Senescence and aging: Causes, consequences, and therapeutic avenues

McHugh, Domhnall; Gil, Jesús

doi:10.1083/jcb.201708092

Cited by 925 publications

(833 citation statements)

References 155 publications

(235 reference statements)

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“…However, in contrast to apoptosis, senescent cells are viable over a long period of time. In addition, they have the potential to influence neighboring tumor cells or cells of the tumor microenvironment through secreted soluble molecules, known as the senescence-associated secretory phenotype (SASP) [35][36][37]. Interestingly, the transcellular regulation of senescence by soluble factors is also true vice versa: our findings that specific immune cells control cancer cells by cytokine secretion and CIS [12] demonstrate that immune surveillance of tumors [16,38] takes advantage of extrinsic, receptor-mediated senescence pathways.…”

Section: Discussionmentioning

confidence: 80%

Nuclear Translocation of Argonaute 2 in Cytokine-Induced Senescence

Rentschler

Chen

Pahl

et al. 2018

Cell Physiol Biochem

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Background/Aims: Cellular senescence, or permanent growth arrest, is known as an effective tumor suppressor mechanism that can be induced by different stressors, such as oncogenes, chemotherapeutics or cytokine cocktails. Previous studies demonstrated that the growth-repressing state of oncogene-induced senescent cells depends on argonaute protein 2 (Ago2)-mediated transcriptional gene silencing and Ago2/Rb corepression of E2F-dependent cell cycle genes. Cytokine-induced senescence (CIS) likewise depends on activation of the p16^Ink4a/Rb pathway, and consecutive inactivation of the E2F family of transcription factors. In the present study, we therefore analyzed the role of Ago2 in CIS. Methods: Human cancer cell lines were treated with interferon-gamma (IFN-γ) and tumor necrosis factor (TNF) to induce senescence. Senescence was determined by growth assays and measurement of senescence-associated β-galactosidase (SA-β-gal) activity, Ago2 translocation by Ago2/ Ki67 immunofluorescence staining and western blot analysis, and gene transcription by quantitative polymerase chain reaction (qPCR). Results: IFN-γ and TNF permanently stopped cell proliferation and time-dependently increased SA-β-gal activity. After 24 – 48 h of cytokine treatment, Ago2 translocated from the cytoplasm into the nucleus of Ki67-negative cells, an effect which was shown to be reversible. Importantly, the proinflammatory cytokine cocktail suppressed Ago2-regulated cell cycle control genes, and siRNA-mediated depletion of Ago2 interfered with cytokine-induced growth inhibition. Conclusion: IFN-γ and TNF induce a stable cell cycle arrest of cancer cells that is accompanied by a fast nuclear Ago2 translocation and repression of Ago2-regulated cell cycle control genes. As Ago2 downregulation impairs cytokine-induced growth regulation, Ago2 may contribute to tissue homeostasis in human cancers.

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Section: Discussionmentioning

confidence: 80%

Nuclear Translocation of Argonaute 2 in Cytokine-Induced Senescence

Rentschler

Chen

Pahl

et al. 2018

Cell Physiol Biochem

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“…OS aggravates the overexpression and secretion of several pro-inflammatory cytokines and chemokines (eg, the interleukins IL-6, IL-1, and IL-8) and initiates/involves a set of cellular pathways that eventually prompt the attraction, activation, and differentiation of immune cells, resulting in the elimination of senescent cells. 14 Throughout human history, herbal-based ingredients have been used constantly and sacredly for medicinal, nutritional, or beauty purposes. 9,10 Under tense conditions, for example, telomeric attrition and oncogenicor oxidative-stress, DNA is damaged, resulting in p53 activation.…”

Section: Introductionmentioning

confidence: 99%

Manipulation of molecular pathways and senescence hallmarks by natural compounds in fibroblast cells

