scholarly journals The Preconditioning of Berberine Suppresses Hydrogen Peroxide-Induced Premature Senescence via Regulation of Sirtuin 1

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Xiaofei Zhu ◽  
Haodi Yue ◽  
Xiaofang Guo ◽  
Jingyi Yang ◽  
Jingshuo Liu ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Cellular Senescence ◽  
Sirtuin 1 ◽  
Premature Senescence ◽  
Low Concentration ◽  
Human Diploid Fibroblasts ◽  
Cycle Arrest ◽  
Age Related ◽  
History Of

With a long history of application in Chinese traditional medicine, berberine (BBR) was reported to exhibit healthspan-extending properties in some age-related diseases, such as type 2 diabetes and atherosclerosis. However, the antiaging mechanism of BBR is not completely clear. By means of hydrogen peroxide- (H2O2-) induced premature cellular senescence model, we found that a low-concentration preconditioning of BBR could resist premature senescence in human diploid fibroblasts (HDFs) measured by senescence-associated β-galactosidase (SA-β-gal), accompanied by a decrease in loss of mitochondrial membrane potential and production of intracellular reactive oxygen species (ROS). Moreover, the low-concentration preconditioning of BBR could make cells less susceptible to subsequent H2O2-induced cell cycle arrest and growth inhibition. Experimental results further showed that the low concentration of BBR could induce a slight increase of ROS and upregulate the expression level of sirtuin 1 (SIRT1), an important longevity regulator. H2O2-induced activation of checkpoint kinase 2 (Chk2) was significantly attenuated after the preconditioning of BBR. The present findings implied that the low-concentration preconditioning of BBR could have a mitohormetic effect against cellular senescence triggered by oxidative stress in some age-related diseases through the regulation of SIRT1.

scholarly journals PGC-1α Protects RPE Cells of the Aging Retina against Oxidative Stress-Induced Degeneration through the Regulation of Senescence and Mitochondrial Quality Control. The Significance for AMD Pathogenesis

2018 ◽  
Vol 19 (8) ◽  
pp. 2317 ◽  
Author(s):  
Kai Kaarniranta ◽  
Jakub Kajdanek ◽  
Jan Morawiec ◽  
Elzbieta Pawlowska ◽  
Janusz Blasiak
Keyword(s):  
Oxidative Stress ◽  
Cellular Senescence ◽  
Mitochondrial Biogenesis ◽  
Vision Loss ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Sirtuin 1 ◽  
Age Related Macular Degeneration ◽  
Rpe Cells ◽  
Age Related

PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha) is a transcriptional coactivator of many genes involved in energy management and mitochondrial biogenesis. PGC-1α expression is associated with cellular senescence, organismal aging, and many age-related diseases, including AMD (age-related macular degeneration), an important global issue concerning vision loss. We and others have developed a model of AMD pathogenesis, in which stress-induced senescence of retinal pigment epithelium (RPE) cells leads to AMD-related pathological changes. PGC-1α can decrease oxidative stress, a key factor of AMD pathogenesis related to senescence, through upregulation of antioxidant enzymes and DNA damage response. PGC-1α is an important regulator of VEGF (vascular endothelial growth factor), which is targeted in the therapy of wet AMD, the most devastating form of AMD. Dysfunction of mitochondria induces cellular senescence associated with AMD pathogenesis. PGC-1α can improve mitochondrial biogenesis and negatively regulate senescence, although this function of PGC-1α in AMD needs further studies. Post-translational modifications of PGC-1α by AMPK (AMP kinase) and SIRT1 (sirtuin 1) are crucial for its activation and important in AMD pathogenesis.

scholarly journals Diverse Roles of Cellular Senescence in Skeletal Muscle Inflammation, Regeneration, and Therapeutics

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuki Saito ◽  
Takako S. Chikenji
Keyword(s):  
Skeletal Muscle ◽  
Cellular Senescence ◽  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Neuromuscular Disorders ◽  
Muscle Stem Cells ◽  
Related Disease ◽  
Tissue Degeneration ◽  
Cycle Arrest ◽  
Age Related

