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A comprehensive approach to the molecular determinants of lifespan using a Boolean model of geroconversion

By Loic Verlingue, Aurélien Dugourd, Gautier Stoll, Emmanuel Barillot, Laurence Calzone and Arturo Londoño-Vallejo

Abstract

International audienceAltered molecular responses to insulin and growth factors (GF) are responsible for late-life shortening diseases such as type-2 diabetes mellitus (T2DM) and cancers. We have built a network of the signaling pathways that control S-phase entry and a specific type of senescence called geroconversion. We have translated this network into a Boolean model to study possible cell phenotype outcomes under diverse molecular signaling conditions. In the context of insulin resistance, the model was able to reproduce the variations of the senescence level observed in tissues related to T2DM's main morbidity and mortality. Furthermore, by calibrating the pharmacodynamics of mTOR inhibitors, we have been able to reproduce the dose-dependent effect of rapamycin on liver degeneration and lifespan expansion in wild-type and HER2–neu mice. Using the model, we have finally performed an in silico prospective screen of the risk–benefit ratio of rapamycin dosage for healthy lifespan expansion strategies. We present here a comprehensive prognostic and predictive systems biology tool for human aging

Topics: cancer, Boolean modeling, lifespan expansion, in silico drug screening, rapamycin, type 2 diabetes mellitus, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology
Publisher: Wiley Open Access
Year: 2016
DOI identifier: 10.1111/acel.12504
OAI identifier: oai:HAL:hal-01366791v1
Provided by: Hal-Diderot

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