wang ◽  
Yuzhi Bai ◽  
Xia Zhao ◽  
Jing Ru ◽  
Ning Kang ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Clinical Intervention ◽  
Ros Generation ◽  
Ros Production ◽  
Caveolin 1 ◽  
Cellular Ageing ◽  
Vascular Endothelia ◽  
Membrane Target ◽  
High Degree ◽  
Atherosclerotic Changes

Atherosclerosis develops as a consequence of inflammation and cell senescence. In critical factors involved in the atherosclerotic changes, reactive oxygen species (ROS) generation is considered a leading cause. While NADPH oxidases, particularly NOX2, are the main sources of ROS, how they are regulated in the disease is incompletely understood. In addition, how caveolae, the membrane structure implicated in oxLDL deposition under vascular endothelia, is involved in the oxLDL-mediated ROS production remains mostly elusive. We report here that macrophages exposed to oxLDL up-regulate its caveolin-1 expression, and the latter in turn up-regulates NOX2 p47phox level. This combination effect results in increased cellular senescence. Interestingly, oxLDL treatment causes the p47phox residing in the cytosol to translocate to the caveolae. Immunoprecipitation assays confirms that cavelin-1 is in high degree association with p47phox. These results suggest caveolin-1 may serve as the membrane target for p47phox and as a switch for ROS production following oxLDL exposure. Our results reveal a previously unknown molecular event in oxLDL-mediated cellular ageing, and may provide a target for clinical intervention for atherosclerosis.

scholarly journals Similarities and interplay between senescent cells and macrophages

2020 ◽  
Vol 220 (2) ◽  
Author(s):  
Jacques Behmoaras ◽  
Jesús Gil
Keyword(s):  
Tumor Microenvironment ◽  
Cellular Senescence ◽  
Immune Cells ◽  
Molecular Mechanisms ◽  
Senescent Cell ◽  
Phenotypic Characteristics ◽  
Effector Functions ◽  
Inflammatory Conditions ◽  
Secretory Phenotype ◽  
Cancerous Cells

Senescence is a cellular program that prevents the replication of old, damaged, or cancerous cells. Senescent cells become growth arrested and undergo changes in their morphology, chromatin organization, and metabolism, and produce a bioactive secretome. This secretome, the senescence-associated secretory phenotype (SASP), mediates many of the pathophysiological effects associated with senescent cells, for example, recruiting and activating immune cells such as macrophages. The relation between senescent cells and macrophages is intriguing: senescent cells recruit macrophages, can induce them to undergo senescence, or can influence their polarization. Senescent cells and macrophages share multiple phenotypic characteristics; both have a high secretory status, increased lysosome numbers, or the ability to activate the inflammasome. Senescent cells accumulate during aging and disease, and killing them results in widespread benefits. Here we discuss similarities between senescent cells and macrophages and interpret the latest developments in macrophage biology to understand the molecular mechanisms of cellular senescence. We describe evidence and effects of senescence in macrophages and speculate on the ontogeny of the senescent-like state in macrophages. Finally, we examine the macrophage–senescent cell interplay and its impact on macrophage effector functions during inflammatory conditions and in the tumor microenvironment.

Towards understanding the biological drivers of cell ageing

2018 ◽  
pp. 131-154
Author(s):  
Lynne S. Cox ◽  
Penelope A. Mason
Keyword(s):  
Cellular Senescence ◽  
Werner Syndrome ◽  
Later Life ◽  
Social Construct ◽  
New Approach ◽  
Age Related ◽  
Proteomics Approach ◽  
Cellular Ageing ◽  
Scientific Ideas

This chapter discusses approaches to understanding cellular ageing (senescence) through molecular biology approaches. Current scientific ideas surrounding the biological and evolutionary basis of senescence are discussed in this chapter, as are recent findings that demonstrate a strong contribution of senescent cells to age-related decline in health. A new approach to generating senescent cells is described, which accelerates cell ageing in the laboratory based on understandings of premature ageing human Werner syndrome, as is a proteomics approach to probing cellular senescence. The premise that ageing is a social construct is refuted from a biological basis, and the importance of approaches to tackling cellular senescence in the human body to improve the quality of later life is strongly advocated.

scholarly journals Cellular Senescence and Inflammaging in the Skin Microenvironment

