Image_5_Cross-Species and Human Inter-Tissue Network Analysis of Genes Implicated in Longevity and Aging Reveal Strong Support for Nutrient Sensing.TIF

Intensive research efforts have been undertaken to slow human aging and therefore potentially delay the onset of age-related diseases. These efforts have generated an enormous amount of high-throughput data covering different levels in the physiologic hierarchy, e.g., genetic, epigenetic, transcriptomic, proteomic, and metabolomic, etc. We gathered 15 independent sources of information about genes potentially involved in human longevity and lifespan (N = 5836) and subjected them to various integrated analyses. Many of these genes were initially identified in non-human species, and we investigated their orthologs in three non-human species [i.e., mice (N = 967), fruit fly (N = 449), and worm (N = 411)] for further analysis. We characterized experimentally determined protein-protein interaction networks (PPIN) involving each species’ genes from 9 known protein databases and studied the enriched biological pathways among the individually constructed PPINs. We observed three important signaling pathways: FoxO signaling, mTOR signaling, and autophagy to be common and highly enriched in all four species (p-value ≤ 0.001). Our study implies that the interaction of proteins involved in the mechanistic target of rapamycin (mTOR) signaling pathway is somewhat limited to each species or that a “rewiring” of specific networks has taken place over time. To corroborate our findings, we repeated our analysis in 43 different human tissues. We investigated conserved modules in various tissue-specific PPINs of the longevity-associated genes based upon their protein expression. This analysis also revealed mTOR signaling as shared biological processes across four different human tissue-specific PPINs for liver, heart, skeletal muscle, and adipose tissue. Further, we explored our results’ translational potential by assessing the protein interactions with all the reported drugs and compounds that have been experimentally verified to promote longevity in the three-comparator species. We observed that the target proteins of the FDA-approved drug rapamycin (a known inhibitor of mTOR) were conserved across all four species. Drugs like melatonin and metformin exhibited shared targets with rapamycin in the human PPIN. The detailed information about the curated gene list, cross-species orthologs, PPIN, and pathways was assembled in an interactive data visualization portal using RStudio’s Shiny framework (https://agingnetwork.shinyapps.io/frontiers/).</p

Image_6_Cross-Species and Human Inter-Tissue Network Analysis of Genes Implicated in Longevity and Aging Reveal Strong Support for Nutrient Sensing.TIF

Intensive research efforts have been undertaken to slow human aging and therefore potentially delay the onset of age-related diseases. These efforts have generated an enormous amount of high-throughput data covering different levels in the physiologic hierarchy, e.g., genetic, epigenetic, transcriptomic, proteomic, and metabolomic, etc. We gathered 15 independent sources of information about genes potentially involved in human longevity and lifespan (N = 5836) and subjected them to various integrated analyses. Many of these genes were initially identified in non-human species, and we investigated their orthologs in three non-human species [i.e., mice (N = 967), fruit fly (N = 449), and worm (N = 411)] for further analysis. We characterized experimentally determined protein-protein interaction networks (PPIN) involving each species’ genes from 9 known protein databases and studied the enriched biological pathways among the individually constructed PPINs. We observed three important signaling pathways: FoxO signaling, mTOR signaling, and autophagy to be common and highly enriched in all four species (p-value ≤ 0.001). Our study implies that the interaction of proteins involved in the mechanistic target of rapamycin (mTOR) signaling pathway is somewhat limited to each species or that a “rewiring” of specific networks has taken place over time. To corroborate our findings, we repeated our analysis in 43 different human tissues. We investigated conserved modules in various tissue-specific PPINs of the longevity-associated genes based upon their protein expression. This analysis also revealed mTOR signaling as shared biological processes across four different human tissue-specific PPINs for liver, heart, skeletal muscle, and adipose tissue. Further, we explored our results’ translational potential by assessing the protein interactions with all the reported drugs and compounds that have been experimentally verified to promote longevity in the three-comparator species. We observed that the target proteins of the FDA-approved drug rapamycin (a known inhibitor of mTOR) were conserved across all four species. Drugs like melatonin and metformin exhibited shared targets with rapamycin in the human PPIN. The detailed information about the curated gene list, cross-species orthologs, PPIN, and pathways was assembled in an interactive data visualization portal using RStudio’s Shiny framework (https://agingnetwork.shinyapps.io/frontiers/).</p

