, Volume 11, Issue 4, pp 463–473 | Cite as

Interaction networks as a tool to investigate the mechanisms of aging

  • Emilie Chautard
  • Nicolas Thierry-Mieg
  • Sylvie Ricard-BlumEmail author
Research Article


Biological systems are made up of very large numbers of different components interacting at various scales. Most genes, proteins and other cell components carry out their functions within a complex network of interactions and a single component can affect a wide range of other components. Interactions involved in biological processes have been first characterized individually but this “reductionist” approach suffers from a lack of information about time, space, and context in which the interactions occur in vivo. A global, integrative, approach has been developed for several years, focusing on the building of protein–protein interaction maps or interactomes. These interaction networks are complex systems, where new properties arise. They are part of the emergent field of systems biology, which focuses on studying complex biological systems such as a cell or organism, viewed as an integrated and interacting network of genes, proteins and biochemical reactions. Aging is associated with many diseases, such as cancer, diabetes, cardiovascular and neurodegenerative disorders and this limits the investigation of the mechanisms underlying the aging process when focusing on a single gene or a single biochemical pathway. The integration of existing intracellular interaction networks with the extracellular interaction network we have developed (MatrixDB, will contribute to provide further insights into the global mechanisms of aging.


Interaction networks Aging Extracellular matrix 



Gene Ontology



This work was supported by a grant from Region Rhône-Alpes (CPER to EC, NTM, and SRB), and by the “Institut Rhône-Alpin des Systèmes Complexes” (IXXI 2007, to EC, NTM, and SRB).

Supplementary material

10522_2010_9268_MOESM1_ESM.pdf (5.7 mb)
Supplementary material 1 (PDF 5831 kb)


