scholarly journals Intercellular Transfer of Mitochondria between Senescent Cells through Cytoskeleton-Supported Intercellular Bridges Requires mTOR and CDC42 Signalling

2021 ◽  
Vol 2021 ◽  
pp. 1-17
Author(s):  
Hannah E. Walters ◽  
Lynne S. Cox
Keyword(s):  
Cell Communication ◽  
Time Lapse ◽  
Proliferating Cells ◽  
Intercellular Bridges ◽  
Telomere Attrition ◽  
Acute Response ◽  
Age Related ◽  
Cell Age ◽  
Organelle Transfer ◽  
Key Factor

Cellular senescence is a state of irreversible cell proliferation arrest induced by various stressors including telomere attrition, DNA damage, and oncogene induction. While beneficial as an acute response to stress, the accumulation of senescent cells with increasing age is thought to contribute adversely to the development of cancer and a number of other age-related diseases, including neurodegenerative diseases for which there are currently no effective disease-modifying therapies. Non-cell-autonomous effects of senescent cells have been suggested to arise through the SASP, a wide variety of proinflammatory cytokines, chemokines, and exosomes secreted by senescent cells. Here, we report an additional means of cell communication utilised by senescent cells via large numbers of membrane-bound intercellular bridges—or tunnelling nanotubes (TNTs)—containing the cytoskeletal components actin and tubulin, which form direct physical connections between cells. We observe the presence of mitochondria in these TNTs and show organelle transfer through the TNTs to adjacent cells. While transport of individual mitochondria along single TNTs appears by time-lapse studies to be unidirectional, we show by differentially labelled co-culture experiments that organelle transfer through TNTs can occur between different cells of equivalent cell age, but that senescent cells, rather than proliferating cells, appear to be predominant mitochondrial donors. Using small molecule inhibitors, we demonstrate that senescent cell TNTs are dependent on signalling through the mTOR pathway, which we further show is mediated at least in part through the downstream actin-cytoskeleton regulatory factor CDC42. These findings have significant implications for the development of senomodifying therapies, as they highlight the need to account for local direct cell-cell contacts as well as the SASP in order to treat cancer and diseases of ageing in which senescence is a key factor.

scholarly journals Intercellular transfer of mitochondria between senescent cells through cytoskeleton-supported intercellular bridges requires mTOR and Cdc42 signalling

2020 ◽  
Author(s):  
Hannah Walters ◽  
Lynne S Cox
Keyword(s):  
Cell Communication ◽  
Senescent Cell ◽  
Proliferating Cells ◽  
Intercellular Bridges ◽  
Telomere Attrition ◽  
Acute Response ◽  
Age Related ◽  
Organelle Transfer ◽  
Key Factor ◽  
Direct Cell

AbstractCellular senescence is a state of irreversible cell proliferation arrest induced by various stressors including telomere attrition, DNA damage and oncogene induction. While beneficial as an acute response to stress, accumulation of senescent cells with increasing age is through to contribute adversely to development of cancer and a number of other age-related diseases, including neurodegenerative diseases for which there are currently no effective disease-modifying therapies. Non-cell autonomous effects of senescent cells have been suggested to arise through the SASP, a wide variety of pro-inflammatory cytokines, chemokines and exosomes secreted by senescent cells. Here, we report an additional means of cell communication utilised by senescent cells via large numbers of membrane-bound intercellular bridges - or tunnelling nanotubes (TNTs) - containing the cytoskeletal components actin and tubulin, and which form direct physical connections between cells. We observe the presence of mitochondria in these TNTs, and show organelle transfer through the TNTs to adjacent cells. While transport of individual mitochondria along single TNTs appears unidirectional, we show by differentially labelled co-culture experiments that organelle transfer through TNTs can occur both between different cells within senescent cell populations, and also between senescent and proliferating cells. Using small molecule inhibitors, we demonstrate that senescent cell TNTs are dependent on signalling through the mTOR pathway, which we further show is mediated at least in part through downstream actin-cytoskeleton regulatory factor Cdc42. These findings have significant implications for development of senomodifying therapies, as they highlight the need to account for local direct cell-cell contacts as well as the SASP in order to treat cancer and diseases of ageing in which senescence is a key factor.