Skeletal muscle undergoes vigorous tissue remodeling after injury. However, aging, chronic inflammatory diseases, sarcopenia, and neuromuscular disorders cause muscle loss and degeneration, resulting in muscular dysfunction. Cellular senescence, a state of irreversible cell cycle arrest, acts during normal embryonic development and remodeling after tissue damage; when these processes are complete, the senescent cells are eliminated. However, the accumulation of senescent cells is a hallmark of aging tissues or pathological contexts and may lead to progressive tissue degeneration. The mechanisms responsible for the effects of senescent cells have not been fully elucidated. Here, we review current knowledge about the beneficial and detrimental effects of senescent cells in tissue repair, regeneration, aging, and age-related disease, especially in skeletal muscle. We also discuss how senescence of muscle stem cells and muscle-resident fibro-adipogenic progenitors affects muscle pathologies or regeneration, and consider the possibility that immunosenescence leads to muscle pathogenesis. Finally, we explore senotherapy, the therapeutic targeting of senescence to treat age-related disease, from the standpoint of improving muscle regeneration.

scholarly journals Insights from In Vivo Studies of Cellular Senescence

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 954
Author(s):  
Luis I. Prieto ◽  
Sara I. Graves ◽  
Darren J. Baker
Keyword(s):  
Cellular Senescence ◽  
Cell Biology ◽  
Senescent Cell ◽  
In Vivo Studies ◽  
Cycle Arrest ◽  
Mammalian Cell Lines ◽  
Age Related ◽  
Cell Accumulation ◽  
Secretory Phenotype

Cellular senescence is the dynamic process of durable cell-cycle arrest. Senescent cells remain metabolically active and often acquire a distinctive bioactive secretory phenotype. Much of our molecular understanding in senescent cell biology comes from studies using mammalian cell lines exposed to stress or extended culture periods. While less well understood mechanistically, senescence in vivo is becoming appreciated for its numerous biological implications, both in the context of beneficial processes, such as development, tumor suppression, and wound healing, and in detrimental conditions, where senescent cell accumulation has been shown to contribute to aging and age-related diseases. Importantly, clearance of senescent cells, through either genetic or pharmacological means, has been shown to not only extend the healthspan of prematurely and naturally aged mice but also attenuate pathology in mouse models of chronic disease. These observations have prompted an investigation of how and why senescent cells accumulate with aging and have renewed exploration into the characteristics of cellular senescence in vivo. Here, we highlight our molecular understanding of the dynamics that lead to a cellular arrest and how various effectors may explain the consequences of senescence in tissues. Lastly, we discuss how exploitation of strategies to eliminate senescent cells or their effects may have clinical utility.

scholarly journals Expression of Caveolin-1 Induces Premature Cellular Senescence in Primary Cultures of Murine Fibroblasts

2002 ◽  
Vol 13 (7) ◽  
pp. 2502-2517 ◽  
Author(s):  
Daniela Volonte ◽  
Kun Zhang ◽  
Michael P. Lisanti ◽  
Ferruccio Galbiati
Keyword(s):  
Hydrogen Peroxide ◽  
Cellular Senescence ◽  
Premature Senescence ◽  
3T3 Cells ◽  
Mouse Embryonic Fibroblasts ◽  
Embryonic Fibroblasts ◽  
Caveolin 1 ◽  
Senescent Phenotype ◽  
Nih 3T3

