Version history

{
  "session_id": "sess_SDA-2026-04-15-gap-debate-20260410-112330-9abf86eb_20260415-165431",
  "round_number": 1,
  "agent_persona": "persona-theorist",
  "agent_backend": "minimax/MiniMax-M2.7",
  "action": "propose",
  "content": "\n\n# Mechanistically-Specific Hypotheses: Astrocytic Ketone Production Therapeutic Window\n\n## Hypothesis 1: Astrocytic MCT1/MCT2 Transport Capacity as the Window Gatekeeper\n\n**Mechanism:** During aging and neurodegeneration, astrocytic monocarboxylate transporter 1 (MCT1) expression declines, limiting export of ketone bodies (βOHB, acetoacetate) to neurons even when intr astrocytic ketone synthesis remains detectable. Neuronal MCT2 expression is more stable, but substrate delivery becomes rate-limiting. This creates a therapeutic window where augmenting astrocytic MCT1 or providing exogenous ketones bypasses the transport bottleneck.\n\n**Key Evidence:** MCT1 deletion in astrocytes impairs brain ketone uptake in mice (PMID: 26753690); MCT2 ablation in neurons reduces cortical βOHB utilization during ketogenic diet (PMID: 33141142).\n\n**Testable Prediction:** Delete astrocyte-specific *Slc16a1* (MCT1) in 3xTg-AD mice at 3, 6, and 12 months. If the therapeutic window for ketone-based intervention closes earlier in knockout mice (accelerated cognitive decline at 6 months vs. 12 months in controls), MCT1 transport capacity defines window duration.\n\n**Target Gene/Protein:** SLC16A1 (MCT1) — astrocytic export\n\n---\n\n## Hypothesis 2: SIRT3-Mediated Neuronal Mitochondrial Resilience Defines Window Boundaries\n\n**Mechanism:** Neuronal SIRT3 deacetylates and activates key ketogenic enzymes (BDH1, SCOT) and mitochondrial electron transport complex I subunits, maintaining oxidation capacity as astrocytic ketone supply dwindles. Early neurodegeneration suppresses neuronal SIRT3 via NAD⁺ depletion and increased PARylation, collapsing the oxidation advantage before ketone deficiency becomes severe. The therapeutic window opens when ketone production falls but SIRT3 remains active, and closes when SIRT3",
  "tokens_used": "453"
}