2021 ◽  
Vol 22 (8) ◽  
pp. 3849
Author(s):  
Young In Lee ◽  
Sooyeon Choi ◽  
Won Seok Roh ◽  
Ju Hee Lee ◽  
Tae-Gyun Kim
Keyword(s):  
Cellular Senescence ◽  
Immune Cells ◽  
Aging Process ◽  
Human Microbiome ◽  
Cell Types ◽  
Skin Aging ◽  
Review Article ◽  
The Body ◽  
Air Particulate ◽  
Cutaneous Immunity

Cellular senescence and aging result in a reduced ability to manage persistent types of inflammation. Thus, the chronic low-level inflammation associated with aging phenotype is called “inflammaging”. Inflammaging is not only related with age-associated chronic systemic diseases such as cardiovascular disease and diabetes, but also skin aging. As the largest organ of the body, skin is continuously exposed to external stressors such as UV radiation, air particulate matter, and human microbiome. In this review article, we present mechanisms for accumulation of senescence cells in different compartments of the skin based on cell types, and their association with skin resident immune cells to describe changes in cutaneous immunity during the aging process.

scholarly journals Acute Kidney Injury is Aggravated in Aged Mice by the Exacerbation of Proinflammatory Processes

2021 ◽  
Vol 12 ◽  
Author(s):  
Laura Marquez-Exposito ◽  
Lucia Tejedor-Santamaria ◽  
Laura Santos-Sanchez ◽  
Floris A. Valentijn ◽  
Elena Cantero-Navarro ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Cell Death ◽  
Cellular Senescence ◽  
Immune Cells ◽  
Kidney Injury ◽  
Tubular Cell ◽  
Nuclear Staining ◽  
Age Related ◽  
Regulated Necrosis ◽  
Old Mice

Acute kidney injury (AKI) is more frequent in elderly patients. Mechanisms contributing to AKI (tubular cell death, inflammatory cell infiltration, impaired mitochondrial function, and prolonged cell-cycle arrest) have been linked to cellular senescence, a process implicated in regeneration failure and progression to fibrosis. However, the molecular and pathological basis of the age-related increase in AKI incidence is not completely understood. To explore these mechanisms, experimental AKI was induced by folic acid (FA) administration in young (3-months-old) and old (1-year-old) mice, and kidneys were evaluated in the early phase of AKI, at 48 h. Tubular damage score, KIM-1 expression, the recruitment of infiltrating immune cells (mainly neutrophils and macrophages) and proinflammatory gene expression were higher in AKI kidneys of old than of young mice. Tubular cell death in FA-AKI involves several pathways, such as regulated necrosis and apoptosis. Ferroptosis and necroptosis cell-death pathways were upregulated in old AKI kidneys. In contrast, caspase-3 activation was only found in young but not in old mice. Moreover, the antiapoptotic factor BCL-xL was significantly overexpressed in old, injured kidneys, suggesting an age-related apoptosis suppression. AKI kidneys displayed evidence of cellular senescence, such as increased levels of cyclin dependent kinase inhibitors p16ink4a and p21cip1, and of the DNA damage response marker γH2AX. Furthermore, p21cip1 mRNA expression and nuclear staining for p21cip1 and γH2AX were higher in old than in young FA-AKI mice, as well as the expression of senescence-associated secretory phenotype (SASP) components (Il-6, Tgfb1, Ctgf, and Serpine1). Interestingly, some infiltrating immune cells were p21 or γH2AX positive, suggesting that molecular senescence in the immune cells (“immunosenescence”) are involved in the increased severity of AKI in old mice. In contrast, expression of renal protective factors was dramatically downregulated in old AKI mice, including the antiaging factor Klotho and the mitochondrial biogenesis driver PGC-1α. In conclusion, aging resulted in more severe AKI after the exposure to toxic compounds. This increased toxicity may be related to magnification of proinflammatory-related pathways in older mice, including a switch to a proinflammatory cell death (necroptosis) instead of apoptosis, and overactivation of cellular senescence of resident renal cells and infiltrating inflammatory cells.

scholarly journals Emerging Dynamics of Macrophage Cellular Senescence and Immunosenescence in Governing Organismal Aging and Disease: Concepts and Opportunities

2021 ◽  
Author(s):  
Rohit Sharma
Keyword(s):  
Immune System ◽  
Cellular Senescence ◽  
Immune Cells ◽  
Innate Immune ◽  
Host Cells ◽  
Macrophage Phenotype ◽  
Immune Functions ◽  
Biological Impact ◽  
Age Related ◽  
Disease Concepts

