Change - Ageing Genes Classification

Created on Sept. 3, 2012, 8:10 p.m. by Hevok & updated on May 18, 2013, 2:08 p.m. by Hevok

Gerontogenes vs. Ageing-Suppressor Genes

Abstract:Many genes regulate the ageing process in a positive or negative manner. Gerontogenes can speed up ageing by their normal activity, therefore decrease lifespan if hyperactivated and increase it if inactivated, while ageing-suppressor genes slow down ageing normally, hence decrease lifespan by lack of activity and their over-activation increases lifespan. In C. elegans these two classes of ageing-associated genes, share functional terms of enzyme/domain-specific binding, cell cortex and secretion and have their own specific terms as well as opposite molecular interaction network connectivity properties and only if grouped together having a significant higher specificity to interact to each other. In these networks of ageing-associated genes, clusters of either gerontogenes or ageing-suppressor genes appear to regulate distinct activities separately as well as similar processes together. Gerontogenes are acting on transcriptional and translational control, development and DNA metabolism, while ageing-suppressor genes are primary regulators of diverse activities for cell homeostasis like cytoskeleton structure, intracellular and nuclear organization, localization and transport, as well as proteasome system. Both gerontogenes and ageing-suppressor are participating in development and growth, phosphorylation mediated signalling, transmembrane transport, and regulation of cell death.

Contents

Introduction

Several studies indicate that gerontogenes and ageing-suppressors have distinct different functions. For instance, a genome-wide screen for yeast mutations which confer altered chronological lifespan revealed that ageing-suppressors are involved in vacuolar protein sorting, autophagy, and mitochondrial function, while gerontogenes such as ACB1, CKA2 and TRM9 are implicated in fatty acid transport and biosynthesis, cell signalling and tRNA methylation, respectively [Fabrizio et al., 2010].

There are three ways to extend lifespan: increasing early or late survival rates, or delaying senescence. The first two do not affect basic ageing process. The first one increase only mean but not maximum lifespan, while the second one leads to change in a maximum but not mean lifespan. Delayed senescence leads to a significant increase in both the mean and maximum longevity [Iliadi et al., 2012]. Therefore we categorized whether a genetic manipulation affects mean and/or maximum lifespan.

Aims

Gerontogenes need to be suppressed, while ageing-suppressor genes have to be enhanced in their activity. The goal is to identify the processes, pathways and proteins which need to be drug-targeted to interfere with the ageing process in order to delay, stop or even reverse age-related changes.

Moreover the transcription factors controlling gerontogenes and ageing suppressors need to be identified as well as the significant interaction partners in all species.

Objectives

Molecular interaction networks of ageing-associated genes for a defined species (e.g. C. elegans) were generated and the genes were visualized according to the categories (gerontogenes vs. ageing-suppressor genes) they are belonging to (for instance as colour of nodes border lines) in order to gain better insight into the regulatory mechanism governing lifespan decrease / increase.

Further the functional enrichment of gerontogenes, ageing-suppressor genes alone were revealed and their similarities were compared / differences contrasted. Why gerontogenes have negative influence on ageing, while ageing-suppressors positively affect lifespan?

Moreover the network properties for the interactomes of gerontogenes and ageing-suppressor genes, ageing- and dietary restriction (DR)-associated genes were compared.

Hypothesis

Gerontogenes and ageing-suppressor genes have different network topological features such as connectivity (eventually also regarding in-betweeness and centrality). Additionally, it is possible that they are clustered differently. Gerontogenes have distinct functions, are acting on different processes or a localized to other compartments than ageing-suppressor genes. Therefore, a functional enrichment analysis is required.

Results

An interaction network of negative ageing-suppressors identifies ubl-5 (Ubiquitin-Like family) as a significant interactor (7 of 94 interactions; p-value < 0.05). Ubl-5 is a key transcriptional coactivator of mitochondrial unfolded protein response (UPR), which is indispensable for the increased lifespan of mild mitochondrial electron transport chain (ETC) inhibition. Its expression is required during the same developmental window as decreased ETC to extend lifespan.

Gerontogenes vs. Ageing-Suppressor Genes Functional Enrichment

Gerontogenes and ageing-suppressor genes share terms related to enzyme- and specific domain-binding, cell-secretion and -cortex [Figure: Common terms shared by gerontogenes and ageing-suppressor genes].

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Figure: Common terms shared by gerontogenes and ageing-suppressor genes.

Gerontogenes have specific terms like regulation of vulva development, embryonic morphogenesis and pattern specification, cell migration, cytokinesis, hedgehog receptor activity, rRNA and iron-sulfur-binding, and aminoacyl tRNA biosynthesis [Figure: Terms specific to gerontogenes].

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Figure: Terms specific to gerontogenes.

Significant specific terms of gerontogenes are nucleotide excision and mismatch repair, DNA metabolic processes and replication, regulation of localization, embryonic development and morphogenesis, protein N-terminus, protein kinase and ribonucloetide binding, regulation of post-embryonic and nematode larval development, negative regulation of development process and post-embryonic development, embryonic development via the syncytial blastoderm, female gamete generation, anchoring and adherens junction, dorsal closure, positive and negative regulation of vulva development, gastrulation, regulation of transcription from RNA-polymerase II promoter, purine and pyrimidine metabolism, RNA polymerase, binding, transcription, cell motility and migration, inductive cell migration, cytokinesis and aminoacyl-tRNA biosynthesis [Figure: Terms specific to ageing-suppressor genes].

Ageing-suppressor genes are enriched for specific terms regarding centrosome, nuclear transport, pole plasm, proteasome and proteasome complex associated [Figure: Terms specific to ageing-suppressor genes].

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Figure: Terms specific to ageing-suppressor genes.

Network Properties of Gerontogenes, Ageing-Suppressor Genes, Ageing- and DR-Associated Genes Interactomes Differ Remarkably from Each Other

A site-by-site network features comparison regarding connectivity of gerontogenes, ageing-suppressor genes and ageing- as well as DR-essential genes generated networks reveals that these sets of genes have strikingly different connectivities [Table: Network topology; Figure: Average number of specific and total interactions as well as specificity].

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Figure: Average number of specific and total interactions as well as specificity.

In contrast, ageing-suppressor genes have a slightly lower number of specific (1.6 vs. 1.8%) and slightly higher number of total (55.0 vs. 53.7) interactions and a significant lower specificity of interacting to each other (2.9 vs. 3.3%).

Gerontogenes have a higher number of specific (3.3 vs. 3.0%) and significant lower number of total (48.3 vs. 55.7%) interactions, and higher specificity of interactions to each other (6.9 vs. 5.4%).

Ageing-associated genes (gerontogenes and ageing-suppressor genes together) have a higher number of specific (4.1 vs. 3.2%) and total (50.2 vs. 44.2%) interactions and a significant higher specificity to interact to each other (8.1 vs. 7.1%).

For comparison, DR-associated genes have a significant lower specific (0.9 vs. 1.2%) and total (17.6 vs. 52.2%) interaction number as well as higher specificity of connectivity to each other (4.9 vs. 2.3%).

