A genomic analysis of chronological longevity factors in budding yeast

Abstract

Chronological life span (CLS) has been studied as an aging paradigm in yeast. A few conserved aging genes have been identified that modulate both chronological and replicative longevity in yeast as well as longevity in the nematode Caenorhabditis elegans; however, a comprehensive analysis of the relationship between genetic control of chronological longevity and aging in other model systems has yet to be reported. To address this question, we performed a functional genomic analysis of chronological longevity for 550 single-gene deletion strains, which accounts for approximately 12% of the viable homozygous diploid deletion strains in the yeast ORF deletion collection. This study identified 33 previously unknown determinants of CLS. We found no significant enrichment for enhanced CLS among deletions corresponding to yeast orthologs of worm aging genes or among replicatively long-lived deletion strains, although a trend toward overlap was noted. In contrast, a subset of gene deletions identified from a screen for reduced acidification of culture media during growth to stationary phase was enriched for increased CLS. These results suggest that genetic control of CLS under the most commonly utilized assay conditions does not strongly overlap with longevity determinants in C. elegans, with the existing confined to a small number of genetic pathways. These data also further support the model that acidification of the culture medium plays an important role in survival during chronological aging in synthetic medium, and suggest that chronological aging studies using alternate medium conditions may be more informative with regard to aging of multicellular eukaryotes.

Figure 1

Scatter plot of survival integrals for all reported long-lived gene deletions. The mean survival integral (SI) for each strain was calculated from at least nine replicate chronological lifespan experiments and plotted by group. The median SI for any of the experimental groups was not found to be significantly greater than an expected median value generated by assaying a randomized list of single-gene deletions (random). The set of genes corresponding to worm homologs, however, had a median SI that was shorter than expected by Dunnett's multiple comparison test (p < 0.05). Whiskers illustrate data within the 1.5 interquartile range.

Figure 2

Survival curves for long-lived strains from the random screen. Eight gene deletions conferring increased chronological life span were identified from 227 randomly selected deletion strains. These data were used to estimate the frequency of long-lived mutations in the deletion collection for comparison against other groups. The survival curves represent pooled lifespan data from multiple experiments with experiment matched wild type (BY4743) lifespan data. The mean survival integral along with the number of biological replicate experiments is shown next to the strain name.

Figure 3

Survival curves for long-lived strains from the worm homolog screen. Twelve of 235 gene deletions corresponding to C. elegans aging genes confer increased chronological life span. The survival curves represent pooled lifespan data from multiple experiments with experiment matched wild type (BY4743) lifespan data. The mean survival integral along with the number of biological replicate experiments is shown next to the strain name.

Figure 4

Survival curves for yeast deletion strains that are both chronologically and replicatively long-lived. Four of 47 single-gene deletions known to increase replicative lifespan also conferred increased chronological life span. The survival curves represent pooled lifespan data from multiple experiments with experiment matched wild type (BY4743) lifespan data. The mean survival integral along with the number of biological replicate experiments is shown next to the strain name.

Figure 5

Survival curves for long-lived strains from the screen for reduced acidification of the culture medium. Eleven of 76 deletions strains exhibiting reduced acidification of the culture medium where chronologically long-lived. Deletion of HOM6 (B; S.I. = 8.08) and VPS51 (C; S.I. = 7.65) had a comparable lifespan to deletion of SCH9 (Fig. 3B; S.I. = 8.59). Vps51p, along with Tlg2p identified in the worm homolog screen (Fig. 3C), is involved in endosome docking at the late Golgi. The survival curves represent pooled lifespan data from multiple experiments with experiment matched wild type (BY4743) lifespan data. The mean survival integral along with the number of biological replicate experiments is shown next to the strain name.

Figure 6

Deletion of VPS51 or TLG2 does not significantly increase RLS. Two gene-deletions (vps51Δ and tlg2Δ) which resulted in extended chronological lifespan mediate Golgi-associated retrograde trafficking. The survival curves represent pooled lifespan data from multiple experiments with experiment matched wild type (BY4742) lifespan data. The mean replicative lifespan along with the number of mother cells examined is shown next to the strain name.

Figure 7

Deletion of components of the GARP complex increase yeast CLS. vps51Δ, a strain that lacks a regulatory unit of the Golgi-associated retrograde protein complex, was identified as extremely long-lived. Mutation in the genes encoding the remaining complex components (VPS52, VPS53 and VPS54) did not have a similar degree of lifespan extension, indicating a role for the regulation of the Vps52/53/54 complex with the t-SNARE in yeast CLS.