Image_7_Cross-Species and Human Inter-Tissue Network Analysis of Genes Implicated in Longevity and Aging Reveal Strong Support for Nutrient Sensing.TIF

Intensive research efforts have been undertaken to slow human aging and therefore potentially delay the onset of age-related diseases. These efforts have generated an enormous amount of high-throughput data covering different levels in the physiologic hierarchy, e.g., genetic, epigenetic, transcriptomic, proteomic, and metabolomic, etc. We gathered 15 independent sources of information about genes potentially involved in human longevity and lifespan (N = 5836) and subjected them to various integrated analyses. Many of these genes were initially identified in non-human species, and we investigated their orthologs in three non-human species [i.e., mice (N = 967), fruit fly (N = 449), and worm (N = 411)] for further analysis. We characterized experimentally determined protein-protein interaction networks (PPIN) involving each species’ genes from 9 known protein databases and studied the enriched biological pathways among the individually constructed PPINs. We observed three important signaling pathways: FoxO signaling, mTOR signaling, and autophagy to be common and highly enriched in all four species (p-value ≤ 0.001). Our study implies that the interaction of proteins involved in the mechanistic target of rapamycin (mTOR) signaling pathway is somewhat limited to each species or that a “rewiring” of specific networks has taken place over time. To corroborate our findings, we repeated our analysis in 43 different human tissues. We investigated conserved modules in various tissue-specific PPINs of the longevity-associated genes based upon their protein expression. This analysis also revealed mTOR signaling as shared biological processes across four different human tissue-specific PPINs for liver, heart, skeletal muscle, and adipose tissue. Further, we explored our results’ translational potential by assessing the protein interactions with all the reported drugs and compounds that have been experimentally verified to promote longevity in the three-comparator species. We observed that the target proteins of the FDA-approved drug rapamycin (a known inhibitor of mTOR) were conserved across all four species. Drugs like melatonin and metformin exhibited shared targets with rapamycin in the human PPIN. The detailed information about the curated gene list, cross-species orthologs, PPIN, and pathways was assembled in an interactive data visualization portal using RStudio’s Shiny framework (https://agingnetwork.shinyapps.io/frontiers/).</p

Image_3_Cross-Species and Human Inter-Tissue Network Analysis of Genes Implicated in Longevity and Aging Reveal Strong Support for Nutrient Sensing.TIFF

Intensive research efforts have been undertaken to slow human aging and therefore potentially delay the onset of age-related diseases. These efforts have generated an enormous amount of high-throughput data covering different levels in the physiologic hierarchy, e.g., genetic, epigenetic, transcriptomic, proteomic, and metabolomic, etc. We gathered 15 independent sources of information about genes potentially involved in human longevity and lifespan (N = 5836) and subjected them to various integrated analyses. Many of these genes were initially identified in non-human species, and we investigated their orthologs in three non-human species [i.e., mice (N = 967), fruit fly (N = 449), and worm (N = 411)] for further analysis. We characterized experimentally determined protein-protein interaction networks (PPIN) involving each species’ genes from 9 known protein databases and studied the enriched biological pathways among the individually constructed PPINs. We observed three important signaling pathways: FoxO signaling, mTOR signaling, and autophagy to be common and highly enriched in all four species (p-value ≤ 0.001). Our study implies that the interaction of proteins involved in the mechanistic target of rapamycin (mTOR) signaling pathway is somewhat limited to each species or that a “rewiring” of specific networks has taken place over time. To corroborate our findings, we repeated our analysis in 43 different human tissues. We investigated conserved modules in various tissue-specific PPINs of the longevity-associated genes based upon their protein expression. This analysis also revealed mTOR signaling as shared biological processes across four different human tissue-specific PPINs for liver, heart, skeletal muscle, and adipose tissue. Further, we explored our results’ translational potential by assessing the protein interactions with all the reported drugs and compounds that have been experimentally verified to promote longevity in the three-comparator species. We observed that the target proteins of the FDA-approved drug rapamycin (a known inhibitor of mTOR) were conserved across all four species. Drugs like melatonin and metformin exhibited shared targets with rapamycin in the human PPIN. The detailed information about the curated gene list, cross-species orthologs, PPIN, and pathways was assembled in an interactive data visualization portal using RStudio’s Shiny framework (https://agingnetwork.shinyapps.io/frontiers/).</p

