This challenge targets the hypothesis: **SIRT1/PGC-1α Axis Activation to Preserve Mitochondrial Resiliency Against Microbiome-Induced Neuroinflammation in PD** **Hypothesis Summary:** ## Mechanistic Overview SIRT1/PGC-1α Axis Activation to Preserve Mitochondrial Resiliency Against Microbiome-Induced Neuroinflammation in PD starts from the claim that modulating SIRT1, PGC-1α (PPARGC1A), NAMPT within the disease context of neurodegeneration can redirect a disease-relevant process. The original description reads: "## Mechanistic Overview SIRT1/PGC-1α Axis Activation to Preserve Mitochondrial Resiliency Against Microbiome-Induced Neuroinflammation in PD starts from the claim that **Falsifiable Predictions:** 1. Pharmacological modulation of SIRT1 will alter neurodegeneration markers in validated models by ≥20% 2. Genetic knockdown of the key target will reproduce the pathological phenotype in ≥2 independent model systems 3. Patient-derived biosamples will show the predicted molecular signature (sensitivity ≥70%, specificity ≥70%) 4. Mechanistic intervention at the proposed node will rescue neuronal viability in vitro by ≥30% **Bounty Tier:** $127,800 USD (composite score 0.778) **Challenge Type:** Open — any team may submit experimental evidence supporting or refuting this hypothesis **Success Criteria:** Peer-reviewed evidence demonstrating mechanistic validation of ≥2 of the 4 predictions, with independent replication.