Concurrent multi-organ responses to chronic physical activity and inactivity intervention to increase research discovery in human health and wellbeing

对慢性身体活动和不活动干预的并发多器官反应，以增加人类健康和福祉的研究发现

• 批准号: BB/X015173/1
• 负责人: Paul Greenhaff
• 金额: $ 218.07万
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FX015173%2F1
• 关键词: Concurrent; multi; organ; responses; chronic

The UK population is getting older, with those aged 65 years and over set to increase to 1 in 4 of the population by 2039. However in the last 30 years the maintenance of good health has not kept pace with this increased lifespan. It follows, that on average, adults in the UK typically spend the last decade of their life in poor-health, which poses major consequences to health and social care services, employment, the individual and their family. The COVID-19 pandemic has further exposed our unhealthy nation, and raised government and public health awareness around the associations between physical inactivity, sedentarism and poor health, which is now a major public health priority. To address this, the UK Government has set a target of "at least five extra healthy, independent years of life by 2035". Furthermore, number of recent high-level reports have highlighted that the UK must maximise strengths in research, technology, innovation, and data analysis to improve the state of the nation's health. It is vital for individual wellbeing and the UK economy that more adults reach old age in better health and maintain a good quality of life for a greater proportion of their older age. Key to achieving this is a requirement to understand the mechanisms underpinning the trajectory of health progression as we age.On this basis, this application sets out to provide ground-breaking whole body and multi-organ insights into physiological and metabolic responses to 6 months of highly controlled physical activity and inactivity intervention in people at key risk of inactivity induced decline (overweight, 55-65 year old men and women). This will be realised through a programme four integrated work packages (WPs):WP 1: Longitudinal physical activity and inactivity interventions that will form the bedrock of the programme of research into which new tools, technologies and multivalent, trans-organ approaches (work packages 2 - 4) will be incorporated at multiple time points.WP 2: involves participants undergoing comprehensive multi-organ magnetic resonance imaging and spectroscopy measurements in the resting state and during within-bore exercise to manifest metabolic and physiological adaptations to the physical activity interventions.WP 3: involves administration of oral stable isotope tracers to provide insight of the impact of the study physical activity interventions on skeletal muscle protein synthesis and muscle protein degradation under "free-living" conditions.WP 4: involves measuring changes in the plasma metabolome (all metabolite levels) in response to physical activity interventions which will represent the culmination of all biological processes within the cell, tissue or whole system.The analytical outputs from WPs 2 to 4 will be deployed alongside the physiological measurements of WP 1 to provide an unprecedented rich multi-dimensional view of human adaptation to altered physical activity. It will ultimately aim to identify measures that indicate organ level adaptation and hence can be deployed as biomarkers in the future.This programme of research will dovetail world-leading magnetic resonance technology, biotechnology and human biology expertise to permit a comprehensive array of non- and minimally invasive structural, metabolic and physiological endpoints to be quantified in the same individuals and monitored over the course of 6 months physical activity interventions. This will deliver unprecedented mechanistic insight of physiological adaptations where and when they happen in the human body and will push the boundary of bioscience discovery. Ultimately it will enable recommendations to be made which will maximise increases in functional capacity in adults at risk of decline, thereby helping adults reach old age in good health. Furthermore, we will make this unprecedented data set and sample/tissue archive available to future researchers to address novel questions/hypotheses.

英国人口正在老龄化，到2039年，65岁及以上的人口将增加到四分之一。然而，在过去的30年里，保持良好的健康并没有跟上寿命的增长。因此，平均而言，英国成年人通常在生命的最后十年中健康状况不佳，这对健康和社会保健服务，就业，个人及其家庭造成了重大影响。COVID-19疫情进一步暴露了我们国家的不健康状况，并提高了政府和公众对缺乏运动、久坐和健康状况不佳之间关系的健康意识，这是现在一个主要的公共卫生优先事项。为了解决这一问题，英国政府制定了一个目标，即“到2035年，至少增加五年的健康和独立生活”。此外，最近的一些高级别报告强调，英国必须最大限度地发挥研究，技术，创新和数据分析的优势，以改善国家的健康状况。这对个人福祉和英国经济至关重要，更多的成年人以更好的健康状态进入老年，并在更大比例的老年时期保持良好的生活质量。实现这一目标的关键是需要了解随着年龄增长，健康发展轨迹的基础机制。在此基础上，该应用程序旨在为处于不活动导致衰退的关键风险的人群提供突破性的全身和多器官洞察，以了解6个月高度控制的身体活动和不活动干预的生理和代谢反应（超重，55-65岁的男性和女性）。这将通过四个综合工作包（WP）方案实现：WP 1：纵向身体活动和不活动干预措施，这将成为研究方案的基石，新工具，技术和多价，跨器官方法（工作包2 - 4）将在多个时间点纳入。WP 2：涉及参与者在静息状态下和在进行锻炼，以显示对身体活动干预的代谢和生理适应。WP 3：包括口服稳定同位素示踪剂，以了解研究体力活动干预对骨骼肌的影响蛋白质合成和肌肉蛋白质降解“自由生活”的条件下。WP 4：包括测量血浆代谢组的变化（所有代谢物水平）响应于将代表细胞内所有生物过程的顶点的身体活动干预，WP 2至4的分析输出将与WP 1的生理测量一起部署，以提供前所未有的丰富的多维视图人类适应改变体力活动。该研究计划将融合世界领先的磁共振技术、生物技术和人类生物学专业知识，以实现一系列全面的非侵入性和微创结构、代谢和生理终点在相同的个体中进行量化，并在6个月的身体活动干预过程中进行监测。这将提供前所未有的生理适应机制的洞察力，它们何时何地发生在人体中，并将推动生物科学发现的边界。最终，它将使人们能够提出建议，最大限度地提高面临衰退风险的成年人的功能能力，从而帮助成年人健康地进入老年。此外，我们将使这一前所未有的数据集和样本/组织档案提供给未来的研究人员，以解决新的问题/假设。