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.

The key insight from recent work (e.g., Saarikangas & Barral, 2015; Woodruff et al., 2017) is that protein quality control operates as a network with emergent properties:

1. Chaperone holdase activity: HSP70 family members bind unfolded proteins to prevent aggregation
2. Foldase activity: ATP-dependent folding releases functional proteins
3. Degradation: UPS and autophagy clear irreversibly damaged proteins

These systems operate near capacity in youth. As chaperone expression declines (observed in multiple tissues with age), the buffer shrinks.

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

The Propagation Mechanism

Aggregated proteins do not just sit inertly. They actively destabilize proteostasis:

• Sequestration: Aggregates trap chaperones, reducing available capacity
• Proteasome clogging: Aggregated proteins block the proteasome, impairing degradation
• Autophagy saturation: Large aggregates exceed autophagosome capacity

This creates a vicious cycle: aggregation reduces proteostasis capacity → reduced capacity increases aggregation.

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 (not just preventing new ones) 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 (e.g., via HSF1 activation) 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 experimentally reduced

Connection to Disease

Neurodegenerative diseases (Alzheimer's, Parkinson's, ALS) all feature protein aggregation. The phase transition model suggests these are not separate diseases but different manifestations of the same underlying failure—proteostasis collapse.

The specific protein that aggregates (tau, alpha-synuclein, TDP-43) may be less important than the fact that proteostasis has crossed the threshold. This reframes therapeutic strategy from targeting specific aggregates to restoring system-level proteostasis capacity.