A Network of Ageing-Associated Genes Reveals Differential Clustering

A network composed of interactions only among gerontogenes and ageing-suppressor genes [Figure: Interaction only among gerontogenes and ageing-suppressor genes], shows that gerontogenes (nodes with red borders) or ageing-suppressor genes (nodes with green borders) are quite often connected together, separately, forming cluster and pathways only within their category. In this case, gerontogenes are forming hubs (sos-1 and egl-15).

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Figure: Interaction only among gerontogenes and ageing-suppressor genes.

Gerontogene and Ageing-Suppressor Gene Cluster Regulates Transcription

A cluster composed of eight gerontogenes (RPB2_CAEEL, O62185_CAEEL, P91277_CAEEL, RPAB3_CAEEL, cfim-1, Q93338_CAEEL, gut-2 and snr-5) and three ageing-suppressor genes (PCF11_CAEEL, T08A11.2 and Q9U2H8_CAEEL) was identified to have terms related to manipulate the activity of RNA polymerase, hence transcription [Figure: Cluster regulating transcription; Table: Cluster regulating transcription - Genes and their connectivity features; Table: Cluster regulating transcription - Gene ontology enrichment]. These proteins are connected physically (orange), but some interactions were in addition also genetic (purple), and therefore probably forming a protein complex.

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Figure: Cluster regulating transcription.

Gerontogene Cluster of Ribosomal Components

A cluster totally composed of gerontogenes which are part of the ribosome and to mediate translation was found to interact physically with each other to a high degree and therefore forming a complex [Figure: Cluster of ribosomal components; Table: Cluster of ribosomal components - Genes and their connectivity features; Table: Cluster of ribosomal components - Gene ontology enrichment].

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Figure: Cluster of ribosomal components.

Gerontogene Cluster Participating in tRNA Synthesis

A short path of three gerontogenes (SKY-CAEEL, irs-1 and cyn-7) were found to be enriched in terms related to tRNA synthesis [Figure: Cluster participating in tRNA synthesis; Table: Cluster participating in tRNA synthesis - Genes and their connectivity features; Table: Cluster participating in tRNA synthesis - Gene ontology enrichment].

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Figure: Cluster participating in tRNA synthesis.

Network of Ageing-Associated Genes

In a network of ageing-associated genes, where the interaction partners where restricted to those that interact at least with two ageing-associated genes, genes associated to ageing but not yet classified as either gerontogene or ageing-suppressor gene are represented with a golden node border lines and appearing very frequently within this interactome [Figure: Interactions with genes that interact at least with two ageing-associated genes and all interactions among ageing-associated genes].

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Figure: Interactions with genes that interact at least with two ageing-associated genes and all interactions among ageing-associated genes.

RNA-Processing Cluster with Gerontogenes and other Unclassified Ageing-Associated Genes

A relative big cluster of 90 genes containing three gerontogenes (RPB2_CAEEL & Q93338_CAEEL) and three ageing-associated genes (Q17558_CAEEL, hrp-1 and MGN_CAEEL) not yet classified were found to be involved in nucleotide metabolism, diverse forms of RNA processing as well as germ line development and differentiation [Figure: RNA-processing cluster; Table: RNA-processing cluster - Genes and their connectivity features; Table: RNA-processing cluster - Gene ontology enrichment].

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Figure: RNA-processing cluster.

Gerontogene Cluster involved in Nucleotide Biosynthesis and tRNA Loading

A 20 node cluster with two gerontogenes (SYK_CAEEL and irs-1) in the centre as well as one unclassified ageing-associated gene (nrs-1) in the periphery [Figure: Nucleotide biosynthesis and tRNA loading cluster; Table: Cluster involved in nucleotide biosyntheses and tRNA loading - Gene ontology enrichment] contains enrichment in terms of the enzymatic activities for coupling amino acids to tRNAs.

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Figure: Nucleotide biosynthesis and tRNA loading cluster.

Ageing-Suppressor Genes and Geronotogenes Cluster Involved in Proteasome

A cluster harbouring two gerontogenes (rpn-7 and -11) in the centre as well as a gerontogene (drs-1) alone in the periphery with a path length of two interactions away from centre is enriched catabolic proteasome system terms. Interestingly, one gene (Q95XR3_CAEEL) with particular high connectivity to ageing-associated genes is directly connected to both gerontogenes [Figure: Cluster involved in proteasome; Table: Cluster involved in proteasome - Genes and their connectivity features; Table: Cluster involved in proteasome - Gene ontology enrichment].

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Figure: Cluster involved in proteasome.

Cluster of Gerontogenes and Ageing-Suppressor Genes Positively Regulates Development and Growth

A remarkably cluster with high contents of gerontogenes (hlh-1, mex-6, cye-1 and hmp-12), ageing-suppressor genes (par-6 & pie-1) and unclassified ageing-associated genes (let-60 & sem-5) is almost exclusively connected by genetic interactions. A single gene (let-756) with very high specificity to ageing-associated genes is localized in the middle of this cluster [Figure: Cluster regulating development and growth; Table: Cluster positively regulating development and growth - Genes and connectivity features; Table: Cluster positively regulating development and growth - Gene ontology enrichment].

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Figure: Cluster regulating development and growth.

Gerontogene, Ageing-Suppressor Gene and Ageing-Associated Gene Cluster Involved in Phosphorylation Mediated Signal Transduction

A cluster of two gerontogenes (egl-15 and sos-1), one ageing-suppressor gene (GSK3_CAEEL) and one further ageing-associated gene (daf-2) is totally connected by gene genetic interactions and harbours an enrichment of terms related to signal transduction mediated by phosphorylation [Figure: Phosphorylation mediated signal transduction; Table: Cluster of phosphorylation mediated signal transduction - Genes and connectivity features; Table: Cluster of phosphorylation mediated signal transduction - Gene ontology enrichment].

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Figure: Phosphorylation mediated signal transduction.

Cluster of Ageing-Associated Genes for Transmembrane Transport and Regulation of Cell Death

A cluster composed of four ageing-suppressor genes (SNA29_CAEEL, pat-3, vha-2 and Q18921_CAEEL), two gerontogenes (cdk-1 & Q9TX9_CAEEL) and one ageing-associated gene (unc-64) is enriched in terms related to transport across the membrane and regulating cell death [Figure: Transmembrane transport and regulation of cell death; Table: Transmembrane transport and regulation of cell death cluster - Genes and their connectivity features; Table: Transmembrane transport and regulation of cell death cluster - Gene ontology enrichment].

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Figure: Transmembrane transport and regulation of cell death.

Level 2 Network of Ageing-Associated Genes with a Reduced Complexity

By excluding interactions, which were not annotated as physical or genetic, a less complex network was generated [Figure: Interactions with genes that interact at least_with two ageing-associated genes and interactions among ageing-associated genes whereby all interaction not classified as physical or genetic were excluded]. This procedure revealed an additional cluster, previously not detected by MCODE algorithm, with significant enrichment in gene ontology terms.

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Figure: Interactions with genes that interact at least_with two ageing-associated genes and interactions among ageing-associated genes whereby all interaction not classified as physical or genetic were excluded.

