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The Achilles' heel of senescent cells: from transcriptome to senolytic drugs.
- Source :
-
Aging cell [Aging Cell] 2015 Aug; Vol. 14 (4), pp. 644-58. Date of Electronic Publication: 2015 Apr 22. - Publication Year :
- 2015
-
Abstract
- The healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene. Achieving the same using small molecules would have a tremendous impact on quality of life and the burden of age-related chronic diseases. Here, we describe the rationale for identification and validation of a new class of drugs termed senolytics, which selectively kill senescent cells. By transcript analysis, we discovered increased expression of pro-survival networks in senescent cells, consistent with their established resistance to apoptosis. Using siRNA to silence expression of key nodes of this network, including ephrins (EFNB1 or 3), PI3Kδ, p21, BCL-xL, or plasminogen-activated inhibitor-2, killed senescent cells, but not proliferating or quiescent, differentiated cells. Drugs targeting these same factors selectively killed senescent cells. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse BM-MSCs. The combination of dasatinib and quercetin was effective in eliminating senescent MEFs. In vivo, this combination reduced senescent cell burden in chronologically aged, radiation-exposed, and progeroid Ercc1(-/Δ) mice. In old mice, cardiac function and carotid vascular reactivity were improved 5 days after a single dose. Following irradiation of one limb in mice, a single dose led to improved exercise capacity for at least 7 months following drug treatment. Periodic drug administration extended healthspan in Ercc1(-/∆) mice, delaying age-related symptoms and pathology, osteoporosis, and loss of intervertebral disk proteoglycans. These results demonstrate the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of frailty and extending healthspan.<br /> (© 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)
- Subjects :
- Adipocytes drug effects
Adipocytes metabolism
Adipocytes pathology
Aging genetics
Aging metabolism
Aging pathology
Animals
Carotid Arteries drug effects
Carotid Arteries pathology
Cellular Senescence genetics
Class I Phosphatidylinositol 3-Kinases
Cyclin-Dependent Kinase Inhibitor p21 genetics
Cyclin-Dependent Kinase Inhibitor p21 metabolism
DNA-Binding Proteins genetics
DNA-Binding Proteins metabolism
Drug Combinations
Endonucleases genetics
Endonucleases metabolism
Endothelial Cells drug effects
Endothelial Cells metabolism
Endothelial Cells pathology
Ephrins genetics
Ephrins metabolism
Fibroblasts drug effects
Fibroblasts metabolism
Fibroblasts pathology
Gene Expression Profiling
Heart drug effects
Heart physiopathology
Intervertebral Disc chemistry
Intervertebral Disc drug effects
Intervertebral Disc pathology
Mesenchymal Stem Cells drug effects
Mesenchymal Stem Cells metabolism
Mesenchymal Stem Cells pathology
Mice
Mice, Knockout
Osteoporosis genetics
Osteoporosis metabolism
Osteoporosis pathology
Phosphatidylinositol 3-Kinases genetics
Phosphatidylinositol 3-Kinases metabolism
Plasminogen Activator Inhibitor 2 genetics
Plasminogen Activator Inhibitor 2 metabolism
bcl-X Protein genetics
bcl-X Protein metabolism
Aging drug effects
Cellular Senescence drug effects
Dasatinib pharmacology
Osteoporosis prevention & control
Quercetin pharmacology
Transcriptome
Subjects
Details
- Language :
- English
- ISSN :
- 1474-9726
- Volume :
- 14
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Aging cell
- Publication Type :
- Academic Journal
- Accession number :
- 25754370
- Full Text :
- https://doi.org/10.1111/acel.12344