Role of pharmacological inhibition of PI3K p110α on healthspan

Abstract

Introduction: Age is a greatest risk factor for multiple chronic morbidities, interventions that delay the onset of age-associated morbidities could have a major impact on healthcare system and an individual’s quality of life. Impaired activation of insulin/IGF1 signalling is one of the most effective approaches to promote healthy ageing. Insulin signalling mediates biological processes that are essential for cellular function. Consequently, complete inhibition of IIS is not viable approach to promote healthy ageing. PI3K is a downstream component of insulin signalling pathway, which consist of several isoforms that are independent in mediating insulin effects. Thus targeting a specific PI3K isoform seems to a viable approach in promoting healthy ageing. Aim: This thesis aims to investigate whether pharmacological inhibition of the p110α isoform of PI3K (BYL719) might be a viable approach to promote healthy ageing in mice. Methods: The present study conducted molecular tests on skeletal muscle of adult mice treated with BYL719 after 72h and six weeks. Whole body metabolism and genes associated with mitochondrial biogenesis, antioxidants, and proteins associated with metabolic stress signalling were analysed. Follow up study was conducted in the 18-month old mice for six months with BYL719. In vivo tests, including physical performance, GTT and ITT, core temperature, body mass were analysed on the ageing cohort. Results: 72h of BYL719 does not alter gene expression of mitochondrial biogenesis or antioxidant response, except nfe2l2 in males and Sod2 in females. Gene expression markers were not different after six weeks. Proteins associated with metabolic stress signalling did not change after six weeks. Complex IV and complex V of OXPHOS showed reduced protein expression in males. Three month of BYL719 mice were hyperglycaemic and after six months they display reduced body mass associated with decrease fat. After six week, males have greater grip strength and females perform better on rotarod. Conclusion: Long term inhibition of BYL719 does not promote glucose homeostasis in both male and females. BYL719 induces reduction in body weight which is associated with loss of fat and increased core temperature. This suggests BYL719 exerts tissue-specific response in attenuating insulin effects on metabolism to promote healthy ageing.