Hypothesis: The protective, chaperone-enriched aggregates that form during healthy aging are maintained in a dynamic, liquid-like state by a redox-sensitive switch involving cysteine sulfonylation of intrinsically disordered regions (IDRs) in aggregation-prone proteins. When autophagic flux declines below a critical threshold, sulfonylated cysteines accumulate, promoting irreversible liquid-to-solid phase conversion and converting these aggregates from sequestering depots into pathogenic seeds. Restoring the reducing environment—specifically by boosting the activity of sulfiredoxin (SRXN1) or thioredoxin (Trx) systems—will re-solubilize solid aggregates, reestablish their liquid dynamics, and rescue age-related proteostatic decline without increasing overall protein misfolding.

Mechanistic rationale: Recent work shows that protein thiol sulfonylation drives aberrant phase separation and solidification of stress granules [6]. We propose that sulfonylation does not merely destabilize granules but acts as a molecular timer: moderate sulfonylation promotes transient liquid assemblies that sequester damaged proteins; persistent sulfonylation, due to impaired clearance of oxidized proteins (e.g., via reduced autophagy or proteasome activity), locks IDRs into β‑sheet‑rich, amyloid‑like cores. This transition explains why long‑lived models with attenuated IIS signaling maintain protective aggregates—they preserve redox balance and autophagic capacity [7]. Conversely, when autophagy falters, sulfonylated aggregates recruit tau and TDP‑43, seeding neurodegeneration [5].

Testable predictions:

1. In primary neurons or fibroblasts from aged mice, pharmacological inhibition of autophagy (e.g., with bafilomycin A1) will increase cysteine sulfonylation on specific IDR‑containing proteins (identified by biotin‑switch assay) and correlate with a shift from FRAP‑recoverable (liquid) to FRAP‑non‑recoverable (solid) aggregates measured by live‑cell imaging.
2. Overexpression of SRXN1 or Trx1 in the same aged cells will reduce sulfonylation levels, restore FRAP recovery, decrease insoluble tau/TDP‑43 seeding (measured by FRET‑based seeding assays), and improve mitochondrial membrane potential and ATP production.
3. In vivo, aged mice treated with an AAV‑SRXN1 vector will show decreased insolubility of aggregated proteins in brain homogenates (SDS‑resistant fraction), reduced microglial activation (Iba1 staining), and improved performance on rotarod and novel object recognition tests compared to AAV‑Control littermates.
4. Conversely, knocking down SRXN1 in young mice will accelerate sulfonylation‑dependent solidification of aggregates and precipitate early‑onset cognitive deficits, establishing causality.

Falsifiability: If enhancing SRXN1/Trx activity fails to revert solid aggregates to a liquid state, does not reduce insoluble tau/TDP‑43, or does not improve functional outcomes despite confirmed reduction in sulfonylation, the hypothesis would be refuted. Similarly, if autophagy inhibition does not increase sulfonylation or solidification, the proposed redox‑autophagy coupling would be untenable.

This hypothesis reframes therapeutic strategies: rather than broadly inhibiting aggregation, targeting the redox enzymes that govern the liquid‑solid transition could re‑activate the proteome’s built‑in containment system, turning a toxic end‑state back into a dynamic, protective depot.