A pipeline for senolytics
Sundeep Khosla
Sundeep Khosla
Published May 1, 2024
Citation Information: J Clin Invest. 2024;134(9):e180558. https://doi.org/10.1172/JCI180558.
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Commentary

A pipeline for senolytics

Abstract

There is intense interest in identifying compounds that selectively kill senescent cells, termed senolytics, for ameliorating age-related comorbidities. However, screening for senolytic compounds currently relies on primary cells or cell lines where senescence is induced in vitro. Given the complexity of senescent cells across tissues and diseases, this approach may not target the senescent cells that develop under specific conditions in vivo. In this issue of the JCI, Lee et al. describe a pipeline for high-throughput drug screening of senolytic compounds where senescence was induced in vivo and identify the HSP90 inhibitor XL888 as a candidate senolytic to treat idiopathic pulmonary fibrosis.

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Sundeep Khosla

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Figure 1

Lee et al. developed an approach for high-throughput screening of senolytic compounds.

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Lee et al. developed an approach for high-throughput screening of senoly...
In Lee et al. (15), senescence is induced in mice that express a highly sensitive p16Ink4a reporter, termed INKBRITE, followed by fluorescence-activated cell sorting (FACS) for GFP+ (p16Ink4a+) and GFP– (p16Ink4a–) cells. The purified GFP+ and GFP– cells are then mixed in a 1:1 ratio and plated into multi-well plates for high-throughput screening of candidate senolytic compounds, which are selected based on selective killing of GFP+ cells (GFP+-to-GFP– cell ratio below a specific threshold). These compounds are then carried forward into secondary validation and ultimately in vivo validation in mice.