Boolean model of geroconversion

Taxon: Mammal
Process: Senescence
Submitter: Claudine Chaouiya (with Laurence Calzone)

Supporting paper: Verlingue, Loic and Dugourd, Aurélien and Stoll, Gautier and Barillot, Emmanuel and Calzone, Laurence and Londoño-Vallejo, Arturo (2016). A comprehensive approach to the molecular determinants of lifespan using a Boolean model of geroconversion. Aging Cell. 10.1111/acel.12504

Model file(s)	Description(s)
ModelT2DM.zginml	GINsim model file (corrected, December 2016)

Summary:
Altered 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.