ABSTRACT
Many genes that affect replicative lifespan (RLS) in the budding yeast Saccharomyces cerevisiae also affect aging in other organisms such as C. elegans and M. musculus. We performed a systematic analysis of yeast RLS in a set of 4,698 viable single-gene deletion strains. Multiple functional gene clusters were identified, and full genome-to-genome comparison demonstrated a significant conservation in longevity pathways between yeast and C. elegans. Among the mechanisms of aging identified, deletion of tRNA exporter LOS1 robustly extended lifespan. Dietary restriction (DR) and inhibition of mechanistic Target of Rapamycin (mTOR) exclude Los1 from the nucleus in a Rad53-dependent manner. Moreover, lifespan extension from deletion of LOS1 is nonadditive with DR or mTOR inhibition, and results in Gcn4 transcription factor activation. Thus, the DNA damage response and mTOR converge on Los1-mediated nuclear tRNA export to regulate Gcn4 activity and aging.
Subject(s)
Aging/genetics , Basic-Leucine Zipper Transcription Factors/genetics , Longevity/genetics , Nuclear Pore Complex Proteins/genetics , Saccharomyces cerevisiae Proteins/genetics , Aging/metabolism , Aging/pathology , Animals , Basic-Leucine Zipper Transcription Factors/metabolism , Caenorhabditis elegans/genetics , Caloric Restriction , DNA Damage/genetics , Gene Deletion , Gene Expression Regulation/genetics , Genome , RNA, Transfer/genetics , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae Proteins/metabolism , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/geneticsABSTRACT
Dietary restriction (DR) increases lifespan and attenuates age-related phenotypes in many organisms; however, the effect of DR on longevity of individuals in genetically heterogeneous populations is not well characterized. Here, we describe a large-scale effort to define molecular mechanisms that underlie genotype-specific responses to DR. The effect of DR on lifespan was determined for 166 single gene deletion strains in Saccharomyces cerevisiae. Resulting changes in mean lifespan ranged from a reduction of 79% to an increase of 103%. Vacuolar pH homeostasis, superoxide dismutase activity, and mitochondrial proteostasis were found to be strong determinants of the response to DR. Proteomic analysis of cells deficient in prohibitins revealed induction of a mitochondrial unfolded protein response (mtUPR), which has not previously been described in yeast. Mitochondrial proteotoxic stress in prohibitin mutants was suppressed by DR via reduced cytoplasmic mRNA translation. A similar relationship between prohibitins, the mtUPR, and longevity was also observed in Caenorhabditis elegans. These observations define conserved molecular processes that underlie genotype-dependent effects of DR that may be important modulators of DR in higher organisms.
Subject(s)
Caenorhabditis elegans/genetics , Caenorhabditis elegans/physiology , Caloric Restriction , Diet , Saccharomyces cerevisiae/genetics , Aerobiosis , Animals , Autophagy , Caenorhabditis elegans/cytology , Caenorhabditis elegans Proteins/metabolism , Genotype , Prohibitins , Saccharomyces cerevisiae/cytology , Unfolded Protein Response/geneticsABSTRACT
Chronological aging of budding yeast cells results in a reduction in subsequent replicative life span through unknown mechanisms. Here we show that dietary restriction during chronological aging delays the reduction in subsequent replicative life span up to at least 23days of chronological age. We further show that among the viable portion of the control population aged 26days, individual cells with the lowest mitochondrial membrane potential have the longest subsequent replicative lifespan. These observations demonstrate that dietary restriction modulates a common molecular mechanism linking chronological and replicative aging in yeast and indicate a critical role for mitochondrial function in this process.
Subject(s)
Caloric Restriction , Mitochondria/physiology , Saccharomyces cerevisiae/growth & development , Animals , Cell Division/physiology , Culture Techniques/methods , Flow Cytometry , Glucose/metabolism , Membrane Potential, Mitochondrial/physiology , Reproduction/physiology , Saccharomyces cerevisiae/metabolism , Saccharomyces cerevisiae/physiology , Time FactorsABSTRACT
Chronological and replicative aging have been studied in yeast as alternative paradigms for post-mitotic and mitotic aging, respectively. It has been known for more than a decade that cells of the S288C background aged chronologically in rich medium have reduced replicative lifespan relative to chronologically young cells. Here we report replication of this observation in the diploid BY4743 strain background. We further show that the reduction in replicative lifespan from chronological aging is accelerated when cells are chronologically aged under standard conditions in synthetic complete medium rather than rich medium. The loss of replicative potential with chronological age is attenuated by buffering the pH of the chronological aging medium to 6.0, an intervention that we have previously shown can extend chronological lifespan. These data demonstrate that extracellular acidification of the culture medium can cause intracellular damage in the chronologically aging population that is asymmetrically segregated by the mother cell to limit subsequent replicative lifespan.
