Aging-associated changes in transcriptional elongation influence metazoan longevity

Abstract

AbstractAging impairs cellular homeostasis, thereby compromising multiple cellular processes, including transcription and splicing. However, the molecular mechanisms at work, and hence ways of preventing loss of transcriptional fidelity, are so far elusive. We analyzed changes in genome-wide, transcription-coupled processes with age inCaenorhabditis elegans, Drosophila melanogaster, Mus musculus, Rattus norvegicus andHomo sapiens. Using total RNA profiling, we quantified transcriptional elongation speed (Pol-II speed). Genome-averaged Pol-II speed increased with age in all five species. Lifespan-extending dietary restriction and lowered insulin signaling both rescued these age-related trends. Experimentally reducing Pol-II speed in worms and flies increased lifespan. These findings uncover fundamental molecular mechanisms driving animal aging and underlying lifespan-extending interventions, and point to possible preventative measures.One-sentence summaryGenome-wide analysis of total RNA during aging reveals increased transcriptional elongation speed and decreased splicing efficiency, with an impact on longevity.