The biochemistry of aging is enormously complex, and it is very hard to pick apart which changes are definitively cause versus effect, and which changes are definitively more important than others. The only robust approach is to build a therapy that fixes just one change in isolation, and observe the results. This is not always possible or practical. When it can be done, a great deal is learned, however. See the outcome of the development of the first senolytic drugs on the state of knowledge regarding the role and relative importance of senescent cells in degenerative aging, for example. But the lack of such targeted and relatively effective therapies for most other potentially important mechanisms of aging allows a wide diversity of viewpoints to arise, as any new hypothesis regarding the importance of any given form of damage or dysfunction is hard to prove or disprove.
Aging is often framed as the gradual erosion of proteostasis, driven by declining chaperone capacity, impaired degradation, and dysregulated protein synthesis. Yet this view implicitly assumes that proteins fail primarily because they misfold or escape clearance. Increasing evidence instead points to a more fundamental problem: aging disrupts the spatial management of the proteome. Gradually, proteins are misplaced, signaling pathways are uncoupled from their compartments, and condensates that were once dynamic become pathological.
At the center of this spatial collapse lies nucleocytoplasmic protein partitioning. Nucleocytoplasmic protein transport has long been treated as a background housekeeping process, that is, essential but largely passive. However, this assumption is no longer reasonable. Karyopherins, the importins, exportins and biportins that mediate selective transport across the nuclear pore complex (NPC), are emerging as active regulators of proteostasis, phase behavior, and signaling fidelity. Rather than simply responding to cargo demand, karyopherins shape intracellular protein solubility, suppress aberrant condensation, and buffer age-associated stress. Their dysfunction therefore constitutes a primary, not secondary, driver of aging phenotypes.
Here, I argue that karyopherins should be repositioned at the core of aging biology. I propose that age-dependent failure of karyopherin-mediated transport represents a unifying mechanism linking proteostasis collapse, altered gene regulation, and the emergence of age-associated diseases. This perspective redefines nucleocytoplasmic protein transport from a logistics challenge into a central regulatory layer and highlights karyopherins as emerging targets for aging interventions.
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