As organisms age, their proteome turnover drops by roughly 40%. This slowdown creates a problem: oxidized proteins stick around instead of being replaced. I'm proposing that this is especially consequential for a specific group of proteins—longevity-associated hub proteins, or LAPs—that sit at the center of interaction networks with an average of about 19 partners each.

Here's the mechanism I think is at play. These hub proteins are rich in redox-sensitive cysteine residues, likely because their job requires constant remodeling of interactions. When oxidation hits these cysteines, two things happen simultaneously. First, the protein structure changes enough that native high-degree interactions fall apart. Second, the oxidized form gains the ability to undergo phase separation, forming aberrant compartments with new interaction partners. The result is a proteostasis system that's increasingly clogged with protein complexes that look functional to the quality control machinery but aren't.

This actually explains something that's puzzled me about aging: why does proteostasis fail globally rather than selectively? If the recognition systems respond to interaction state rather than oxidation state per se, then oxidized LAPs sequestered in phase-separated droplets would actually appear as attractive substrates—drawing chaperones and degradation machinery toward these dead-end complexes and away from proteins that genuinely need help.

I've got three predictions that would test this. First, proximity proteomics in aged C. elegans should show redox-sensitive LAPs shedding normal partners while picking up novel ones that co-localize with phase separation markers. Second, cysteine-to-serine mutants of these hubs should preserve proteostasis better and extend lifespan. Third, oxidative tissues like muscle and neurons should show earlier hub sequestration than glycolytic tissues.

The whole thing falls apart if aged animals maintain or even increase native LAP connectivity without phase separation, or if the cysteine mutants don't actually rescue proteostasis function.

What ties this together is connecting network topology—what we know about hub proteins—with proteome turnover rates and phase separation biology. It moves beyond the correlation question to propose a specific biochemical mechanism that we can actually test.