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P A Y W A L L E D S O U R C E : Cell Metabolism
Highlights
• p16High senescence is a slow process that manifests around 10–12 months of age
• p16High cells in the liver of 12-month-old mice are LSECs and macrophages
• Senescent p16High LSECs are structurally and functionally important
• Elimination of p16High senescent cells induces liver and perivascular tissue fibrosis
Summary
The accumulation of senescent cells can drive many age-associated phenotypes and pathologies. Consequently, it has been proposed that removing senescent cells might extend lifespan. Here, we generated two knockin mouse models targeting the best-characterized marker of senescence, p16Ink4a. Using a genetic lineage tracing approach, we found that age-induced p16High senescence is a slow process that manifests around 10–12 months of age.
The majority of p16High cells were vascular endothelial cells mostly in liver sinusoids (LSECs), and to lesser extent macrophages and adipocytes. In turn, continuous or acute elimination of p16High senescent cells disrupted blood-tissue barriers with subsequent liver and perivascular tissue fibrosis and health deterioration. Our data show that senescent LSECs are not replaced after removal and have important structural and functional roles in the aging organism. In turn, delaying senescence or replacement of senescent LSECs could represent a powerful tool in slowing down aging.
O U T L I N E :
Context and Significance
Introduction
Results
- Novel Mouse Model for Continuous Labeling and Elimination of p16High Senescent Cells
- Identification of p16High Senescent Cells In Vivo
- Senescent LSECs Exhibit Metabolic Alterations and Enhanced Detoxifying Function with Age
- Senescent p16High CD31-Positive Cells Are Not Replaced after Removal by Similar Cell Types
- Continuous Removal of p16High Senescent Cells In Vivo Results in Liver and Systemic Perivascular Fibrosis
- Acute Removal of p16High Senescent Cells In Vivo Results in Deregulation of Blood-Vessel Permeability and Subsequent Fibrosis
- Senolytic Combination of Dasatinib and Quercetin Efficiently Removes p16High Macrophages
Discussion
- Limitations of Study
STAR★Methods
- Key Resources Table
- Resource Availability
- Lead Contact
- Materials Availability
- Data and Code Availability
- Experimental Model and Subject Details
- Mouse Models
- Cell Culture
- Method Details
- Histological Analysis
- Scanning Electron Microscopy (SEM)
- Transmission Electron Microscopy (TEM)
- Cell Count and Proliferation Assay
- Evans Blue Retention Analysis
- Uptake ox-LDL and acLDL Analyses
- Measurement of LDL and ox-LDL
- SA- beta-Gal Staining
- Gene Expression Analysis
- RNA-Seq Sample Preparation
- Quantification and Statistical Analysis
- RNA-Seq Data Analysis
- Data Representation and Statistical Analysis
Acknowledgments
- Author Contributions
- Declaration of Interests
Supplemental Information
References
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Edited by Engadin, 04 June 2020 - 02:17 PM.