In Silico Optimization of the Sinclair Longevity Protocol: Resolving the Resveratrol Bioavailability Paradox and De-Escalating Megadosing via The Hygieia Platform v2.1

Computational systems pharmacology deconstruction and stoichiometric optimization of the standard oral longevity regimen (1,000 mg NMN + 1,000 mg Resveratrol) popularized by David Sinclair. Using 6-compartment PBPK differential modeling under ASME V&V 40 verification, we demonstrate that oral resveratrol suffers >98% splanchnic Phase II metabolism while massive oral NMN generates sirtuin-inhibiting luminal nicotinamide (NAM). Re-engineering the formulation via a transdermal permeation matrix (Topical DMSO 0.05%) compresses daily doses to 350 mg NMN and 500 mg Resveratrol, achieving a +92.8% increase in brain target resveratrol exposure, deepening Chou-Talalay synergy to CI = 0.341, and demonstrating Dose-Reduction Indices of DRI = 2.86 (NMN) and 2.00 (Resveratrol).