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• Research Paper Volume 12, Issue 13 pp 12534-12581

  Healthspan pathway maps in C. elegans and humans highlight transcription, proliferation/biosynthesis and lipids

  Relevance score: 15.4251375

  Steffen Möller, Nadine Saul, Alan A. Cohen, Rüdiger Köhling, Sina Sender, Hugo Murua Escobar, Christian Junghanss, Francesca Cirulli, Alessandra Berry, Peter Antal, Priit Adler, Jaak Vilo, Michele Boiani, Ludger Jansen, Dirk Repsilber, Hans Jörgen Grabe, Stephan Struckmann, Israel Barrantes, Mohamed Hamed, Brecht Wouters, Liliane Schoofs, Walter Luyten, Georg Fuellen

  Keywords: gene expression analysis, network biology analysis

  Published in Aging on July 7, 2020

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  The molecular basis of aging and of aging-associated diseases is being unraveled at an increasing pace. An extended healthspan, and not merely an extension of lifespan, has become the aim of medical practice. Here, we define health based on the absence of diseases and dysfunctions. Based on an extensive review of the literature, in particular for humans and C. elegans, we compile a list of features of health and of the genes associated with them. These genes may or may not be associated with survival/lifespan. In turn, survival/lifespan genes that are not known to be directly associated with health are not considered. Clusters of these genes based on molecular interaction data give rise to maps of healthspan pathways for humans and for C. elegans. Overlaying healthspan-related gene expression data onto the healthspan pathway maps, we observe the downregulation of (pro-inflammatory) Notch signaling in humans and of proliferation in C. elegans. We identify transcription, proliferation/biosynthesis and lipids as a common theme on the annotation level, and proliferation-related kinases on the gene/protein level. Our literature-based data corpus, including visualization, should be seen as a pilot investigation of the molecular underpinnings of health in two different species. Web address: http://pathways.h2020awe.eu.

  

  A healthspan pathway map for humans, based on Supplementary Tables 1–3, including the list of pathways/clusters with their labels as assigned by AutoAnnotate and their size (number of genes). The largest pathway is zoomed in to reveal details. The size of a gene node is proportional to its GeneMANIA score, which indicates the relevance of the gene with respect to the original list of genes to which another 20 genes are added by GeneMANIA, based on the network data. Genes upregulated by CR are shown in yellow, downregulated genes are shown in blue, and grey denotes genes for which no expression values are available in the caloric restriction dataset [37]. The color of an edge refers to the source of the edge in the underlying network, that is co-expression (pink), common pathway (green), physical interactions (red), shared protein domains (brown), co-localization (blue), predicted (orange), and genetic interaction (green). The thickness of an edge is proportional to its GeneMANIA “normalized max weight”, based on the network data. Genes from the GeneMANIA input list feature a thick circle, while genes added by GeneMANIA do not.

  
  
  

  

  A healthspan pathway map for C. elegans, based on Supplementary Tables 4, 5. See also Figure 1. Gene expression data reflect the effect of rapamycin [38].

  
  
  

  

  A healthspan pathway map for C. elegans, based on genes affected the most by healthspan-extending interventions, using WormBase gene expression data. See also Figures 1, 2.

  
  
  

  

  Workflow of the main analysis steps. First, 52 human health genes (Supplementary Tables 1–3) were processed with GeneMANIA and AutoAnnotate to determine the human healthspan pathway map (left, see also Figure 1). Analogously, 58 worm health genes (based on gene expression analysis using WormBase) were studied, yielding the C. elegans healthspan pathway map (right, see also Figure 3). Then, to determine overlap across species, the gene lists were extended by the orthologs (calculated by WORMHOLE, see Supplemental Methods) from the respective other species. We then employed GeneMANIA as before, to generate two interaction networks (one per list). and overlaps between these two networks of health genes were determined by GASOLINE (middle, see also Figure 5).

  
  
  

  

  The two alignments demonstrating overlap of (putative) healthspan pathways in human and C. elegans, based on a GASOLINE alignment of the network of genes implicated in health-related gene expression changes in WormBase (top), and in human health based on genetic studies (bottom), and of corresponding orthologs. Dashed edges indicate orthologs, green edges indicate interactions based on GeneMANIA known for the respective species; the node shape is square if the gene originates from the original lists of health genes and it is circular if the gene is an ortholog, and node colors are based on gene expression changes triggered by rapamycin (in case of C. elegans) or by caloric restriction (in case of human), as in Figures 1–3.