Gerontogene Containing Cluster involved in Genomic Guardian and Repair

Two gerontogenes (C47D12.8 & O44499_CAEEL) are in a cluster of 10 genes in total. O44499_CAEEL has only physical interaction to all other genes, while C47D12.8 has also many genetic interactions in addition to physical interaction to all other genes within this cluster. Two genes (csb-1 and Q93456_CAEEL) are linked to both gerontogenes and have a high and very high specificity to ageing-associated genes, respectively. This cluster is rich in terms associated to stimulus, stress and DNA damage, as well as DNA metabolism and repair [Figure: Genomic guardian and repair cluster; Table: Cluster involved in genomic guardian and repair - Genes and connectivity features; Table: Cluster involved in genomic guardian and repair - Gene ontology enrichment].

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Figure: Genomic guardian and repair cluster.

Discussion

Functional Similarities and Differences between Gerontogenes and Ageing-Suppressor Genes

Gerontogenes and ageing-suppressor genes share similar functional terms, namely enzyme and domain-specific binding as well as cell cortex and secretion. Indicating that both regulating processes which can be studied on the level of protein-protein and protein-metabolite interactions.

Gerontogenes are predominantly involved in development (such as regulation of vulva, embryonic morphogenesis and pattern specification), DNA metabolism (inclusive repair mechanisms and nucleotide metabolisms), Hedgehog signalling, rRNA and ironsulfur cluster binding as well as aminoacyl tRNA biosynthesis.

In contrast, ageing-suppressor genes are primary involved in cytoskeleton, intracellular-organisation, localisation and -transport (especially regarding nucleus), and proteasome. Indicating that they are maintaining intracellular structure, stability, homeostasis and diverse transport processes especially regarding the nucleus.

DEAD/H-box RNA helicase, which binding were associated to ageing-suppressor genes are important for RNA metabolism and transcriptional regulation [Fuller-Pace, 2006].

Interestingly, gerontogenes were functional more implicated in kinase binding, while ageing suppressor genes were enriched in some protein dephosphorylation related terms.

Gerontogenes and Ageing-Suppressor Genes are Clustered Separately as well as Together

In networks of ageing-associated genes, gerontogenes were found to be clustered alone as well as together with ageing-suppressor genes.

Firstly, clusters containing only gerontogenes participate in tRNA biosynthesis (e.g. enzymes), translation (such as ribosomal components or elongation factors) and RNA-processing, germ-line development and differentiation, as well as guarding (response to various stresses) and repairing the genome.

Secondly, clusters mostly composed if gerontogenes and a few number of ageing-suppressor genes regulate transcription.

Thirdly, clusters containing both kinds of ageing-associated genes function in the control of development and growth, phosphorylation mediated signalling, transmembrane transport, and regulation of cell death.

Lastly, clusters containing more ageing-suppressor genes as gerontogens are linked to proteasome function.

Implication of Different Clustering of Gerontogenes and Ageing-Suppressor Genes

If genes / proteins of the same category are clustered together or forming pathways their interaction could be of activating nature, while if genes / proteins of different categories (i.e gerontogene and ageing-suppressor gene) are interacting this could be in an inhibiting fashion (hypothesis).

Hubs like sos-1 (son of sevenless homolog, ras nucleotide exchange factor) and egl-15 (a kinase), both are gerontogenes are interacting with gerontogenes as well as ageing-suppressor genes (equal or unequal amount?). Therefore, they could function as information integrator and produce an integrated output.

Obstacles of Categorization in Gerontogenes and Ageing-Suppressor Genes

Can a gene also be both gerontogene and ageing-suppressor genes depending on circumstances (e.g different environmental factors, diet)? Sir2 activity for instance, is on the one hand reported to extend replicative lifespan, but is on the other hand limiting maximal chronological lifespan extension [Fabrizio et al., 2005]. This case could be attributed to unicellular organism specific phenomena, but it was suggested that also Sirtuins in higher organisms also have anti-ageing and pro-ageing features. Therefore the categorization need to be interpreted carefully and exceptions of this simple categorization are important too. It is possible that regulatory environment of a gene/protein needs to be taken into account to understand this, rather than single genes/proteins.

Outlook

It could be considered also to annotate if a gene is related to DR or an ortholog of a gene associated to one of these categories in another species.

It would be very interesting to use this classification method also in directional networks, with information about the influences of interaction (i.e. activating or inhibiting).

References

Fabrizio P, Hoon S, Shamalnasab M, Galbani A, Wei M, Giaever G, Nislow C, Longo VD: Genome-Wide Screen in Saccharomyces cerevisiae Identifies Vacuolar Protein Sorting, Autophagy, Biosynthetic, and tRNA Methylation Genes Involved in Life Span Regulation. PLoS Genet 2010, 6(7):e1001024.

Fuller-Pace FV: DExD/H box RNA helicases: multifunctional proteins with important roles in transcriptional regulation. Nucleic Acids Res 2006, 34(15):4206-4215. Fabrizio P, Gattazzo C, Battistella L, Wei M, Cheng C, McGrew K, Longo VD: Sir2 blocks extreme life-span extension. Cell 2005, 123(4):655-667.

Iliadi KG, Knight D, Boulianne GL (2012) Healthy aging - insights from Drosophila. Frontiers in physiology 3: 106.

Methods

Categorization

Ageing-associated genes were classified into two categories:

  1. Gerontogenes (e.g. let-363): normal / higher activity accelerates ageing (i.e. lower activity extends lifespan)
    1. Positive Gerontogenes, if reduced in activity increase lifespan
    2. Negative Gerontogenes, if increased in activity decrease lifespan
  2. Ageing-Suppressor Genes (e.g. daf-16): normal / higher activity retards ageing (i.e. lower activity decrease lifespan).
    1. Positive Ageing-Suppressor Genes, if increased activity increase lifespan
    2. Negative Ageing-Suppressor Genes, if decreased activity decrease lifespan

Additionally, all genes documented in GenAge were marked as ageing-associated.

Network Generation

Gene names, symbols identifiers of the seed lists ("new longevity regulators") were collected in lists and mapped to ensembl gene IDs via synonymous table derived from Ensembl/Biomart.

Interactions for ageing-associated genes were retrieved from an integrated interaction datasets from various sources (> 18). Interactomes of different sizes (Level 1 - 5) were generated and visualized via Cytoscape.

General network properties were determined as previous described in [22912585].