  1. Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, Harris MA, Hill DP, Issel-Tarver L, Kasarskis A, Lewis S, Matese JC, Richardson JE, Ringwald M, Rubin GM, Sherlock G (2000) Gene ontology: tool for the unification of biology. The gene ontology consortium. Nat Genet 25:25–29. doi: 10.1038/75556 CrossRefPubMedGoogle Scholar
  2. Assenov Y, Ramírez F, Schelhorn SE, Lengauer T, Albrecht M (2008) Computing topological parameters of biological networks. Bioinformatics 24:282–284. doi: 10.1093/bioinformatics/btm554 CrossRefPubMedGoogle Scholar
  3. Barabási AL, Oltvai ZN (2004) Network biology: understanding the cell’s functional organization. Nat Rev Genet 5:101–113. doi: 10.1038/nrg1272 CrossRefPubMedGoogle Scholar
  4. Bindea G, Mlecnik B, Hackl H, Charoentong P, Tosolini M, Kirilovsky A, Fridman WH, Pagès F, Trajanoski Z, Galon J (2009) ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics 25:1091–1093. doi: 10.1093/bioinformatics/btp101 CrossRefPubMedGoogle Scholar
  5. Bishop JR, Schuksz M, Esko JD (2007) Heparan sulphate proteoglycans fine-tune mammalian physiology. Nature 446:1030–1037. doi: 10.1038/nature05817 CrossRefPubMedGoogle Scholar
  6. Breitkreutz BJ, Stark C, Reguly T, Boucher L, Breitkreutz A, Livstone M, Oughtred R, Lackner DH, Bähler J, Wood V, Dolinski K, Tyers M (2008) The BioGRID Interaction Database: 2008 update. Nucleic Acids Res 36:D637–D640. doi: 10.1093/nar/gkm1001 CrossRefPubMedGoogle Scholar
  7. Budovsky A, Abramovich A, Cohen R, Chalifa-Caspi V, Fraifeld V (2007) Longevity network: construction and implications. Mech Aging Dev 128:117–124. doi: 10.1016/j.mad.2006.11.018 CrossRefPubMedGoogle Scholar
  8. Budovsky A, Tacutu R, Yanai H, Abramovich A, Wolfson M, Fraifeld V (2009) Common gene signature of cancer and longevity. Mech Aging Dev 130:33–39. doi: 10.1016/j.mad.2008.04.002 CrossRefPubMedGoogle Scholar
  9. Callaghan TM, Wilhelm KP (2008) A review of ageing and an examination of clinical methods in the assessment of ageing skin. Part I: Cellular and molecular perspectives of skin ageing. Int J Cosmet Sci 30:313–322. doi: 10.1111/j.1468-2494.2008.00454.x CrossRefPubMedGoogle Scholar
  10. Chatr-aryamontri A, Ceol A, Palazzi LM, Nardelli G, Schneider MV, Castagnoli L, Cesareni G (2007) MINT: the Molecular INTeraction database. Nucleic Acids Res 35:D572–D574. doi: 10.1093/nar/gkl950 CrossRefPubMedGoogle Scholar
  11. Chautard E, Thierry-Mieg N, Ricard-Blum S (2009a) Interaction networks: from protein functions to drug discovery. A review. Pathol Biol 57:324–333. doi: 10.1016/j.patbio.2008.10.004 CrossRefPubMedGoogle Scholar
  12. Chautard E, Ballut L, Thierry-Mieg N, Ricard-Blum S (2009b) MatrixDB, a database focused on extracellular protein-protein and protein-carbohydrate interactions. Bioinformatics 25:690–691. doi: 10.1093/bioinformatics/btp025 CrossRefPubMedGoogle Scholar
  13. Cline MS, Smoot M, Cerami E, Kuchinsky A, Landys N, Workman C, Christmas R, Avila-Campilo I, Creech M, Gross B, Hanspers K, Isserlin R, Kelley R, Killcoyne S, Lotia S, Maere S, Morris J, Ono K, Pavlovic V, Pico AR, Vailaya A, Wang PL, Adler A, Conklin BR, Hood L, Kuiper M, Sander C, Schmulevich I, Schwikowski B, Warner GJ, Ideker T, Bader GD (2007) Integration of biological networks and gene expression data using Cytoscape. Nat Protoc 2:2366–2382. doi: 10.1038/nprot.2007.324 CrossRefPubMedGoogle Scholar
  14. de Magalhães JP, Toussaint O (2004) GenAge: a genomic and proteomic network map of human aging. FEBS Lett 571:243–247. doi: 10.1016/j.febslet.2004.07.006 CrossRefPubMedGoogle Scholar
  15. de Magalhães JP, Costa J, Toussaint O (2005) HAGR: the Human Aging Genomic Resources. Nucleic Acids Res 33:D537–D543. doi: 10.1093/nar/gki017 CrossRefPubMedGoogle Scholar
  16. de Magalhães JP, Budovsky A, Lehmann G, Costa J, Li Y, Fraifeld V, Church GM (2009) The Human Aging Genomic Resources: online databases and tools for biogerontologists. Aging Cell 8:65–72. doi: 10.1111/j.1474-9726.2008.00442.x CrossRefPubMedGoogle Scholar
  17. Faye C, Chautard E, Olsen BR, Ricard-Blum S (2009a) The first draft of the endostatin interaction network. J Biol Chem 284:22041–22047. doi: 10.1074/jbc.M109.002964 CrossRefPubMedGoogle Scholar
  18. Faye C, Moreau C, Chautard E, Jetne R, Fukai N, Ruggiero F, Humphries MJ, Olsen BR, Ricard-Blum S (2009b) Molecular interplay between endostatin, integrins, and heparan sulfate. J Biol Chem 284:22029–22040. doi: 10.1074/jbc.M109.002840 CrossRefPubMedGoogle Scholar
  19. Garcia O, Saveanu C, Cline M, Fromont-Racine M, Jacquier A, Schwikowski B, Aittokallio T (2007) GOlorize: a Cytoscape plug-in for network visualization with Gene Ontology-based layout and coloring. Bioinformatics 23:394–396. doi: 10.1093/bioinformatics/btl605 CrossRefPubMedGoogle Scholar
  20. Ito T, Chiba T, Ozawa R, Yoshida M, Hattori M, Sakaki Y (2001) Comprehensive two-hybrid analysis to explore the yeast protein interactome. Proc Natl Acad Sci USA 98:4569–4574. doi: 10.1073/pnas.061034498 CrossRefPubMedGoogle Scholar
  21. Kaeberlein M, Jegalian B, McVey M (2002) AGEID: a database of aging genes and interventions. Mech Aging Dev 123:1115–1119CrossRefPubMedGoogle Scholar
