Math and the Fountain of Youth

Abstract

Ageing is associated with impairments in a number of regulatory processes, including in energy dysregulation that affects multiple metabolic pathways and in the circadian rhythms. In the management of metabolic stress and ageing mechanisms, key proteins such as mTORC, AMPK, and sirtuins are known to play an essential role. 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 healthspan, we developed a computational model of metabolic 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-1a. The model can be used as an essential component to simulate gene manipulation, therapies (e.g., rapamycin and wortmannin), calorie restrictions, and chronic stress, and to assess their functional implications on longevity and ageing‐related diseases. Another goal of this research project is to unravel the complex interactions among ageing, metabolism, and the circadian clock. We seek to identify key factors that inform the liver circadian clock of cellular energy status, and to reveal the mechanisms by which variations in food intake may disrupt the clock. To address these questions, we develop a comprehensive mathematical model that represents the circadian pathway in the mouse liver, together with the insulin/IGF-1 pathway, mTORC1, AMPK, NAD+ and the NAD+-consuming factor SIRT1. The model is age-specific and can simulate the liver of a young mouse or an aged mouse. Simulation results suggest that the reduced NAD+ and SIRT1 bioavailability may explain the shortened circadian period in aged rodents. Importantly, the model identifies the dosing schedules for maximizing the efficacy of some antiageing medications