Ribosomal DNA and the nucleolus at the heart of aging.

The rRNA genes [ribosomal DNA (rDNA)] are organized in a prominent nuclear compartment, the nucleolus. It is now well established that the nucleolus functions beyond ribosome biosynthesis, regulating several physiological cellular responses. The nucleoli constitute dynamic genomic/nuclear hubs and demonstrate unique inherent characteristics, rendering them ideal to sense, signal, and respond to various intrinsic and environmental insults. Here, we discuss emerging findings supporting direct links between rDNA/nucleolar instability and cellular senescence/organismal aging from yeast to mammals. Moreover, we highlight evidence that nucleolar functionality and rDNA architecture impact on meiotic/transgenerational rejuvenation, thus revealing causality underlying connections between rDNA/nucleolar instability and aging. The ribosomal DNA (rDNA) consists of multiple tandem arrayed rRNA-coding genes and organizes the nucleolus, a dynamic, phase-separated subnuclear compartment where rRNA synthesis, processing, and ribosome assembly takes place. rDNA is the most intensely transcribed region of the eukaryotic genome and constitutes a phylogenetically conserved fragile site, which is inherently unstable and capable of sensing and disseminating stress signals. Recent data directly implicate rDNA/nucleolar instability with senescence onset and organismal aging from yeast to mammals. The nucleolus undergoes characteristic morphological and functional alterations early upon senescence/aging establishment, driving the senescence phenotype. Reversal of rDNA/nucleolar instability was shown to take place upon cellular/organismal rejuvenescence, highlighting causality linking rDNA/nucleolar instability with aging. [ABSTRACT FROM AUTHOR]