scholarly journals Keeping the ageing brain wired: a role for purine signalling in regulating cellular metabolism in oligodendrocyte progenitors

2021 ◽  
Author(s):  
Andrea D. Rivera ◽  
Irene Chacon-De-La-Rocha ◽  
Francesca Pieropan ◽  
Maria Papanikolau ◽  
Kasum Azim ◽  
...  
Keyword(s):  
Chondroitin Sulphate ◽  
Adult Brain ◽  
Receptor Subtype ◽  
Proliferating Cells ◽  
Specific Expression ◽  
Self Renewal ◽  
Neuronal Signalling ◽  
Age Related ◽  
Neuronal Connections ◽  
Key Factor

AbstractWhite matter (WM) is a highly prominent feature in the human cerebrum and is comprised of bundles of myelinated axons that form the connectome of the brain. Myelin is formed by oligodendrocytes and is essential for rapid neuronal electrical communication that underlies the massive computing power of the human brain. Oligodendrocytes are generated throughout life by oligodendrocyte precursor cells (OPCs), which are identified by expression of the chondroitin sulphate proteoglycan NG2 (Cspg4), and are often termed NG2-glia. Adult NG2+ OPCs are slowly proliferating cells that have the stem cell–like property of self-renewal and differentiation into a pool of ‘late OPCs’ or ‘differentiation committed’ OPCs(COPs) identified by specific expression of the G-protein-coupled receptor GPR17, which are capable of differentiation into myelinating oligodendrocytes. In the adult brain, these reservoirs of OPCs and COPs ensure rapid myelination of new neuronal connections formed in response to neuronal signalling, which underpins learning and cognitive function. However, there is an age-related decline in myelination that is associated with a loss of neuronal function and cognitive decline. The underlying causes of myelin loss in ageing are manifold, but a key factor is the decay in OPC ‘stemness’ and a decline in their replenishment of COPs, which results in the ultimate failure of myelin regeneration. These changes in ageing OPCs are underpinned by dysregulation of neuronal signalling and OPC metabolic function. Here, we highlight the role of purine signalling in regulating OPC self-renewal and the potential importance of GPR17 and the P2X7 receptor subtype in age-related changes in OPC metabolism. Moreover, age is the main factor in the failure of myelination in chronic multiple sclerosis and myelin loss in Alzheimer’s disease, hence understanding the importance of purine signalling in OPC regeneration and myelination is critical for developing new strategies for promoting repair in age-dependent neuropathology.

HEAT SHOCK PROTEIN 90 (90) IN AGE-DEPENDENT CHANGES IN THE NUMBER OF FIBROBLASTS IN HUMAN SKIN

2020 ◽  
pp. 40-45
Author(s):  
А. Г. Гунин ◽  
Н. Н. Голубцова ◽  
Н. К. Корнилова
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Heat Shock Protein 90 ◽  
Nuclear Antigen ◽  
Positive Staining ◽  
Proliferating Cells ◽  
Age Related ◽  
Age Dependent ◽  
Human Dermis ◽  
Hsp 90

