Evolution of natural lifespan variation and molecular strategies of extended lifespan in yeast
- Department of Biology, Virginia Commonwealth University, United States
- Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore
- Department of Laboratory Medicine and Pathology, University of Washington, United States
- Department of Environmental and Occupational Health Sciences, University of Washington, United States
- Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, United States
- Key Laboratory of Animal Ecology and Conservation Biology, Chinese Academy of Sciences, Institute of Zoology, China
- Department of Biology, University of Houston - Clear Lake, United States
- Department of Biology, University of Washington, United States
Figures
Figure 1 with 1 supplement
Doubling time and replicative lifespan of yeast wild isolates.
(A) Distribution of mean doubling time (DT, in minutes) on yeast peptone dextrose (YPD; 2 % glucose) and yeast peptone glycerol (YPG; 3 % glycerol). (B) Examples of lifespan curves for the selected …
Figure 1—figure supplement 1
Replicative lifespan (RLS) phenotype across wild isolates.
(A) Median RLS (error bars are the 95% confidence interval [CI] of the median lifespan) distribution across S. cerevisiae and S. paradoxus isolates grown in yeast peptone dextrose (YPD). Dashed …
Figure 2 with 3 supplements
Endophenotypic variation across strains.
(A) Phylogenetic relationship based on the transcriptome data of 76 strains of 2 species. Principal component analysis (PCA) of (B) transcriptomics and (C) metabolomics. Percent variance explained …
Figure 2—figure supplement 1
Read alignment rate for RNA-seq data.
RNA-seq reads were mapped to the pseudo genome using STAR aligner software and mean value of alignment rate (three replicates per strain) from STAR outputs are shown here. Error bars show standard …
Figure 2—figure supplement 2
Correlation of genome-wide transcript levels across wild isolates.
Heatmap shows pairwise, 1 − Pearson correlation matrix of gene expression data across wild isolates. Caloric restriction (CR) data were obtained from NCBI GEO (SRA: SRX403444) and placed into the …
Figure 2—figure supplement 3
Principal component analysis.
Graphs show cumulative percentage of variance explained by principal components for (A) genes and (B) metabolites.
Figure 3
Selected genes whose expression correlates with median replicative lifespan (RLS).
(A) Gene expression level (log2-cpm) of CMR3, ZRG8, and PNC1 positively correlates with median RLS. (B) Transcript abundance of PHO85, RTT107, and BNA2 negatively correlates with median RLS. …
Figure 4 with 1 supplement
Comparative analysis of lab yeast knockout (KO) and wild isolates.
(A) Significant genes (padj < 0.05) associated with maximum, median, and mean replicative lifespan (RLS; or log maximum, median, and mean) across deletion strains based on transcriptomics data …
Figure 4—figure supplement 1
Replicative lifespan (RLS) phenotype of yeast knockout strains.
(A) Distribution of mean, median, and maximum RLS across deletion strains with measured gene expression profile. RLS are sorted from the smallest to the greatest value. Black lines represent …
Figure 5 with 1 supplement
Selected metabolites correlating with median replicative lifespan (RLS).
(A) Abundance (liquid chromatography–mass spectrometry [LC–MS] counts) of lactate, tryptophan (Trp), and hydroxyisobutyrate that positively correlate, and (B) abundance of quinolinic acid, lysine …
Figure 5—figure supplement 1
Correlation of LYS20 and LYS21 genes with median replicative lifespan (RLS).
Gene expression level (log2-cpm) of LYS20 and LYS21 negatively correlates with median RLS. Regression slope p values can be found in Supplementary file 2.
Figure 6 with 4 supplements
Summary of metabolic changes associated with replicative lifespan (RLS).
(A) Summary depiction of genes and metabolites from the interconnected glycolytic pathway, TCA cycle and amino acid metabolism that are found to be associated with RLS. Associated genes are colored …
Figure 6—figure supplement 1
Genes and metabolites from shikimate, kynurenine, and salvage pathways associated with replicative lifespan (RLS).
