Determinants of healthy ageing in the Whitehall II study

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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.