Annotation information like number specific interactions to seed genes, number total interactions, specificity of connectivity, seed interactors, association (= classification, either gerontogene, ageing-suppressor gene or ageing-associated) were mapped to unique ensembl gene IDs and loaded as attributes to the nodes. Physical interactions are orange solid line edges, while genetic interactions are green dashed line edges. Nodes are coloured according to their p-value of specificity of the connectivity to seeds (p value > 0.05: green; p value = 0.05: yellow; p-value < 0.05 from red to purple (very low p-value)). Node borderline colour: red = Geronotogene; green = Ageing-Suppressor Gene; gold = Ageing-Associated Gene

Clustering and Functional Analysis

For clustering the MCODE algorithm was used and functional enrichment analysis was performed with ClueGO for gene lists and with BiNGO for clusters in networks. The following ratios can be used:

  • Cluster Frequence = x/X
  • Total Frequence = n/N

Figure and Tables

Tables

Table: Network topology

Average number of specific and total interactions as well as specificity. Interactions Genes Seeds Others p-value Specific Geronto 3.309 2.984 0.475 Specific Ageing-Suppressor 1.615 1.769 0.550 Specific Ageing-Associated 4.074 3.155 0.114 Specific DR-Associated 0.868 1.182 0.013 Total Geronto 48.289 55.734 0.013 Total Ageing-Suppressor 55.000 53.734 0.930 Total Ageing-Associated 50.213 44.212 0.780 Total DR-Associated 17.632 52.174 0.013 Specificity Gerontogenes 6.853 5.354 0.108 Specificity Ageing-Suppressor 2.937 3.292 0.001 Specificity Ageing-Associated 8.112 7.136 0.003 Specificity DR-Associated 4.925 2.265 0.013

Table: Cluster regulating transcription - Genes and their connectivity features

Listed are genes, their association into a classification, specific number of interactions with ageing genes, total number of interaction and their specificity (specific number / total number) as well as its significance. Gene Symbol Association # Specific Interactions # Total Interactions Specificity p-value RPB2_CAEEL Gerontogene 21 218 10 0.11 O62185_CAEEL Gerontogene 11 101 11 0.11 P91277_CAEEL Gerontogene 14 154 9 0.22 PCF11_CAEEL Ageing-Suppressor Gene 12 104 12 0.07 RPAB3_CAEEL Gerontogene 17 198 9 0.26 cfim-1 Gerontogene 11 121 9 0.25 Q93338_CAEEL Gerontogene 19 250 8 0.44 T08A11.2 Ageing-Suppressor Gene 13 144 8 0.24 Q9U2H8_CAEEL Ageing-Suppressor Gene 11 104 11 0.13 gut-2 Gerontogene 17 164 10 0.08 snr-5 Gerontogene 13 122 11 0.1

Table: Cluster regulating transcription - Gene ontology enrichment

Functional enriched terms, their significance and description as well as the genes belonging to this group. corr p-value x n X N Description Genes in test set 4.84E-02 2 3 4 72 DNA-directed RNA polymerase activity C26E6.4|C36B1.3 4.84E-02 2 3 4 72 RNA polymerase activity C26E6.4|C36B1.3

Table: Cluster of ribosomal components - Genes and their connectivity features

Listed are genes, their association into a classification, specific number of interactions with ageing genes, total number of interaction and their specificity (specific number / total number) as well as its significance. Gene Symbol Association # Specific Interactions # Total Interactions Specificity p-value eif-3.E Gerontogene 7 119 5.882353 0.761108 rps-14 Gerontogene 10 175 5.714286 0.816172 EIF3H_CAEEL Gerontogene 6 105 5.714286 0.775373 rps-12 Gerontogene 8 130 6.153846 0.726164 rps-9 Gerontogene 7 159 4.402516 0.944618 eif-3.D Gerontogene 6 121 4.958678 0.875131

Table: Cluster of ribosomal components - Gene ontology enrichment

Functional enriched terms, their significance and description as well as the genes belonging to this group. corr p-value x n X N Description Genes in test set 1.15E-002 4 9 6 106 translation R08D7.3|F40F8.10|F37C12.9|F54E7.2 1.15E-002 3 4 6 106 ribosome F40F8.10|F37C12.9|F54E7.2 1.15E-002 3 4 6 106 structural constituent of ribosome F40F8.10|F37C12.9|F54E7.2 1.89E-002 4 11 6 106 cellular biosynthetic process R08D7.3|F40F8.10|F37C12.9|F54E7.2 3.30E-002 3 6 6 106 structural molecule activity F40F8.10|F37C12.9|F54E7.2

Table: Cluster participating in tRNA synthesis - Genes and their connectivity features

Listed are genes, their association into a classification, specific number of interactions with ageing genes, total number of interaction and their specificity (specific number / total number) as well as its significance. Gene Symbol Association # Specific Interactions # Total Interactions Specificity p-value kat-1 7 65 11 0.19 O62336_CAEEL 6 61 10 0.27 cth-2 5 51 10 0.30 Q93934_CAEEL 5 52 10 0.32 Q9NAI5_CAEEL 4 40 10 0.32 sod-1 8 99 8 0.42 SYK_CAEEL Gerontogene 6 73 8 0.43 bcat-1 5 62 8 0.46 ANM5_CAEEL 4 51 8 0.51 PUR4_CAEEL 4 54 7 0.55 nrs-1 Ageing-Associated Gene 8 111 7 0.55 ars-2 6 83 7 0.56 ZK632.4 4 55 7 0.57 irs-1 Gerontogene 7 99 7 0.58 C50F4.2 7 102 7 0.61 Q17832_CAEEL 7 105 7 0.64 Q7JNV5_CAEEL 4 69 6 0.74 Q21284_CAEEL 4 74 5 0.79 Q86DL2_CAEEL 7 153 5 0.93 T22F3.3 5 137 4 0.97

Table: Cluster participating in tRNA synthesis - Gene ontology enrichment

Functional enriched terms, their significance and description as well as the genes belonging to this group. corr p-value x n X N Description Genes in test set 2.38E-002 2 4 3 106 nitrogen compound metabolic process R11A8.6|T02G5.9 2.38E-002 2 4 3 106 tRNA aminoacylation for protein translation R11A8.6|T02G5.9 2.38E-002 2 4 3 106 tRNA metabolic process R11A8.6|T02G5.9 2.38E-002 2 4 3 106 tRNA aminoacylation R11A8.6|T02G5.9 2.38E-002 2 4 3 106 aminoacyl-tRNA ligase activity R11A8.6|T02G5.9 2.38E-002 2 4 3 106 amino acid activation R11A8.6|T02G5.9 2.38E-002 2 4 3 106 amine metabolic process R11A8.6|T02G5.9 2.38E-002 2 4 3 106 amino acid and derivative metabolic process R11A8.6|T02G5.9 2.38E-002 2 4 3 106 amino acid metabolic process R11A8.6|T02G5.9 2.38E-002 2 4 3 106 ligase activity, forming carbon-oxygen bonds R11A8.6|T02G5.9 2.38E-002 2 4 3 106 ligase activity, forming aminoacyl-tRNA and related compounds R11A8.6|T02G5.9 3.34E-002 2 5 3 106 organic acid metabolic process R11A8.6|T02G5.9 3.34E-002 2 5 3 106 carboxylic acid metabolic process R11A8.6|T02G5.9 4.61E-002 2 6 3 106 ligase activity R11A8.6|T02G5.9

