Female-specific quercetin resistance in vascular endothelial senolysis is driven by an ERα/ERβ-skewed BCL-2-dominant ...

IF fisetin (100 mg/kg oral gavage, every-other-day for 5 days per cycle, two cycles separated by 2 weeks) or navitoclax-galactose (Nav-Gal, 10 mg/kg intraperitoneal, matched intermittent schedule) is administered to aged (20–22 month) female C57BL/6 mice bearing established vascular endothelial senescence, in direct head-to-head comparison with an identical quercetin regimen (50 mg/kg oral, same schedule),

THEN fisetin and Nav-Gal — but not quercetin — will reduce aortic endothelial p21⁺ (CDKN1A⁺) and p16⁺ (CDKN2A⁺) senescent cell burden by ≥50% relative to vehicle, restore endothelium-dependent vasodilation (acetylcholine EC₅₀ shift ≥30% vs. vehicle in ex vivo aortic ring assay), and reduce circulating SASP cytokines (IL-6, MMP-3) by ≥40%, while quercetin will produce no significant endothelial senescent cell clearance in females — mirroring the human CAD observation (31.2%→6.2% male vs. null female response),

BECAUSE the following step-by-step causal chain operates in aged female but not aged male endothelial cells:

1. Aged female endothelial cells accumulate senescent burden with a distinct, BCL-2-dominant Senescent Cell Anti-Apoptotic Pathway (SCAP) profile, driven by residual or chronically declining estrogen receptor (ERα/ERβ) signaling that transcriptionally upregulates BCL2 but not BCL2L1 (BCL-xL) or PI3K/AKT survival nodes. SCAP transcriptional profiling has confirmed that senescent cells acquire pro-survival pathway expression in a context-dependent, cell-type-specific manner, and functional perturbation of these pathways is required for senolytic efficacy (Senolytic SCAPs)[https://doi.org/10.1016/j.ebiom.2017.04.013]. [SPECULATIVE: the sex-specific SCAP skew toward BCL-2 over BCL-xL in female endothelial cells has not been directly demonstrated; it is inferred from the sex-differential clinical observation and ER-BCL-2 crosstalk literature.]

2. Quercetin's senolytic mechanism is mechanistically concentrated on PI3K/AKT, HIF-1α, and BCL-xL inhibition. Transcriptomic SCAP analyses confirm that quercetin-sensitive senescent cells rely preferentially on PI3K/AKT and BCL-xL for survival (Transcriptomic SCAP signatures)[https://doi.org/10.1101/2024.05.28.596326]. In male endothelial cells, where PI3K/AKT and BCL-xL dominate the SCAP landscape (consistent with the observed 31.2%→6.2% male clearance), quercetin is mechanistically matched. In female endothelial cells with BCL-2-dominant SCAPs, quercetin's principal targets are functionally subordinate, rendering it ineffective.

3. Fisetin targets a broader BCL-2 family node spectrum including BCL-2 itself, as well as PI3K/AKT, and has been validated as a senotherapeutic extending health and lifespan in aged mice (Fisetin senotherapeutic)[https://doi.org/10.1038/s41591-018-0092-9], and demonstrated to selectively clear senescent cells across multiple tissue types including cardiovascular progenitor cell populations (Aged senescent CPCs)[https://doi.org/10.1111/acel.12931]. F...

SENS category: GlycoSENS

Key references: • doi.org/10.1016/j.ebiom.2017.04.013]. • doi.org/10.1101/2024.05.28.596326]. • doi.org/10.1038/s41591-018-0092-9], • doi.org/10.1111/acel.12931]. • doi.org/10.1111/acel.12458].