Momtaz

Baeeri

Rahimifard

et al. 2018

J of Cellular Biochemistry

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Aging contributes to an increased risk of developing a number of neurodegenerative and chronic disorders, predominantly related to oxidative stress (OS) and defects in the antioxidant balance. This study focused on the antisenescence effect of four plant species (Falcaria vulgaris, Ixiolirion tataricum, Ajuga chamaecistus, and Scabiosa flavida) on H2O2‐induced premature senescence in rat NIH3T3 fibroblasts, which were found to be rich in effective phytochemicals with traditional ethnobotanical backgrounds. Plant materials were collected, identified, and extracted. To determine the viability of NIH3T3 cells, an MTT assay was conducted. The levels of OS markers and the senescence‐associated ß‐galactosidase (SA‐ß‐GAL) activity were analyzed by the Elisa reader. The cell cycle pattern was evaluated by flow cytometry. The expression of senescence‐related inflammatory cytokines and the molecules involved in aging signaling pathways were investigated using the real‐time reverse transcription polymerase chain reaction (RT‐PCR). H2O2 treatment decreased cell viability and increased lipid peroxidation (LPO) and the reactive oxygen species (ROS) in NIH3T3s. However, S. flavida exhibited low cytotoxicity, reduced OS and SA‐ß‐GAL activities in NIH3T3 cells compared with the H2O2‐treated group. I. tataricum was the second best plant, although it was more toxic to NIHT3T cells. S. flavida decreased G0/G1 arrest and facilitated the G2/M transition of NIH3T3s, also downregulated the expression of p38, p53, p16, and the related inflammatory mediators. S. flavida potentially modulated senescence‐associated hallmarks in fibroblasts exposed to H2O2, thus it may inhibit the aging process via controlling the OS. Therefore it is a promising candidate for future antiaging explorations.

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“…If so, the question is: What determines the accumulation of ROS in aged myofibers and SCs/myoblasts? 78 In addition, cell senescence caused by telomere erosion; DNA damage; mitochondrial, proteostatic, and nutrient signalling dysfunction; and epigenetic factors is a central hallmark of aging: a combination of these conditions can induce senescence manifesting as the cell's inability to proliferate in response to appropriate stimuli owing to the hyperactivity of two main signalling pathways, p16 INK4a /Rb and p53/p21 CIP1 , which concur to repress cyclin-dependent kinase 4/6 (CDK4/6) activity ultimately leading to stem cell exhaustion 79 (Figure 3). Mechanistically, myostatin was shown to increase ROS and TNF-α production in myoblasts, and the elevated TNF-α in turn stimulates myostatin expression with resultant proteasomal-mediated catabolism of intracellular proteins.…”

Section: Deranged Satellite Cell Propertiesmentioning

confidence: 99%

“…111,113,114 On the other hand, in low-density myoblast cultures and at early phases of muscle regeneration following acute injury (i.e. Given the enhanced activity of the p53/p21 CIP1 in senescent cells, which concurs to stem cell exhaustion 79 and since S100B inhibits p53 phosphorylation and tetramerization, i.e. 22,104 Incidentally, promyogenic effects of RAGE in myoblast cultures and following acute (reversible) injury have been reported; RAGE signalling by HMGB1 promotes myoblast differentiation and myotube formation, 115 and absence of RAGE delays muscle regeneration via altered dynamics of activated SCs, delays macrophage infiltration of damage sites, and prolongs the M1 macrophage inflammatory phase.…”

Section: Deranged Satellite Cell Propertiesmentioning

confidence: 99%

Cellular and molecular mechanisms of sarcopenia: the S100B perspective

Riuzzi

Sorci

Arcuri

et al. 2018

J cachexia sarcopenia muscle

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Primary sarcopenia is a condition of reduced skeletal muscle mass and strength, reduced agility, and increased fatigability and risk of bone fractures characteristic of aged, otherwise healthy people. The pathogenesis of primary sarcopenia is not completely understood. Herein, we review the essentials of the cellular and molecular mechanisms of skeletal mass maintenance; the alterations of myofiber metabolism and deranged properties of muscle satellite cells (the adult stem cells of skeletal muscles) that underpin the pathophysiology of primary sarcopenia; the role of the Ca2+‐sensor protein, S100B, as an intracellular factor and an extracellular signal regulating cell functions; and the functional role of S100B in muscle tissue. Lastly, building on recent results pointing to S100B as to a molecular determinant of myoblast–brown adipocyte transition, we propose S100B as a transducer of the deleterious effects of accumulation of reactive oxygen species in myoblasts and, potentially, myofibers concurring to the pathophysiology of sarcopenia.

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Senescence and aging: Causes, consequences, and therapeutic avenues

Abstract: McHugh and Gil review the role of senescence in age-related diseases and how targeting senescence may improve health span and extend life span.

Cited by 925 publications

References 155 publications

Nuclear Translocation of Argonaute 2 in Cytokine-Induced Senescence

Nuclear Translocation of Argonaute 2 in Cytokine-Induced Senescence

Manipulation of molecular pathways and senescence hallmarks by natural compounds in fibroblast cells

Cellular and molecular mechanisms of sarcopenia: the S100B perspective

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