Целью работы стало исследование содержания белка теплового шока 90 ( HSP 90) в фибробластах дермы человека от эмбрионального развития и до глубокой старости (от 20 нед беременности до 85 лет), а также определение значения HSP 90 для возрастных изменений численности фибробластов в дерме человека. HSP 90, ядерный антиген пролиферирующих клеток ( PCNA ) выявляли в срезах кожи непрямым иммуногистохимическим методом. Результаты показали, что в коже человека от 20 нед беременности до 20 лет доля фибробластов дермы с положительной окраской на HSP 90 остается постоянной. С 21 года до 60 лет наблюдают планомерное уменьшение доли фибробластов дермы, имеющих положительную окраску на HSP 90. У людей 61-85 лет происходит резкое увеличение доли фибробластов дермы с положительной окраской на HSP 90. Возрастные изменения содержания HSP 90 положительных фибробластов в дерме статистически не связаны с возрастным уменьшением общего количества и доли PCNA -положительных фибробластов в дерме. The aim of this work was to examine the content of heat shock protein 90 ( HSP 90) in fibroblasts of human dermis from the development until deep aging (from 20 weeks of pregnancy until 85 years old), and defining of a role of HSP 90 in age-dependent changes in the number of fibroblasts in the dermis. HSP 90, proliferating cells nuclear antigen ( PCNA ) were detected with indirect immunohistochemical technique. Results showed that a portion of fibroblasts with positive staining for HSP 90 in the dermis is not changed from 20 weeks of development to 20 years old. Percent of HSP 90 positive fibroblasts in dermis is decreased from 21 to 60 years old. From 61 year, the number of HSP 90 positive fibroblasts in dermis is increased. Age-related changes in the number of HSP 90 positive fibroblasts is not statistically associated with an age-related decrease in a total number and percent of PCNA positive fibroblasts the dermis.

scholarly journals Telomere Attrition and Clonal Hematopoiesis of Indeterminate Potential in Cardiovascular Disease

2021 ◽  
Vol 22 (18) ◽  
pp. 9867
Author(s):  
Yi-Chun Huang ◽  
Chao-Yung Wang
Keyword(s):  
Cardiovascular Disease ◽  
Dna Methyltransferase ◽  
Gene Mutations ◽  
Cvd Risk ◽  
Telomere Attrition ◽  
Clonal Hematopoiesis ◽  
Age Related ◽  
Cell Clones ◽  
Important Relationship ◽  
Increased Risk

Clinical evidence suggests that conventional cardiovascular disease (CVD) risk factors cannot explain all CVD incidences. Recent studies have shown that telomere attrition, clonal hematopoiesis of indeterminate potential (CHIP), and atherosclerosis (telomere–CHIP–atherosclerosis, TCA) evolve to play a crucial role in CVD. Telomere dynamics and telomerase have an important relationship with age-related CVD. Telomere attrition is associated with CHIP. CHIP is commonly observed in elderly patients. It is characterized by an increase in blood cell clones with somatic mutations, resulting in an increased risk of hematological cancer and atherosclerotic CVD. The most common gene mutations are DNA methyltransferase 3 alpha (DNMT3A), Tet methylcytosine dioxygenase 2 (TET2), and additional sex combs-like 1 (ASXL1). Telomeres, CHIP, and atherosclerosis increase chronic inflammation and proinflammatory cytokine expression. Currently, their epidemiology and detailed mechanisms related to the TCA axis remain incompletely understood. In this article, we reviewed recent research results regarding the development of telomeres and CHIP and their relationship with atherosclerotic CVD.

scholarly journals Peptide location fingerprinting reveals modification-associated biomarkers of ageing in human tissue proteomes

2020 ◽  
Author(s):  
Matiss Ozols ◽  
Alexander Eckersley ◽  
Kieran T Mellody ◽  
Venkatesh Mallikarjun ◽  
Stacey Warwood ◽  
...  
Keyword(s):  
Structural Modification ◽  
Protein Structures ◽  
Cytoskeletal Proteins ◽  
Structural Modifications ◽  
Location Fingerprinting ◽  
Age Related ◽  
Analysis Technique ◽  
Key Factor ◽  
Aged Skin ◽  
Novel Biomarkers

AbstractAlthough dysfunctional protein homeostasis (proteostasis) is a key factor in many age-related diseases, the untargeted identification of structural modifications in proteins remains challenging. Peptide location fingerprinting is a proteomic analysis technique capable of identifying structural modification-associated differences in mass spectrometry (MS) datasets of complex biological samples. A new webtool (Manchester Peptide Location Fingerprinter), applied to photoaged and intrinsically aged skin proteomes, can relatively quantify peptides (spectral counting) and map statistically significant differences to regions within protein structures. New photoageing biomarkers were identified in multiple proteins including matrix components (collagens and proteoglycans), oxidation and protease modulators (peroxiredoxins and SERPINs) and cytoskeletal proteins (keratins). Crucially, for many extracellular biomarkers, structural modification-associated differences were not correlated with relative abundance (by ion intensity). By applying peptide location fingerprinting to published MS datasets, (identifying biomarkers including collagen V and versican in ageing tendon) we demonstrate the potential of the MPLF webtool to discover novel biomarkers.