Caveolae are vesicular invaginations of the plasma membrane. Caveolin-1 is the principal structural component of caveolae in vivo. Several lines of evidence are consistent with the idea that caveolin-1 functions as a “transformation suppressor” protein. In fact, caveolin-1 mRNA and protein expression are lost or reduced during cell transformation by activated oncogenes. Interestingly, the human caveolin-1 gene is localized to a suspected tumor suppressor locus (7q31.1). We have previously demonstrated that overexpression of caveolin-1 arrests mouse embryonic fibroblasts in the G0/G1 phase of the cell cycle through activation of a p53/p21-dependent pathway, indicating a role of caveolin-1 in mediating growth arrest. However, it remains unknown whether overexpression of caveolin-1 promotes cellular senescence in vivo. Here, we demonstrate that mouse embryonic fibroblasts transgenically overexpressing caveolin-1 show: 1) a reduced proliferative lifespan; 2) senescence-like cell morphology; and 3) a senescence-associated increase in β-galactosidase activity. These results indicate for the first time that the expression of caveolin-1 in vivo is sufficient to promote and maintain the senescent phenotype. Subcytotoxic oxidative stress is known to induce premature senescence in diploid fibroblasts. Interestingly, we show that subcytotoxic level of hydrogen peroxide induces premature senescence in NIH 3T3 cells and increases endogenous caveolin-1 expression. Importantly, quercetin and vitamin E, two antioxidant agents, successfully prevent the premature senescent phenotype and the up-regulation of caveolin-1 induced by hydrogen peroxide. Also, we demonstrate that hydrogen peroxide alone, but not in combination with quercetin, stimulates the caveolin-1 promoter activity. Interestingly, premature senescence induced by hydrogen peroxide is greatly reduced in NIH 3T3 cells harboring antisense caveolin-1. Importantly, induction of premature senescence is recovered when caveolin-1 levels are restored. Taken together, these results clearly indicate a central role for caveolin-1 in promoting cellular senescence and they suggest the hypothesis that premature senescence may represent a tumor suppressor function mediated by caveolin-1 in vivo.

scholarly journals Aging, Cellular Senescence and Diabetes Mellitus: Clinicopathological Correlates, Trends and Targets

2019 ◽  
pp. 1-10
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Cellular Senescence ◽  
Pancreatic Beta Cells ◽  
Healthy Aging ◽  
Cellular Aging ◽  
Treatment Modalities ◽  
Therapeutic Modalities ◽  
Age Related

Diabetes and aging correlate with identical organ and system perturbations which are enhanced by concomitant molecular processes such as cellular senescence. Age represents a major risk factor for type 2 diabetes mellitus. It is unclear how senescence contributes to diabetes pathogenesis. Thus, available treatment modalities have not targeted the vital area of the disease. Reversal of untoward features of cellular aging represents a formidable trajectory for novel type 2 diabetes therapies where dissipation of pancreatic beta cells are impaired for insulin secretion. Furthermore, appropriate therapeutic modalities require characterization of defined senescent beta cell populations and the spatiotemporal variations of the expression of senescence genes. Aging is a dynamic public health dilemma in the prevailing demographic transitions in which a vast majority of those from the sixth decade of life increase exponentially in populations. Researchers have attempted to explicate senescence mechanisms via the identification of novel factors which interact with aging and age-related disorders in furtherance of treatment management, quality of life and lifespan regarding diabetes and its complications. An elucidation of the fundamental mechanisms which result in aging and research-oriented focus on healthy aging will mitigate numerous socioeconomic and healthcare encumbrance now and in the future for diabetes mellitus and related conditions.

scholarly journals DRG2 Accelerates Senescence via Negative Regulation of SIRT1 in Human Diploid Fibroblasts

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Bing Si Li ◽  
Ai Lin Jin ◽  
ZiQi Zhou ◽  
Jae Ho Seo ◽  
Byung-Min Choi
Keyword(s):  
Oxidative Stress ◽  
Cell Growth ◽  
Binding Protein ◽  
Ectopic Expression ◽  
Sirtuin 1 ◽  
Premature Senescence ◽  
Gtp Binding Protein ◽  
Human Diploid Fibroblasts ◽  
Gtp Binding ◽  
Stress Induced Premature Senescence

Accumulating evidence suggests that developmentally regulated GTP-binding protein 2 (DRG2), an evolutionarily conserved GTP-binding protein, plays an important role in regulating cell growth, inflammation, and mitochondria dynamics. However, the effect of DRG2 in aging remains unclear. In this study, we found that endogenous DRG2 protein expression is upregulated in oxidative stress-induced premature senescence models and tissues of aged mice. Ectopic expression of DRG2 significantly promoted senescence-associated β-galactosidase (SA-β-gal) activity and inhibited cell growth, concomitant with increase in levels of acetyl (ac)-p53 (Lys382), ac-nuclear factor-kB (NF-κB) p65 (Lys310), p21Waf1/Cip1, and p16Ink4a and a decrease in cyclin D1. In this process, reactive oxygen species (ROS) and phosphorylation of H2A histone family member X (H2A.X), forming γ-H2A.X, were enhanced. Mechanistically, ectopic expression of DRG2 downregulated Sirtuin-1 (SIRT1), resulting in augmented acetylation of p53 and NF-κB p65. Additionally, DRG2 knockdown significantly abolished oxidative stress-induced premature senescence. Our results provide a possible molecular mechanism for investigation of cellular senescence and aging regulated by DRG2.

