Nucleocytoplasmic transport—mediated by karyopherins moving proteins across nuclear pores—declines with age and drives proteostasis collapse, altered gene regulation, and age-associated disease. This positions spatial protein management, not merely protein synthesis or degradation, as a primary mechanism of aging.
Key Points
- Karyopherins actively regulate protein solubility and suppress pathological condensation
- Age-dependent karyopherin dysfunction disrupts signaling fidelity and cellular compartmentalization
- Nucleocytoplasmic transport dysfunction unifies proteostasis collapse and disease emergence
Longevity Analysis
The failure to maintain proper protein compartmentalization across cellular boundaries emerges as foundational to aging—upstream of protein misfolding and clearance defects. This reframing shifts intervention strategy from attempting to clear damaged proteins after the fact toward preserving the spatial barriers and active transport machinery that prevent mislocalization in the first place. Understanding how karyopherin capacity erodes reveals why many aging-associated disease pathways activate simultaneously: loss of compartmental integrity compromises gene regulation, stress signaling, and protein solubility across multiple systems at once. Strategies that preserve or restore nucleocytoplasmic transport selectivity represent a distinct therapeutic direction from conventional proteostasis approaches.
Original published by Wiley Aging Cell, by Louis R. Lapierre .