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.
Full text
1,816 characters
· extracted from
oa-doi-fallback
· click to expand
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.
Competing Interest Statement
LJN and PDR are cofounders of Itasca Therapeutics, developing senotherapeutics for aging and age-related diseases. LJZ, LJN, PDR and the University of Minnesota have filed a provisional patent on the application of flavonoid analogs, including SR29384 and SR31133, as a strategy to treat age-related diseases.
Footnotes
↵4 Lead contact
Address for Lead Contact: Paul D. Robbins, Ph.D. Institute on the Biology of Aging and Metabolism Department of Biochemistry, Molecular Biology and Biophysics University of Minnesota 4-112 Nils Hasselmo Hall 312 Church Street SE Minneapolis, MN 55455 Phone: 612-626-2291 Fax: 612-625-2163
https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE279349
Text is read by the "Ask this paper" AI Q&A widget below.
Extraction quality varies by source — PMC NXML preserves structure
cleanly, OA-HTML may include some navigation residue, and OA-PDF can
have broken hyphenation. The publisher copy
(via DOI)
is the canonical version.