Image_2_Cross-Species and Human Inter-Tissue Network Analysis of Genes Implicated in Longevity and Aging Reveal Strong Support for Nutrient Sensing.TIF

Intensive research efforts have been undertaken to slow human aging and therefore potentially delay the onset of age-related diseases. These efforts have generated an enormous amount of high-throughput data covering different levels in the physiologic hierarchy, e.g., genetic, epigenetic, transcriptomic, proteomic, and metabolomic, etc. We gathered 15 independent sources of information about genes potentially involved in human longevity and lifespan (N = 5836) and subjected them to various integrated analyses. Many of these genes were initially identified in non-human species, and we investigated their orthologs in three non-human species [i.e., mice (N = 967), fruit fly (N = 449), and worm (N = 411)] for further analysis. We characterized experimentally determined protein-protein interaction networks (PPIN) involving each species’ genes from 9 known protein databases and studied the enriched biological pathways among the individually constructed PPINs. We observed three important signaling pathways: FoxO signaling, mTOR signaling, and autophagy to be common and highly enriched in all four species (p-value ≤ 0.001). Our study implies that the interaction of proteins involved in the mechanistic target of rapamycin (mTOR) signaling pathway is somewhat limited to each species or that a “rewiring” of specific networks has taken place over time. To corroborate our findings, we repeated our analysis in 43 different human tissues. We investigated conserved modules in various tissue-specific PPINs of the longevity-associated genes based upon their protein expression. This analysis also revealed mTOR signaling as shared biological processes across four different human tissue-specific PPINs for liver, heart, skeletal muscle, and adipose tissue. Further, we explored our results’ translational potential by assessing the protein interactions with all the reported drugs and compounds that have been experimentally verified to promote longevity in the three-comparator species. We observed that the target proteins of the FDA-approved drug rapamycin (a known inhibitor of mTOR) were conserved across all four species. Drugs like melatonin and metformin exhibited shared targets with rapamycin in the human PPIN. The detailed information about the curated gene list, cross-species orthologs, PPIN, and pathways was assembled in an interactive data visualization portal using RStudio’s Shiny framework (https://agingnetwork.shinyapps.io/frontiers/).</p

Image_8_Cross-Species and Human Inter-Tissue Network Analysis of Genes Implicated in Longevity and Aging Reveal Strong Support for Nutrient Sensing.TIFF

Intensive research efforts have been undertaken to slow human aging and therefore potentially delay the onset of age-related diseases. These efforts have generated an enormous amount of high-throughput data covering different levels in the physiologic hierarchy, e.g., genetic, epigenetic, transcriptomic, proteomic, and metabolomic, etc. We gathered 15 independent sources of information about genes potentially involved in human longevity and lifespan (N = 5836) and subjected them to various integrated analyses. Many of these genes were initially identified in non-human species, and we investigated their orthologs in three non-human species [i.e., mice (N = 967), fruit fly (N = 449), and worm (N = 411)] for further analysis. We characterized experimentally determined protein-protein interaction networks (PPIN) involving each species’ genes from 9 known protein databases and studied the enriched biological pathways among the individually constructed PPINs. We observed three important signaling pathways: FoxO signaling, mTOR signaling, and autophagy to be common and highly enriched in all four species (p-value ≤ 0.001). Our study implies that the interaction of proteins involved in the mechanistic target of rapamycin (mTOR) signaling pathway is somewhat limited to each species or that a “rewiring” of specific networks has taken place over time. To corroborate our findings, we repeated our analysis in 43 different human tissues. We investigated conserved modules in various tissue-specific PPINs of the longevity-associated genes based upon their protein expression. This analysis also revealed mTOR signaling as shared biological processes across four different human tissue-specific PPINs for liver, heart, skeletal muscle, and adipose tissue. Further, we explored our results’ translational potential by assessing the protein interactions with all the reported drugs and compounds that have been experimentally verified to promote longevity in the three-comparator species. We observed that the target proteins of the FDA-approved drug rapamycin (a known inhibitor of mTOR) were conserved across all four species. Drugs like melatonin and metformin exhibited shared targets with rapamycin in the human PPIN. The detailed information about the curated gene list, cross-species orthologs, PPIN, and pathways was assembled in an interactive data visualization portal using RStudio’s Shiny framework (https://agingnetwork.shinyapps.io/frontiers/).</p