Genes and metabolites from each pathway that are found to be associated with RLS are colored with red (negatively associated with RLS) or green (positively associated with RLS). Genes and …
Figure 6—figure supplement 2
Lysine biosynthesis and replicative lifespan (RLS).
Genes and metabolites from the lysine biosynthetic pathway that are found to be negatively associated with RLS are colored in red. Genes and metabolites that are known to be involved in tryptophan …
Figure 6—figure supplement 3
Genes from the branched chain amino acid (BCAA) metabolic pathway are negatively associated with replicative lifespan (RLS).
Genes involved in BCAA biosynthesis that are found to be negatively associated with RLS are colored in red. Threonine (positively associated with RLS) catabolism, is shown in green, and contributes …
Figure 6—figure supplement 4
Association of mitochondrial respiration with median replicative lifespan (RLS).
(A) Spearman correlation between median RLS and oxygen consumption rate (OCR; pmol/min). (B) Western blot analysis for mitochondrial protein abundance across the strain. Similar expression of …
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Figure 6—figure supplement 4—source data 1
Raw western Blot images are provided as source data.
- https://cdn.elifesciences.org/articles/64860/elife-64860-fig6-figsupp4-data1-v2.zip
Figure 7
Replicative lifespan (RLS) effect of GLN1 and BNA2 overexpression in selected long- and short-lived strains.
Lifespan curves for control (gray), BNA2 (black), and GLN1 (red) overexpression in (A) long- and (B) short-lived strains. Lifespan data and significance of lifespan changes can be found in Supplement…
Figure 8 with 1 supplement
Growth properties of long-lived trains in medium supplemented with alpha-ketoglutarate (α-KG) and effect of mitochondrial DNA (mtDNA) elimination on α-KG utilization and replicative lifespan (RLS).
(A) The growth of three long-lived strain was further supported with α-KG supplementation (10 g/l). However, strains lost the ability of α-KG utilization upon mtDNA elimination (red). Growth data of …
Figure 8—figure supplement 1
Effect of alpha-ketoglutarate (α-KG) on growth.
Spot assay for wild isolates on medium containing YP (yeast extract and peptone), YP supplemented with α-KG (10 g/l), and YP supplemented with both α-KG (10 g/l) and glucose (0.02%). Each spot …
Additional files
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Supplementary file 1
Strain list, used in this study and their replicative lifespan along with doubling time are listed.
This file also includes replicative lifespan of the laboratory KO strains, analyzed in this study.
- https://cdn.elifesciences.org/articles/64860/elife-64860-supp1-v2.xlsx
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Supplementary file 2
File includes raw and normalized counts from RNA-seq.
Normalized metabolite count is also included. Results from phylogenetic generalized least square (PGLS) analysis from both datasets along with statistical values are listed for natural isolates. Similarly, genes associated with RLS (mean, median, and maximum) of KO strains along with statistical values are also listed. This file also includes result GSE enrichment terms with statistical values for natural isolates and KO strains.
- https://cdn.elifesciences.org/articles/64860/elife-64860-supp2-v2.xlsx
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Supplementary file 3
PCA loadings for normalized RNA-seq and metabolomics datasets.
- https://cdn.elifesciences.org/articles/64860/elife-64860-supp3-v2.xlsx
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Supplementary file 4
List of yeast longevity genes from GenAge database.
Identified set of CR-related genes from our analysis is also listed.
- https://cdn.elifesciences.org/articles/64860/elife-64860-supp4-v2.xlsx
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Supplementary file 5
Values for oxygen consumption rate (OCR) measurement across the strains.
- https://cdn.elifesciences.org/articles/64860/elife-64860-supp5-v2.xlsx
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Transparent reporting form
- https://cdn.elifesciences.org/articles/64860/elife-64860-transrepform1-v2.docx
