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Reduction in Lens Epithelial Cell Senescence Burden through Dasatinib Plus Quercetin or Rapamycin Alleviates
Yinhao Wang1,2, Yulin Tseng1,2, Keyu Chen3
1Department of Ophthalmology, Peking University Third Hospital, Beijing 100191, China.
Abstract:
Senescent cells accumulate in aged organisms and promote the progression of age-related diseases including cataracts. Therefore, we aimed to study the therapeutic effects of senescence-targeting drugs on cataracts. In this study, a 28-day D-galactose-induced cataract rat model was used. The opacity index, a grading based on slit-lamp observations, was used to assess lens cloudiness. Furthermore, the average lens density (ALD), lens density standard deviation (LDSD), and maximum lens density (MLD) obtained from Scheimpflug images were used to assess lens transparency. Immunohistochemical stainings for p16 and γH2AX were used as hallmarks of senescence. We treated rat cataract models with the senolytic drug combination dasatinib plus quercetin (D+Q) and senescence-associated secretory phenotype (SASP) inhibitors. In comparison to control lenses, D-galactose-induced cataract lenses showed a higher opacity index, ALD, LDSD, and MLD values, as well as accumulation of senescent lens epithelial cells (LECs). After D+Q treatment, ALD, LDSD, and MLD values on day 21 were significantly lower than those of vehicle-treated model rats. The expression levels of p16 and γH2AX were also reduced after D+Q administration. In addition, the SASP inhibitor rapamycin decreased the opacity index, ALD, LDSD, and MLD values on day 21. In conclusion, D+Q alleviated D-galactose-induced cataract progression by reducing the senescent LEC burden in the early stage of cataract.
Insights
Senescence-targeting drugs, dasatinib plus quercetin (D+Q), effectively treat cataracts by reducing senescent lens epithelial cells. This study demonstrates D+Q
Area of Science:
- Ophthalmology
- Gerontology
- Cellular Biology
Background:
- Cellular senescence accumulates in aging tissues, contributing to age-related diseases like cataracts.
- Senescent lens epithelial cells (LECs) are implicated in the progression of cataract formation.
- Targeting cellular senescence presents a potential therapeutic strategy for age-related eye conditions.
Purpose of the Study:
- To investigate the therapeutic efficacy of senescence-targeting drugs on a D-galactose-induced rat cataract model.
- To evaluate the impact of dasatinib plus quercetin (D+Q) and senescence-associated secretory phenotype (SASP) inhibitors on cataract progression.
- To assess the reduction of senescent cell markers and lens opacity following treatment.
Main Methods:
- Established a 28-day D-galactose-induced cataract rat model.
- Quantified lens cloudiness using opacity index and Scheimpflug imaging (ALD, LDSD, MLD).
- Assessed senescence via immunohistochemical staining for p16 and γH2AX in lens tissues.
Main Results:
- D-galactose-induced cataracts exhibited increased opacity index, ALD, LDSD, MLD, and senescent LECs compared to controls.
- D+Q treatment significantly reduced ALD, LDSD, and MLD, and decreased p16 and γH2AX expression.
- Rapamycin (SASP inhibitor) also reduced opacity index, ALD, LDSD, and MLD.
Conclusions:
- Dasatinib plus quercetin (D+Q) effectively alleviates D-galactose-induced cataract progression.
- The therapeutic effect is attributed to the reduction of senescent lens epithelial cells (LECs).
- Senescence-targeting therapies show promise for early-stage cataract intervention.
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