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      How good is the evidence that cellular senescence causes skin ageing?


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          Skin is the largest organ of the body with important protective functions, which become compromised with time due to both intrinsic and extrinsic ageing processes. Cellular senescence is the primary ageing process at cell level, associated with loss of proliferative capacity, mitochondrial dysfunction and significantly altered patterns of expression and secretion of bioactive molecules. Intervention experiments have proven cell senescence as a relevant cause of ageing in many organs. In case of skin, accumulation of senescence in all major compartments with ageing is well documented and might be responsible for most, if not all, the molecular changes observed during ageing. Incorporation of senescent cells into in-vitro skin models (specifically 3D full thickness models) recapitulates changes typically associated with skin ageing. However, crucial evidence is still missing. A beneficial effect of senescent cell ablation on skin ageing has so far only been shown following rather unspecific interventions or in transgenic mouse models. We conclude that evidence for cellular senescence as a relevant cause of intrinsic skin ageing is highly suggestive but not yet completely conclusive.


          • Senescent cells accumulate in all major compartments of the skin during ageing.

          • Senescent cells have the potential to drive typical skin ageing phenotypes.

          • Impact of specific senescence modifications on skin ageing is not fully established.

          • Role of senescence for chronic wound healing needs experimental clarification.

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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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            Cellular Senescence: Defining a Path Forward

            Cellular senescence is a cell state implicated in various physiological processes and a wide spectrum of age-related diseases. Recently, interest in therapeutically targeting senescence to improve healthy aging and age-related disease, otherwise known as senotherapy, has been growing rapidly. Thus, the accurate detection of senescent cells, especially in vivo, is essential. Here, we present a consensus from the International Cell Senescence Association (ICSA), defining and discussing key cellular and molecular features of senescence and offering recommendations on how to use them as biomarkers. We also present a resource tool to facilitate the identification of genes linked with senescence, SeneQuest (available at http://Senequest.net). Lastly, we propose an algorithm to accurately assess and quantify senescence, both in cultured cells and in vivo.
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              The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs

              The healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene. Achieving the same using small molecules would have a tremendous impact on quality of life and the burden of age-related chronic diseases. Here, we describe the rationale for identification and validation of a new class of drugs termed senolytics, which selectively kill senescent cells. By transcript analysis, we discovered increased expression of pro-survival networks in senescent cells, consistent with their established resistance to apoptosis. Using siRNA to silence expression of key nodes of this network, including ephrins (EFNB1 or 3), PI3Kδ, p21, BCL-xL, or plasminogen-activated inhibitor-2, killed senescent cells, but not proliferating or quiescent, differentiated cells. Drugs targeting these same factors selectively killed senescent cells. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse BM-MSCs. The combination of dasatinib and quercetin was effective in eliminating senescent MEFs. In vivo, this combination reduced senescent cell burden in chronologically aged, radiation-exposed, and progeroid Ercc1 −/Δ mice. In old mice, cardiac function and carotid vascular reactivity were improved 5 days after a single dose. Following irradiation of one limb in mice, a single dose led to improved exercise capacity for at least 7 months following drug treatment. Periodic drug administration extended healthspan in Ercc1 −/Δ mice, delaying age-related symptoms and pathology, osteoporosis, and loss of intervertebral disk proteoglycans. These results demonstrate the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of frailty and extending healthspan.

                Author and article information

                Ageing Res Rev
                Ageing Res Rev
                Ageing Research Reviews
                Elsevier Science
                1 November 2021
                November 2021
                : 71
                : 101456
                [a ]Ageing Biology Laboratories, Newcastle University Biosciences Institute, Newcastle University, Newcastle upon Tyne NE4 5PL, UK
                [b ]Department of Biosciences, Durham University, South Road, Durham DH1 3LE, UK
                Author notes
                [* ]Correspondence to: Ageing Biology Laboratories, Campus for Ageing and Health, Newcastle University Biosciences Institute, Newcastle University, Newcastle upon Tyne NE4 5PL, UK. t.vonzglinicki@ 123456ncl.ac.uk
                S1568-1637(21)00203-8 101456
                © 2021 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                : 18 June 2021
                : 25 August 2021
                : 31 August 2021

                skin,senescence,ageing,wound healing
                skin, senescence, ageing, wound healing


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