PMID- 34512728
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240404
IS  - 1664-8021 (Print)
IS  - 1664-8021 (Electronic)
IS  - 1664-8021 (Linking)
VI  - 12
DP  - 2021
TI  - Cross-Species and Human Inter-Tissue Network Analysis of Genes Implicated in 
      Longevity and Aging Reveal Strong Support for Nutrient Sensing.
PG  - 719713
LID - 10.3389/fgene.2021.719713 [doi]
LID - 719713
AB  - 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/).
CI  - Copyright (c) 2021 Podder, Raju and Schork.
FAU - Podder, Avijit
AU  - Podder A
AD  - Department of Quantitative Medicine, The Translational Genomics Research 
      Institute (TGen), Phoenix, AZ, United States.
FAU - Raju, Anish
AU  - Raju A
AD  - Department of Quantitative Medicine, The Translational Genomics Research 
      Institute (TGen), Phoenix, AZ, United States.
FAU - Schork, Nicholas J
AU  - Schork NJ
AD  - Department of Quantitative Medicine, The Translational Genomics Research 
      Institute (TGen), Phoenix, AZ, United States.
AD  - Department of Population Sciences and Molecular and Cell Biology, The City of 
      Hope National Medical Center, Duarte, CA, United States.
LA  - eng
GR  - U19 AG023122/AG/NIA NIH HHS/United States
GR  - U24 AG051129/AG/NIA NIH HHS/United States
GR  - UH2 AG064706/AG/NIA NIH HHS/United States
GR  - UH3 AG064706/AG/NIA NIH HHS/United States
PT  - Journal Article
DEP - 20210827
PL  - Switzerland
TA  - Front Genet
JT  - Frontiers in genetics
JID - 101560621
PMC - PMC8430347
OTO - NOTNLM
OT  - cross-species orthologs
OT  - drug targets
OT  - human aging
OT  - nutrient sensing
OT  - pathway enrichments
OT  - protein-protein interaction network
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2021/09/14 06:00
MHDA- 2021/09/14 06:01
PMCR- 2021/08/27
CRDT- 2021/09/13 06:44
PHST- 2021/06/02 00:00 [received]
PHST- 2021/08/10 00:00 [accepted]
PHST- 2021/09/13 06:44 [entrez]
PHST- 2021/09/14 06:00 [pubmed]
PHST- 2021/09/14 06:01 [medline]
PHST- 2021/08/27 00:00 [pmc-release]
AID - 10.3389/fgene.2021.719713 [doi]
PST - epublish
SO  - Front Genet. 2021 Aug 27;12:719713. doi: 10.3389/fgene.2021.719713. eCollection 
      2021.