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      A BDNF-TrkB autocrine loop enhances senescent cell viability

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          Abstract

          Cellular senescence is characterized by cell cycle arrest, resistance to apoptosis, and a senescence-associated secretory phenotype (SASP) whereby cells secrete pro-inflammatory and tissue-remodeling factors. Given that the SASP exacerbates age-associated pathologies, some aging interventions aim at selectively eliminating senescent cells. In this study, a drug library screen uncovered TrkB (NTRK2) inhibitors capable of triggering apoptosis of several senescent, but not proliferating, human cells. Senescent cells expressed high levels of TrkB, which supported senescent cell viability, and secreted the TrkB ligand BDNF. The reduced viability of senescent cells after ablating BDNF signaling suggested an autocrine function for TrkB and BDNF, which activated ERK5 and elevated BCL2L2 levels, favoring senescent cell survival. Treatment with TrkB inhibitors reduced the accumulation of senescent cells in aged mouse organs. We propose that the activation of TrkB by SASP factor BDNF promotes cell survival and could be exploited therapeutically to reduce the senescent-cell burden.

          Abstract

          Selective elimination of senescent cells is an approach that has shown promise to ameliorate age-associated pathologies in preclinical models. Here the authors report that BDNF enhances senescent cell viability via TrkB in cultured cells, and that TrkB inhibition can reduce the accumulation of senescent cells in aged mouse organs.

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          Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2

          In comparative high-throughput sequencing assays, a fundamental task is the analysis of count data, such as read counts per gene in RNA-seq, for evidence of systematic changes across experimental conditions. Small replicate numbers, discreteness, large dynamic range and the presence of outliers require a suitable statistical approach. We present DESeq2, a method for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates. This enables a more quantitative analysis focused on the strength rather than the mere presence of differential expression. The DESeq2 package is available at http://www.bioconductor.org/packages/release/bioc/html/DESeq2.html. Electronic supplementary material The online version of this article (doi:10.1186/s13059-014-0550-8) contains supplementary material, which is available to authorized users.
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            Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles

            Although genomewide RNA expression analysis has become a routine tool in biomedical research, extracting biological insight from such information remains a major challenge. Here, we describe a powerful analytical method called Gene Set Enrichment Analysis (GSEA) for interpreting gene expression data. The method derives its power by focusing on gene sets, that is, groups of genes that share common biological function, chromosomal location, or regulation. We demonstrate how GSEA yields insights into several cancer-related data sets, including leukemia and lung cancer. Notably, where single-gene analysis finds little similarity between two independent studies of patient survival in lung cancer, GSEA reveals many biological pathways in common. The GSEA method is embodied in a freely available software package, together with an initial database of 1,325 biologically defined gene sets.
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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
                carlos.anerillasaljama@nih.gov
                myriam-gorospe@nih.gov
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                20 October 2022
                20 October 2022
                2022
                : 13
                : 6228
                Affiliations
                [1 ]GRID grid.94365.3d, ISNI 0000 0001 2297 5165, Laboratory of Genetics and Genomics, National Institute on Aging Intramural Research Program, , National Institutes of Health, ; Baltimore, MD USA
                [2 ]GRID grid.94365.3d, ISNI 0000 0001 2297 5165, Translational Gerontology Branch, National Institute on Aging Intramural Research Program, , National Institutes of Health, ; Baltimore, MD USA
                Author information
                http://orcid.org/0000-0003-4424-7913
                http://orcid.org/0000-0003-3140-3251
                http://orcid.org/0000-0003-2527-9186
                http://orcid.org/0000-0001-7738-9841
                http://orcid.org/0000-0002-3234-6861
                http://orcid.org/0000-0001-6240-5810
                http://orcid.org/0000-0002-3354-2442
                http://orcid.org/0000-0001-5439-3434
                Article
                33709
                10.1038/s41467-022-33709-8
                9585019
                36266274
                b54dd167-9ffe-45ad-9260-af622d58a91b
                © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2022

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 15 January 2022
                : 26 September 2022
                Funding
                Funded by: NIA IRP, NIH, Z01-AG000511
                Categories
                Article
                Custom metadata
                © The Author(s) 2022

                Uncategorized
                dna damage response,senescence,ageing
                Uncategorized
                dna damage response, senescence, ageing

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