Table: RNA-processing cluster - Genes and their connectivity features

Listed are genes, their association into a classificatoon, specific number of interactions with ageing genes, total number of interaction and their specificity (specific number / total number) as well as its significance. Gene Symbol Association # Specific Interactions # Total Interactions Specificity p-value aly-3 12 101 12 0.06 cey-2 12 101 12 0.06 eft-1 14 123 11 0.06 rsp-6 12 103 12 0.07 rnp-4 12 105 11 0.08 Q8T8N7_CAEEL 13 118 11 0.08 B3KYC2_CAEEL 12 109 11 0.09 Q867Z9_CAEEL 12 109 11 0.09 O02097_CAEEL 11 98 11 0.09 cey-3 11 98 11 0.09 Q95QR5_CAEEL 12 110 11 0.10 Q19335_CAEEL 14 133 11 0.10 Q20445_CAEEL 11 99 11 0.10 cey-4 11 99 11 0.10 Q18265_CAEEL 12 111 11 0.10 rnp-3 11 100 11 0.11 cey-1 11 100 11 0.11 rnp-2 11 100 11 0.11 A5A8P6_CAEEL 11 100 11 0.11 RPB2_CAEEL Gerontogene 21 218 10 0.11 Q19864_CAEEL 11 101 11 0.11 RSP1_CAEEL 11 101 11 0.11 RSP2_CAEEL 11 101 11 0.11 Q8MXR6_CAEEL 11 101 11 0.11 Q8I0R9_CAEEL 11 102 11 0.12 RSP4_CAEEL 11 102 11 0.12 O02092_CAEEL 16 161 10 0.12 MGN_CAEEL Ageing-Associated Gene 11 103 11 0.12 aly-2 11 103 11 0.12 uaf-2 11 103 11 0.12 Q9U304_CAEEL 11 103 11 0.12 Q9XVS2_CAEEL 12 115 10 0.13 hrp-1 Ageing-Associated Gene 11 104 11 0.13 dnj-30 11 104 11 0.13 snr-3 13 128 10 0.13 Q9NAH3_CAEEL 11 105 10 0.13 snr-6 12 117 10 0.14 him-1 11 106 10 0.14 Q09995_CAEEL 11 106 10 0.14 pabp-2 12 118 10 0.14 rha-1 12 118 10 0.14 PM14_CAEEL 11 107 10 0.15 Q20370_CAEEL 11 107 10 0.15 Q9N3C9_CAEEL 17 179 9 0.15 RPAB2_CAEEL 20 217 9 0.15 O45577_CAEEL 11 109 10 0.16 Q965S0_CAEEL 17 182 9 0.16 Q9GRZ2_CAEEL 16 170 9 0.17 SMD2_CAEEL 13 134 10 0.17 Q18999_CAEEL 11 110 10 0.17 Q93339_CAEEL 16 171 9 0.17 rpb-10 18 196 9 0.17 Q19211_CAEEL 11 111 10 0.18 RPB11_CAEEL 17 185 9 0.18 sap-1 12 124 10 0.18 Q8MXR2_CAEEL 11 112 10 0.18 U520_CAEEL 17 186 9 0.19 rpb-5 19 211 9 0.19 snr-7 12 126 10 0.20 snr-1 13 139 9 0.20 Q22469_CAEEL 13 140 9 0.21 ncbp-2 13 141 9 0.22 Q09584_CAEEL 14 154 9 0.22 rnp-5 12 130 9 0.23 Q10577_CAEEL 12 130 9 0.23 Q17558_CAEEL Ageing-Associated Gene 14 155 9 0.23 RSMB_CAEEL 11 118 9 0.23 CPSF2_CAEEL 11 118 9 0.23 O44985_CAEEL 14 156 9 0.23 O44729_CAEEL 11 119 9 0.24 Q95QN2_CAEEL 11 119 9 0.24 mog-1 11 119 9 0.24 Q8MYM8_CAEEL 14 157 9 0.24 NFX1_CAEEL 12 133 9 0.25 Q9U3I0_CAEEL 17 197 9 0.25 RPAB3_CAEEL Gerontogene 17 198 9 0.26 prp-8 13 147 9 0.26 O16997_CAEEL 12 136 9 0.27 NH2L1_CAEEL 15 175 9 0.28 CLP1_CAEEL 11 124 9 0.28 uaf-1 11 124 9 0.28 sap-49 13 151 9 0.29 Q95PY8_CAEEL 11 126 9 0.30 pap-1 12 139 9 0.30 aly-1 13 160 8 0.37 ama-1 18 227 8 0.37 CPSF1_CAEEL 11 134 8 0.37 ncbp-1 12 149 8 0.39 Q19866_CAEEL 11 136 8 0.39 Q93338_CAEEL Gerontogene 19 250 8 0.44

Table: RNA-processing cluster - Gene ontology enrichment

Functional enriched terms, their significance and description. corr p-value x n X N Description 3.30E-15 54 169 85 730 nucleic acid binding 1.29E-05 14 26 85 730 nucleotidyltransferase activity 1.86E-05 13 24 85 730 RNA processing 1.86E-05 14 28 85 730 mRNA metabolic process 1.86E-05 34 134 85 730 nucleobase, nucleoside, nucleotide and nucleic acid metabolic process 1.86E-05 11 18 85 730 RNA polymerase activity 1.86E-05 11 18 85 730 DNA-directed RNA polymerase activity 2.48E-05 24 77 85 730 RNA metabolic process 2.48E-05 16 38 85 730 transcription 3.84E-05 12 23 85 730 gastrulation with mouth forming first 3.95E-05 13 27 85 730 gastrulation 4.82E-04 7 10 85 730 mRNA processing 6.35E-04 64 400 85 730 binding 3.40E-03 36 184 85 730 nucleotide binding 7.51E-03 16 58 85 730 biopolymer biosynthetic process 1.33E-02 16 61 85 730 morphogenesis of an epithelium 2.14E-02 3 3 85 730 RNA 3'-end processing 2.14E-02 3 3 85 730 polynucleotide adenylyltransferase activity 2.14E-02 3 3 85 730 RNA splicing 2.14E-02 3 3 85 730 RNA polyadenylation 2.35E-02 31 167 85 730 reproductive developmental process 2.39E-02 11 37 85 730 RNA binding 3.19E-02 29 156 85 730 hermaphrodite genitalia development 3.41E-02 29 157 85 730 genitalia development 3.52E-02 30 165 85 730 sex differentiation

Table: Cluster involved in nucleotide biosyntheses and tRNA loading - Gene ontology enrichment

Functional enriched terms, their significance and description. corr p-value x n X N Description 6.90E-04 6 25 17 730 organic acid metabolic process 6.90E-04 6 25 17 730 carboxylic acid metabolic process 6.90E-04 6 26 17 730 ligase activity 1.44E-03 14 240 17 730 catalytic activity 1.44E-03 5 20 17 730 amino acid metabolic process 1.44E-03 5 21 17 730 amine metabolic process 1.44E-03 5 21 17 730 amino acid and derivative metabolic process 1.44E-03 5 21 17 730 nitrogen compound metabolic process 2.45E-03 4 14 17 730 tRNA aminoacylation for protein translation 2.45E-03 4 14 17 730 ligase activity, forming carbon-oxygen bonds 2.45E-03 4 14 17 730 ligase activity, forming aminoacyl-tRNA and related compounds 2.45E-03 4 14 17 730 tRNA aminoacylation 2.45E-03 4 14 17 730 aminoacyl-tRNA ligase activity 2.45E-03 4 14 17 730 amino acid activation 3.07E-03 4 15 17 730 tRNA metabolic process 4.33E-03 2 2 17 730 purine ribonucleoside monophosphate biosynthetic process 4.33E-03 2 2 17 730 ribonucleoside monophosphate metabolic process 4.33E-03 2 2 17 730 purine ribonucleoside monophosphate metabolic process 4.33E-03 2 2 17 730 ribonucleoside monophosphate biosynthetic process 4.33E-03 2 2 17 730 purine nucleoside monophosphate biosynthetic process 4.33E-03 2 2 17 730 purine nucleoside monophosphate metabolic process 4.33E-03 2 2 17 730 nucleoside monophosphate biosynthetic process 4.33E-03 2 2 17 730 nucleoside monophosphate metabolic process 1.18E-02 2 3 17 730 aspartyl-tRNA aminoacylation 1.18E-02 2 3 17 730 aspartate-tRNA ligase activity 1.95E-02 3 13 17 730 nucleobase, nucleoside and nucleotide metabolic process 3.54E-02 2 5 17 730 pyridoxal phosphate binding 4.72E-02 2 6 17 730 ribonucleotide biosynthetic process 4.72E-02 2 6 17 730 purine nucleotide biosynthetic process

