Abstract
Aging and longevity are considered to be highly complex genetic traits. In order to gain insight into aging as a polygenic trait, we employed an outbred Saccharomyces cerevisiae model, generated by crossing a vineyard strain RM11 and a laboratory strain S288c, to identify quantitative trait loci that control chronological lifespan. Among the major loci that regulate chronological lifespan in this cross, one genetic linkage was found to be congruent with a previously mapped locus that controls telomere length variation. We found that a single nucleotide polymorphism in BUL2, encoding a component of an ubiquitin ligase complex involved in trafficking of amino acid permeases, controls chronological lifespan and telomere length as well as amino acid uptake. Cellular amino acid availability changes conferred by the BUL2 polymorphism alter telomere length by modulating activity of a transcription factor Gln3. Among the GLN3 transcriptional targets relevant to this phenotype, we identified Wtm1, whose upregulation promotes nuclear retention of ribonucleotide reductase (RNR) components and inhibits the assembly of the RNR enzyme complex during S-phase. Inhibition of RNR is one of the mechanisms by which Gln3 modulates telomere length. Identification of a polymorphism in BUL2 in this outbred yeast population revealed a link among cellular amino acid availability, chronological lifespan, and telomere length control.
Highlights
The observation that dietary restriction promotes longevity in organisms ranging from yeast to primates raises the expectation that molecular mechanisms mediating this lifespan extension may be shared among species
In order to explore a broader spectrum of genetic variation and to gain insight into aging-related phenotypes as polygenic traits, we analyzed the chronological lifespan of 122 S. cerevisiae strains derived from a cross between laboratory and vineyard yeast strains
Identification of the responsible polymorphism in BUL2, a gene involved in controlling amino acid permeases, allowed us to establish a previously unrecognized link among cellular amino acid intake, chronological aging, and telomere maintenance
Summary
The observation that dietary restriction promotes longevity in organisms ranging from yeast to primates raises the expectation that molecular mechanisms mediating this lifespan extension may be shared among species. The budding yeast Saccharomyces cerevisiae has become a popular model for studying the genetic and molecular basis for variation in lifespan. Two different forms of aging have been studied in yeast. Replicative lifespan (RLS) is defined by the number of daughter cells that are generated by a budding mother cell whereas chronological lifespan (CLS) is defined as the ability of yeast cells to survive in stationary phase as judged by the their capability to reenter the cell cycle after nutrients are reintroduced [3,4]. In addition to replicative and chronological aging, mutant yeast cells dividing in the absence of telomerase components exhibit loss of viability [5] similarl to replicative senescence of human fibroblasts in culture [6]
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