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Cellular senescence is a biological process associated with the degeneration of cell structure and function, which contribute to age-related diseases. Atherosclerosis is a chronic inflammatory disease that can cause a variety of cardiovascular disorders. In this article, we review the effects of cellular senescence on the development of atherosclerosis through diverse physiopathological changes, focusing on the alterations in senescent organelles and the increased senescence-associated secretory phenotype (SASP), and exploring the relevant therapeutic strategies for atherosclerosis by clearing senescent cells and reducing SASP, to provide new insights for the treatment of atherosclerosis.
Subject(s)
Humans , Aging , Atherosclerosis , Cardiovascular Diseases , Cellular Senescence , Chronic Disease , Senescence-Associated Secretory PhenotypeABSTRACT
The senescence-associated secretory phenotype (SASP) is a generic term for the secretion of a series of cytokines such as pro-inflammatory factors, chemokines and proteases, and is a key feature of senescent cells. SASP is a double-edged sword that can resist a harmful environment in normal cells, but with the decline of body function, the massive secretion of cytokines, chemokines and proteases accelerates aging while inducing inflammation, leading to the development of various aging-related diseases. This article reviews the composition and physiological functions of SASP, the changes in SASP during aging, the regulatory pathways associated with SASP, and the anti-aging drugs that regulate SASP. This article aims to present a more comprehensive understanding of SASP and lay the foundation for SASP-based anti-aging research and the discovery of new targets for anti-SASP drugs.
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@#[Abstract] Objective: To investigate the effect of metformin on the senescence-associated secretory phenotype (SASP) of doxorubicin-induced gastric cancer BGC823 cells. Methods: Human gastric cancer BGC823 cells were cultured in vitro and treated with doxorubicin at gradient concentrations (50, 100, 150 and 200 nmol/L). Cell senescence was detected by SA-β-gal staining, and SASP factor expression was detected by ELISA. The effects of metformin on cell senescence and SASP factor secretion induced by doxorubicin (100 nmol/L) were observed by adding gradient concentrations of metformin (0, 5, 10 and 20 mmol/L). Results: With the increase of doxorubicin concentration and treatment time, the senescence rate of gastric cancer BGC823 cells increased first and then decreased. At 96 h after 100 nmol/L doxorubicin treatment, the peak aging rate reached 68.7%, accompanied with significantly increased expressions of SASP factors IL-1a, IL-6, IL-8 and CXCL1. The proportion of senescent cells was (55.2±1.9)%, (48.7±2.2)% and (40.8±2.3)% respectively under the effects of 5, 10 and 20 mmol/L metformin, which was significantly lower than that in the non-metformin treatment group (P< 0.01). At the same time, with the increase of metformin concentration, the production of SASP factors IL-1α, IL-6, IL-8 and CXCL1 showed a gradient decline. Compared with the non-metformin treatment group, IL-6 and IL-8 decreased significantly under the effect of metformin above 10 mmol/L (P<0.05 or P<0.01), while IL-1α and CXCL1 decreased significantly under the effect of 20 mmol/L metformin (all P<0.05). Conclusion: Metformin can inhibit the senescence and SASP production of gastric cancer cells induced by doxorubicin.
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Aging is age-related degeneration of the whole body,and skin aging is one of the most visualized changes in aging.Cellular senescence is a stress response to stable cell cycle arrest,and it is both the hallmark of aging and the important mechanism of the occurrence and development of aging.With the development of skin aging,senescent cells gradually accumulate in both the epidermis and dennis,and further exacerbate aging.Thus,when these senescent cells are eliminated,the aging skin seems to be rejuvenated.Cellular senescence is involved in the process of skin aging,which may be related to activation of DNA damage response pathway,up-regulation of regulatory proteins blocking cell cycle,and increase of senescence-associated secretory phenotypes.Cellular senescence is expected to be a novel target for preventing skin aging in the future.
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Brain aging induces neuropsychological changes, such as decreased memory capacity, language ability, and attention; and is also associated with neurodegenerative diseases. However, most of the studies on brain aging are focused on neurons, while senescence in astrocytes has received less attention. Astrocytes constitute the majority of cell types in the brain and perform various functions in the brain such as supporting brain structures, regulating blood-brain barrier permeability, transmitter uptake and regulation, and immunity modulation. Recent studies have shown that SIRT1 and SIRT2 play certain roles in cellular senescence in peripheral systems. Both SIRT1 and SIRT2 inhibitors delay tumor growth in vivo without significant general toxicity. In this study, we investigated the role of tenovin-1, an inhibitor of SIRT1 and SIRT2, on rat primary astrocytes where we observed senescence and other functional changes. Cellular senescence usually is characterized by irreversible cell cycle arrest and induces senescence-associated β-galactosidase (SA-β-gal) activity. Tenovin-1-treated astrocytes showed increased SA-β-gal-positive cell number, senescence-associated secretory phenotypes, including IL-6 and IL-1β, and cell cycle-related proteins like phospho-histone H3 and CDK2. Along with the molecular changes, tenovin-1 impaired the wound-healing activity of cultured primary astrocytes. These data suggest that tenovin-1 can induce cellular senescence in astrocytes possibly by inhibiting SIRT1 and SIRT2, which may play particular roles in brain aging and neurodegenerative conditions.
Subject(s)
Animals , Rats , Aging , Astrocytes , Blood-Brain Barrier , Brain , Cellular Senescence , Cell Count , Cell Cycle Checkpoints , Interleukin-6 , Language , Memory , Neurodegenerative Diseases , Neurons , Permeability , Phenotype , Wound HealingABSTRACT
Aging is the primary risk factor for many of the most common chronic diseases. The association of cellular senescence with aging-associated conditions has gaining increasing attention. There is now considerable evidence that senescent cell accumulation is an underlying mechanism of aging and age-related diseases. Senescent cells have been emerging as a target for new therapeutic strategies against aging-related pathology. Herein, we review the evidence that cellular senescence drives age-related deterioration and senolytics produce beneficial effect by selective elimination of senescent cells.