scholarly journals G-CSF: One of The Vehicles for Communication Between Trophoblasts and Macrophages, Which May Cause Problems in Recurrent Spontaneous Abortion

2021 ◽  
Author(s):  
Peng Gao ◽  
Haiyi Liu ◽  
Ying Zha ◽  
Lijie Wei ◽  
Xuan Zhou ◽  
...  
Keyword(s):  
Spontaneous Abortion ◽  
Macrophage Activation ◽  
Cell Activity ◽  
Cell Communication ◽  
Recurrent Spontaneous Abortion ◽  
Granulocyte Colony Stimulating Factor ◽  
Pregnancy Failure ◽  
Normal Tissues ◽  
Key Factor ◽  
Stimulating Factor

Abstract Background The etiology of about half of the patients with recurrent spontaneous abortion (RSA) remains unclear, and the imbalance of the immune inflammatory response at the mother-foetal interface may be one of the keys to the onset. Granulocyte-colony stimulating factor (G-CSF) is thought to have a protective effect on pregnancy, and its absence may lead to pregnancy failure, but the evidence is scant. This study aims at investigating whether the loss of G-CSF induced RSA by affecting cell communication at the maternal-foetal interface. Results G-CSF was mainly expressed in villus rather than decidua, and the expression in RSA tissues was lower than that in normal tissues. Down-regulation of G-CSF in trophoblasts resulted in decreased cell activity. Trophoblast-derived exosomes inhibited macrophage activation, while G-CSF free exosomes did not. Intraperitoneal injection of G-CSF improved the pregnancy outcome of RSA mice, and the expression of G-CSF and its receptor at the mother-foetal interface also changed. Conclusion The expression of G-CSF was found to be decreased in villi of patients with RSA. The absence of G-CSF weakens the immune suppression of trophoblasts against macrophages, and the function of trophoblasts is impaired, which may be a key factor in the occurrence of RSA. G-CSF decreased the rate of abortion in RSA mice, and might provide some assistance in the treatment of patients with RSA.

Correlation Between Telomere Attrition of Zona Fasciculata and Adrenal Weight Reduction in Older Men

2019 ◽  
Vol 105 (3) ◽  
pp. e200-e210
Author(s):  
K Nonaka ◽  
Junko Aida ◽  
Kaiyo Takubo ◽  
Yuto Yamazaki ◽  
Xin Gao ◽  
...  
Keyword(s):  
Sex Differences ◽  
Weight Reduction ◽  
Adrenal Glands ◽  
Older Men ◽  
Adrenal Weight ◽  
Zona Fasciculata ◽  
Biological Mechanisms ◽  
Telomere Attrition ◽  
Age Related ◽  
Age Related Changes

Abstract Context Although numerous theories are reported on sex differences in longevity, the underlying biological mechanisms remain unknown. We previously reported that telomere length in the zona reticularis cells of the human adrenal cortex was significantly longer in older than that in younger subjects. However, we could not evaluate sex differences in the telomere lengths. Objective To compare the telomere lengths of adrenocortical and adrenal medullar cells between men and women from infancy through older adulthood. Methods Adrenal glands of 30 male (aged 0 to 100 years) and 25 female (aged 0 to 104 years) autopsied subjects were retrieved from autopsy files. Using quantitative fluorescence in situ hybridization, relative telomere lengths were determined in the parenchymal cells of the 3 adrenocortical zones and medulla. Age-related changes in the weight of adrenal glands were also investigated. Main results Older male subjects (aged 65 years or older) had significantly shorter telomere lengths in zona fasciculata (ZF) cells compared to the corresponding female subjects. In men, older subjects exhibited a significant age-related reduction in adrenal weight; however, no age-related changes in adrenal weight were detected in women. Conclusion Telomere attrition of ZF cells was correlated with adrenal weight reduction in older men but not in older women, suggesting a decreased number of ZF cells in older men. This may help us understand the possible biological mechanisms of sex difference in longevity of humans.

