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. 2017 Dec;16(6):1267-1275.
doi: 10.1111/acel.12659. Epub 2017 Aug 24.

Wide-scale Comparative Analysis of Longevity Genes and Interventions

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Free PMC article

Wide-scale Comparative Analysis of Longevity Genes and Interventions

Hagai Yanai et al. Aging Cell. .
Free PMC article

Abstract

Hundreds of genes, when manipulated, affect the lifespan of model organisms (yeast, worm, fruit fly, and mouse) and thus can be defined as longevity-associated genes (LAGs). A major challenge is to determine whether these LAGs are model-specific or may play a universal role as longevity regulators across diverse taxa. A wide-scale comparative analysis of the 1805 known LAGs across 205 species revealed that (i) LAG orthologs are substantially overrepresented, from bacteria to mammals, compared to the entire genomes or interactomes, and this was especially noted for essential LAGs; (ii) the effects on lifespan, when manipulating orthologous LAGs in different model organisms, were mostly concordant, despite a high evolutionary distance between them; (iii) LAGs that have orthologs across a high number of phyla were enriched in translational processes, energy metabolism, and DNA repair genes; (iv) LAGs that have no orthologs out of the taxa in which they were discovered were enriched in autophagy (Ascomycota/Fungi), G proteins (Nematodes), and neuroactive ligand-receptor interactions (Chordata). The results also suggest that antagonistic pleiotropy might be a conserved principle of aging and highlight the importance of overexpression studies in the search for longevity regulators.

Keywords: comparative analysis; evolutionary conservation; gene enrichment; gene orthology; longevity genes; proteome; public and private mechanisms of aging/longevity.

Figures

Figure 1
Figure 1
Percentage of orthologs of longevity‐associated genes (LAGs) from the four model organisms across 205 species. Each graph represents one of the four model organisms and the LAGs discovered for that species. Each dot represents the percentage of orthologs between the model species and a single other species (total of 205 species from all Kingdoms; for a full list of species see Table S1). The entire proteome of the model species (extracted from the InParanoid database) was used as control. The species (X‐axis) are ordered in descending order of the percentage of orthologs for the entire proteome. Presented are the ortholog percentage of the entire proteome (gray triangle), LAGs (black circle), LAGs discovered by lifespan extension (LSELAGs, gray circle), Caenorhabditis elegans essential LAGs discovered by postdevelopmental RNAi (PD RNAi LAGs, gray x), and C. elegans essential LAGs discovered by postdevelopmental RNAi that resulted in lifespan extension (PD RNAi LSELAGs, black +). (a) Saccharomyces cerevisiae, n = 6590 for control, 824 for all LAGs, and 277 for LSELAGs. (b) C. elegans, n = 20 325 for control, 733 for all LAGs, 491 for LSELAGs, 127 for PD RNAi LAGs, and 107 for PD RNAi LSELAGs. (c) Drosophila melanogaster,= 13 250 for control, 136 for all LAGs, and 85 for LSELAGs. (d) Mus musculus, n = 21 895 for control, 112 for all LAGs, and 42 for LSELAGs. The vast majority of pairwise differences between LAGs and the entire proteome are significant (P < 0.05), with a few exceptions of fringe cases as described in the text. For most Mmusculus LSELAGs, the pairwise differences are insignificant (P > 0.05), with a few exceptions where the number of orthologs was relatively high.
Figure 2
Figure 2
Ratio of LAGs orthologs to the entire proteome. Each graph represents the LAGs discovered in the indicated model species. Each dot represents the ratio between the number of LAG orthologs to the orthologs from the entire proteome, for a single other species (total of 205 species from all Kingdoms; for a full list of species see Table S1). The species (X‐axis) are ordered in descending order of ortholog percentage for the entire proteome. (a) Saccharomyces cerevisiae, n = 6590 for control and 824 for LAGs; (b) Caenorhabditis elegans, n = 20 325 for control and 733 for LAGs; (c) Drosophila melanogaster,= 13 250 for control and 136 for LAGs; (d) Mus musculus, n = 21 895 for control and 112 for LAGs.
Figure 3
Figure 3
Distribution of LAGs according to the number of phyla in which LAGs have orthologs. Each graph represents the distribution of LAGs (gray area) discovered in the indicated model species. The entire proteome was used as a control (dotted line). X‐axis depicts the number of phyla in which the genes have orthologs. The medians of the distributions are presented as vertical lines: dotted line for all genes and smooth black line for LAGs.
Figure 4
Figure 4
Percentage of manipulations on stress response LAGs that extended the lifespan. Only LAGs which were termed as ‘stress response’ under the GO classification system are included. Depicted is the percentage of overexpression (black) and knockout/knockdown (gray) interventions that resulted in lifespan extension. All intraspecies differences between the effects of overexpression and knockout/knockdown on lifespan were significant (P < 0.001). The full list of stress response LAGs is available in Table S7.
Figure 5
Figure 5
Concordancy in LAG manipulations across model organisms. Concordancy was determined according to the classification of LAGs as pro‐ or anti‐longevity genes (Tacutu et al., 2013). That is, if a given LAG was determined as a pro‐ or anti‐longevity gene in two or more species, it was termed ‘concordant’; otherwise, it was termed ‘discordant’. A detailed table is available in Table S8. (a) Summary of the concordancy for LAGs from each model species which have also been tested in two or more species (interspecies). (b) Venn diagram of the concordancy between species. (c+d) Summary of the concordancy of LAG manipulations within the same species (intraspecies).

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