Abstract
Chronic oxidative stress and oxidative damage has become one of the most convincing theories in ageing pathology. NADPH oxidase 2 (Nox2) is a reactive oxygen species (ROS) generating enzyme expressed constitutively in the vasculature and the central nervous system, however the role of this enzyme in ageing-related cardiovascular dysfunction and neurodegenerative diseases remains unclear. Therefore, the overall aim of this PhD research project is to investigate the role of Nox2-induced oxidative stress in ageing-associated metabolic syndrome, endothelial dysfunction and neurodegeneration using age-matched littermates of wild-type (WT) versus Nox2 null (Nox2-/-) mice on a C57BI/6 background at young (3-4 months), middle aged (10-12 months) and ageing (20-22 months). Compared to young mice, there were ageing-related increases in bodyweight and fasting insulin levels along with impaired glucose tolerance, hyperlipidaemia and hypertension in WT ageing mice (p<0.05). These metabolic syndrome risk factors were accompanied by significant increases in aortic ROS production and Nox2 expression and a significant decrease in the endothelium-dependent relaxation to acetylcholine (Emax 75% for young and 64% for ageing, p<0.05). However, all these ageing-related metabolic and endothelial abnormalities were significantly reduced in Nox2-/-ageing mice. We then examined the role of Nox2 in ageing-related neurodegeneration and found that compared to young mice, there was a significantly reduced locomotor activity and dopaminergic neuron firing frequency accompanied by increased brain ROS production in WT but not in Nox2-/- mouse brain. Ageing-associated increases in brain ROS production was further confirmed using human post-mortem brain tissues. In conclusion, Nox2-derived oxidative stress plays an important role in ageing-associated metabolic syndrome, vascular dysfunction, and neurodegeneration. Targeting Nox2 represents a valuable therapeutic strategy to treat these ageing-related diseases.