Paracetamol Toxicity: Influence Of Ageing, Frailty, Resveratrol And Sirt1

Abstract

The objective of this thesis was to help improve the safety of paracetamol for patients of all ages by adding evidence to the body of knowledge on the changing risks of paracetamol toxicity in ageing, frailty and non-acute exposures, and the potential for lifespan and healthspan increasing interventions to provide novel mechanisms of paracetamol hepatotoxicity protection. Furthermore, this thesis aimed to investigate the potential of both paracetamol, and lifespan and healthspan interventions in delaying or preventing frailty. Overall the work presented in this thesis used a series of mouse models to contribute to three main findings with clinical significance. Firstly, they demonstrated that there is no increase in susceptibility to paracetamol toxicity in old age or frailty, with either acute, chronic or sub-acute paracetamol exposure. Secondly, they showed that the currently used paracetamol hepatotoxicity therapy, NAC, does not protect against toxicity induced by sub-acute paracetamol exposure. Further studies showed that the mechanism of SIRT1 activation does not provide an alternative protective mechanism. Finally, this thesis found that the lifespan and healthspan increasing interventions of resveratrol and calorie restriction, but not therapeutic paracetamol, were able to delay frailty in aged mice.