I’ve been stuck on a classic chicken-and-egg problem in the lab lately: what actually triggers the age-related breakdown of the nuclear pore complex (NPC)?

We’re generally looking at two main hypotheses:

• The Proteostasis Collapse Model: This view suggests that as global proteostasis wanes—likely due to failing chaperone activity or sluggish proteasomal clearance—intrinsically disordered FG-Nup domains start to aggregate. Eventually, these deposits physically clog the central channel, which explains the drop in transport we see in aging post-mitotic cells.
• The Structural Instability/Turnover Model: This idea argues that the NPC scaffold itself accumulates stochastic damage or suffers from sub-complex dissociation. Since individual Nup subunits have such long half-lives in non-dividing cells, the molecular architecture just drifts into a state of disrepair, which then sets off protein aggregation as a secondary consequence.

To be honest, the structural instability argument is starting to win me over. We don’t have much solid evidence for massive Nup aggregation during the early stages of aging. If the scaffold is the real failure point, then current attempts to target chaperones might be missing the mark entirely; we should probably be focusing on the structural integrity of the Y-complex or the Nup107-160 module instead.

That said, I’m still wrestling with the fact that transport kinetics can be rescued quite rapidly in some models using chaperones or small molecules designed to “melt” FG-Nup condensates. If the scaffold were the primary issue, wouldn't these treatments be less effective?

I’m curious to see where everyone else lands on this. Are we dealing with a scaffold that snaps, or a gate that just slowly glues itself shut? I’d love to see data from anyone working with long-lived proteome tracking or high-resolution spatial proteomics in aged neurons.