rule-based cell systems model of aging using feedback loop motifs mediated by stress responses基于规则的细胞衰老的系统模型使用反馈循环图案由压力反应.pdfVIP

Rule-Based Cell Systems Model of Aging using Feedback Loop Motifs Mediated by Stress Responses 1 2 1,3 Andres Kriete *, William J. Bosl , Glenn Booker 1 School of Biomedical Engineering, Science and Health Systems, Drexel University, Bossone Research Center, Philadelphia, Pennsylvania, United States of America, 2 Harvard Medical School, Children’s Hospital Informatics Program, Boston, Massachusetts, United States of America, 3 College of Information Science and Technology, Drexel University, Philadelphia, Pennsylvania, United States of America Abstract 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-kB and mTOR, counteract accumulating damage and dysfunction by modulating mitochondrial respiration, metabolic fluxes, biosynthesis, and autophagy, crucial for cellular surv