Image_1_Cross-Species and Human Inter-Tissue Network Analysis of Genes Implicated in Longevity and Aging Reveal Strong Support for Nutrient Sensing.TIF

Intensive research efforts have been undertaken to slow human aging and therefore potentially delay the onset of age-related diseases. These efforts have generated an enormous amount of high-throughput data covering different levels in the physiologic hierarchy, e.g., genetic, epigenetic, transcriptomic, proteomic, and metabolomic, etc. We gathered 15 independent sources of information about genes potentially involved in human longevity and lifespan (N = 5836) and subjected them to various integrated analyses. Many of these genes were initially identified in non-human species, and we investigated their orthologs in three non-human species [i.e., mice (N = 967), fruit fly (N = 449), and worm (N = 411)] for further analysis. We characterized experimentally determined protein-protein interaction networks (PPIN) involving each species’ genes from 9 known protein databases and studied the enriched biological pathways among the individually constructed PPINs. We observed three important signaling pathways: FoxO signaling, mTOR signaling, and autophagy to be common and highly enriched in all four species (p-value ≤ 0.001). Our study implies that the interaction of proteins involved in the mechanistic target of rapamycin (mTOR) signaling pathway is somewhat limited to each species or that a “rewiring” of specific networks has taken place over time. To corroborate our findings, we repeated our analysis in 43 different human tissues. We investigated conserved modules in various tissue-specific PPINs of the longevity-associated genes based upon their protein expression. This analysis also revealed mTOR signaling as shared biological processes across four different human tissue-specific PPINs for liver, heart, skeletal muscle, and adipose tissue. Further, we explored our results’ translational potential by assessing the protein interactions with all the reported drugs and compounds that have been experimentally verified to promote longevity in the three-comparator species. We observed that the target proteins of the FDA-approved drug rapamycin (a known inhibitor of mTOR) were conserved across all four species. Drugs like melatonin and metformin exhibited shared targets with rapamycin in the human PPIN. The detailed information about the curated gene list, cross-species orthologs, PPIN, and pathways was assembled in an interactive data visualization portal using RStudio’s Shiny framework (https://agingnetwork.shinyapps.io/frontiers/).</p

Data_Sheet_1_Cross-Species and Human Inter-Tissue Network Analysis of Genes Implicated in Longevity and Aging Reveal Strong Support for Nutrient Sensing.xlsx

Intensive research efforts have been undertaken to slow human aging and therefore potentially delay the onset of age-related diseases. These efforts have generated an enormous amount of high-throughput data covering different levels in the physiologic hierarchy, e.g., genetic, epigenetic, transcriptomic, proteomic, and metabolomic, etc. We gathered 15 independent sources of information about genes potentially involved in human longevity and lifespan (N = 5836) and subjected them to various integrated analyses. Many of these genes were initially identified in non-human species, and we investigated their orthologs in three non-human species [i.e., mice (N = 967), fruit fly (N = 449), and worm (N = 411)] for further analysis. We characterized experimentally determined protein-protein interaction networks (PPIN) involving each species’ genes from 9 known protein databases and studied the enriched biological pathways among the individually constructed PPINs. We observed three important signaling pathways: FoxO signaling, mTOR signaling, and autophagy to be common and highly enriched in all four species (p-value ≤ 0.001). Our study implies that the interaction of proteins involved in the mechanistic target of rapamycin (mTOR) signaling pathway is somewhat limited to each species or that a “rewiring” of specific networks has taken place over time. To corroborate our findings, we repeated our analysis in 43 different human tissues. We investigated conserved modules in various tissue-specific PPINs of the longevity-associated genes based upon their protein expression. This analysis also revealed mTOR signaling as shared biological processes across four different human tissue-specific PPINs for liver, heart, skeletal muscle, and adipose tissue. Further, we explored our results’ translational potential by assessing the protein interactions with all the reported drugs and compounds that have been experimentally verified to promote longevity in the three-comparator species. We observed that the target proteins of the FDA-approved drug rapamycin (a known inhibitor of mTOR) were conserved across all four species. Drugs like melatonin and metformin exhibited shared targets with rapamycin in the human PPIN. The detailed information about the curated gene list, cross-species orthologs, PPIN, and pathways was assembled in an interactive data visualization portal using RStudio’s Shiny framework (https://agingnetwork.shinyapps.io/frontiers/).</p

