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The heterogeneity of cellular senescence: insights at the single-cell level

TRENDS IN CELL BIOLOGY (2023)

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Targeting p21Cip1 highly expressing cells in adipose tissue alleviates insulin resistance in obesity

Lichao Wang et al.

Summary: This study identifies a small population of p21 high-expressing cells that accumulate in adipose tissue with obesity and shows that intermittent clearance of these cells can prevent and alleviate insulin resistance. Inactivation of the NF-kB pathway within these cells attenuates insulin resistance. Additionally, a drug combination of dasatinib and quercetin can eliminate p21 high-expressing cells in human fat and mitigate insulin resistance.

CELL METABOLISM (2022)

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Article Neurosciences

The landscape of human tissue and cell type specific expression and co-regulation of senescence genes

Peng Xu et al.

Summary: This study analyzed gene network data from healthy human tissues to investigate co-expression signatures of senescence genes (SnGs) and their specificity in different cell types. The research identified highly conserved SnGs across human tissues, with specific enrichment in fibroblasts, endothelial cells, and immune cells. Single-cell RNA-seq and spatial transcriptomic data further confirmed the cell-type specific SnG signatures predicted by the network analysis, providing insights for future studies on senescent cells in human tissues.

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Article Cell Biology

Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice

Mikolaj Ogrodnik et al.

Summary: Clearing senescent cells, either through drug treatment or senolytic cocktail, has been shown to improve cognitive function, providing proof-of-concept for senolytic interventions as a potential therapeutic avenue for alleviating age-associated cognitive impairment.

AGING CELL (2021)

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Review Cell Biology

Cellular senescence in ageing: from mechanisms to therapeutic opportunities

Raffaella Di Micco et al.

Summary: Cellular senescence is characterized by permanent proliferation arrest and can occur in response to various stresses like telomere dysfunction. Apart from stress-induced senescence, it can also be part of controlled programs in biological processes like embryonic development. Senescent cells contribute to impaired tissue regeneration, chronic diseases, and organismal aging, but also present an opportunity for intervention in aging and associated diseases.

NATURE REVIEWS MOLECULAR CELL BIOLOGY (2021)

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Article Cell Biology

Pathological angiogenesis in retinopathy engages cellular senescence and is amenable to therapeutic elimination via BCL-xL inhibition

Sergio Crespo-Garcia et al.

Summary: The study reveals that pathological blood vessels engage pathways of cellular senescence, while healthy blood vessels do not. Eliminating p16(INK4A)-expressing cells or inhibiting the anti-apoptotic protein BCL-xL can suppress pathological angiogenesis, promoting physiological vascular repair in the retina. These findings suggest that BCL-xL inhibitors may hold potential as treatments for neovascular retinal diseases.

CELL METABOLISM (2021)

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Article Multidisciplinary Sciences

p21 produces a bioactive secretome that places stressed cells under immunosurveillance

Ines Sturmlechner et al.

Summary: The cell-cycle inhibitor p21 activates Rb-dependent transcription to generate a complex bioactive secretome, known as PASP, which includes chemokine CXCL14 that attracts macrophages. Macrophages disengage if cells normalize p21 within 4 days, but persisting p21 induction leads to M1 polarization and cytotoxic T cell response for eliminating target cells, including preneoplastic cells. Thus, p21 concurrently induces proliferative arrest and immunosurveillance of cells under duress.

SCIENCE (2021)

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Article Medicine, General & Internal

Transcriptional and Proteomic Characterization of Telomere-Induced Senescence in a Human Alveolar Epithelial Cell Line

Daniel Sullivan et al.

Summary: Research on telomere dysfunction-induced cellular senescence in human alveolar epithelial cells revealed a distinct senescence-associated secretory phenotype compared to murine cells. Candidate biomarkers identified through transcriptional and secretome analysis were found to be differentially expressed in IPF and control patient plasma. This suggests the importance of validating animal models due to the possibility of species-specific responses to telomere dysfunction.

FRONTIERS IN MEDICINE (2021)

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Jeffrey M. Perkel

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Senolytic vaccination improves normal and pathological age-related phenotypes and increases lifespan in progeroid mice

Masayoshi Suda et al.

Summary: The study identified GPNMB as a target for senolytic therapy, and immunization against GPNMB improved normal and pathological phenotypes associated with aging, extending the lifespan of aging mice.

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Article Cell Biology

Profiling senescent cells in human brains reveals neurons with CDKN2D/p19 and tau neuropathology

Shiva Kazempour Dehkordi et al.