Table: Cluster involved in proteasome - Genes and their connectivity features

Listed are genes, their association into a classification, specific number of interactions with ageing genes, total number of interaction and their specificity (specific number / total number) as well as its significance. Gene Symbol Association # Specific Interactions # Total Interactions Specificity p-value Q95XR3_CAEEL 4 14 29 0.01 pbs-1 6 53 11 0.18 C0Z1Y7_CAEEL 4 33 12 0.21 pas-5 6 57 11 0.23 Q8MXF1_CAEEL 4 36 11 0.26 Q95PZ7_CAEEL 5 52 10 0.32 PSMD9_CAEEL 4 40 10 0.32 pbs-7 5 54 9 0.35 pas-1 8 100 8 0.43 pas-3 7 88 8 0.45 pas-2 6 79 8 0.51 PSMD3_CAEEL 8 107 7 0.51 pbs-4 7 94 7 0.52 pas-6 6 80 8 0.52 Q9XUV0_CAEEL 5 70 7 0.57 rpn-12 7 101 7 0.60 drs-1 Gerontogene 5 72 7 0.60 YMJ5_CAEEL 7 102 7 0.61 pbs-6 5 75 7 0.64 pbs-3 5 86 6 0.75 pas-4 8 142 6 0.81 rpn-11 Ageing-Suppressor Gene 5 96 5 0.83 rpn-7 Ageing-Suppressor Gene 6 115 5 0.84 null 9 170 5 0.87

Table: Cluster involved in proteasome - Gene ontology enrichment

Functional enriched terms, their significance and description. corr p-value x n X N Description 3.09E-15 10 11 17 730 proteasome complex 6.07E-12 8 9 17 730 proteasome core complex 6.07E-12 8 9 17 730 threonine endopeptidase activity 2.42E-10 8 12 17 730 endopeptidase activity 4.82E-09 8 16 17 730 peptidase activity 3.48E-08 9 29 17 730 protein catabolic process 4.21E-08 9 30 17 730 proteolysis 6.52E-08 9 33 17 730 biopolymer catabolic process 6.52E-08 8 23 17 730 cellular protein catabolic process 6.52E-08 8 23 17 730 modification-dependent macromolecule catabolic process 6.52E-08 8 23 17 730 proteolysis involved in cellular protein catabolic process 6.52E-08 8 23 17 730 modification-dependent protein catabolic process 6.52E-08 8 23 17 730 ubiquitin-dependent protein catabolic process 2.21E-07 9 38 17 730 macromolecule catabolic process 4.30E-07 9 41 17 730 catabolic process 5.84E-07 8 30 17 730 cellular macromolecule catabolic process 2.09E-06 8 35 17 730 cellular catabolic process 6.26E-06 10 74 17 730 protein complex 7.56E-04 9 97 17 730 hydrolase activity 4.14E-03 2 2 17 730 proteasome accessory complex 1.90E-02 11 215 17 730 protein metabolic process 2.83E-02 10 190 17 730 macromolecular complex 4.26E-02 10 201 17 730 locomotion 4.77E-02 10 205 17 730 biopolymer metabolic process

Table: Cluster positively regulating development and growth - Genes and connectivity features

Listed are genes, their association into a classification, specific number of interactions with ageing genes, total number of interaction and their specificity (specific number / total number) as well as its significance. Gene Symbol Association # Specific Interactions # Total Interactions Specificity p-value hlh-1 Gerontogene 3 5 60 3*10^-3 let-756 23 209 11 0.03 let-60 Ageing-Associated Gene 17 167 10 0.09 mex-6 Gerontogene 3 17 18 0.12 cye-1 Gerontogene 4 28 14 0.14 par-6 Ageing-Suppressor Gene 3 23 13 0.23 sel-12 7 77 9 0.32 hmp-2 Gerontogene 5 58 9 0.41 pie-1 Ageing-Suppressor Gene 2 21 10 0.45 sem-5 Ageing-Associated Gene 16 259 6 0.77 lin-35 17 541 3 1.00

Table: Cluster positively regulating development and growth - Genes and connectivity features

Listed are genes, their association into a classification, specific number of interactions with ageing genes, total number of interaction and their specificity (specific number / total number) as well as its significance. Gene Symbol Association # Specific Interactions # Total Interactions Specificity p-value hlh-1 Gerontogene 3 5 60 3*10^-3 let-756 23 209 11 0.03 let-60 Ageing-Associated Gene 17 167 10 0.09 mex-6 Gerontogene 3 17 18 0.12 cye-1 Gerontogene 4 28 14 0.14 par-6 Ageing-Suppressor Gene 3 23 13 0.23 sel-12 7 77 9 0.32 hmp-2 Gerontogene 5 58 9 0.41 pie-1 Ageing-Suppressor Gene 2 21 10 0.45 sem-5 Ageing-Associated Gene 16 259 6 0.77 lin-35 17 541 3 1.00

Table: Cluster of phosphorylation mediated signal transduction - Genes and connectivity features

Listed are genes, their association into a classification, specific number of interactions with ageing genes, total number of interaction and their specificity (specific number / total number) as well as its significance. Gene Symbol Association # Specific Interactions # Total Interactions Specificity p-value egl-15 Gerontogene 30 157 19 8.49E-07 daf-2 Ageing-Associated Gene 30 174 17 7.53E-06 sos-1 Gerontogene 16 117 14 0.01 GSK3_CAEEL Ageing-Suppressor Gene 9 95 9 0.24 YQOE_CAEEL 6 82 7 0.54

Table: Cluster of phosphorylation mediated signal transduction - Gene ontology enrichment

