An analysis of the transcriptional changes that occur at a cellular level during aging in humans and various other organisms is reported in Nature this week, offering new insights into the fundamental mechanisms underlying animal aging and pointing to potential ways to extend lifespan. Aging affects physiological homeostasis through the impairment of various cellular processes including transcription and RNA splicing, but the molecular mechanisms leading to the loss of transcriptional fidelity are unclear. In their study, researchers from the University of Cologne and elsewhere used high-throughput transcriptome profiling to investigate how the kinetics of transcription are affected by aging in five organisms — nematodes, fruit flies, mice, rats, and humans — how such changes affect mRNA biosynthesis, and to elucidate the role of these changes in age-related loss of function at the organismal level. They find that average transcriptional elongation speed increased with age in all the species, accompanied by changes in splicing, such as a reduction of unspliced transcripts and the formation of more circular RNAs. Two lifespan-extending interventions — dietary restriction and lowered insulin-IGF signaling — reversed most of these aging-related changes. In worms and flies, genetic variants in RNA polymerase II that reduced its speed increased lifespan, while reducing the speed of RNA polymerase II by overexpressing histone components also extended lifespan in flies and the division potential of human cells. The data reveal a "molecular mechanism contributing to aging and serve as a means for assessing the fidelity of the cellular machinery during aging and disease," the study's authors conclude.
Analysis Reveals Molecular Mechanisms Underlying Aging in Humans, Other Species
Apr 13, 2023