Year: 2020
Type: dissertation
Abstract: Ageing is associated with impairments in a number of regulatory processes, including in energy \ndysregulation that affects multiple metabolic pathways and in the circadian rhythms. In the \nmanagement of metabolic stress and ageing mechanisms, key proteins such as mTORC, AMPK, and \nsirtuins are known to play an essential role. An impairment in these mechanisms is commonly \nassociated with cellular ageing and degenerative diseases. To understand the complex interactions of \nageing‐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) \nthe insulin/IGF-1 pathway, which couples energy and nutrient abundance to the execution of cell \ngrowth and division, (ii) mTORC1 and amino acid sensors, (iii) the Preiss-Handler and salvage \npathways, which regulate the metabolism of NAD+ and the NAD+-consuming factor SIRT1, (iv) the \nenergy sensor AMPK, and (v) transcription factors FOXO and PGC-1a. The model can be used as an \nessential component to simulate gene manipulation, therapies (e.g., rapamycin and wortmannin), \ncalorie restrictions, and chronic stress, and to assess their functional implications on longevity and \nageing‐related diseases. \nAnother goal of this research project is to unravel the complex interactions among ageing, \nmetabolism, and the circadian clock. We seek to identify key factors that inform the liver circadian \nclock of cellular energy status, and to reveal the mechanisms by which variations in food intake may \ndisrupt the clock. To address these questions, we develop a comprehensive mathematical model that \nrepresents the circadian pathway in the mouse liver, together with the insulin/IGF-1 pathway, \nmTORC1, AMPK, NAD+ and the NAD+-consuming factor SIRT1. The model is age-specific and \ncan simulate the liver of a young mouse or an aged mouse. Simulation results suggest that the reduced \nNAD+ and SIRT1 bioavailability may explain the shortened circadian period in aged rodents. \nImportantly, the model identifies the dosing schedules for maximizing the efficacy of some antiageing medications
Source: UWSpace (University of Waterloo)
Author: Mehrshad Sadria
Language: English
Subfield: Aging
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W3154494352