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      The right time for senescence

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          Abstract

          Cellular senescence is a highly complex and programmed cellular state with diverse and, at times, conflicting physiological and pathological roles across the lifespan of an organism. Initially considered a cell culture artifact, senescence evolved from an age-related circumstance to an intricate cellular defense mechanism in response to stress, implicated in a wide spectrum of biological processes like tissue remodelling, injury and cancer. The development of new tools to study senescence in vivo paved the way to uncover its functional roles in various frameworks, which are sometimes hard to reconcile. Here, we review the functional impact of senescent cells on different organismal contexts. We provide updated insights on the role of senescent cells in tissue repair and regeneration, in which they essentially modulate the levels of fibrosis and inflammation, discussing how “time” seems to be the key maestro of their effects. Finally, we overview the current clinical research landscape to target senescent cells and contemplate its repercussions on this fast-evolving field.

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          Most cited references123

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          Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.

          Differentiated cells can be reprogrammed to an embryonic-like state by transfer of nuclear contents into oocytes or by fusion with embryonic stem (ES) cells. Little is known about factors that induce this reprogramming. Here, we demonstrate induction of pluripotent stem cells from mouse embryonic or adult fibroblasts by introducing four factors, Oct3/4, Sox2, c-Myc, and Klf4, under ES cell culture conditions. Unexpectedly, Nanog was dispensable. These cells, which we designated iPS (induced pluripotent stem) cells, exhibit the morphology and growth properties of ES cells and express ES cell marker genes. Subcutaneous transplantation of iPS cells into nude mice resulted in tumors containing a variety of tissues from all three germ layers. Following injection into blastocysts, iPS cells contributed to mouse embryonic development. These data demonstrate that pluripotent stem cells can be directly generated from fibroblast cultures by the addition of only a few defined factors.
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            Induction of pluripotent stem cells from adult human fibroblasts by defined factors.

            Successful reprogramming of differentiated human somatic cells into a pluripotent state would allow creation of patient- and disease-specific stem cells. We previously reported generation of induced pluripotent stem (iPS) cells, capable of germline transmission, from mouse somatic cells by transduction of four defined transcription factors. Here, we demonstrate the generation of iPS cells from adult human dermal fibroblasts with the same four factors: Oct3/4, Sox2, Klf4, and c-Myc. Human iPS cells were similar to human embryonic stem (ES) cells in morphology, proliferation, surface antigens, gene expression, epigenetic status of pluripotent cell-specific genes, and telomerase activity. Furthermore, these cells could differentiate into cell types of the three germ layers in vitro and in teratomas. These findings demonstrate that iPS cells can be generated from adult human fibroblasts.
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              The senescence-associated secretory phenotype: the dark side of tumor suppression.

              Cellular senescence is a tumor-suppressive mechanism that permanently arrests cells at risk for malignant transformation. However, accumulating evidence shows that senescent cells can have deleterious effects on the tissue microenvironment. The most significant of these effects is the acquisition of a senescence-associated secretory phenotype (SASP) that turns senescent fibroblasts into proinflammatory cells that have the ability to promote tumor progression.
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                Author and article information

                Contributors
                Role: Reviewing Editor
                Role: Senior Editor
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                10 November 2021
                2021
                : 10
                : e72449
                Affiliations
                [1 ] Instituto de Medicina Molecular – João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa Lisbon Portugal
                [2 ] CEDOC, NOVA Medical School, Faculdade de Ciências Médicas da Universidade Nova de Lisboa Lisbon Portugal
                [3 ] Instituto de Medicina Molecular – João Lobo Antunes e Instituto de Histologia e Biologia do Desenvolvimento, Faculdade de Medicina da Universidade de Lisboa Lisbon Portugal
                California Institute of Technology United States
                California Institute of Technology United States
                Author information
                https://orcid.org/0000-0003-2274-7167
                https://orcid.org/0000-0002-4193-6089
                https://orcid.org/0000-0001-5933-8872
                Article
                72449
                10.7554/eLife.72449
                8580479
                34756162
                0b79cb0d-73d5-441c-80b5-da87da8b30a5
                © 2021, Paramos-de-Carvalho et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 26 July 2021
                : 20 October 2021
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001871, Fundação para a Ciência e a Tecnologia;
                Award ID: PD/BD/105770/2014
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001871, Fundação para a Ciência e a Tecnologia;
                Award ID: PTDC/MED-NEU/30428/2017
                Award Recipient :
                Funded by: "la Caixa" Banking Foundation;
                Award ID: HR18-00187
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001871, Fundação para a Ciência e a Tecnologia;
                Award ID: HR18-00187
                Award Recipient :
                Funded by: Santa Casa da Misericórdia de Lisboa;
                Award ID: MC36-2020 (Melo e Castro Award)
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Review Article
                Cell Biology
                Custom metadata
                A time-gated model is proposed to reconcile the transient vs. persistent biological activities of cellular senescence, in which 'time' seems to be the main orchestrator of the beneficial vs. detrimental effects of the senescent programme.

                Life sciences
                senescence,time,tissue remodelling,pathophysiology,senotherapies
                Life sciences
                senescence, time, tissue remodelling, pathophysiology, senotherapies

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