Interactions among mTORC, AMPK, and SIRT: A Computational Model for Cell Energy Balance and Metabolism

Abstract Key proteins such as mTORC, AMPK, and sirtuins are known to play an essential role in the management of metabolic stress and ageing mechanisms. An impairment in these mechanisms is commonly associated with cellular ageing and degenerative diseases. To understand the complex interactions of ageing□related signalling pathways and environmental signals, and the impacts on lifespan and health-span, we developed a computational model of ageing signalling pathways. The model includes (i) the insulin/IGF-1 pathway, which couples energy and nutrient abundance to the execution of cell growth and division, (ii) mTORC1 and amino acid sensors, (iii) the Preiss-Handler and salvage pathways, which regulate the metabolism of NAD+ and the NAD+-consuming factor SIRT1, (iv) the energy sensor AMPK, and (v) transcription factors FOXO and PGC-1α. Key findings include the clinically important role of PRAS40, sestrin2, and diet in the treatment of cancers and other diseases, and a potential link between SIRT1-activating compounds and premature autophagy(definition). The model can be used as an essential component to simulate gene manipulation, therapies (e.g., mTOR(definition)-inhibiting drug studied for extending healthspan and lifespan." style="text-decoration:underline dotted; text-underline-offset:2px; cursor:help;">rapamycin(definition) and wortmannin), calorie restrictions, and chronic stress, and to assess their functional implications on longevity and ageing□related diseases. Author Summary In cellular ageing, mitochondrial function declines over time, which affects normal mechanisms of cells and organisms and leads to myriad of degenerative diseases and other health problems. To investigate the mechanisms that affect the ageing process, we focus on pathways that play a key role in the management of metabolic stress: the mTORC, AMPK, and sirtuins pathways. Our goal is to understand the complex interactions of ageing and metabolism related signalling pathways and environmental signals, and the impacts on lifespan and health-span. To accomplish that goal, we developed a computational model of signalling pathways related to ageing and metabolism. By conducting model simulations, we have unraveled the clinically important role of PRAS40, sestrin2, and diet in the treatment of cancers and other diseases, and a double-edged sword effect of SIRT1-activating compounds in their use as a health remedy. We view this model as an essential step towards a tool for studying metabolism, longevity, and ageing-related diseases. By extending the present model as appropriate, we can simulate gene manipulation, therapies (e.g., rapamycin and wortmannin), calorie restrictions, and chronic stress,.