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A comprehensive approach to the molecular determinants of lifespan using a Boolean model of geroconversion
- Source :
- Aging Cell, Aging Cell, Wiley Open Access, 2016, 15 (6), pp.1018-1026. ⟨10.1111/acel.12504⟩, Aging Cell, 2016, 15 (6), pp.1018-1026. ⟨10.1111/acel.12504⟩, Aging Cell, Wiley Open Access, 2016, 〈10.1111/acel.12504〉
- Publication Year :
- 2016
- Publisher :
- HAL CCSD, 2016.
-
Abstract
- International audience; 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.
- Subjects :
- 0301 basic medicine
Senescence
Boolean modeling
Aging
type 2 diabetes mellitus
In silico
medicine.medical_treatment
lifespan expansion
Context (language use)
Biology
Bioinformatics
03 medical and health sciences
Insulin resistance
[ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology
Diabetes mellitus
medicine
cancer
[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology
[SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM]
rapamycin
Insulin
Type 2 Diabetes Mellitus
in silico drug screening
Original Articles
Cell Biology
medicine.disease
[SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM]
3. Good health
030104 developmental biology
Original Article
Signal transduction
[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Subjects
Details
- Language :
- English
- ISSN :
- 14749718
- Database :
- OpenAIRE
- Journal :
- Aging Cell, Aging Cell, Wiley Open Access, 2016, 15 (6), pp.1018-1026. ⟨10.1111/acel.12504⟩, Aging Cell, 2016, 15 (6), pp.1018-1026. ⟨10.1111/acel.12504⟩, Aging Cell, Wiley Open Access, 2016, 〈10.1111/acel.12504〉
- Accession number :
- edsair.doi.dedup.....c751968be2c5747fc7323b29741a416e