Misplaced proteins: how nuclear transport redefines aging

Aging biology has long fixated on misfolded proteins and failing cellular cleanup systems, but an emerging perspective upends this orthodoxy: the true culprit is spatial disorganization of the proteome itself. Karyopherins—the selective transport proteins governing traffic across nuclear pores—are not passive logistical shuttles but active regulators that shape protein solubility, suppress pathological condensation, and buffer age-related cellular stress. Their progressive dysfunction constitutes a primary mechanism of aging, not a secondary consequence, linking proteostasis collapse, altered gene regulation, and the emergence of age-associated disease. This repositioning of karyopherins at the center of aging biology opens a new therapeutic frontier: rather than pursuing individually broken proteins, future interventions may focus on restoring intracellular spatial order through modulation of these nuclear transporters, transforming how longevity researchers approach degenerative aging.