Here, we clarify the nature of cellular senescence by. Cellular senescence was formally described more than four decades ago when hayflick and colleagues showed that normal cells had a limited ability to proliferate in culture 1, see box 1 for. Accumulating evidence suggests that cellular senescence is a potent barrier to tumorigenesis in vivo, however oncogene induced senescence can also promote cellular transformation. Vascular cell senescence contributes to bloodbrain barrier. Institute of cellular medicine, faculty of medical sciences, newcastle university, newcastle upon tyne, uk dina tiniakos department of pathology, aretaieion hospital, medical school, national and kapodistrian university of athens, athens, greece. Vascular cell senescence impairs the barrier integrity in an in vitro bbb model. One cellular phenomenon associated with changes in both ecm components expression and in ecm remodeling enzymes secretion is cellular senescence. Telomere theory considers telomere shortening to be the main trigger of aging. Cellular senescence and the senescent secretory phenotype. A novel sudan black bbased analogue revives lipofuscin as.
Cellular senescence is a homeostatic biological process characterized by a permanent state of cell cycle arrest that can contribute to the decline of the regenerative potential and function of tissues. Cancer versus cellular senescence tradeoff theory of aging. However, several lines of evidence show that senescent cells, which often. Cellular senescence refers to a state of irreversible growth arrest and altered function of normal somatic cells after a finite number of divisions 1. Through its numerous inducers that lead to altered gene expression, senescence is able to influence many contrasting functions and pathologies, namely tumour suppression, tumour promotion, wound healing and ageing. To investigate the effects of cellular senescence on bbb function, we examined the barrier integrity of an in vitro bbb model composed of ecspericytes from middleaged senescent bbb model or young mice young bbb model. From the large emerging class of noncoding rnas, mirnas have only recently been functionally implied in the regulatory.
The reactivation of senescence in cancer and the subsequent clearance of senescent cells are suggested as therapeutic intervention in the eradication of cancer. In their seminal experiments from the early 1960s, leonard hayflick and paul moorhead found out that normal human fetal fibroblasts in culture reach a maximum of approximately 50 cell population doublings before becoming senescent. Another prominent theory is the theory of oxidative stress or mitochondrial theory, a major competitor of the telomere theory. Pdf cellular senescence is an important mechanism for preventing the proliferation of potential cancer cells. It represents a stable state form of cell cycle arrest induced in proliferating cells by various forms of stress. What are the differences between cell aging and cell senescence. Senescence surveillance of premalignant hepatocytes limits liver cancer development.
It was first described by hayflick and moorhead at 1961, who demonstrated that human fibroblasts remain viable for many weeks in culture, even after completion of their finite number of cellular divisions 11. Cellular senescence is a major driver of agerelated diseases, and senotherapies are being tested in clinical trials. Four faces of cellular senescence rockefeller university press. Vascular cell senescence contributes to bloodbrain. Cancer cells avoid replicative senescence to become immortal. In addition to suppressing tumorigenesis, cellular senescence might also promote tissue repair and. In this article we hypothesize that cellular senescence is a phenotype that results from the coordination of two processes. The present study revealed that mir30a induced g1 cycle arrest and promoted cellular senescence in aging vsmcs, while rapamycin significantly reversed. Jane maienschein, chair james hurlbut karin ellison. Cellular senescence is the dynamic process of durable cell cycle arrest. Cellular senescence may play an important role in tumor. As we discuss later, this senescenceassociated secretory phenotype sasp helps explain some of the biological activities of senescent cells.
Four faces of cellular senescence journal of cell biology. Cellular senescence is a biological phenomenon by which normal cells cease to divide. From cellular senescence to ageassociated diseases. Four faces of cellular senescence, the journal of cell. Implications of oxidative stress and cellular senescence in. By imposing a growth arrest, senescence limits the replication of old or damaged cells. Cellular senescence is an important process for the removal of damaged cells, but if senescent cells are not removed a chronic proinflammatory environment ensues, increasing the risk of many agerelated diseases.
Senescent cells exhibit the following four interde. This information is current as myeloma cells release of nkg 2. Telomere theory basis the best marker of cellular senescence should provide insight into the root causes of aging. Cellular senescence is a cell state implicated in various physiological processes and a wide spec. The word senescence can refer either to cellular senescence or to senescence of the whole organism. Overexpression of mir30a increases cell apoptosis and induces cell cycle arrest in nonsmall cell lung cancer. Paracrine roles of cellular senescence in promoting tumourigenesis. A history of cellular senescence asu digital repository. Jun 06, 2017 cellular senescence is a process that results from a variety of stresses and leads to a state of irreversible growth arrest. Besides exiting the cell cycle, senescent cells undergo many other phenotypic alterations such as metabolic reprogramming, chromatin rearrangement. Cellular senescence is the state of essentially irreversible cell cycle arrest induced by a variety of potentially oncogenic stimuli, such as telomere erosion, oxidative stress or activation of certain oncogenes, and is considered to act as an important tumor suppression mechanism. A history of cellular senescence and its relation to stem cells in the twentieth and twentyfirst centuries by zane bartlett a thesis presented in partial fulfillment of the requirements for the degree master of science approved november 2015 by the graduate supervisory committee. Implications of oxidative stress and cellular senescence.
