This challenge targets the hypothesis: **H3: SIRT1 Insufficiency Disconnects Metabolic Sensing from Epigenomic Homeostasis** **Hypothesis Summary:** ## Mechanistic Overview H3: SIRT1 Insufficiency Disconnects Metabolic Sensing from Epigenomic Homeostasis starts from the claim that modulating SIRT1, NAMPT, NAD+ salvage pathway within the disease context of neurodegeneration can redirect a disease-relevant process. The original description reads: "## Mechanistic Overview H3: SIRT1 Insufficiency Disconnects Metabolic Sensing from Epigenomic Homeostasis starts from the claim that modulating SIRT1, NAMPT, NAD+ salvage pathway within the disease c **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:** $127,000 USD (composite score 0.770) **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.