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Amelioration of the autonomic imbalances of old age with exercise - exploring the molecular and physiological mechanisms.

There is considerable anecdotal evidence that a sedentary lifestyle can lead to ill heath in old age, whereas physical activity has long-term health and wellbeing benefits. The reasons why homeostatic systems deteriorate in the elderly, and why exercise can ameliorate this deterioration, are not well understood. However, there is growing evidence that autonomic nervous system (ANS) imbalance, where sympathetic nervous system over-activity dominates over parasympathetic activity, is involved in a wide range of chronic conditions of old-age, such as obesity, insulin resistance, diabetes, heart failure, stroke and hypertension. Whilst exercise can help restore ANS balance, physiological understanding of this phenomenon is scant. We hypothesise that the development and/or maintenance of the autonomic imbalance is associated with changes in the expression of a large number of genes in the brain that, through their activity, form one or more functional networks that can be influenced by both age and by lifestyle factors, such as physical activity. In order to test this hypothesis, we will: • identify putative networks by carrying out detailed and comprehensive transcriptome analysis on brain regions involved in the regulation of autonomic ouflow. Expression will be compared in normal animals (WKY rats), and in animals with a genetic predisposition to autonomic imbalance characterised by the development of hypertension and loss of heart rate variability (SHRs). • examine gene expression changes as animals age • ask if gene expression is altered by physical exercise, initiated either before or after the onset of autonomic imbalance. • use the latest bioinformatic tools to construct putative pathways and networks that may govern these processes, and we will identify nodal, or hub genes with many connections. • test whether these hubs are important physiologically by altering the expression of these nodal genes using in vivo somatic gene transfer approaches. This will be followed by robust molecular, cellular and, importantly, physiological analysis, that will reveal the roles of these hub genes in network stability and their response to external cues.