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Cycloastragenol: A Novel Senolytic Agent That Induces Senescent Cell Apoptosis and Restores Physical Function in
Yanghuan Zhang1, Dongxiao Gao1, Yang Yuan1
1Laboratory of Molecular Genetics of Aging and Tumor, Medical School, Kunming University of Science and Technology, Kunming 650500, China.
Abstract:
Accumulating evidence indicates that the increased burden of senescent cells (SCs) in aged organisms plays an important role in many age-associated diseases. The pharmacological elimination of SCs with "senolytics" has been emerging as a new therapy for age-related diseases and extending the healthy lifespan. In the present study, we identified that cycloastragenol (CAG), a secondary metabolite isolated from Astragalus membrananceus, delays age-related symptoms in mice through its senolytic activity against SCs. By screening a series of compounds, we found that CAG selectively kills SCs by inducing SCs apoptosis and that this process is associated with the inhibition of Bcl-2 antiapoptotic family proteins and the PI3K/AKT/mTOR pathway. In addition, CAG treatment also suppressed the development of the senescence-associated secretory phenotype (SASP) in SCs, thereby inhibiting cell migration mediated by the SASP. Furthermore, the administration of CAG for 2 weeks to mice with irradiation-induced aging alleviated the burden of SCs and improved the animals' age-related physical dysfunction. Overall, our studies demonstrate that CAG is a novel senolytic agent with in vivo activity that has the potential to be used in the treatment of age-related diseases.
Insights
Cycloastragenol (CAG) is a novel senolytic compound that eliminates senescent cells (SCs) and reduces age-related symptoms in mice. This research highlights CAG
Area of Science:
- Gerontology and aging research
- Pharmacology and drug discovery
- Cellular senescence and molecular biology
Background:
- Accumulating evidence links increased senescent cells (SCs) to age-associated diseases.
- Senolytics, drugs that eliminate SCs, are a promising therapeutic strategy for age-related conditions and lifespan extension.
Purpose of the Study:
- To identify novel senolytic compounds for treating age-related diseases.
- To investigate the senolytic activity and mechanism of cycloastragenol (CAG), a metabolite from *Astragalus membrananceus*.
Main Methods:
- Screening of compounds to identify senolytic activity.
- Investigating the molecular mechanisms of CAG-induced senescent cell apoptosis, including Bcl-2 family proteins and the PI3K/AKT/mTOR pathway.
- Assessing the effect of CAG on the senescence-associated secretory phenotype (SASP).
- Evaluating CAG's efficacy in alleviating physical dysfunction in irradiation-induced aged mice.
Main Results:
- Cycloastragenol (CAG) selectively induces apoptosis in senescent cells (SCs).
- CAG's senolytic activity involves the inhibition of Bcl-2 antiapoptotic proteins and the PI3K/AKT/mTOR pathway.
- CAG suppresses the senescence-associated secretory phenotype (SASP) and inhibits SASP-mediated cell migration.
- In vivo administration of CAG reduced SC burden and improved physical function in aged mice.
Conclusions:
- Cycloastragenol (CAG) demonstrates significant senolytic activity against senescent cells.
- CAG effectively alleviates age-related physical dysfunction in vivo.
- CAG represents a novel senolytic agent with therapeutic potential for age-related diseases.
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