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Updated: Sep 9, 2025
SA-β-Galactosidase-Based Screening Assay for the Identification of Senotherapeutic Drugs
Published on: June 28, 2019
Senolytic-Resistant Senescent Cells Have a Distinct SASP Profile and Functional Impact: The Path to Developing
Senolytics eliminate senescent cells (SCs), but some SCs resist treatment. These resistant SCs exhibit altered senescence-associated secretory phenotypes (SASPs) and cause less dysfunction, suggesting interconvertibility.
Area of Science:
- Cellular senescence
- Aging research
- Senotherapeutics
Background:
- Senescent cells (SCs) accumulate with age and contribute to age-related diseases and dysfunction.
- Senolytics are agents that selectively eliminate SCs by targeting their anti-apoptotic pathways.
- A subset of SCs exhibits resistance to senolytic treatments, complicating therapeutic strategies.
Purpose of the Study:
- To investigate the characteristics of senolytic-resistant senescent cells (SCs).
- To understand the impact of senolytic resistance on the senescence-associated secretory phenotype (SASP).
- To evaluate the in vivo consequences of senolytic-resistant SCs on physical function.
Main Methods:
- Treatment of senescent human preadipocytes and HUVECs with senolytics (Dasatinib, Quercetin) and JAK/STAT inhibitor (Ruxolitinib).
- Analysis of senescent markers (p16INK4a, p21CIP1, SAβgal, γH2AX) and SASP composition in senolytic-sensitive and -resistant SCs.
- Assessment of mitochondrial DNA (mtDNA) and GPNMB expression.
- In vivo transplantation of senolytic-resistant SCs into mice to evaluate physical dysfunction.
Main Results:
- Senolytic-resistant SCs retained senescence markers but exhibited an altered SASP with reduced pro-inflammatory factors and increased growth/fibrotic factors.
- Resistant SCs released less mtDNA and higher levels of GPNMB, an immune evasion signal.
- Transplantation of senolytic-resistant SCs induced less physical dysfunction compared to total SC populations.
- JAK/STAT inhibition (Ruxolitinib) induced senolytic resistance, and senolytic-resistant and -sensitive SCs appear interconvertible.
Conclusions:
- Senolytic resistance in SCs is characterized by a distinct SASP profile that may mitigate inflammation but potentially promote fibrosis.
- The interconvertibility of senolytic-sensitive and -resistant SC states suggests dynamic regulation of SASP.
- Targeting senolytic resistance mechanisms or modulating the SASP of resistant SCs could offer novel therapeutic avenues in aging and disease.
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