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Identification of HSP90 inhibitors as a novel class of senolytics
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Identification of HSP90 inhibitors as a novel class of senolytics
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Journal Article
Identification of HSP90 inhibitors as a novel class of senolytics
2017
Overview
Aging is the main risk factor for many chronic degenerative diseases and cancer. Increased senescent cell burden in various tissues is a major contributor to aging and age-related diseases. Recently, a new class of drugs termed senolytics were demonstrated to extending healthspan, reducing frailty and improving stem cell function in multiple murine models of aging. To identify novel and more optimal senotherapeutic drugs and combinations, we established a senescence associated β-galactosidase assay as a screening platform to rapidly identify drugs that specifically affect senescent cells. We used primary
Ercc1
−/−
murine embryonic fibroblasts with reduced DNA repair capacity, which senesce rapidly if grown at atmospheric oxygen. This platform was used to screen a small library of compounds that regulate autophagy, identifying two inhibitors of the HSP90 chaperone family as having significant senolytic activity in mouse and human cells. Treatment of
Ercc1
−/∆
mice, a mouse model of a human progeroid syndrome, with the HSP90 inhibitor 17-DMAG extended healthspan, delayed the onset of several age-related symptoms and reduced p16
INK4a
expression. These results demonstrate the utility of our screening platform to identify senotherapeutic agents as well as identified HSP90 inhibitors as a promising new class of senolytic drugs.
The accumulation of senescent cells is thought to contribute to the age-associated decline in tissue function. Here, the authors identify HSP90 inhibitors as a new class of senolytic compounds in an in vitro screening and show that administration of a HSP90 inhibitor reduces age-related symptoms in progeroid mice.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ Age
/ Aging
/ Animals
/ Benzoquinones - pharmacology
/ Cellular Senescence - drug effects
/ DNA-Binding Proteins - metabolism
/ Down-Regulation - drug effects
/ Drug Evaluation, Preclinical
/ Drugs
/ Female
/ HSP90 Heat-Shock Proteins - antagonists & inhibitors
/ HSP90 Heat-Shock Proteins - metabolism
/ Human Umbilical Vein Endothelial Cells
/ Humanities and Social Sciences
/ Humans
/ Lactams, Macrocyclic - pharmacology
/ Mice
/ Phosphatidylinositol 3-Kinases - metabolism
/ Proto-Oncogene Proteins c-akt - metabolism
/ Science
/ Signal Transduction - drug effects
