The natural flavonoid dihydromyricetin targets senescent cells via PRDX2 and alleviates age-related diseases

Abstract Aging is a preeminent risk factor for chronic diseases, with cellular senescence as one of the major hallmarks and an effective target to delay, prevent or alleviate age-related disorders. Here we report in vitro screening outputs from a natural medicinal agent (NMA) library, wherein dihydromyricetin (DMY), a natural flavonoid, showed senotherapeutic potential. DMY protected senescent fibroblasts from further DNA damage and attenuated the senescence-associated secretory phenotype (SASP), acting as a senomorphic agent. Proteomics suggested that DMY promotes nuclear translocation of peroxiredoxin 2 (PRDX2), a reactive oxygen species (ROS) scavenger, facilitating DNA repair in senescent cells. In prematurely aged mice, DMY administration mitigated tissue aging changes and age-related physiological decline. In anticancer regimens, DMY improved outcomes of chemotherapy. However, DMY demonstrated senolytic activity against senescent microglial cells, wherein basal PRDX2 expression remains low, by impairing mitochondrial function to promote ROS-mediated apoptosis. In mice developing an Alzheimer’s disease (AD)-like state, DMY eliminated senescent microglial cells from amyloid β-protein (Aβ) plaques, alleviating Aβ-associated pathological phenotypes. Together, our study proposes DMY to be a natural senotherapeutic agent representing a therapeutic solution for mitigating age-related morbidities including but not limited to cancers and AD. Competing Interest Statement The authors have declared no competing interest.