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

据估计，到2050年，25%的人口将超过65岁。虽然寿命的大幅增加值得庆祝，但由此带来的人口结构变化是一个重大挑战。这是因为老年的幸福和健康并没有随着寿命的延长而成比例地改善。这种不平衡不仅影响到个人，他们显然希望在退休后过上健康的生活，而且还给家庭和社会带来了相当大的经济和社会负担。老年人身体系统恶化的原因尚不清楚。然而，越来越多的证据表明，大脑功能障碍与老年的一系列慢性病有关。有两种可能的方法来解决老年虚弱的问题。一种是将问题视为医学问题，解决方案是随着个人年龄的增长而增加临床干预。另一种更可取的方法是，将老年的恶化视为一个无法预防、但可以改善的过程。人们认识到，特定的环境条件、营养选择、生活事件和生活方式在遗传基础上起作用，随着我们年龄的增长，可能会导致幸福，也可能会导致健康不佳。因此，例如，有相当多的轶事证据表明，久坐的生活方式会导致老年健康状况不佳，而体育活动则有长期的健康和福祉好处。然而，对这些现象的生理学理解还很少。我们建议在自主神经失衡的大鼠模型中研究衰老和体力活动的影响，随着年龄的增长，这种模型会自发地发展成高血压。我们将使用使我们能够识别和量化所有在参与自主神经系统活动的大脑部分表达的基因的技术。然后我们将询问基因表达如何随着年龄的变化而变化。我们还将允许这些动物锻炼，我们将测量随着它们年龄的增长，这将如何影响它们的身体健康。我们将寻找通过运动而开启或关闭的基因，我们将使用最先进的基因操作技术来确定它们在动物体内的生理功能(S)。总体而言，我们建议识别衰老基因(大脑不良基因)和锻炼基因(大脑良好基因)，并了解这一点，我们将发现我们是否可以改善与衰老相关的一些病理生理问题。这些知识有朝一日可能有助于提高老一辈人的生活质量。

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.