Rule-based cell systems model of aging using feedback loop motifs mediated by stress responses.

Investigating the complex systems dynamics of the aging process requires integration of a broad range of cellular processes describing damage and functional decline co-existing with adaptive and protective regulatory mechanisms. We evolve an integrated generic cell network to represent the connectiv...

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Autores principales:	Andres Kriete, William J Bosl, Glenn Booker
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/c9b0d1145bcc48f8a85cd12cb540420b
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spelling	oai:doaj.org-article:c9b0d1145bcc48f8a85cd12cb540420b2021-12-02T19:58:21ZRule-based cell systems model of aging using feedback loop motifs mediated by stress responses.1553-734X1553-735810.1371/journal.pcbi.1000820https://doaj.org/article/c9b0d1145bcc48f8a85cd12cb540420b2010-06-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20585546/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Investigating the complex systems dynamics of the aging process requires integration of a broad range of cellular processes describing damage and functional decline co-existing with adaptive and protective regulatory mechanisms. We evolve an integrated generic cell network to represent the connectivity of key cellular mechanisms structured into positive and negative feedback loop motifs centrally important for aging. The conceptual network is casted into a fuzzy-logic, hybrid-intelligent framework based on interaction rules assembled from a priori knowledge. Based upon a classical homeostatic representation of cellular energy metabolism, we first demonstrate how positive-feedback loops accelerate damage and decline consistent with a vicious cycle. This model is iteratively extended towards an adaptive response model by incorporating protective negative-feedback loop circuits. Time-lapse simulations of the adaptive response model uncover how transcriptional and translational changes, mediated by stress sensors NF-kappaB and mTOR, counteract accumulating damage and dysfunction by modulating mitochondrial respiration, metabolic fluxes, biosynthesis, and autophagy, crucial for cellular survival. The model allows consideration of lifespan optimization scenarios with respect to fitness criteria using a sensitivity analysis. Our work establishes a novel extendable and scalable computational approach capable to connect tractable molecular mechanisms with cellular network dynamics underlying the emerging aging phenotype.Andres KrieteWilliam J BoslGlenn BookerPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 6, Iss 6, p e1000820 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Andres Kriete William J Bosl Glenn Booker Rule-based cell systems model of aging using feedback loop motifs mediated by stress responses.
description	Investigating the complex systems dynamics of the aging process requires integration of a broad range of cellular processes describing damage and functional decline co-existing with adaptive and protective regulatory mechanisms. We evolve an integrated generic cell network to represent the connectivity of key cellular mechanisms structured into positive and negative feedback loop motifs centrally important for aging. The conceptual network is casted into a fuzzy-logic, hybrid-intelligent framework based on interaction rules assembled from a priori knowledge. Based upon a classical homeostatic representation of cellular energy metabolism, we first demonstrate how positive-feedback loops accelerate damage and decline consistent with a vicious cycle. This model is iteratively extended towards an adaptive response model by incorporating protective negative-feedback loop circuits. Time-lapse simulations of the adaptive response model uncover how transcriptional and translational changes, mediated by stress sensors NF-kappaB and mTOR, counteract accumulating damage and dysfunction by modulating mitochondrial respiration, metabolic fluxes, biosynthesis, and autophagy, crucial for cellular survival. The model allows consideration of lifespan optimization scenarios with respect to fitness criteria using a sensitivity analysis. Our work establishes a novel extendable and scalable computational approach capable to connect tractable molecular mechanisms with cellular network dynamics underlying the emerging aging phenotype.
format	article
author	Andres Kriete William J Bosl Glenn Booker
author_facet	Andres Kriete William J Bosl Glenn Booker
author_sort	Andres Kriete
title	Rule-based cell systems model of aging using feedback loop motifs mediated by stress responses.
title_short	Rule-based cell systems model of aging using feedback loop motifs mediated by stress responses.
title_full	Rule-based cell systems model of aging using feedback loop motifs mediated by stress responses.
title_fullStr	Rule-based cell systems model of aging using feedback loop motifs mediated by stress responses.
title_full_unstemmed	Rule-based cell systems model of aging using feedback loop motifs mediated by stress responses.
title_sort	rule-based cell systems model of aging using feedback loop motifs mediated by stress responses.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/c9b0d1145bcc48f8a85cd12cb540420b
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_version_	1718375804940845056

Rule-based cell systems model of aging using feedback loop motifs mediated by stress responses.

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