Rheostatic Network Consolidation Drives Physical Aging in Biomolecular Condensates

Abstract

While the physical aging of biomolecular condensates into macroscopic glasses is heavily linked to pathological disease states, the nanoscale topological rules governing this non-equilibrium relaxation remain elusive. Using heterotypic -synuclein-Tau coacervates, we combine variable-stringency dissolution and FLIM-FRET to provide direct experimental mapping of the internal network reorganization over time. Rather than a passive, isotropic kinetic jamming event typical of classic glasses, we demonstrate that this physical aging is driven by continuous rheostatic network consolidation; a progressive, directed topological relaxation toward deeper free-energy minima powered by the cooperative spatial optimization of sticker motifs. We formalize these dynamics into a mesoscale series-resistance model derived from size-resolved kinetics, proving that thermodynamic quench depth dictates the initial network state while clustered sticker patterning introduces configurational frustration that kinetically stalls maturation to preserve liquidity. This multi-scale framework links sequence grammar to non-equilibrium transport laws, revealing how biomolecular assemblies navigate the boundary between physiological utility and pathological arrest.