scholarly journals Cellular Senescence in Bone

2021 ◽  
Author(s):  
Danielle Wang ◽  
Haitao Wang
Keyword(s):  
Cellular Senescence ◽  
Bone Diseases ◽  
Epigenetic Alterations ◽  
Pharmacological Interventions ◽  
Telomere Attrition ◽  
Cycle Arrest ◽  
Age Related ◽  
The Common ◽  
Common Problems

Senescence is an irreversible cell-cycle arrest process induced by environmental, genetic, and epigenetic factors. An accumulation of senescent cells in bone results in age-related disorders, and one of the common problems is osteoporosis. Deciphering the basic mechanisms contributing to the chronic ailments of aging may uncover new avenues for targeted treatment. This review focuses on the mechanisms and the most relevant research advancements in skeletal cellular senescence. To identify new options for the treatment or prevention of age-related chronic diseases, researchers have targeted hallmarks of aging, including telomere attrition, genomic instability, cellular senescence, and epigenetic alterations. First, this chapter provides an overview of the fundamentals of bone tissue, the causes of skeletal involution, and the role of cellular senescence in bone and bone diseases such as osteoporosis. Next, this review will discuss the utilization of pharmacological interventions in aging tissues and, more specifically, highlight the role of senescent cells to identify the most effective and safe strategies.

scholarly journals Aging, Cellular Senescence and Diabetes Mellitus: Clinicopathological Correlates, Trends and Targets

2020 ◽  
pp. 1-10
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Cellular Senescence ◽  
Pancreatic Beta Cells ◽  
Healthy Aging ◽  
Cellular Aging ◽  
Treatment Modalities ◽  
Therapeutic Modalities ◽  
Age Related

Diabetes and aging correlate with identical organ and system perturbations which are enhanced by concomitant molecular processes such as cellular senescence. Age represents a major risk factor for type 2 diabetes mellitus. It is unclear how senescence contributes to diabetes pathogenesis. Thus, available treatment modalities have not targeted the vital area of the disease. Reversal of untoward features of cellular aging represents a formidable trajectory for novel type 2 diabetes therapies where dissipation of pancreatic beta cells are impaired for insulin secretion. Furthermore, appropriate therapeutic modalities require characterization of defined senescent beta cell populations and the spatiotemporal variations of the expression of senescence genes. Aging is a dynamic public health dilemma in the prevailing demographic transitions in which a vast majority of those from the sixth decade of life increase exponentially in populations. Researchers have attempted to explicate senescence mechanisms via the identification of novel factors which interact with aging and age-related disorders in furtherance of treatment management, quality of life and lifespan regarding diabetes and its complications. An elucidation of the fundamental mechanisms which result in aging and research-oriented focus on healthy aging will mitigate numerous socioeconomic and healthcare encumbrance now and in the future for diabetes mellitus and related conditions.

scholarly journals Induction of Stress-Induced Renal Cellular Senescence In Vitro: Impact of Mouse Strain Genetic Diversity

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1437
Author(s):  
Chieh Ming Liao ◽  
Vera Christine Wulfmeyer ◽  
Maxine Swallow ◽  
Christine Susanne Falk ◽  
Hermann Haller ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Cellular Senescence ◽  
Inbred Strains ◽  
Cycle Arrest ◽  
Age Related ◽  
New Information ◽  
Immortalized Cell ◽  
Different Strains ◽  
Candidate Loci

