Unknown

Dataset Information

0

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


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), PI3K?, 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(-/?) 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.

SUBMITTER: Zhu Y 

PROVIDER: S-EPMC4531078 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

altmetric image

Publications

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

Zhu Yi Y   Tchkonia Tamara T   Pirtskhalava Tamar T   Gower Adam C AC   Ding Husheng H   Giorgadze Nino N   Palmer Allyson K AK   Ikeno Yuji Y   Hubbard Gene B GB   Lenburg Marc M   O'Hara Steven P SP   LaRusso Nicholas F NF   Miller Jordan D JD   Roos Carolyn M CM   Verzosa Grace C GC   LeBrasseur Nathan K NK   Wren Jonathan D JD   Farr Joshua N JN   Khosla Sundeep S   Stout Michael B MB   McGowan Sara J SJ   Fuhrmann-Stroissnigg Heike H   Gurkar Aditi U AU   Zhao Jing J   Colangelo Debora D   Dorronsoro Akaitz A   Ling Yuan Yuan YY   Barghouthy Amira S AS   Navarro Diana C DC   Sano Tokio T   Robbins Paul D PD   Niedernhofer Laura J LJ   Kirkland James L JL  

Aging cell 20150422 4


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 wi  ...[more]

Similar Datasets

2015-03-10 | E-GEOD-66236 | biostudies-arrayexpress
2015-03-10 | GSE66236 | GEO
| S-EPMC6351840 | biostudies-literature
| S-EPMC7790861 | biostudies-literature
| S-EPMC6286845 | biostudies-literature
| S-EPMC6912996 | biostudies-literature
| S-EPMC7552172 | biostudies-literature
2016-08-25 | GSE66883 | GEO
| S-EPMC3799760 | biostudies-literature
| S-EPMC5907463 | biostudies-literature