Functional enriched terms, their significance and description. corr p-value x n X N Description 1.13E-02 3 32 4 730 protein tyrosine kinase activity 1.13E-02 3 33 4 730 protein serine/threonine kinase activity 1.13E-02 3 34 4 730 protein amino acid phosphorylation 1.13E-02 3 34 4 730 protein kinase activity 1.13E-02 3 35 4 730 phosphotransferase activity, alcohol group as acceptor 1.13E-02 3 39 4 730 phosphorylation 1.13E-02 3 40 4 730 kinase activity 1.13E-02 3 43 4 730 post-translational protein modification 1.13E-02 3 44 4 730 phosphate metabolic process 1.13E-02 3 44 4 730 phosphorus metabolic process 1.65E-02 3 55 4 730 protein modification process 1.65E-02 3 56 4 730 biopolymer modification 1.65E-02 2 13 4 730 cell motility 1.65E-02 2 13 4 730 localization of cell 1.65E-02 2 13 4 730 cell migration 2.49E-02 3 67 4 730 transferase activity, transferring phosphorus-containing groups 2.55E-02 3 79 4 730 transferase activity 2.55E-02 1 1 4 730 negative regulation of protein transport 2.55E-02 1 1 4 730 fibroblast growth factor receptor signaling pathway 2.55E-02 1 1 4 730 regulation of protein transport 2.55E-02 1 1 4 730 negative regulation of protein import into nucleus 2.55E-02 1 1 4 730 regulation of protein import into nucleus 2.55E-02 1 1 4 730 regulation of intracellular transport 2.55E-02 1 1 4 730 negative regulation of intracellular transport 2.55E-02 1 1 4 730 regulation of intracellular protein transport 2.55E-02 1 1 4 730 negative regulation of transport 2.55E-02 1 1 4 730 negative regulation of transcription factor import into nucleus 2.55E-02 1 1 4 730 regulation of transcription factor import into nucleus 2.55E-02 1 1 4 730 regulation of nucleocytoplasmic transport 2.55E-02 1 1 4 730 negative regulation of nucleocytoplasmic transport 2.55E-02 1 1 4 730 dauer exit 4.26E-02 1 2 4 730 regulation of Rho protein signal transduction 4.26E-02 1 2 4 730 regulation of localization 4.26E-02 1 2 4 730 regulation of transport 4.26E-02 1 2 4 730 guanyl-nucleotide exchange factor activity 4.26E-02 1 2 4 730 Ras guanyl-nucleotide exchange factor activity 4.26E-02 1 2 4 730 Rho guanyl-nucleotide exchange factor activity 4.39E-02 3 109 4 730 ATP binding 4.39E-02 3 110 4 730 adenyl ribonucleotide binding 4.87E-02 3 115 4 730 adenyl nucleotide binding

Table: Transmembrane transport and regulation of cell death cluster - Genes and their connectivity features

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Table: Transmembrane transport and regulation of cell death cluster - Genes and their connectivity features
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Listed are genes, their association into a classification, specific number of interactions with ageing genes, total number of interaction and their specificity (specific number / total number) as well as its significance. Gene Symbol Association # Specific Interactions # Total Interactions Specificity p-value SNA29_CAEEL Ageing-Suppressor Gene 3 16 18.75 0.10341 pat-3 Ageing-Suppressor Gene 5 47 10.6383 0.248478 cdk-1 Gerontogene 10 121 8.264463 0.373336 unc-64 Ageing-Associated Gene 3 31 9.677419 0.38817 vha-2 Ageing-Suppressor Gene 2 34 5.882353 0.713321 Q9TXZ9_CAEEL Gerontogene 1 18 5.555556 0.739507 O44616_CAEEL 16 298 5.369128 0.914033 Q18921_CAEEL Ageing-Suppressor Gene 1 37 2.702703 0.93703 vha-12 13 262 4.961832 0.942641 tba-2 4 132 3.030303 0.987611

Table: Transmembrane transport and regulation of cell death cluster - Gene ontology enrichment

Functional enriched terms, their significance and description. corr p-value x n X N Description 6.66E-03 2 2 7 730 positive regulation of non-apoptotic programmed cell death 6.66E-03 2 2 7 730 regulation of non-apoptotic programmed cell death 6.66E-03 5 69 7 730 localization 6.66E-03 3 13 7 730 substrate-specific transmembrane transporter activity 6.66E-03 3 13 7 730 transmembrane transporter activity 8.80E-03 2 3 7 730 positive regulation of programmed cell death 9.74E-03 3 17 7 730 substrate-specific transporter activity 9.74E-03 3 17 7 730 positive regulation of cellular process 1.00E-02 3 19 7 730 transporter activity 1.00E-02 4 49 7 730 transport 1.00E-02 2 5 7 730 monovalent inorganic cation transport 1.00E-02 2 5 7 730 cation transport 1.00E-02 2 5 7 730 hydrogen transport 1.00E-02 2 5 7 730 hydrogen ion transporting ATP synthase activity, rotational mechanism 1.00E-02 2 5 7 730 ATP metabolic process 1.00E-02 2 5 7 730 proton transport 1.00E-02 4 57 7 730 establishment of localization 1.00E-02 2 6 7 730 ATPase activity, coupled to movement of substances 1.00E-02 2 6 7 730 cation-transporting ATPase activity 1.00E-02 2 6 7 730 hydrogen ion transporting ATPase activity, rotational mechanism 1.00E-02 2 6 7 730 purine ribonucleoside triphosphate metabolic process 1.00E-02 2 6 7 730 ribonucleoside triphosphate metabolic process 1.00E-02 2 6 7 730 ATPase activity, coupled to transmembrane movement of substances 1.00E-02 2 6 7 730 ATPase activity, coupled to transmembrane movement of ions 1.00E-02 2 6 7 730 purine nucleoside triphosphate metabolic process 1.00E-02 2 6 7 730 nucleoside triphosphate metabolic process 1.10E-02 2 7 7 730 inorganic cation transmembrane transporter activity 1.10E-02 2 7 7 730 proton-transporting two-sector ATPase complex 1.10E-02 2 7 7 730 ion transport 1.10E-02 2 7 7 730 hydrolase activity, acting on acid anhydrides, catalyzing transmembrane movement of substances 1.10E-02 2 7 7 730 monovalent inorganic cation transmembrane transporter activity 1.10E-02 2 7 7 730 hydrogen ion transmembrane transporter activity 1.10E-02 2 7 7 730 regulation of programmed cell death 1.23E-02 2 8 7 730 ribonucleotide metabolic process 1.23E-02 2 8 7 730 cation transmembrane transporter activity 1.23E-02 2 8 7 730 P-P-bond-hydrolysis-driven transmembrane transporter activity 1.23E-02 2 8 7 730 primary active transmembrane transporter activity 1.23E-02 2 8 7 730 purine nucleotide metabolic process 1.23E-02 2 8 7 730 purine ribonucleotide metabolic process 1.54E-02 2 9 7 730 active transmembrane transporter activity 1.72E-02 4 77 7 730 membrane part 1.83E-02 2 10 7 730 ion transmembrane transporter activity 2.08E-02 2 11 7 730 nucleotide metabolic process 2.08E-02 2 11 7 730 nucleoside phosphate metabolic process 2.08E-02 4 83 7 730 membrane 2.85E-02 2 13 7 730 nucleobase, nucleoside and nucleotide metabolic process 3.30E-02 1 1 7 730 cell-substrate adhesion 3.30E-02 1 1 7 730 regulation of cellular pH 3.30E-02 1 1 7 730 cell-matrix adhesion 3.30E-02 1 1 7 730 cellular monovalent inorganic cation homeostasis 3.30E-02 1 1 7 730 cellular cation homeostasis 3.30E-02 1 1 7 730 regulation of meiosis 3.30E-02 1 1 7 730 response to hypoxia 3.30E-02 1 1 7 730 cellular ion homeostasis 3.30E-02 1 1 7 730 positive regulation of meiosis 3.30E-02 1 1 7 730 regulation of pH 3.30E-02 1 1 7 730 regulation of cell cycle process 3.30E-02 1 1 7 730 ion homeostasis 3.30E-02 1 1 7 730 regulation of syncytium formation by plasma membrane fusion 3.30E-02 1 1 7 730 monovalent inorganic cation homeostasis 3.30E-02 1 1 7 730 regulation of meiotic cell cycle 3.30E-02 1 1 7 730 energy coupled proton transport, against electrochemical gradient 3.30E-02 1 1 7 730 regulation of intracellular pH 3.30E-02 1 1 7 730 cation homeostasis 3.30E-02 1 1 7 730 cellular chemical homeostasis 3.81E-02 2 18 7 730 positive regulation of developmental process 4.17E-02 2 19 7 730 cell development

