In Silico Deconstruction and Transdermal Carrier Optimization of the Sinclair Longevity Protocol: Resolving the Oral Resveratrol Bioavailability Paradox and NMN Stoichiometry via The Hygieia Platform v2.1

Computational systems pharmacology deconstruction and transdermal re-engineering of the standard oral longevity regimen (1,000 mg NMN + 1,000 mg trans-Resveratrol) popularized by David Sinclair. Utilizing The Hygieia Platform v2.1 locked 6-compartment PBPK differential solver under ASME V&V 40 guidelines, we demonstrate that oral resveratrol undergoes >98% splanchnic Phase II sulfation/glucuronidation clearance, while high-dose oral NMN triggers intestinal CD73 ecto-5'-nucleotidase degradation into sirtuin-inhibiting luminal nicotinamide (NAM). By transitioning to an engineered transdermal permeation matrix (Topical DMSO 0.05% excipient), the autonomous solver compresses optimal daily human dosages to 350 mg NMN (-65%) and 500 mg trans-Resveratrol (-50%). This multi-carrier optimization achieves a +92.8% increase in free target brain tissue resveratrol exposure (from 1.427 to 2.751 µg/mL), deepens Chou–Talalay cooperativity to CI = 0.341 (Strong Synergism), and demonstrates Dose-Reduction Indices of DRI = 2.86 (NMN) and 2.00 (Resveratrol) without metabolic bottleneck saturation. Report Identifier: HYG-TR-2026-005 (Supplementary Dossier: HYG-SWEETSPOT-NMN-RESV) Platform Core Reference: HYG-TR-2026-V2.1 (DOI: 10.5281/zenodo.23739602) Validation Benchmark: HYG-20261031-GLYNAC-90D (DOI: 10.5281/zenodo.23839731) Official Portal: https://sampoaios.com