@article{125c288bb28e477d88ad82a6e002a858,
title = "ROS networks: designs, aging, Parkinson's disease and precision therapies",
abstract = "How the network around ROS protects against oxidative stress and Parkinson's disease (PD), and how processes at the minutes timescale cause disease and aging after decades, remains enigmatic. Challenging whether the ROS network is as complex as it seems, we built a fairly comprehensive version thereof which we disentangled into a hierarchy of only five simpler subnetworks each delivering one type of robustness. The comprehensive dynamic model described in vitro data sets from two independent laboratories. Notwithstanding its five-fold robustness, it exhibited a relatively sudden breakdown, after some 80 years of virtually steady performance: it predicted aging. PD-related conditions such as lack of DJ-1 protein or increased alpha-synuclein accelerated the collapse, while antioxidants or caffeine retarded it. Introducing a new concept (aging-time-control coefficient), we found that as many as 25 out of 57 molecular processes controlled aging. We identified new targets for {"}life-extending interventions{"}: mitochondrial synthesis, KEAP1 degradation, and p62 metabolism.",
keywords = "OXIDATIVE STRESS-RESPONSE, NF-KAPPA-B, MITOCHONDRIAL RESPIRATION, PINK1, PROTEIN, PHOSPHORYLATION, ACTIVATION, EXPRESSION, UBIQUITIN, PATHWAY",
author = "Kolodkin, {Alexey N.} and Sharma, {Raju Prasad} and Colangelo, {Anna Maria} and Andrew Ignatenko and Francesca Martorana and Danyel Jennen and Bried, {Jacco J.} and Nathan Brady and Matteo Barberis and Mondeel, {Thierry D. G. A.} and Michele Papa and Vikas Kumar and Bernhard Peters and Alexander Skupin and Lilia Alberghina and Rudi Balling and Hans Westerhoff",
note = "Funding Information: We cordially thank Nathan Price and Evangelos Simeonidis from ISB (Seattle), Nilg{\"u}n Sahin from the VU University Amsterdam, and Ewelina Weglarz-Tomczak of the University of Amsterdam for highly influential discussions and support. We thank Stephan Gebel for his great help with the PD map and Olga Krebs for her help with FAIRDOMHub. A.K. acknowledges funding from the Luxembourg BioTech Initiative and LCSB; A.K. and A.I. acknowledge the financial support from an FNR grant for the Ph.D. project ROSIM. H.V.W. thanks the EU, the BBSRC, EPSRC, and NWO for extensive research support throughout many years, such as in grants BB/F003528/1, BB/ C008219/1, BB/F003528/1, BB/G530225/1, BB/I004696/1, BB/I017186/1, BB/I00470X/1, BB/I004688/1, BB/J500422/1, BB/J003883/1, BB/J020060/1, and the EU-FP7 projects SYNPOL, EC-MOAN, NUCSYS, UNI-CELLSYS, ITFoM, BioSiM, and EPIPredict. M.B. acknowledges the Systems Biology Grants of the University of Surrey and of the Swammerdam Institute for Life Science Starting Grant of the University of Amsterdam. This work was further supported by the Corbel EU-H2020 through Hans V. Westerhoff and Anna M Colangelo; and grants from the Italian Ministry of University and Research (MIUR): SYSBIO-Italian ROADMAP ESFRI Infrastructures to L.A., A.M.C., and M.P.; MIUR ALISEI-IVASCOMAR-Italian National Cluster to A.M.C., and grant Dipartimenti di Eccellenza-2017 to the University of Milano-Bicocca Department of Biotechnology and Biosciences. Publisher Copyright: {\textcopyright} 2020, The Author(s).",
year = "2020",
month = oct,
day = "26",
doi = "10.1038/s41540-020-00150-w",
language = "English",
volume = "6",
journal = "NPJ systems biology and applications",
issn = "2056-7189",
publisher = "Nature Publishing Group",
number = "1",
}