An intricate relationship between impaired immune functions and the age-related accumulation of tissue senescent cells (SC) is rapidly emerging. The immune system is unique as it undergoes mutually inclusive and deleterious processes of immunosenescence and cellular senescence with advancing age. While factors inducing immunosenescence and cellular senescence may be shared, however, both these processes are fundamentally different which holistically influence the aging immune system. Immunosenescence is a well-characterized phenomenon, but our understanding and biological impact of cellular senescence in immune cells, especially in the innate immune cells such as macrophages, is only beginning to be understood. Tissue-resident macrophages are long-lived, and while functioning in tissue-specific and niche-specific microenvironments, senescence in macrophages can be directly influenced by senescent host cells which may impact organismal aging. In addition, evidence of age-associated immunometabolic changes as drivers of altered macrophage phenotype and functions such as inflamm-aging is also emerging. The present review describes the emerging impact of cellular senescence vis-à-vis immunosenescence in aging macrophages, its biological relevance with other senescent non-immune cells, and known immunometabolic regulators. Gaps in our present knowledge, as well as strategies aimed at understanding cellular senescence and its therapeutics in the context of macrophages, have been reviewed.

scholarly journals Locus-specific induction of gene expression from heterochromatin loci during cellular senescence

2020 ◽  
Author(s):  
Kosuke Tomimatsu ◽  
Dóra Bihary ◽  
Ioana Olan ◽  
Aled Parry ◽  
Stefan Schoenfelder ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Immune Cells ◽  
Nuclear Periphery ◽  
Open Chromatin ◽  
Facultative Heterochromatin ◽  
Specific Induction ◽  
Functional Relevance ◽  
Heterochromatic Genes ◽  
Chromatin Reorganization

Abstract Cellular senescence is a fate-determined state, accompanied by reorganization of heterochromatin. While lineage-appropriate genes can be temporarily repressed through facultative heterochromatin, stable silencing of lineage-inappropriate genes often involves the constitutive heterochromatic mark, histone H3K9me3. The fate of these heterochromatic genes during the chromatin reorganization accompanying senescence is unclear. Here we show a small number of lineage-inappropriate genes are derepressed in senescent cells from H3K9me3 regions that gain open chromatin marks. DNA FISH experiments reveal that these gene loci, which are tightly condensed at the nuclear periphery in proliferative cells, are physically decompacted during senescence. Among these gene loci, NLRP3 is predominantly expressed in immune cells, such as macrophages, where it resides within an open topologically associated domain (TAD). In contrast, NLRP3 is derepressed in senescent fibroblasts, potentially due to the local disruption of the H3K9me3-rich TAD that contains it. The role of NLRP3 has been implicated in the amplification of inflammatory cytokine signalling in senescence and aging, underscoring the functional relevance of gene induction from ‘permissive’ H3K9me3 regions in senescent cells.

scholarly journals MO338INCREASED INFLAMMATORY RESPONSE IS A HALLMARK OF AGE-RELATED AGGRAVATION OF EXPERIMENTAL AKI

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Laura Marquez-Exposito ◽  
Lucia Tejedor ◽  
Laura Santos-Sanchez ◽  
Floris A Valentijn ◽  
Elena Cantero-Navarro ◽  
...  
Keyword(s):  
Cell Death ◽  
Inflammatory Response ◽  
Cellular Senescence ◽  
Immune Cells ◽  
Molecular Mechanisms ◽  
Nuclear Staining ◽  
Cell Death Pathway ◽  
Age Related ◽  
Regulated Necrosis ◽  
Young Mice

