title: A natural polymorphism in rDNA replication origins links origin activation with calorie restriction and lifespan.
abstract: 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.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Elizabeth X
authors.initials: EX
authors.lastname: Kwan
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Foss
authors.forename: Scott
authors.initials: S
authors.lastname: Tsuchiyama
authors.forename: Gina M
authors.initials: GM
authors.lastname: Alvino
authors.forename: Leonid
authors.initials: L
authors.lastname: Kruglyak
authors.forename: Matt
authors.initials: M
authors.lastname: Kaeberlein
authors.forename: M K
authors.initials: MK
authors.lastname: Raghuraman
authors.forename: Bonita J
authors.initials: BJ
authors.lastname: Brewer
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kennedy
authors.forename: Antonio
authors.initials: A
authors.lastname: Bedalov
mesh_terms: D000375:Aging / Q000235:genetics*; D031204:Caloric Restriction; D004261:DNA Replication / Q000235:genetics; D004275:DNA, Ribosomal / Q000235:genetics* / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics; D015966:Gene Expression Regulation, Fungal / Q000235:genetics; D008136:Longevity / Q000235:genetics; D011110:Polymorphism, Genetic; D040641:Quantitative Trait Loci / Q000235:genetics*; D018741:Replication Origin / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics; D056565:Sirtuin 2 / Q000235:genetics
chemical_list: D004275:DNA, Ribosomal; D004268:DNA-Binding Proteins; C105579:FOB1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D056565:Sirtuin 2