Image_4_Cross-Species and Human Inter-Tissue Network Analysis of Genes Implicated in Longevity and Aging Reveal Strong Support for Nutrient Sensing.TIFF

Intensive research efforts have been undertaken to slow human aging and therefore potentially delay the onset of age-related diseases. These efforts have generated an enormous amount of high-throughput data covering different levels in the physiologic hierarchy, e.g., genetic, epigenetic, transcriptomic, proteomic, and metabolomic, etc. We gathered 15 independent sources of information about genes potentially involved in human longevity and lifespan (N = 5836) and subjected them to various integrated analyses. Many of these genes were initially identified in non-human species, and we investigated their orthologs in three non-human species [i.e., mice (N = 967), fruit fly (N = 449), and worm (N = 411)] for further analysis. We characterized experimentally determined protein-protein interaction networks (PPIN) involving each species’ genes from 9 known protein databases and studied the enriched biological pathways among the individually constructed PPINs. We observed three important signaling pathways: FoxO signaling, mTOR signaling, and autophagy to be common and highly enriched in all four species (p-value ≤ 0.001). Our study implies that the interaction of proteins involved in the mechanistic target of rapamycin (mTOR) signaling pathway is somewhat limited to each species or that a “rewiring” of specific networks has taken place over time. To corroborate our findings, we repeated our analysis in 43 different human tissues. We investigated conserved modules in various tissue-specific PPINs of the longevity-associated genes based upon their protein expression. This analysis also revealed mTOR signaling as shared biological processes across four different human tissue-specific PPINs for liver, heart, skeletal muscle, and adipose tissue. Further, we explored our results’ translational potential by assessing the protein interactions with all the reported drugs and compounds that have been experimentally verified to promote longevity in the three-comparator species. We observed that the target proteins of the FDA-approved drug rapamycin (a known inhibitor of mTOR) were conserved across all four species. Drugs like melatonin and metformin exhibited shared targets with rapamycin in the human PPIN. The detailed information about the curated gene list, cross-species orthologs, PPIN, and pathways was assembled in an interactive data visualization portal using RStudio’s Shiny framework (https://agingnetwork.shinyapps.io/frontiers/).</p

Comparison of phasing strategies for whole human genomes

<div><p>Humans are a diploid species that inherit one set of chromosomes paternally and one homologous set of chromosomes maternally. Unfortunately, most human sequencing initiatives ignore this fact in that they do not directly delineate the nucleotide content of the maternal and paternal copies of the 23 chromosomes individuals possess (i.e., they do not ‘phase’ the genome) often because of the costs and complexities of doing so. We compared 11 different widely-used approaches to phasing human genomes using the publicly available ‘Genome-In-A-Bottle’ (GIAB) phased version of the NA12878 genome as a gold standard. The phasing strategies we compared included laboratory-based assays that prepare DNA in unique ways to facilitate phasing as well as purely computational approaches that seek to reconstruct phase information from general sequencing reads and constructs or population-level haplotype frequency information obtained through a reference panel of haplotypes. To assess the performance of the 11 approaches, we used metrics that included, among others, switch error rates, haplotype block lengths, the proportion of fully phase-resolved genes, phasing accuracy and yield between pairs of SNVs. Our comparisons suggest that a hybrid or combined approach that leverages: 1. population-based phasing using the SHAPEIT software suite, 2. either genome-wide sequencing read data or parental genotypes, and 3. a large reference panel of variant and haplotype frequencies, provides a fast and efficient way to produce highly accurate phase-resolved individual human genomes. We found that for population-based approaches, phasing performance is enhanced with the addition of genome-wide read data; e.g., whole genome shotgun and/or RNA sequencing reads. Further, we found that the inclusion of parental genotype data within a population-based phasing strategy can provide as much as a ten-fold reduction in phasing errors. We also considered a majority voting scheme for the construction of a consensus haplotype combining multiple predictions for enhanced performance and site coverage. Finally, we also identified DNA sequence signatures associated with the genomic regions harboring phasing switch errors, which included regions of low polymorphism or SNV density.</p></div