Bilateral BBSRC-FAPESP: Amelioration of the autonomic imbalances of old age with exercise - exploring the molecular and physiological mechanisms

It is estimated that by 2050, 25% of the populous will be over 65. Whilst this dramatic increase in lifespan should be celebrated, the resultant demographic change represents a major challenge. This is because wellbeing and health in old age has not improved proportionally with longevity. This imbalance not only impacts on the individual, who would obviously wish to enjoy a healthy life post-retirement, but it also imposes considerable economic and social burdens on families and society. The reasons why bodily systems deteriorate in the elderly is not well understood. However, there is growing evidence that brain dysfunction is involved in a wide range of chronic conditions of old age. It is thought that an imbalance develops in the autonomic nervous system, that is responsible for controlling certain bodily functions, and that this can lead to chronic pathological conditions associated with growing old, such as obesity, insulin resistance, diabetes, heart failure, stroke, and high blood pressure.
There are two possible approaches to the problem of frailty in old age. One is to view the problem as being medical, with the solution residing in increased clinical interventions as the individual gets older. Another, preferable, approach is to view the deterioration of old age as a process that cannot be prevented, but can be ameliorated. It is recognized that particular environmental conditions, nutritional choices, life events and lifestyles, acting on a genetic substrate, can contribute to either wellbeing, or ill health, as we get older. Thus, for example, 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. However, physiological understanding of these phenomena is scant.
We propose to study the effects of ageing and physical activity in a rat model of autonomic imbalance that spontaneously develops high blood-pressure as it gets older. We will use techniques that enable us to identify and quantify all of the genes that are expressed in parts of the brain involved in autonomic nervous system activity. We will then ask how gene expression changes with age. We will also allow these animals to exercise, and we will measure how this affects their physical wellbeing as they age. We will look for genes that are turned on or off by exercise, and we will use state-of-the-art gene manipulation techniques to determine their physiological function(s) in the animal.
Overall, we propose to identify ageing genes (bad brain genes) and exercise genes (good brain genes), and knowing this we will find out whether we can ameliorate some of the pathophysiological problems associated with ageing. This knowledge may one day contribute to improving the quality of life of the older generation.

The reasons why homeostatic systems deteriorate in the elderly is not well understood. However, there is growing evidence for autonomic nervous system dysfunction in a wide range of chronic conditions of old age. Whilst it is known that age and a sedentary lifestyle are risk factors in the development of autonomic imbalance, there is evidence in humans that physical activity can both prevent or delay its development, and ameliorate the condition once established. We hypothesise that the development and/or maintenance of 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 lifestyle factors (eg. physical activity) and age. In order to test this hypothesis, will identify putative networks by carrying out detailed and comprehensive transcriptome analysis on brain regions involved in the regulation of autonomic outflow. Expression will be compared in normal animals (Wistar Kyoto rats), and in animals with a genetic predisposition to autonomic imbalance characterised by the development of hypertension and loss of heart rate variability (Spontaneously Hypertensive rats). We will compare gene expression in young and old animals, and we will ask if expression is altered by physical exercise, initiated either before or after the onset of hypertension. Using bioinformatic tools, we will construct putative pathways and networks that may govern these processes, and we will identify nodal genes with many connections. We will then test whether these hubs are important physiologically by altering their expression using in vivo somatic gene transfer approaches. This will be followed by robust physiological analysis (arterial blood pressure, heart rate/period, spontaneous cardiac baroreceptor reflex gain) that will reveal the roles of these hub genes in network stability and their response to external cues such as exercise training.

Academic Impact
In the short-term, the proposed studies will generate important new basic scientific knowledge about the way that the brain regulates homeostasis, about how these processes go wrong as we age, and how this deterioration is ameliorated by physical activity. The new information gleaned from these studies will be published in high-impact, peer reviewed international journals, and will also be presented at national and international conferences. We will also train new scientific researchers in Brazil, whose integrative skills will be in great demand. Our collaborative activities will also contribute to scientific capacity building in Brazil, through the transfer of key technologies such as the use of viral vectors in physiological research. In contrast, the research will bolster in vivo systems physiology in the UK, which has been in serious decline of late yet crucial for the understanding of the function of the genome.
Economic Impact
It is unlikely that our results will be clinically or commercially relevant, at least in the short term. However, it is possible that genes will be uncovered that are possible targets for the treatment or amelioration of ageing disorders. If this is the case, we will seek to exploit our findings in collaboration with the BBSRC and the University of Bristol Research and Enterprise Development unit. We already have excellent links with industry (Source BioScience, DuPont, Merck Sharp and Dohme, Pfizer, Astellas, Eli Lilly, Ardian). In the long-term, it may well be that our findings will improve quality of life and functionality in old age. This would reduce welfare and health costs whilst boosting economic productivity.
Social Impact
We hope that the knowledge gleaned from the proposed studies will ultimately enhance quality of life, health and well being as we get older. This has clear benefits for the individual, for families and for society in general. We also envisage a contribution towards evidence based policy-making and influencing public policies and legislation at a local, regional, national and
international level on the benefits of exercise for health. These scientific advancements will have global impact, as the ageing population is a world-wide phenomenon. Policy makers and governments are keen to encourage us to exercise, but this has not been based on too much solid empirical evidence of the benefits, particularly in relation to combating diseases of old age. Our studies will provide such evidence through revelation of mechanistic insights. As such we also expect an impact with occupational- and physio-therapists, and with sporting organisations, clubs and charities, gyms and the general "keep-fit" fraternity.