Determinants of healthy ageing in the Whitehall II study

利用著名的白厅II研究（n=10,000）和各种重复队列（n= 170,000）的25年重复数据，我们将检查成年期认知储备、长期和不断变化的健康行为和心理社会因素（体育活动、饮食、社会参与）对年龄相关功能状况(如：(1)认知障碍、（2)晚发性抑郁症和(3)残疾）风险的预测程度。此外，我们将探讨这些关联的生物学基础。除了研究危险因素改变大脑结构和功能的能力外，人们对大脑抵抗这些变化的能力也越来越感兴趣。老化和认知的脚手架理论和认知储备强调了代偿活动在应对神经结构和功能下降所带来的挑战中的作用。更高的认知储备将使个体能够忍受大脑中与年龄相关的变化和与疾病相关的病理，而不会出现临床症状。白厅II研究采用社会经济地位、教育、职业经历和心理参与等指标，以评估认知储备在塑造认知衰老轨迹中所起的作用。我们假设高等教育以及社会关系和背景因素，如社会经济环境、退休和丧亲之痛，在很大程度上改变了晚年抑郁和身体功能的风险。受衰老过程影响的合理生物介质包括成年期低度慢性炎症、血管和代谢变化（血压、血糖）。我们将使用重复数据来量化它们的影响，并确定社会关系和环境因素是否会诱导生物学变化，或者炎症和心脏代谢谱的年龄相关变化是否独立于上游因素驱动衰老结果。我们之前已经表明，考虑变化对于理解情境行为影响至关重要。使用重复数据测量的随时间变化的健康行为占心血管死亡率社会梯度的45%，而使用这些行为的单一基线测量则占29%。随时间变化的健康行为，如吸烟、饮酒、饮食和体育活动，在成年过程中对老年抑郁症和残疾变化的影响程度尚不清楚，因此将在本研究中进行研究。在检查成人生活过程中致残过程的决定因素时，我们的主要结果是虚弱，这是一种由多系统储备能力下降导致的综合征，这样一些生理系统就接近或超过了症状性临床失败的阈值。重要的是，原发性虚弱不是合并症的结果，例如明显的心血管疾病（称为“继发性”虚弱）。为了捕捉残疾的不同阶段，我们将使用一系列额外的结果来表征功能丧失：身体功能（平衡、上半身和下半身力量、步态速度）、住院（包括骨折）、日常生活活动能力的丧失，最后是自主性和制度化的丧失。该方案将对健康老龄化的决定因素提供重要见解。

Utilising 25-year repeat data from the prestigious Whitehall II study (n=10,000) and various replication cohorts (total n=170,000), we will examine the extent to which cognitive reserve, long-term and changing health behaviours and psychosocial factors (physical activity, diet, social engagement) in adulthood predict the risk for age-related functional conditions, such as (1) cognitive impairment, (2) late-onset depression, and (3) disability. Furthermore, we will explore the biological underpinnings of these associations. Besides research on the ability of risk factors to change brain structure and function, there is increasing interest in the brain's ability to resist these changes. The scaffolding theory of ageing and cognition and that of cognitive reserve highlight the role of compensatory activity in response to the challenges posed by declining neural structures and function. Higher cognitive reserve would allow individuals to tolerate age-related changes and disease-related pathology in the brain without developing clinical symptoms. The Whitehall II study with measures of socioeconomic position, education, occupational history and mental engagement is uniquely characterised to assess the role played by cognitive reserve in shaping cognitive ageing trajectories. We hypothesise that higher education as well as social relations and contextual factors, such as socioeconomic circumstances, retirement and bereavement, importantly modify the risk for later-life depression and physical functioning. Plausible biological mediators, also influenced by ageing process, include adulthood low-grade chronic inflammation, vascular and metabolic changes (blood pressure, blood sugar). We will use repeat data to quantify their impact and to determine whether social relations and contextual factors induce change in biology or whether age-related changes in inflammation and cardiometabolic profile are driving ageing outcomes independently of upstream factors.We have previously shown that taking into account change is crucial in understanding contextual behavioural effects. Time varying health behaviours, measured with repeat data, accounted for 45% of the social gradient in cardiovascular mortality compared with 29% with a single baseline measure of these behaviours. The extent to which time varying health behaviours, such as smoking, alcohol intake, diet, and physical activity, over the adult life course account of the variation in old-age depression and disability is unknown, and therefore will be examined in this study.In examining adult-life course determinants of the disabling process, our main outcome is frailty, a syndrome which results from a multi-system reduction in reserve capacity such that a number of physiological systems become close to, or past, the threshold of symptomatic clinical failure. Importantly, primary frailty is not a consequence of comorbidity, such as overt cardiovascular disease (referred to as "secondary" frailty). In order to capture the different stages of disability we will use a range of additional outcomes to characterise functional loss: physical function (balance, upper and lower body strength, gait speed), hospitalisation (including fractures), loss of ability to perform activities of daily living and, finally, loss of autonomy and institutionalization.This programme will provide important insights into determinants of healthy ageing.