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Updated: Jan 27, 2026
Measurement of Lifespan in Drosophila melanogaster
Published on: January 7, 2013
Celastrol Targets Hsc70-Bim Interaction as a Novel Senolytic to Extend Lifespan and Mitigate Organ Fibrosis
Weitong Xu1, Honghan Chen1, Hui Gong1
1Sichuan University, State Key Laboratory of Biotherapy, Chengdu, China.
Abstract:
Senolysis holds promise for geroprotection but is limited by efficacy and safety; here we show that Celastrol, a pentacyclic triterpenoid, surpasses benchmark agents ABT-263 and fisetin in senolytic potency and elucidate its mechanism and a prodrug strategy to improve safety. Using stress- and replication-induced senescent cells, we demonstrate that Celastrol selectively triggers intrinsic apoptosis-evidenced by viability assays, Annexin V/PI, cleaved caspase-3 and blockade by the pan-caspase inhibitor Z-VAD-FMK-while ferroptosis is excluded by specific inhibitors. Proteomic, co-immunoprecipitation/mass spectrometry, biolayer interferometry, ubiquitination assays and RNAi identify Hsc70 as a binding partner; Celastrol disrupts an Hsc70-Bim-CHIP complex, reduces Bim ubiquitination and stabilizes Bim protein, and Bim knockdown attenuates caspase activation and senolysis. In vivo, Celastrol reduces intestinal senescence and extends Drosophila median and maximum lifespan, and mitigates bleomycin- and CCl₄-induced pulmonary and hepatic fibrosis in mice with increased cleaved caspase-3 in p16⁺ cells. A β-galactosidase-activated prodrug (CeGal) preserves efficacy, preferentially releases Celastrol in β-galactosidase-high cells, and markedly reduces systemic toxicity, supporting clinical translation of this targeted senolytic approach.
Insights
Celastrol demonstrates potent senolytic activity, surpassing existing agents by selectively inducing apoptosis in senescent cells. A novel prodrug strategy enhances safety and supports clinical translation for aging interventions.
Area of Science:
- Geroprotection
- Cellular Senescence
- Apoptosis Induction
Background:
- Senolysis offers therapeutic potential for aging but faces challenges in efficacy and safety.
- Existing senolytic agents have limitations that necessitate the development of improved compounds.
Purpose of the Study:
- To evaluate Celastrol as a senolytic agent, elucidate its mechanism of action, and develop a safer prodrug strategy.
- To compare Celastrol's senolytic potency against benchmark agents like ABT-263 and fisetin.
Main Methods:
- Utilized stress- and replication-induced senescent cells for in vitro studies.
- Employed viability assays, Annexin V/PI staining, cleaved caspase-3 assessment, and specific inhibitor blockade to determine apoptosis.
- Integrated proteomics, co-immunoprecipitation/mass spectrometry, biolayer interferometry, ubiquitination assays, and RNAi to identify molecular targets.
- Administered Celastrol and its prodrug (CeGal) in vivo in Drosophila and mouse models of aging and fibrosis.
Main Results:
- Celastrol selectively induced intrinsic apoptosis in senescent cells, distinct from ferroptosis.
- Identified Heat Shock Cognate 70 (Hsc70) as a binding partner, revealing Celastrol disrupts an Hsc70-Bim-CHIP complex, stabilizing Bim and promoting apoptosis.
- Celastrol extended lifespan in Drosophila and reduced fibrosis in mice, with increased cleaved caspase-3 in senescent cells.
- The β-galactosidase-activated prodrug (CeGal) maintained senolytic efficacy while significantly reducing systemic toxicity.
Conclusions:
- Celastrol is a potent senolytic agent with a novel mechanism involving Hsc70-Bim complex disruption.
- A targeted prodrug approach (CeGal) improves the safety profile of Celastrol, paving the way for clinical translation.
- Celastrol and its prodrug represent a promising strategy for geroprotection and treating age-related diseases.
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