Wandi Xu

Senescent cells are a key driver of aging and contribute to many age‐related diseases. Senolytics, agents that selectively eliminate senescent cells, offer a promising therapeutic strategy to treat age‐related diseases but face significant barriers to clinical translation. Fisetin, a natural flavonoid senolytic, has progressed to clinical trials but is limited by suboptimal efficacy and poor bioavailability. To address these challenges, we developed two novel fisetin‐derived flavonoid senolytics, SR29384 and SR31133, using an integrative phenotypic drug discovery approach. These compounds exhibit enhanced senolytic activity, targeting a broad range of senescent cell types, reducing tissue senescence, and improving healthspan‐associated parameters in mouse models of aging. Mechanistic investigations combining transcriptomics, machine learning, network pharmacology, and molecular docking revealed that these novel senolytics may target key molecular pathways, including PARP1, CDK2, and possibly BCL‐xL to selectively induce apoptosis in senescent cells. These findings provide novel senolytics with high translational potential for clinical applications in promoting healthy aging and treating age‐related diseases.

Dissipative particle dynamics and MARTINI coarse-grained models are benchmarked against all-atom simulations, showing structural and dynamical consistency across scales for lipid vesicles from ultrasmall to small unilamellar sizes.

Aging is marked by the accumulation of senescent cells (SnCs), which contribute to tissue dysfunction and age-related diseases. Senotherapeutics, including senolytics which specifically induce lysis of SnCs and senomorphics, which suppress the senescence phenotype, represent promising therapeutic interventions for mitigating age-related pathologies and extending healthspan. Using a phenotypic-based senescent cell screening assay, we identified fucoidans, a class of sulfated polysaccharides derived from brown algae and seaweed, as novel senotherapeutics. In particular, fucoidan from Fucus vesiculosus (Fucoidan-FV) displayed potent senomorphic activity in different types of SnCs, reduced senescence in multiple tissues in aged mice, and extended healthspan in a mouse model of accelerated aging. Fucoidan-FV also enhanced the deacetylation and mono-ADP-ribosylation (mADPr) activity of SIRT6 and improved DNA repair and reduced senescence, in part, through SIRT6-dependent pathways. In addition, Fucoidan-FV downregulated genes associated with inflammation, Wnt signaling, and ECM remodeling pathways in SnCs and increased expression of genes involved with DNA repair. These findings support the translational potential of fucoidans as novel senotherapeutics that also are able to improve SIRT6-mediated DNA repair.