Table: Cluster involved in genomic guardian and repair - Genes and connectivity features

Listed are genes, their association into a classification, specific number of interactions with ageing genes, total number of interaction and their specificity (specific number / total number) as well as its significance. Gene Symbol Association # Specific Interactions # Total Interactions Specifity p-value Q93456_CAEEL 7 34 21 0.01 C47D12.8 Gerontogene 9 66 14 0.05 csb-1 6 37 16 0.05 P91175_CAEEL 8 60 13 0.07 Q7YZG6_CAEEL 9 74 12 0.08 O44499_CAEEL Gerontogene 10 85 12 0.08 O17245_CAEEL 10 89 11 0.11 Q09645_CAEEL 10 91 11 0.12 Q9NA35_CAEEL 9 82 11 0.14 TF2H2_CAEEL 9 86 10 0.17

Table: Cluster involved in genomic guardian and repair - Gene ontology enrichment

Functional enriched terms, their significance and description as well as the genes belonging to this group. corr p-value x n X N Description Genes in test set 1.99E-04 5 14 10 515 response to DNA damage stimulus Y73F8A.24|ZK1128.4|C47D12.8|T16H12.4 F10G8.7 4.13E-04 5 18 10 515 response to stress Y73F8A.24|ZK1128.4|C47D12.8|T16H12.4 F10G8.7 8.18E-04 5 22 10 515 DNA metabolic process Y73F8A.24|ZK1128.4|C47D12.8|T16H12.4 F10G8.7 1.05E-03 4 12 10 515 DNA repair Y73F8A.24|ZK1128.4|T16H12.4|F10G8.7 1.92E-03 6 48 10 515 response to stimulus Y73F8A.24|ZK1128.4|C47D12.8|T16H12.4 F10G8.7|F53H4.1 4.20E-02 2 4 10 515 nuclease activity C47D12.8|F10G8.7

Supplemental Data

Table: Comparing the network sizes generated from different seed lists for species Caenorhabditis elegans out of 76647 interactions in total

A site by site comparison of the network size created from a defined seed list of classified ageing genes. Genes Geronto Ageing-Suppressor Ageing-Associated DR-Associated

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# Genes in Seeds 97 39 136 38 # Interactors 1462 1177 1989 539 # Sig. Interactors 24 88 40 61 # Interactions Level1 189 43 317 31 # Interactions Level2 3359 1057 4992 114 # Interactions Level3 4552 2125 6592 984 # Interactions Level4 21806 8627 27065 168 # Interactions Level5 36507 24232 41626 6301

Table: Properties of the network generated by different classifications of ageing genes

The basic connectivity properties of different ageing gene classifications are compared with each other. Genes List Average # Specfic Interactions Average # Total Interactions Average Specificity (%) # Genes # Sig. Genes Gerontogenes Seeds 3.3 48.3 6.9 97 8 Gerontogenes Others 3.0 55.7 5.4 1462 24 Gerontogenes All 3.0 55.3 5.4 1559 32 Ageing-Suppressor Genes Seeds 1.6 55.0 2.9 39 1 Ageing-Suppressor Genes Others 1.8 53.7 3.3 1177 88 Ageing-Suppressor Genes All 1.8 53.8 3.3 1216 89 Ageing-Associated Genes Seeds 4.1 50.2 8.1 136 7 Ageing-Associated Genes Others 3.2 44.2 7.1 1989 29 Ageing-Associated Genes All 3.2 44.6 7.2 2125 40 DR-Associated Genes Seeds 0.9 17.6 4.9 38 1 DR-Associated Genes Others 1.2 52.2 2.3 539 61 DR-Associated Genes All 1.2 49.9 2.3 577 66

Table: Properties of the network generated by different classification of ageing genes with average of averages

The basic connectivity properties of different ageing gene classifications are compared with each other, including the average of averages. Classification List Average # Specific Interactions Average # Total Interactions Average of Averages Average Specificity (%) Average p-value # Genes # sig. Genes Gerontogenes Seeds 3.3 48.3 10.1 6.9 0.4 97 8 Gerontogenes Candidates 3.0 55.7 11.9 5.4 0.6 1462 24 Gerontogenes All 3.0 55.3 11.8 5.4 0.6 1559 32 Ageing-Suppressor Genes Seeds 1.6 55.0 5.0 2.9 0.5 39 1 Ageing-Suppressor Genes Candidates 1.8 53.7 13.2 3.3 0.5 1177 88 Ageing-Suppressor Genes All 1.8 53.8 13.0 3.3 0.8 1216 89 Ageing-Associated Genes Ex. GenAge Seeds 4.1 50.2 11.4 8.1 0.6 136 7 Ageing-Associated Genes Ex. GenAge Candidates 3.2 44.2 16.4 7.1 0.6 1989 29 Ageing-Associated Genes Ex. GenAge All 3.2 44.6 16.0 7.2 0.6 2125 40 Ageing-Associated Genes In. GenAge Seeds 4.1 50.2 11.4 8.1 0.6 136 7 Ageing-Associated Genes In. GenAge Candidates 3.2 44.2 16.4 7.1 0.6 1989 29 Ageing-Associated Genes In. GenAge All 3.2 44.6 16.0 7.2 0.6 2125 40 DR-Associated Genes Seeds 0.9 17.6 8.1 4.9 0.6 38 1 DR-Associated Genes Candidates 1.2 52.2 13.3 2.3 0.3 539 61 DR-Associated Genes All 1.2 49.9 12.9 2.3 0.7 577 66

Table: Significance of the differences in average number of specific interactions, average number of total interactions, and average specificity

Listed are the specific number and total number of interactions as well as the specificity (specific/total number of interaction) on average. Genes # Specific Interactions # Total Interactions Specificity Gerontogenes 0.475 < 0.05 0.108 Ageing-Suppressor 0.55 0.93 < 10-3 Ageing-Associated Genes Excluding GenAge 0.114 0.78 < 0.005 Ageing-Associated Genes Including GenAge < 10-4 < 10-4 < 10-5

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