The Phase Transition Model

Traditional views of proteostasis in aging focus on gradual accumulation: damage builds up slowly over decades. But phase separation physics suggests a different picture—systems can remain stable across a wide parameter range, then collapse catastrophically when a threshold is crossed.

Evidence for Phase Transition Behavior

1. Threshold effects: Cells tolerate significant chaperone depletion with minimal phenotype—until a critical point where aggregation suddenly accelerates (Powers et al., 2009)

2. Cooperative aggregation: Once seed aggregates form, they recruit soluble proteins via prion-like domains, creating a positive feedback loop

3. Rescue effects: Overexpressing even a single chaperone (e.g., HSP70) can rescue the entire proteome in aging models—consistent with pushing the system back across the phase boundary

Therapeutic Implications

If proteostasis collapse is a phase transition:

• Early intervention is critical: Once the threshold is crossed, rescue becomes exponentially harder
• Chaperone upregulation: Even modest increases in HSP70/HSP90 might push the system back into the stable regime
• Aggregate dissolution: Breaking existing aggregates may be necessary to restore proteostasis capacity

Testable Predictions

1. Single-cell proteomics should reveal bimodal distribution: cells either have healthy proteostasis or collapsed proteostasis, with few intermediates

2. Chaperone induction should show threshold-dependent rescue—small increases have little effect until a critical level is reached

3. Proteasome activity measurements should reveal sudden collapse rather than gradual decline when chaperone capacity is reduced