The senescenceassociated secretory phenotype induces cellular. Cellular senescence in mouse hippocampus after irradiation. Cellular senescence can be induced by a variety of stress. Rodier f, campisi j 2011 four faces of cellular senescence. Cellular aging and senescence characteristics of human. Shibata kr, aoyama t, shima y, fukiage k, otsuka s, furu m, kohno y, ito k, fujibayashi s, neo m, et al. Cellular senescence has historically been viewed as an irreversible cellcycle arrest mechanism. Organismal senescence involves an increase in death rates andor a decrease in fecundity with increasing age. In about 85% of tumors, this evasion of cellular senescence is the result of upactivation of their telomerase genes.
Citeseerx document details isaac councill, lee giles, pradeep teregowda. Evaluation of cellular senescence through fluorescence. Cellular senescence is a cell state implicated in various physiological processes and a wide spectrum of agerelated diseases. Cellular senescence is an established tumoursuppressive mechanism that prevents the proliferation of premalignant cells. Cs induction may occur by a variety of cell intrinsic and cell extrinsic stresses, including dna. Expression of the p16ink4a gene is associated closely with senescence of human mesenchymal stem cells and is potentially silenced by dna methylation during in vitro expansion. It can also be triggered by mutations that activate oncogenesnormal cellular genes that, when mutated, contribute to the development of cancer.
Pdf four faces of cellular senescence researchgate. The challenge now is to understand the senescence response well enough to harness its benefits while suppressing its drawbacks. A multidimensional systems biology analysis of cellular. Senescent cells accumulate during aging and have been implicated in promoting a variety of agerelated diseases. Cellular senescence is a permanent state of cell cycle arrest that promotes tissue remodeling during development and after injury, but can also contribute to the decline of the regenerative potential and function of tissues, to inflammation, and to tumorigenesis in aged organisms. Four faces of cellular senescence four faces of cellular senescence rodier, francis. Cellular senescence is a highly stable cell cycle arrest that is elicited in response to different stresses. Frontiers cellular senescence in neurodegenerative diseases. In their groundbreaking experiments during the early 1960s, leonard hayflick and paul moorhead found that normal human fetal fibroblasts in culture reach a maximum of approximately 50 cell population doublings before becoming senescent. They also offer insights into why, beyond the simple growth arrest, the complex senescent phenotypes may have evolved.
Hallmarks of cellular senescence alejandra hernandezsegura,1 jamil nehme,1 and marco demaria1, cellular senescence is a permanent state of cell cycle arrest that promotes tissue remodeling during development and after injury, but can also contribute to the decline of the regenerative potential and function of tissues, to in. Cellular senescence is a stable state of cell cycle arrest 710. Thus, cellular senescence might participate in four complex biological processes tumor suppression, tumor promotion, aging, and tissue repair, some of which. The increased presence of senescent cells in different neurodegenerative diseases suggests the contribution of senescence in the pathophysiology of these disorders. Mechanistically, replicative senescence is triggered by a dna damage response which results from the shortening of telomeres during each cellular division process. Schmitt ca 2007 cellular senescence and cancer treatment. Attenuation of torc1 signaling delays replicative and. Cellular senescence refers to the essentially irreversible arrest of cell proliferation growth that occurs when cells experience potentially oncogenic stress. Cellular senescence is a phenomenon characterized by the cessation of cell division. Cs induced by ir contributes to tumour cell control and often even causes side effects in normal cells.
Cellular senescence is a stable proliferation arrest that is associated with extensive cellular remodelling and an altered secretory pathway. Cellular senescence cellular senescence refers to a process in which cell growth and development are irreversibly halted. Cellular senescence is an irreversible form of cell cycle arrest that can be induced by persistent dna damage, and is well known to function as an important tumour suppression mechanism. Internal elevated ros levels can directly damage cellular components through the oxidation of biomolecules or can act as second messengers to modulate specific signaling cascades.
