Increased Intron Retention Propagates Aging from the Nucleus to the Cytoplasm

Abstract

Proteostasis decline, mitochondrial dysfunction, chromatin changes and nuclear envelope alteration are all cellular hallmarks of aging. However, how these defects arise, influence each other and lead to death is unclear. Here, we show that anchorage of accumulating DNA circles to nuclear pore complexes (NPCs) in old yeast cells displaces the nuclear basket from NPCs and impairs the surveillance machinery that restricts pre-mRNA export and increases intron retention. This caused aberrant pre-mRNA translation and formation of protein aggregates. Mutations preventing NPC remodeling restored the repression of pre-mRNA translation, delayed protein aggregation and extended the replicative lifespan of the cells. In contrast, perturbations promoting or mimicking NPC remodeling promoted pre-mRNA translation, protein aggregation and aging. Together, our data indicate that impairment of pre-mRNA retention in the nucleus mediates the effect of nuclear aging events on longevity. We propose that intron retention is a central mechanism that propagates aging to diverse cellular processes.