Summary: Senescent cells, contributing to pathology and dysfunction, were successfully identified in postmortem human brain tissues using a novel eigengene approach. These cells were found to be mainly excitatory neurons and overlapped with neurons containing neurofibrillary tangle pathology. The CDKN2D/p19 gene may play a significant role in these senescent cells.

NATURE AGING (2021)

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Article Cell Biology

An inducible p21-Cre mouse model to monitor and manipulate p21-highly-expressing senescent cells in vivo

Binsheng Wang et al.

Summary: Researchers have developed a p21-Cre mouse model for studying cells with high p21 expression, which play a critical role in aging. By crossing p21-Cre mice with different floxed mice, they were able to monitor and modulate these cells in vivo, providing a valuable tool for studying senescent cells.

NATURE AGING (2021)

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Review Cell Biology

Strategies for targeting senescent cells in human disease

Nathan S. Gasek et al.

Summary: Cellular senescence is a unique cell fate that plays a role in development and wound healing, while also limiting tumor formation. However, the pathologic accumulation of senescent cells is associated with various diseases and age-related morbidities. Research shows that treatments targeting senescent cells through apoptosis induction or inhibition of senescence-related secretory phenotype are beneficial for geriatric decline and chronic diseases.

NATURE AGING (2021)

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Transplanting cells from old but not young donors causes physical dysfunction in older recipients

Binsheng Wang et al.

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Defined p16High Senescent Cell Types Are Indispensable for Mouse Healthspan

Laurent Grosse et al.

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Generation of a p16 Reporter Mouse and Its Use to Characterize and Target p16high Cells In Vivo

Satotaka Omori et al.

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A single-cell transcriptomic atlas characterizes ageing tissues in the mouse

Nicole Almanzar et al.

NATURE (2020)

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Senolytic CAR T cells reverse senescence-associated pathologies

Corina Amor et al.

NATURE (2020)

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A multidimensional systems biology analysis of cellular senescence in aging and disease

Roberto A. Avelar et al.

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Transcriptome-scale super-resolved imaging in tissues by RNA seqFISH

Chee-Huat Linus Eng et al.

NATURE (2019)

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Review Biochemistry & Molecular Biology

Cellular Senescence: Defining a Path Forward

Vassilis Gorgoulis et al.

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Murine single-cell RNA-seq reveals cell-identity- and tissue-specific trajectories of aging

Jacob C. Kimmel et al.

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Senescent cell turnover slows with age providing an explanation for the Gompertz law

Omer Karin et al.

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Deep Profiling of Mouse Splenic Architecture with CODEX Multiplexed Imaging

Yury Goltsev et al.

CELL (2018)

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Fisetin is a senotherapeutic that extends health and lifespan

Matthew J. Yousefzadeh et al.

EBIOMEDICINE (2018)

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Molecular, spatial, and functional single-cell profiling of the hypothalamic preoptic region

Jeffrey R. Moffitt et al.

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Analysis of individual cells identifies cell-to-cell variability following induction of cellular senescence

Christopher D. Wiley et al.

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Murine mesenchymal cells that express elevated levels of the CDK inhibitor p16(Ink4a) in vivo are not necessarily senescent

David Frescas et al.

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Unmasking Transcriptional Heterogeneity in Senescent Cells

Alejandra Hernandez-Segura et al.

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Quantitative identification of senescent cells in aging and disease

Anat Biran et al.

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p21 maintains senescent cell viability under persistent DNA damage response by restraining JNK and caspase signaling

Reut Yosef et al.

EMBO JOURNAL (2017)

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p16(Ink4a) and senescence-associated β-galactosidase can be induced in macrophages as part of a reversible response to physiological stimuli

Brandon M. Hall et al.

AGING-US (2017)

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Article Biochemistry & Molecular Biology

Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice

Jianhui Chang et al.

NATURE MEDICINE (2016)

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Review Biotechnology & Applied Microbiology

Single-cell analysis tools for drug discovery and development

James R. Heath et al.

NATURE REVIEWS DRUG DISCOVERY (2016)

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p16Ink4a-induced senescence of pancreatic beta cells enhances insulin secretion

Aharon Helman et al.

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Visualization and analysis of gene expression in tissue sections by spatial transcriptomics

Patrik L. Stahl et al.

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The Achilles' heel of senescent cells: from transcriptome to senolytic drugs

Yi Zhu et al.

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Geroscience: Linking Aging to Chronic Disease

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An Essential Role for Senescent Cells in Optimal Wound Healing through Secretion of PDGF-AA

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Substantial Health And Economic Returns From Delayed Aging May Warrant A New Focus For Medical Research

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The role of nuclear lamin B1 in cell proliferation and senescence

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Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders

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Critical pathways in cellular senescence and immortalization revealed by gene expression profiling

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