Oxidative damage is a wellknown trigger of cellular senescence. A nice article answering your question is four faces of cellular senescence 1 recommendation. Sorry, we are unable to provide the full text but you may find it at the following locations. Kirkland 1 1 robert and arlene kogod center on aging, mayo clinic, rochester, minnesota, usa. Cellular senescence is a response to potentially oncogenic stimuli. Inducers of senescence, toxic compounds, and senolytics. Senescent cells remain metabolically active and often acquire a distinctive bioactive secretory phenotype. Special issue molecular mechanisms to target cellular. Cellular senescence has evolved from an invitro model system to study aging in vitro to a multifaceted phenomenon of invivo importance as senescent cells in vivo have been identified and their removal delays the onset of ageassociated diseases in a mouse model system. We envision the senescent phenotype progressing through temporally regulated steps that orchestrate its activities fig. One lineage then undergoes cellular senescence faster than the other. Pdf cellular aging and senescence characteristics of. Thus, cellular senescence might participate in four complex biological processes tumor suppression, tumor promotion, aging, and tissue repair.
Cellular senescence, in which the cells enter a phase in which they have different functions than they have while reproducing, can come about after a. Four faces of cellular senescence pubmed central pmc. Recently, however, it has become apparent that this process entails more than a simple cessation of cell growth. Deciphering the mechanism for induction of senescence. Feb 21, 2011 four faces of cellular senescence four faces of cellular senescence rodier, francis. She noted that telomere shortening induces replicative senescence, the cessation of cell division.
Stress stimuli such as activation of oncogenes and dna damage can trigger normal mitotic cells to go into senescence. Cellular senescence is also induced upon replicative ag. A history of cellular senescence and its relation to stem cells in the twentieth and twentyfirst centuries by zane bartlett a thesis presented in partial fulfillment of the requirements for the degree master of science approved november 2015 by the graduate. Pdf four faces of cellular senescence semantic scholar. Cellular senescence cs is permanent arrested state of cell division induced by various factors, including exposure to ionizing radiation ir. Senescence stable cell cycle arrest limits the development of cancer, raising the possibility that selectively enhanced senescence in cancer cells could be used for the therapy of various tumours.
Cellular senescence is defined as irreversible cell cycle arrest driven by a variety of mechanisms, including telomere shortening, other forms of genotoxic stress, or mitogens or inflammatory cytokines, that culminate in the activation of the p53 tumor suppressor andor the cyclindependent kinase inhibitor p16. Jci cellular senescence and the senescent secretory. Semantic scholar extracted view of this information is current as myeloma cells release of nkg 2 d mic ligands in multiple senescence associated adam 10dependent genotoxic stress induces by santoni et al. Cellular senescence can also be triggered by any type of severe damage to the genome or epigenome the packaging and organization of the genome. Despite its popularity, cellular senescence is weakly defined and is frequently referred to as irreversible cellcycle arrest. Much of our molecular understanding in senescent cell biology comes from studies using mammalian cell lines exposed to stress or extended culture periods. These stimuli include damage to dna, whether at telomeres or elsewhere in.
Here, using a comprehensive set of markers for cell cycle arrest, dna damage response, oxidative stress, and sasp, our results based on gene expression and immunohistochemistry were consistent with the presence of cellular senescence in mouse hippocampus 9 weeks after cranial irradiation. Jun 18, 20 rodier f, campisi j 2011 four faces of cellular senescence. By contrast,bitinggenes inhi cell senescence overlapped with pro. So, how does cellular senescence participate in four complex processes tumor suppression, tumor promotion, aging, and tissue repair, some of which have apparently opposing effects. Recently, interest in therapeutically targeting senescence to improve healthy aging and agerelated disease, otherwise known as senotherapy, has been growing rapidly. Cellular senescence in agerelated thymic involution.
Contextdependent effects of cellular senescence in cancer. These cells accumulate as a result of cancer chemotherapy, are. Cells can also be induced to senesce independent of the number of cellular divisions via dna damage in response to elevated reactive oxygen species ros. Cellular senescence is an important mechanism for preventing the proliferation of potential cancer cells. Roles and mechanisms of cellular senescence in regulation. Four faces of cellular senescence recently, however, it has become apparent that this process entails more than a simple cessation of cell growth. Thus, cellular senescence might participate in four complex biological processes tumor suppression, tumor promotion, aging, and tissue repair, some of which have apparently opposing effects. Progressive slowdownprevention of cellular senescence by. Cellular senescence an overview sciencedirect topics. Biomarkers of cellular senescence cell cycle arrestcell cycle arrest longterm exit from the cell cycle is the central and only indispensable marker for the identification of all types of cellular senescence both in vitro and in vivo. Jci mechanisms and functions of cellular senescence.
1476 1588 247 885 1344 678 829 730 1205 448 481 361 752 965 1111 880 1276 46 363 82 480 486 882 1141 725 1183 629 503 1315 76 234 85 1227 1219