Simulation of Cellular Energy Restriction in Quiescence (ERiQ)—A Theoretical Model for Aging

Abstract

Cellular responses to energy stress involve activation of pro-survival signaling nodes, compensation in regulatory pathways and adaptations in organelle function. Specifically, energy restriction in quiescent cells (ERiQ) through energetic perturbations causes adaptive changes in response to reduced ATP, NAD+ and NADP levels in a regulatory network spanned by AKT, NF-κB, p53 and mTOR. Based on the experimental ERiQ platform, we have constructed a minimalistic theoretical model consisting of feedback motifs that enable investigation of stress-signaling pathways. The computer simulations reveal responses to acute energetic perturbations, promoting cellular survival and recovery to homeostasis. We speculated that the very same stress mechanisms are activated during aging in post-mitotic cells. To test this hypothesis, we modified the model to be deficient in protein damage clearance and demonstrate the formation of energy stress. Contrasting the network’s pro-survival role in acute energetic challenges, conflicting responses in aging disrupt mitochondrial maintenance and contribute to a lockstep progression of decline when chronically activated. The model was analyzed by a local sensitivity analysis with respect to lifespan and makes predictions consistent with inhibitory and gain-of-function experiments in aging.

Keywords

• retrograde response
• energy stress
• signaling pathways
• mitochondrial dysfunction