Ageing-associated changes in transcription and splicing efficiency influence longevity

Ageing alters cellular homeostasis thereby compromising multiple cellular processes such as transcription and splicing. However, both the extent of these changes and the molecular mechanisms are not well understood so far. In order to address this question, we analyzed transcription-coupled processes on a genomic scale in five animal species (C. elegans, D. melanogaster, M. musculus, R. norvegicus, H. sapiens) at different adult life stages. Using total RNA profiling, we quantified alterations of transcriptional elongation speed, splicing efficiency, and splicing precision. We consistently observed across all analyzed species, that the genome-average speed of RNA polymerase II (Pol-II) increased with age. These effects were reverted under lifespan-extending conditions, such as dietary restriction or modulation of insulin signaling. Reducing the speed of Pol-II in worms and flies improved splicing efficiency and increased lifespan. We further observed reduced precision in nucleosome positioning in senescent compared to proliferating cells, which correlated with reduced splicing efficiency. Thus, an age-associated increase of transcriptional speed results in reduced splicing efficiency and splicing quality. These findings substantially extend our understanding about the molecular mechanisms driving animal aging, and suggest new mechanisms underlying lifespan-extending interventions. We used total RNA-seq to quantify changes in transcription speed on a genomic scale in five animal species: the worm Caenorhabditis elegans, the fruit fly Drosophila melanogaster, the mouse Mus musculus, the rat Rattus norvegicus, and humans Homo sapiens, at different adult life-stages. To address whether the lifespan-extending interventions dietary restriction (DR) and inhibition of insulin/insulin-like growth factor signaling (IIS) affect transcriptional elongation speeds, we sequenced samples from IIS mutants, using daf-2 mutant worms at day 14 and fly heads from dilp2-3,5 mutants at day 30 and day 50, and hypothalamus from aged wild type and IRS1-/- null mice. Further, we sequenced samples from kidney and liver of dietary restricted (DR) and ad libitum fed mice.