Open AccessA comprehensive approach to the molecular determinants of lifespan using a Boolean model of geroconversion
Author(s) -
Verlingue Loic,
Dugourd Aurélien,
Stoll Gautier,
Barillot Emmanuel,
Calzone Laurence,
LondoñoVallejo Arturo
Publication year - 2016
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12504
Subject(s) - biology , context (archaeology) , senescence , in silico , pi3k/akt/mtor pathway , insulin resistance , phenotype , cell cycle , type 2 diabetes mellitus , pharmacodynamics , computational biology , cancer research , diabetes mellitus , bioinformatics , cancer , apoptosis , genetics , gene , endocrinology , pharmacokinetics , paleontology
Summary Altered molecular responses to insulin and growth factors ( GF ) are responsible for late‐life shortening diseases such as type‐2 diabetes mellitus (T2 DM ) 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 T2 DM '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 HER 2–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.