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. 2008 Apr;18(4):564-70.
doi: 10.1101/gr.074724.107. Epub 2008 Mar 13.

Quantitative Evidence for Conserved Longevity Pathways Between Divergent Eukaryotic Species

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Free PMC article

Quantitative Evidence for Conserved Longevity Pathways Between Divergent Eukaryotic Species

Erica D Smith et al. Genome Res. .
Free PMC article

Abstract

Studies in invertebrate model organisms have been a driving force in aging research, leading to the identification of many genes that influence life span. Few of these genes have been examined in the context of mammalian aging, however, and it remains an open question as to whether and to what extent the pathways that modulate longevity are conserved across different eukaryotic species. Using a comparative functional genomics approach, we have performed the first quantitative analysis of the degree to which longevity genes are conserved between two highly divergent eukaryotic species, the yeast Saccharomyces cerevisiae and the nematode Caenorhabditis elegans. Here, we report the replicative life span phenotypes for single-gene deletions of the yeast orthologs of worm aging genes. We find that 15% of these yeast deletions are long-lived. In contrast, only 3.4% of a random set of deletion mutants are long-lived-a statistically significant difference. These data suggest that genes that modulate aging have been conserved not only in sequence, but also in function, over a billion years of evolution. Among the longevity determining ortholog pairs, we note a substantial enrichment for genes involved in an evolutionarily conserved pathway linking nutrient sensing and protein translation. In addition, we have identified several conserved aging genes that may represent novel longevity pathways. Together, these findings indicate that the genetic component of life span determination is significantly conserved between divergent eukaryotic species, and suggest pathways that are likely to play a similar role in mammalian aging.

Figures

Figure 1.
Figure 1.
Novel modulators of yeast replicative life span (RLS). Replicative life span is significantly extended by deletion of 11 of 76 yeast ORFs in the RBH set, including the transcription elongation factor SPT4 (A), ATP-dependent metalloprotease AFG3 (B), inositol polyphosphate 5-phosphatase INP53 (C), ribosomal proteins RPL9A (D), and RPL19A (E), and translation initiation factors TIF4631 (F), TIF1 (G), and TIF2 (H). Deletion alleles of TOR1, RPL6B, and IDH2 have been previously shown to increase RLS (Kaeberlein et al. 2005). Mortality curves were generated from life span data in both the MATα and MATa mating types; the mean life span for each deletion strain and the experiment-matched wild-type (wt) control is given in parentheses in the key of each panel.
Figure 2.
Figure 2.
Conserved aging genes are enriched for ribosome-associated genes. (A) Gene ontology analysis of the 276 worm aging genes, their yeast putative yeast orthologs in the reciprocal best-hit set (RBH, gene total = 103), and the 11 conserved aging genes (Table 2) revealed a significant enrichment in the ribosome cellular component when compared with the entire worm or yeast genome ([*] P <0.05, after Bonferroni Correction for multiple comparisons). Mitochondrial genes are highly enriched in worm aging genes and their corresponding yeast homologs and orthologs, but there is no significant enrichment for mitochondrial genes in the group of conserved longevity genes identified in this study. Essential genes were included in the gene ontology analysis, but replicative life span was not measured for these (RBH/ribosome = 8; RBH/mitochondrion = 8). (B) Conserved aging genes highlight the role of the TOR signaling pathway in modulating longevity. Orthologous gene pairs are shown in parentheses (worm genes are in blue and yeast genes are in red). The nutrient sensing kinases are enclosed in the gray box. Many downstream targets of TOR signaling, including ribosomal proteins and translation initiation factors, play a conserved role in life span determination. (*SCH9 was recently shown to have S6K activity (Urban et al. 2007), but also has homology with worm aging genes in the Akt family of kinases, such as akt-1 and sgk-1.)

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