Hypothesis

The aging brain does not lose plasticity; it becomes over‑confident in its predictive models, leading to rigid cognition. If senescent astrocytes and microglia drive this rigidity by secreting a pro‑inflammatory SASP that stabilizes perineuronal nets and dampens synaptic turnover, then a compound that reaches the CNS and selectively clears these cells should re‑introduce controlled uncertainty and improve cognitive flexibility. Quercetin phytosome achieves plasma concentrations that approach in‑vitro senolytic ranges, and its lecithin complex increases lipophilicity, predicting superior blood‑brain barrier (BBB) transit compared with hydrophilic isoquercetin. We therefore hypothesize that oral quercetin phytosome will (1) raise cerebrospinal fluid (quercetin) to ≥1 µM, (2) reduce biomarkers of CNS senescence, and (3) enhance behavioral measures of surprise tolerance and reversal learning in older adults.

Mechanistic Rationale

• BBB permeability: Phytosome formulation raises quercetin’s logP, facilitating passive diffusion across the BBB, whereas isoquercetin’s glucose moiety retains high polarity and limits CNS entry (1).
• Senolytic action in glia: At 1‑10 µM, quercetin inhibits SCF‑β‑TrCP and blocks NF‑κB‑driven SASP IL‑1β, IL‑6, and CXCL8 in microglia and astrocytes, promoting a shift toward a phagocytic, anti‑inflammatory state.
• Extracellular matrix remodeling: Quercetin upregulates MMP‑9 and downregulates tissue inhibitors of metalloproteinases (TIMP‑1), loosening perineuronal nets and increasing spine motility, a prerequisite for model updating.
• Restoring surprise tolerance: Reduced SASP lowers tonic GABAergic astrocyte release, raising neuronal signal‑to‑noise and reinstating responsiveness to unexpected outcomes, which correlates with improved performance on reversal‑learning and probabilistic‑choice tasks.

Testable Predictions

1. Pharmacokinetics: In a crossover study, 1000 mg quercetin phytosome will produce CSF quercetin concentrations ≥1 µM within 4 h post‑dose, while isoquercetin (equimolar dose) will remain <0.2 µM.
2. Target engagement: CSF levels of senescence‑associated secretory phenotype (SASP) factors (IL‑6, CXCL8, MMP‑3) will decline by ≥30 % after 4 weeks of daily phytosome, unchanged with placebo or isoquercetin.
3. Cognitive outcome: Participants receiving phytosome will show a ≥15 % improvement in reversal‑learning accuracy and increased entropy of choice behavior (measured via model‑based reinforcement‑learning fits), indicating heightened sensitivity to unexpected outcomes.
4. Falsifiability: If CSF quercetin fails to reach senolytic concentrations, or if SASP biomarkers and cognitive flexibility remain unchanged despite adequate exposure, the hypothesis is refuted.

Proposed Experimental Design

• Population: 60 healthy adults aged 65‑80, stratified by baseline cognitive flexibility.
• Arms: (A) quercetin phytosome 1000 mg daily, (B) isoquercetin matched for quercetin aglycone equivalent, (C) placebo; 20 per arm, double‑blind.
• Duration: 8 weeks treatment, with washout.
• Measures: Pre‑ and post‑treatment lumbar puncture for CSF quercetin and SASP panel; amyloid‑PET and TSPO‑PET to rule off‑target neuroinflammation; computerized reversal‑learning task; computational modeling of learning rates and surprise sensitivity.

By linking a concrete pharmacokinetic target (CSF quercetin ≥1 µM) to a mechanistic cascade (senescent glia clearance → ECM remodeling → restored surprise tolerance), this hypothesis moves beyond speculation and offers a clear, falsifiable path to test whether enhancing CNS quercetin bioavailability can treat cognitive rigidity not by "repairing" a broken system, but by re‑introducing the uncertainty that keeps predictions adaptive.