Development of novel flavonoid senolytics through phenotypic drug screening and drug design
Abstract
Accumulation of senescent cells drives aging and age-related diseases. Senolytics, which selectively kill senescent cells, offer a promising approach for treating many age-related diseases. Using a senescent cell-based phenotypic drug discovery approach that combines drug screening and drug design, we developed two novel flavonoid senolytics, SR29384 and SR31133, derived from the senolytic fisetin. These compounds demonstrated enhanced senolytic activities, effectively eliminating multiple senescent cell types, reducing tissue senescence in vivo, and extending healthspan in a mouse model of accelerated aging. Mechanistic studies utilizing RNA-Seq, machine learning, network pharmacology, and computational simulation suggest that these novel flavonoid senolytics target PARP1, BCL-xL, and CDK2 to induce selective senescent cell death. This phenotype-based discovery of novel flavonoid senolytics, coupled with mechanistic insights, represents a key advancement in developing next-generation senolyticss with potential clinical applications in treating aging and age-related diseases.
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Research summary
The paper addresses the development of novel flavonoid senolytics aimed at selectively eliminating senescent cells, which are implicated in the aging process and age-related diseases. This focus on senolytics as a means to potentially extend healthspan and address the root causes of aging makes it relevant to longevity research. The findings contribute important insights into the mechanisms of action of these compounds and their potential clinical applications, marking a significant advancement in the field, though it may not be groundbreaking enough to warrant a higher impact score.
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