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。虽然寿命的急剧增加值得庆祝，但由此产生的人口变化代表了一个重大挑战。这是因为老年人的幸福感和健康状况并没有随着寿命的延长而相应改善。这种不平衡不仅影响到显然希望在退休后享受健康生活的个人，而且还给家庭和社会带来了相当大的经济和社会负担。老年人身体系统退化的原因尚不清楚。然而，越来越多的证据表明，大脑功能障碍与老年的各种慢性疾病有关。据认为，负责控制某些身体功能的自主神经系统出现了失衡，这可能导致与衰老相关的慢性病理状况，如肥胖、胰岛素抵抗、糖尿病、心力衰竭、中风和高血压。老年虚弱的问题有两种可能的解决方法。一种是将问题视为医学问题，随着个人年龄的增长，解决方案在于增加临床干预。另一种更可取的方法是将老年的恶化视为一个无法阻止但可以改善的过程。人们认识到，随着年龄的增长，特定的环境条件、营养选择、生活事件和生活方式会对我们的健康或不健康产生影响，这些都与基因基础有关。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，而体育活动对健康和福祉有长期的好处。然而，对这些现象的生理理解是不足的。我们建议研究衰老和身体活动对自主神经失衡的大鼠模型的影响，这种模型随着年龄的增长会自发地产生高血压。我们将使用技术，使我们能够识别和量化所有基因，这些基因在参与自主神经系统活动的大脑部分中表达。然后我们会问基因表达是如何随着年龄变化的。我们还将允许这些动物进行锻炼，我们将测量随着年龄的增长，这对它们的身体健康有何影响。我们将寻找通过运动开启或关闭的基因，我们将使用最先进的基因操作技术来确定它们在动物中的生理功能。总的来说，我们建议识别衰老基因（坏的大脑基因）和运动基因（好的大脑基因），知道这一点，我们将发现我们是否可以改善一些与衰老相关的病理生理问题。这些知识有一天可能有助于提高老年人的生活质量。

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.