Intracellular proteins with long lifespans have recently been linked to age-dependent defects, ranging from decreased fertility to the functional decline of neurons. Why long-lived proteins exist in metabolically active cellular environments and how they are maintained over time remains poorly understood. Here, we provide a system-wide identification of proteins with exceptional lifespans in the rat brain. These proteins are inefficiently replenished despite being translated robustly throughout adulthood. Using nucleoporins as a paradigm for long-term protein persistence, we found that nuclear pore complexes (NPCs) are maintained over a cell’s life through slow but finite exchange of even its most stable subcomplexes. This maintenance is limited, however, as some nucleoporin levels decrease during aging, providing a rationale for the previously observed age-dependent deterioration of NPC function. Our identification of a long-lived proteome reveals cellular components that are at increased risk for damage accumulation, linking long-term protein persistence to the cellular aging process. Display omitted Display omitted •Metabolic pulse-chase labeling of rats identified long-lived proteins in rats•Long-lived proteins include nucleoporins, histone variants, and enzymes•Long-lived proteins cannot be replaced despite their robust translation•Nuclear pores are maintained over the lifespan of the organism A system-wide identification of proteins with exceptional lifespans in the rat brain suggests that these have a higher propensity for damage. Cells utilize specific mechanisms to ensure that such proteins are maintained in a functional state through aging.