Ribosomal DNA and cellular senescence: new evidence supporting the connection between rDNA and aging

The yeast Saccharomyces cerevisiae is a powerful model system to understand the molecular basis of aging. It has been known for over 50 years that yeast cells have a finite replicative capacity and develop an aging phenotype, and much recent research has focused on the molecular changes that underlie this replicative senescence. A common thread in many yeast replicative aging studies is the involvement of the ribosomal DNA gene repeats (rDNA), beginning with the discovery that the rDNA silencing gene, SIR2, regulates life span. In 2008, a novel aging hypothesis, termed the rDNA theory of aging, was presented where the high level of genomic instability at the rDNA repeats was proposed to dominate global genome stability and determine the life span. Here, we review the rDNA theory of aging and discuss a number of recent studies that provide important new data on the roles of the rDNA in yeast replicative aging. Based on these recent results, we propose an integrative model of the rDNA theory of aging that encompasses genomic instability, chromatin relocalization following DNA repair, and replication stress in a self-reinforcing cyclical pathway that is primarily manifested at the rDNA repeats and results in the aging phenotype.