Abstract Background and Aims Acute kidney injury (AKI) is associated with elevated mortality and morbidity presenting higher frequency in aged patients. Different mechanisms are activated in AKI, including tubular epithelial cell death (apoptosis and regulated necrosis), inflammatory cell infiltration, impaired mitochondrial function, and prolonged cell-cycle arrest (or cellular senescence). There is a strong connection between pathways activated in AKI and development of cellular senescence, a process implicated in regeneration failure and progression to fibrosis. However, the molecular mechanisms in ageing-associated mortality are not completely understood. Our aim was to investigate age-related molecular mechanisms of AKI. Method Experimental nephropathy by folic acid administration (FA, 125mg/kg) was induced in young (3 months) and old (12 months) mice. Renal lesions and mechanisms were evaluated at 48 hours (AKI acute phase). Results AKI mortality was higher in old (50 %) than in young (15%) mice 4 days after FA injection (pilot study). Tubular damage score (PAS evaluation) and KIM-1 tubular expression (renal damage biomarker) were also higher in old than in young FA-injected mice after 48h. The number of infiltrating immune cells (mainly neutrophils and macrophages) and gene expression levels of proinflammatory genes (Lcn-2 and ccl2) were significantly higher in FA kidneys of old as compared to young mice. Regulated necrosis (necroptosis), contrary to apoptosis, induces an inflammatory response and necroinflammation, being macrophages the key effector immune cells of this cell death pathway. Among some of the key necroptosis mediators, MLKL and RIPK3 were higher in old FA kidneys. These data could indicate a magnification of the inflammatory response to AKI in older mice. In contrast, expression of protective factors was dramatically downregulated in old FA mice, including the mitochondrial biogenesis driver PGC-1α, and the antiaging factor Klotho. Cellular senescence was induced in FA kidneys, as indicated by increased levels of cyclin-dependent kinase inhibitors p16ink4a and p21cip1, and of the DNA Damage Response marker yH2AX. Importantly, p21 mRNA expression and nuclear staining for p21 and yH2AX were increased in FA kidneys, and the fold increase was significantly higher in old than in young mice. Also, the expression of senescence-associated secretory phenotype (SASP) components (Tgfb1, Il-6, and Serpine-1) was significantly higher in old FA mouse kidneys. Interestingly, also some infiltrating immune cells were p21/yH2AX positive, suggesting molecular senescence in the immune cells (“immunesenescence”) and inflammation in the ageing kidney (“inflammaging”) are involved in the aggravated AKI response to FA in old mice. Conclusion Our data indicate that in advanced age, exposure to toxic compounds results in a more severe AKI response that might relate to an early inflammatory response characterize by more extensive necroptosis and activation of pathways related to cellular senescence of resident kidney cells and infiltrating inflammatory cells.

scholarly journals Effects of cellular senescence on metabolic pathways in non-immune and immune cells

2021 ◽  
Vol 194 ◽  
pp. 111428
Author(s):  
Daniela Frasca ◽  
Yara Bou Saada ◽  
Denisse Garcia ◽  
Bertrand Friguet
Keyword(s):  
Cellular Senescence ◽  
Immune Cells ◽  
Metabolic Pathways

Lamin B receptor: role on chromatin structure, cellular senescence and possibly aging

2020 ◽  
Vol 477 (14) ◽  
pp. 2715-2720
Author(s):  
Susana Castro-Obregón
Keyword(s):  
Cellular Senescence ◽  
Nuclear Membrane ◽  
Chromatin Structure ◽  
Cholesterol Synthesis ◽  
Reductase Activity ◽  
Chimeric Protein ◽  
Nuclear Lamina ◽  
Lamin B ◽  
Inner Nuclear Membrane ◽  
Lamin B Receptor

The nuclear envelope is composed by an outer nuclear membrane and an inner nuclear membrane, which is underlain by the nuclear lamina that provides the nucleus with mechanical strength for maintaining structure and regulates chromatin organization for modulating gene expression and silencing. A layer of heterochromatin is beneath the nuclear lamina, attached by inner nuclear membrane integral proteins such as Lamin B receptor (LBR). LBR is a chimeric protein, having also a sterol reductase activity with which it contributes to cholesterol synthesis. Lukasova et al. showed that when DNA is damaged by ɣ-radiation in cancer cells, LBR is lost causing chromatin structure changes and promoting cellular senescence. Cellular senescence is characterized by terminal cell cycle arrest and the expression and secretion of various growth factors, cytokines, metalloproteinases, etc., collectively known as senescence-associated secretory phenotype (SASP) that cause chronic inflammation and tumor progression when they persist in the tissue. Therefore, it is fundamental to understand the molecular basis for senescence establishment, maintenance and the regulation of SASP. The work of Lukasova et al. contributed to our understanding of cellular senescence establishment and provided the basis that lead to the further discovery that chromatin changes caused by LBR reduction induce an up-regulated expression of SASP factors. LBR dysfunction has relevance in several diseases and possibly in physiological aging. The potential bifunctional role of LBR on cellular senescence establishment, namely its role in chromatin structure together with its enzymatic activity contributing to cholesterol synthesis, provide a new target to develop potential anti-aging therapies.

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