Rule-Based Cell Systems Model of Aging using Feedback Loop Motifs Mediated by Stress Responses
Figure 4
Circuitry of the Adaptive Response model.
The Adaptive Response (AR) model represents an interaction network topology with both positive-destructive and negative-protective feedback mechanisms co-existing in cellular aging. Dysfunctional mitochondria and a decrease in protein turnover are positive feedbacks and contribute to the accumulation of oxidized proteins. Increased levels of ROS and oxidized proteins activate the redox-sensitive stress response transcription factor NF-κB, while declining ATP levels inhibit the energy sensor mTOR, which supports negative feedbacks through changes in transcription and translation (dotted green lines indicate flow of information and arrow endstyles the suggested function in aging). This includes downregulation of protein biosynthesis and genes coding for mitochondrial proteins. In addition, the activity of scavengers and autophagy is enhanced. A compensatory mechanism to mitochondrial dysfunction is upregulation of aerobic glycolysis. Secondary positive feedback-loops incorporate the production of cytokines as a byproduct of the cell-autonomous response of NF-κB, activating the NADPH oxidase system in an autocrine fashion, as well as reduced protein turnover rates. The beneficial role of mTOR inhibition in aging may be blunted by high ROS concentrations (see Results for details).