Adulthood depletion of Integrator extends lifespan and healthspan via defective pre-mRNA processing

. We show that loss of the catalytic subunit INTS-11 disrupts 3' end formation of small nuclear and spliced leader RNAs, impairing trans-splicing and promoting outron retention in a subset of transcripts enriched for spliceosomal and nucleocytoplasmic transport genes. These RNA-processing defects lead to altered levels of endogenous siRNAs, which are required for the longevity and healthspan benefits of INTS-11 depletion. In parallel, outron retention disrupts nuclear-encoded mitochondrial gene expression and protein production, inducing mitochondrial dysfunction and promoting lifespan extension. We also demonstrate that loss of INTS-11 perturbs transcription elongation at genes where Integrator is present at promoters, and that upregulation of enhancer elements within intragenic regions can affect the expression and isoform usage of nearby genes. Together, our findings identify Integrator as a key upstream regulator of non-coding RNA transcription, which in turn impacts protein-coding gene expression and mitochondrial function to shape the ageing process.