A comprehensive approach to the molecular determinants of lifespan using a Boolean model of geroconversion.
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.
Institut Curie, CNRS, UMR3244, Telomere and Cancer Laboratory, PSL Research University, 75005, Paris, France.|Department of Medical Oncology, Institut Curie, 75005, Paris, France.
Loic
L
Verlingue
Institut Curie, Mines Paris Tech, Inserm, U900, PSL Research University, F-75005, Paris, France.
Aurélien
A
Dugourd
Sorbonne Paris Cité, Université Paris Descartes, 12 Rue de l'École de Médecine, 75006, Paris, France.|Equipe 11 labellisée Ligue contre le Cancer, INSERM U 1138, Centre de Recherche des Cordeliers, 15 rue de l'Ecole de Médecine, 75006, Paris, France.|Université Pierre et Marie Curie, 4 Place Jussieu, 75005, Paris, France.
Gautier
G
Stoll
Institut Curie, Mines Paris Tech, Inserm, U900, PSL Research University, F-75005, Paris, France.
Emmanuel
E
Barillot
Institut Curie, Mines Paris Tech, Inserm, U900, PSL Research University, F-75005, Paris, France.
Laurence
L
Calzone
Institut Curie, CNRS, UMR3244, Telomere and Cancer Laboratory, PSL Research University, 75005, Paris, France.|UPMC Univ Paris 06, CNRS, UMR3244, Sorbonne Universités, 75005, Paris, France.
Arturo
A
Londoño-Vallejo
Boolean modeling; cancer; in silico drug screening; lifespan expansion; rapamycin; type 2 diabetes mellitus