Cellular senescence, a stress-induced state of irreversible cell cycle arrest, is associated with organ dysfunction and age-related disease. While immortalized cell lines bypass key pathways of senescence, important mechanisms of cellular senescence can be studied in primary cells. Primary tubular epithelial cells (PTEC) derived from mouse kidney are highly susceptible to develop cellular senescence, providing a valuable tool for studying such mechanisms. Here, we tested whether genetic differences between mouse inbred strains have an impact on the development of stress-induced cellular senescence in cultured PTEC. Kidneys from 129S1, B6, NOD, NZO, CAST, and WSB mice were used to isolate PTEC. Cells were monitored for expression of typical senescence markers (SA-β-galactosidase, γ-H2AX+/Ki67−, expression levels of CDKN2A, lamin B1, IL-1a/b, IL-6, G/M-CSF, IFN-g, and KC) at 3 and 10 days after pro-senescent gamma irradiation. Clear differences were found between PTEC from different strains with the highest senescence values for PTEC from WSB mice and the lowest for PTEC from 129S1 mice. PTEC from B6 mice, the most commonly used inbred strain in senescence research, had a senescence score lower than PTEC from WSB and CAST mice but higher than PTEC from NZO and 129S1 mice. These data provide new information regarding the influence of genetic diversity and help explain heterogeneity in existing data. The observed differences should be considered when designing new experiments and will be the basis for further investigation with the goal of identifying candidate loci driving pro- or anti-senescent pathways.

scholarly journals Inhibition of miR-199a-5p rejuvenates aged mesenchymal stem cells derived from patients with idiopathic pulmonary fibrosis and improves their therapeutic efficacy in experimental pulmonary fibrosis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Linli Shi ◽  
Qian Han ◽  
Yimei Hong ◽  
Weifeng Li ◽  
Gencheng Gong ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Signaling Pathway ◽  
Cellular Senescence ◽  
Therapeutic Efficacy ◽  
Sirtuin 1 ◽  
Ampk Signaling ◽  
Beneficial Effects ◽  
Age Related ◽  
Control Mscs

Abstract Background Idiopathic pulmonary fibrosis (IPF) is an age-related disease with no cure. Mesenchymal stem cell (MSC)-based therapy has emerged as a novel strategy for IPF treatment. Nevertheless, MSCs derived from patients with IPF (IPF-MSCs) become senescent, thereby reducing their beneficial effects in IPF. MicroRNAs (miRNAs) mediate the senescence of MSCs, but the underlying mechanisms are not fully understood. We investigated the mechanisms by which miR-199a-5p regulates IPF-MSC senescence and whether its inhibition could rejuvenate IPF-MSCs and enhance their therapeutic efficacy. Methods Control-MSCs and IPF-MSCs were isolated from the adipose tissue of age-matched healthy and IPF donors, respectively. Cell senescence was examined by senescence-associated β-galactosidase (SA-β-gal) staining. The level of miR-199a-5p was measured by RT-PCR. Autophagy was determined using a transmission electron microscope (TEM). The therapeutic efficacy of anti-miR-199a-5p-IPF-MSCs was assessed using a mouse model of bleomycin-induced lung fibrosis. Results Despite similar surface makers, IPF-MSCs exhibited increased cellular senescence and decreased proliferative capacity compared with control-MSCs. The expression of miR-199a-5p was significantly enhanced in the serum of IPF patients and IPF-MSCs compared with that of healthy donors and control-MSCs. The upregulation of miR-199a-5p induced senescence of control-MSCs, whereas the downregulation rescued IPF-MSC senescence. Mechanistically, miR-155-5p suppressed autophagy of MSCs via the AMPK signaling pathway by downregulating the expression of Sirtuin 1(Sirt1), resulting in cellular senescence. Accordingly, miR-155-5p inhibition promoted autophagy and ameliorated IPF-MSC senescence by activating the Sirt1/AMPK signaling pathway. Compared with IPF-MSCs, the transplantation of anti-miR-199a-5p-IPF-MSCs increased the ability to prevent progression of pulmonary fibrosis in bleomycin-treated mice. Conclusions Our study shows that miR-199a-5p regulates MSC senescence in patients with IPF by regulating the Sirt1/AMPK signaling pathway and miR-199a-5p is a novel target to rejuvenate IPF-MSCs and enhance their beneficial effects.

Sign in / Sign up

Export Citation Format

Share Document