Nuclear pore complex aging

Nuclear pore complex (NPC) aging refers to the progressive structural and functional deterioration of NPCs — the approximately 120 MDa protein channels that perforate the nuclear envelope and regulate all traffic between nucleus and cytoplasm — in post-mitotic (non-dividing) cells over time. Because neurons, cardiomyocytes, and skeletal muscle fibers rarely divide, their NPCs cannot be diluted by cell replication. Scaffold nucleoporins such as the Nup107-160 ring complex persist for the entire lifespan of the cell without turnover, and as cells age, the inner-ring scaffold nucleoporin Nup93 accumulates oxidative damage, particularly carbonylation, while Nup107 itself remains unmodified (D'Angelo et al., Cell 2009). This molecular damage causes the NPC's selectivity filter — normally maintained by intrinsically disordered phenylalanine-glycine (FG) repeat nucleoporins — to become progressively leaky, allowing cytoplasmic proteins such as tubulin to enter the nuclear interior, a phenomenon demonstrated in aged rat neurons and C. elegans. The resulting loss of nucleocytoplasmic compartmentalization disrupts the spatial separation of nuclear processes (transcription, DNA repair, RNA processing) from cytoplasmic ones, potentially compounding other aging-associated defects in DNA damage signaling and proteostasis. In humans, NPC dysfunction has been linked to age-related neurodegenerative conditions including Alzheimer's disease and ALS/FTD, though causal directionality in vivo remains under investigation; current evidence is primarily from rodent models and invertebrate genetics, with human data largely associational.