  22. Kerrien S, Alam-Faruque Y, Aranda B, Bancarz I, Bridge A, Derow C, Dimmer E, Feuermann M, Friedrichsen A, Huntley R, Kohler C, Khadake J, Leroy C, Liban A, Lieftink C, Montecchi-Palazzi L, Orchard S, Risse J, Robbe K, Roechert B, Thorneycroft D, Zhang Y, Apweiler R, Hermjakob H (2007) IntAct—open source resource for molecular interaction data. Nucleic Acids Res 35:D561–D565. doi: 10.1093/nar/gkl958 CrossRefPubMedGoogle Scholar
  23. Keshava Prasad TS, Goel R, Kandasamy K, Keerthikumar S, Kumar S, Mathivanan S, Telikicherla D, Raju R, Shafreen B, Venugopal A, Balakrishnan L, Marimuthu A, Banerjee S, Somanathan DS, Sebastian A, Rani S, Ray S, Harrys Kishore CJ, Kanth S, Ahmed M, Kashyap MK, Mohmood R, Ramachandra YL, Krishna V, Rahiman BA, Mohan S, Ranganathan P, Ramabadran S, Chaerkady R, Pandey A (2009) Human Protein Reference Database—2009 update. Nucleic Acids Res 37:D767–D772. doi: 10.1093/nar/gkn892 CrossRefPubMedGoogle Scholar
  24. Lever R, Page CP (2002) Novel drug development opportunities for heparin. Nat Rev Drug Discov 1:140–148. doi: 10.1038/nrd724 CrossRefPubMedGoogle Scholar
  25. Maere S, Heymans K, Kuiper M (2005) BiNGO: a Cytoscape plugin to assess overrepresentation of gene ontology categories in biological networks. Bioinformatics 21:3448–3449. doi: 10.1093/bioinformatics/bti551 CrossRefPubMedGoogle Scholar
  26. Managbanag JR, Witten TM, Bonchev D, Fox LA, Tsuchiya M, Kennedy BK, Kaeberlein M (2008) Shortest-path network analysis is a useful approach toward identifying genetic determinants of longevity. PLoS One 3:e3802. doi: 10.1371/journal.pone.0003802 CrossRefPubMedGoogle Scholar
  27. Mattai J, Kwak JC (1988) Quantitative similarity of zinc and calcium binding to heparin in excess salt solution. Biophys Chem 31:295–299CrossRefPubMedGoogle Scholar
  28. Maurer P, Hohenester E (1997) Structural and functional aspects of calcium binding in extracellular matrix proteins. Matrix Biol 8–9:569–580CrossRefGoogle Scholar
  29. Oliver S (2000) Guilt-by-association goes global. Nature 403:601–603. doi: 10.1038/35001165 CrossRefPubMedGoogle Scholar
  30. Ricard-Blum S, Ruggiero F (2005) The collagen superfamily: from the extracellular matrix to the cell membrane. Pathol Biol 53:430–442. doi: 10.1016/j.patbio.2004.12.024 CrossRefPubMedGoogle Scholar
  31. Ricard-Blum S, Ruggiero F, van der Rest M (2005) Collagen: primer in structure, processing and assembly. In: Brinckmann J, Notbohm H, Müller PK (eds) Topics in current chemistry: collagen, vol 247. Springer, Berlin, pp 35–84Google Scholar
  32. Robert L, Labat-Robert J (2000) Aging of connective tissues: from genetic to epigenetic mechanisms. Biogerontology 1:123–131. doi: 10.1023/A:1010048014925 CrossRefPubMedGoogle Scholar
  33. Robert L, Labat-Robert J, Robert AM (2009) Physiology of skin aging. Pathol Biol (Paris) 57:336–341. doi: 10.1016/j.patbio.2008.09.007 Google Scholar
  34. Rodgers KD, San Antonio JD, Jacenko O (2008) Heparan sulfate proteoglycans: a GAGgle of skeletal-hematopoietic regulators. Dev Dyn 237:2622–2642. doi: 10.1002/dvdy.21593 CrossRefPubMedGoogle Scholar
  35. Salwinski L, Miller CS, Smith AJ, Pettit FK, Bowie JU, Eisenberg D (2004) The Database of Interacting Proteins: 2004 update. Nucleic Acids Res 32:D449–D451. doi: 10.1093/nar/gkh086 CrossRefPubMedGoogle Scholar
  36. Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13:2498–2504. doi: 10.1101/gr.1239303 CrossRefPubMedGoogle Scholar
  37. The UniProt Consortium (2009) The Universal Protein Resource (UniProt). Nucleic Acids Res 37:D169–D174. doi: 10.1093/nar/gkn664 CrossRefGoogle Scholar
  38. Uetz P, Giot L, Cagney G, Mansfield TA, Judson RS, Knight JR, Lockshon D, Narayan V, Srinivasan M, Pochart P, Qureshi-Emili A, Li Y, Godwin B, Conover D, Kalbfleisch T, Vijayadamodar G, Yang M, Johnston M, Fields S, Rothberg JM (2000) A comprehensive analysis of protein-protein interactions in Saccharomyces cerevisiae. Nature 403:623–627. doi: 10.1038/35001009 CrossRefPubMedGoogle Scholar
  39. Uitto J (2008) The role of elastin and collagen in cutaneous aging: intrinsic aging versus photoexposure. J Drugs Dermatol 7(2 Suppl):s12–s16PubMedGoogle Scholar
  40. Witten TM, Bonchev D (2007) Predicting aging/longevity-related genes in the nematode Caenorhabditis elegans. Chem Biodivers 4:2639–2655. doi: 10.1002/cbdv.200790216 CrossRefPubMedGoogle Scholar
  41. Wolfson M, Budovsky A, Tacutu R, Fraifeld V (2009) The signaling hubs at the crossroad of longevity and age-related disease networks. Int J Biochem Cell Biol 41:516–520. doi: 10.1016/j.biocel.2008.08.026 CrossRefPubMedGoogle Scholar
  42. Xue H, Xian B, Dong D, Xia K, Zhu S, Zhang Z, Hou L, Zhang Q, Zhang Y, Han JD (2007) A modular network model of aging. Mol Syst Biol 3:147. doi: 10.1038/msb4100189 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • Emilie Chautard
    • 1
  • Nicolas Thierry-Mieg
    • 2
  • Sylvie Ricard-Blum
    • 1
    Email author
  1. 1.Institut de Biologie et Chimie des ProtéinesUMR 5086 CNRS, Université Lyon 1Lyon Cedex 07France
  2. 2.Faculté de MédecineTIMC-IMAG, UMR 5525 CNRS, Université Grenoble 1La Tronche CedexFrance

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