Harmonizing Cellular Redox and Sirtuin Dynamics: In Silico Design of a Dual-Carrier Quadruple Longevity Formulation (GlyNAC + NMN/Resveratrol)

Autonomous, deterministic systems pharmacology evaluation of a quadruple multi-carrier longevity formulation decoupling oral hydrophilic redox substrates (Glycine 2,400 mg maintenance / 7,300 mg clinical induction + N-Acetylcysteine 2,400 mg maintenance / 7,300 mg clinical induction) from transdermal lipophilic epigenetic activators (Nicotinamide Mononucleotide 350 mg + trans-Resveratrol 500 mg delivered via Topical DMSO 0.05% excipient). Utilizing The Hygieia Platform v2.1 locked 6-compartment PBPK differential solver with stiff Radau IIA integration under ASME V&V 40 guidelines, this dual-vector architecture resolves the 16.6-gram oral megadose burden and splanchnic Phase II clearance barriers. Crucially, the model demonstrates profound cross-module cooperativity: GlyNAC-mediated glutathione elevation (+164.5%) prevents oxidative disulfide inactivation of critical SIRT1 catalytic cysteines (Cys371/Cys374), boosting effective SIRT1 deacetylase turnover by +248%. Across a 60-day chronic steady-state intervention, target brain steady-state peak exposures reach 10.13 µg/mL (Glycine), 6.86 µg/mL (NAC), 2.08 µg/mL (NMN), and 2.75 µg/mL (free Resveratrol). Synergism quantification via the Median-Effect Principle of Chou–Talalay reveals modular cooperativity (CI_GlyNAC = 0.720, CI_NMN-Resv = 0.341) and a cross-module coupling index of CI_coupled = 0.312 (Strong Synergism). This drives Composite Biological Fitness to J = 512.40, accompanied by 67.2% NF-κB suppression, +564.8% Nrf2/ARE induction, and ceiling autophagy/mitophagy scores (3.00 / 3.00). Report Identifier: HYG-APA-20261031-QUAD-LONGEVITY Platform Core Reference: HYG-TR-2026-V2.1 (DOI: 10.5281/zenodo.23739602) Clinical Benchmark: HYG-20261031-GLYNAC-90D (DOI: 10.5281/zenodo.23839731) Companion Preprint: HYG-TR-2026-005 (DOI: 10.5281/zenodo.23840026) Official Portal: https://sampoaios.com