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Cellular senescence is a tumor-suppressive mechanism that permanently arrests cells at risk for malignant transformation.However,accumulating evidence show that senescent cells can have deleterious effects on the tissue microenvironment.The most significance of these effects is the acquisition of a senescenceassociated secretory phenotype (SASP) that could promote tumor progression.Even with our currently limited knowledge of the SASP and its potential effects on carcinogenesis,promising new strategies for cancer therapies are possible.
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Objectives To investigate the effects of cell aging on the disorders relating to gastric mucosa aging.Methods A treatment of 200 μmol/L H2O2 was used to induce senescence of human gastric epithelial cell line GES-1,and the cell growth curve was monitored.Senescence secretory phenotypes were observed by detecting the protein level of p53 and p16INK4a with senescence-associated β-galactosidase(SA-β gal)staining and Western blot testing.The mRNA levels of senescence-associated secretory phenotype(SASP)factors in human gastric epithelial GES-1 cell including IL-1β,IL-6,IL-8,TGF-β、IFN-γ,and VEGF-A were detected by RT PCR.The mRNA expression levels of IL-1β,IL-6,IL-8,TGF-β,IFN-γ,and VEGF in the conditioned medium were detected by ELISA analysis.Results The 200 μmol/L H2O2-induced GES-1 cells stopped proliferating after 3 days of treatment,and cells enlarged and flattened at 10 days.The increased SA-β-gal staining(P＜0.001) and the increased expression levels of p53 and p16INK4a proteins indicated the success of establishing the aging model of GES-1.The mRNA levels of IL 1β,IL6,IL8,TGF-β,and IFNγ were higher(t=2.94,3.38,3.15,3.64,2.97;P=0.015,0.000,0.000,0.000,0.000)and the mRNA level of VEGF-A was lower(t=2.31,P =0.20) in senescent GES-1 cells than in the control group.In the conditioned medium of senescent GES-1 cells,the levels of IL-1β,IL6,IL8,TGF-β1,and IFNγ were higher in the H2O2-induced group [(3.12±0.21)μg/L,(4.26±0.15)μg/L,(3.37±0.14)μg/L,(5.34±0.19)μg/L,and(2.90±0.47)μg/L]than in the negative control group[(0.24±0.04,0.04±0.07,0.52±0.02,1.05±0.10,0.52±0.02,respectively,P＜0.001)],while the level of VEGF was lower in the H2O2-induced group than in the negative control group(0.21±0.03)μg/L vs (0.59±0.07)μg/L(P＜0.05).Conclusions The changes in senescence-associated secretory phenotype factors of the aging human gastric epithelial cells induced by oxidative stress may promote chronic gastritis and gastric cancer.
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Cellular senescence is a state of permanent growth arrest characterized by an irreversible exit from the cell cycle and the secretion of senescence-associated secretory phenotype (SASP). The secretory process of SASP can be roughly divided into three steps: DNA damage response (DDR)-rapid paracrine, early and mature stages. The complex molecular regulation mechanisms of SASP involve DDR, p38 mitogen-activated protein kinase (MAPK) signal pathway, activation of nuclear factor κB (NF-κB) and CCAAT/enhancer-binding protein β (C/EBPβ), epigenetic alterations of SASP gene, posttranscriptional regulation of gene and autophagy. SASP regulates a variety of pathological states caused by microenvironment changes and has been a drug target to regulate the aging effect, which providing a new therapeutic method for tumor and agerelated pathological states. In this paper, we classified the different types of SASP, reviewed the role of SASP in biological processes and discussed the related molecular mechanisms.
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Objective To investigate the effect of senescence-associated secretory phenotype-conditioned medium (SASP-CM) on the proliferation of human gastric cancer cell lines BGC823. Methods BGC823 cells were divided into three groups: SASP-CM group, tumor cells control-conditioned medium (CTR-CM) group, and normal-conditioned medium (NOR-CM) group. BGC823 cells in theSASP-CM group were treated with paclitaxel (PTX) to establish senescent cell model and to prepare SASP-CM. The establishment of senescent cell model was confirmed by senescence- associated (Fgalactosidase staining. The concentrations of major SASP factors in SASP-CM were detected by enzyme linked lmmunosorbent assay, the proliferationability ofBGC823 cells was detected by CCK-8 assay and cell clone formation assay, and the cell cycle and apoptosis were detected by flow cytometry. Results After treating BGC823 cells with 35 nmol/L PTX for 72 h, a steady senescence modll was established, which had the highest percentage of senescence cells ([66.95±3.54]%). The concentrations of lnterleukin (IL)-6, IL-8, chemokine (C-X-Cmotif) ligand 1 (CXCL1), chemokine (C-C motif) ligand 2 (CCL2), and lnterferon γ (INF-γ) in the SASP-CM were significantly higher than those ln the CTR-CM (all P<0.01). The relative clone formation rate of BGC823 cells in the SASP-CM group was significantly higher than those ln the CTR-CM group (P<0.01) and NOR-CM group (P<0. 05). The proliferation activity of BGC823 cells in the SASP-CM group was significantly higher than that in the CTR-CM and NOR-CM groups after incubation for 48, 72 and 96 h (all P<0.05). The percentage of S phase cells in the SASP-CM group was significantly higher than that in the CTR-CM and NOR-CM groups (both P<0.01), and there was no significant difference in cell apoptosis rate between groups. Conclusion SASP-CM can promote the proliferation of human gastric cancer cell lines BGC823.