A natural polymorphism in rDNA replication origins links origin activation with calorie restriction and lifespan

Aging and longevity are complex traits influenced by genetic and environmental factors. To identify quantitative trait loci (QTLs) that control replicative lifespan, we employed an outbred Saccharomyces cerevisiae model, generated by crossing a vineyard and a laboratory strain. The predominant QTL mapped to the rDNA, with the vineyard rDNA conferring a lifespan increase of 41%. The lifespan extension was independent of Sir2 and Fob1, but depended on a polymorphism in the rDNA origin of replication from the vineyard strain that reduced origin activation relative to the laboratory origin. Strains carrying vineyard rDNA origins have increased capacity for replication initiation at weak plasmid and genomic origins, suggesting that inability to complete genome replication presents a major impediment to replicative lifespan. Calorie restriction, a conserved mediator of lifespan extension that is also independent of Sir2 and Fob1, reduces rDNA origin firing in both laboratory and vineyard rDNA. Our results are consistent with the possibility that calorie restriction, similarly to the vineyard rDNA polymorphism, modulates replicative lifespan through control of rDNA origin activation, which in turn affects genome replication dynamics.
Author Summary Although many aging regulators have been discovered, we are still uncovering how each contributes to the basic biology underlying cell lifespan and how certain longevity-promoting regimens, such as calorie restriction, manipulate the aging process across species. Since many cellular aging processes between human cells and budding yeast are related, we examined a collection of genetically diverse yeast and discovered that a genetic variant in vineyard yeast confers a 41% lifespan increase. The responsible sequence in the vineyard yeast reduces the amount of DNA replication that initiates at the ribosomal DNA (rDNA) locus, a chromosome-sized region of the genome that is dedicated to the production of ribosomal RNA required for protein synthesis and growth. Strikingly, we find that calorie restriction conditions also reduce rDNA replication, potentially promoting longevity by the same mechanism. While the rDNA has been previously linked to lifespan control, how this single locus affects global cell function has remained elusive. We find that a weakly replicating rDNA promotes DNA replication across the rest of the cell's genome, perhaps through the re-allocation of replication resources from decreased rDNA demand. Our findings suggest that the cell's inability to complete genome replication is one of the major impediments to yeast longevity.