Nuclear pore complexes (NPCs) bridge the nucleus and the cytoplasm and are indispensable for crucial cellular activities, such as bidirectional molecular trafficking and gene transcription regulation. The discovery of long-lived proteins (LLPs) in NPCs from postmitotic cells raises the exciting possibility that the maintenance of NPC integrity might play an inherent role in lifelong cell function. Age-dependent deterioration of NPCs and loss of nuclear integrity have been linked to age-related decline in postmitotic cell function and degenerative diseases. In this review, we discuss our current understanding of NPC maintenance in proliferating and postmitotic cells, and how malfunction of nucleoporins (Nups) might contribute to the pathogenesis of various neurodegenerative and cardiovascular diseases.