Defining Molecular Basis for Longevity Traits in Natural Yeast Isolates

Abstract

The budding yeast has served as a useful model organism in aging studies, leading to the identification of genetic determinants of longevity, many of which are conserved in higher eukaryotes. However, factors that promote longevity in laboratory setting often have severe fitness disadvantage in the wild. Here, to obtain an unbiased view on longevity regulation we analyzed how replicative lifespan is shaped by transcriptional, translational, metabolic, and morphological factors across 22 wild-type Saccharomyces cerevisiae isolates. We observed significant differences in lifespan across these strains and found that their longevity is strongly associated with up-regulation of oxidative phosphorylation and respiration and down-regulation of amino acid and nitrogen compound biosynthesis. Since calorie restriction and TOR signaling also extend lifespan by adjusting many of the identified pathways, the data suggest that natural plasticity of yeast lifespan is shaped by processes that not only do not impose cost on fitness, but are amenable to dietary intervention.

Figure 1

Yeast strains examined in this study. (a) Phylogenetic relationship. The tree was constructed based on the alignment of complete genome sequences of the strains, using MEGA 6.06 and neighbor joining method. The branches are colored according to strain types shown in the legend in the lower right corner. (b) Mean replicative lifespan and (c) mean growth rate (doubling time) of the strains in glucose media. The strains are ordered by phylogeny. The error bars indicate s.e. Red dotted lines indicate the mean replicative lifespan (b) and doubling time (c) of the reference strain BY4743.

Figure 2

Phenotypic variation across the strains. (a) Principal component analysis (PCA) of combined data. PCA was performed by combining transcripts, proteins (peptides), and morphology data (metabolite data were not available for strain 378604X and were omitted). Percentage variance explained by each principal component (PC) is shown in the parentheses. The strains are colored using the same scheme as Figure 1a. See Supplementary Figure 2 for separate PCA plots on each class of phenotype data and for cumulative percentage of variance explained by the PCs. (b) Relative levels of transcripts and proteins involved in aerobic respiration or fermentation. The heat map shows the transcripts and proteins with top contribution to PC 1 and involved in aerobic respiration or fermentation (Supplementary Table 1). Hierarchical clustering was performed using complete linkage.

Figure 3

Selected phenotypes correlating with replicative lifespan. Levels of (a) asparagine, (b) glutamine, and (c) 2-octenoic acid negatively correlate with maximum replicative lifespan (Max RLS). Regression slope P values: (a) 0.014; (b) 0.042; and (c) 0.019. (d) Protein–protein interaction network of the top hits identified by the mean protein values. The interaction network is based on STRING database (evidence view). Genes without interacting partners are omitted. Selected pathways are indicated by colored rings. Most of the proteins here showed significant correlation to all four RLS measures. See Supplementary Table 2 for more details.

Figure 4

Mitochondrial respiratory composition varies across the strains according to lifespan. (a) Mean replicative lifespan of strains. Strains are ordered according to their mean lifespan (see also Figure 1b). (b) Levels of certain proteins correlate with lifespan. The mean values of the selected proteins (related to mitochondrial function) are shown. For each protein, the levels were standardized by setting mean=0 and s.d.=1 across the strains. The patterns of DBPVG1373, YJM981, YJM975, and Y12 strains showed different patterns. See Supplementary Table 2 for more detail. (c) Effect of growth on a respiratory substrate on lifespan. Replicative lifespan of 10 strains was tested on yeast peptone glycerol (3% YPG) plates and expressed as mean (left) and maximum (right) replicative lifespan. Except for the three long-lived outlier strains (YJM981, YJM975, and Y12), all strains either increased or did not change lifespan when their growth substrate was switched from glucose to glycerol.