Plant Flavonoid DMY Clears Senescent Cells and Eases Alzheimer's in Mice
Dihydromyricetin, found in vine tea, acts as a dual senotherapeutic—suppressing SASP in fibroblasts and eliminating senescent microglia in Alzheimer's mice.
Summary
Researchers screened a 50-compound natural medicinal agent library and identified dihydromyricetin (DMY), a flavonoid from vine tea, as a potent senotherapeutic. In fibroblasts and endothelial cells, DMY suppressed the senescence-associated secretory phenotype (SASP) without killing cells—acting as a senomorphic. The mechanism involves DMY promoting nuclear translocation of the antioxidant protein PRDX2, which facilitates DNA repair in senescent cells. In microglia—which express low baseline PRDX2—DMY instead impairs mitochondrial function and triggers apoptosis, acting as a senolytic. In mouse models, DMY mitigated premature aging, enhanced chemotherapy outcomes, reduced amyloid-beta plaques, and improved cognition in an Alzheimer's disease model.
Detailed Summary
Cellular senescence—the state in which damaged cells cease dividing but persist and secrete inflammatory factors (the SASP)—is a central driver of age-related diseases. Targeting senescent cells, either by eliminating them (senolytics) or suppressing their harmful secretions (senomorphics), is a major frontier in longevity medicine. This study searched for naturally derived compounds that could serve this role.
The research team screened a library of 50 natural medicinal agents (mostly phytochemicals) against bleomycin- and radiation-induced senescent human fibroblasts (PSC27), endothelial cells (HUVECs), and breast fibroblasts (HBF1203). Dihydromyricetin (DMY), abundant in vine tea, emerged as a leading senomorphic candidate. At 100 µM, DMY markedly reduced expression of canonical SASP factors (IL-6, IL-8, MMPs) at both mRNA and protein levels, lowered reactive oxygen species, and modulated hundreds of senescence-related genes without killing non-senescent or senescent fibroblasts. RNA-seq and KEGG analysis highlighted suppression of NF-κB, PI3K-Akt, and MAPK pathways as key effects.
Proteomics revealed a critical mechanistic insight: DMY promotes nuclear translocation of peroxiredoxin 2 (PRDX2), a redox-regulatory protein. In the nucleus, PRDX2 facilitates DNA damage repair in senescent fibroblasts—cells that normally carry high PRDX2 expression. This mechanism explains DMY's cytoprotective, senomorphic behavior in stromal cells. However, microglial cells express very low baseline PRDX2, so DMY cannot activate this repair pathway there. Instead, in microglia, DMY impairs mitochondrial function and triggers apoptosis, effectively acting as a senolytic and selectively eliminating senescent microglia.
In vivo, DMY administration in a premature aging mouse model (driven by genotoxic stress) reduced tissue aging markers and age-related physiological decline across multiple organs. In cancer treatment experiments, combining DMY with DNA-damaging chemotherapy reduced tumor size and improved outcomes compared to chemotherapy alone—suggesting DMY can mitigate therapy-induced senescence in the tumor microenvironment without blunting antitumor efficacy. In 5xFAD Alzheimer's disease mice, DMY cleared senescent microglia from amyloid-beta plaques, reduced Aβ accumulation, and measurably improved cognitive performance.
The dual senomorphic/senolytic activity of DMY—governed by cell-type-specific PRDX2 expression—represents a novel and nuanced mechanism distinct from most known senotherapeutics. The findings position DMY as a promising natural compound for clinical investigation in aging, cancer survivorship, and neurodegenerative disease.
Key Findings
- DMY suppresses SASP factors (IL-6, IL-8, MMPs) in senescent fibroblasts and endothelial cells via senomorphic activity.
- DMY promotes nuclear PRDX2 translocation in fibroblasts, enabling DNA damage repair and explaining its cytoprotective effects.
- In microglia—low PRDX2 expressors—DMY acts as a senolytic by impairing mitochondria and inducing apoptosis.
- In 5xFAD Alzheimer's mice, DMY cleared senescent microglia, reduced amyloid-beta plaques, and improved cognition.
- DMY combined with chemotherapy enhanced tumor suppression in preclinical cancer models.
Methodology
Researchers used in vitro screening of 50 natural compounds in genotoxin-induced senescent human fibroblasts (PSC27), endothelial cells, and breast fibroblasts, validated with RNA-seq and proteomics. In vivo studies employed premature aging mouse models, cancer co-treatment models, and 5xFAD Alzheimer's transgenic mice with cognitive and histological endpoints.
Study Limitations
All in vivo data are from mouse models; human pharmacokinetics and effective tissue concentrations of DMY after oral administration remain to be confirmed. The 100–400 µM concentrations used in vitro may exceed physiologically achievable plasma levels, and long-term safety of repeated DMY dosing in aged populations has not been assessed.
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