scholarly journals Lysosomal Exocytosis, Exosome Release and Secretory Autophagy: The Autophagic- and Endo-Lysosomal Systems Go Extracellular

2020 ◽  
Vol 21 (7) ◽  
pp. 2576 ◽  
Author(s):  
Sandra Buratta ◽  
Brunella Tancini ◽  
Krizia Sagini ◽  
Federica Delo ◽  
Elisabetta Chiaradia ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Cell Communication ◽  
Lysosomal Storage ◽  
Cellular Processes ◽  
Age Related ◽  
Extracellular Release ◽  
A Cell ◽  
Endosomal System

Beyond the consolidated role in degrading and recycling cellular waste, the autophagic- and endo-lysosomal systems play a crucial role in extracellular release pathways. Lysosomal exocytosis is a process leading to the secretion of lysosomal content upon lysosome fusion with plasma membrane and is an important mechanism of cellular clearance, necessary to maintain cell fitness. Exosomes are a class of extracellular vesicles originating from the inward budding of the membrane of late endosomes, which may not fuse with lysosomes but be released extracellularly upon exocytosis. In addition to garbage disposal tools, they are now considered a cell-to-cell communication mechanism. Autophagy is a cellular process leading to sequestration of cytosolic cargoes for their degradation within lysosomes. However, the autophagic machinery is also involved in unconventional protein secretion and autophagy-dependent secretion, which are fundamental mechanisms for toxic protein disposal, immune signalling and pathogen surveillance. These cellular processes underline the crosstalk between the autophagic and the endosomal system and indicate an intersection between degradative and secretory functions. Further, they suggest that the molecular mechanisms underlying fusion, either with lysosomes or plasma membrane, are key determinants to maintain cell homeostasis upon stressing stimuli. When they fail, the accumulation of undigested substrates leads to pathological consequences, as indicated by the involvement of autophagic and lysosomal alteration in human diseases, namely lysosomal storage disorders, age-related neurodegenerative diseases and cancer. In this paper, we reviewed the current knowledge on the functional role of extracellular release pathways involving lysosomes and the autophagic- and endo-lysosomal systems, evaluating their implication in health and disease.

scholarly journals Telomere length and age-dependent telomere attrition: the blood-and-muscle model

2019 ◽  
Vol 97 (4) ◽  
pp. 328-334 ◽  
Author(s):  
Mirna N. Chahine ◽  
Simon Toupance ◽  
Sandy El-Hakim ◽  
Carlos Labat ◽  
Sylvie Gautier ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Telomere Length ◽  
Cross Sectional Study ◽  
Muscle Model ◽  
Atherosclerotic Cardiovascular Disease ◽  
Cross Sectional ◽  
Telomere Attrition ◽  
Age Related ◽  
Age Dependent ◽  
Muscle Biopsies

Short telomere length (TL) is associated with atherosclerotic cardiovascular disease (ACVD) and other age-related diseases. It is unclear whether these associations originate from having inherently short TL or a faster TL attrition before or during disease development. We proposed the blood-and-muscle model to assess TL dynamics throughout life course. Our objective was to measure TL in leukocytes (LTL) and in skeletal muscle (MTL), which served as a proxy of TL at birth. The delta (MTL–LTL) represented life-long telomere attrition. Blood draws and skeletal muscle biopsies were performed on 35 Lebanese individuals undergoing surgery. Following DNA extraction, LTL and MTL were measured by Southern blot. In every individual aged between 30 and 85 years, MTL was longer than LTL. With age, MTL and LTL decreased, but the delta (MTL–LTL) increased by 14 bp/year. We validated the blood-and-muscle model that allowed us to identify TL, TL at birth, and lifelong TL attrition in a cross-sectional study. This model can be used in larger cross-sectional studies to evaluate the association of telomere dynamics with age-related diseases onset and progression.

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