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1.  Long-term Adherence to Healthy Dietary Guidelines and Chronic Inflammation in the Prospective Whitehall II Study☆ 
The American Journal of Medicine  2015;128(2):152-160.e4.
Inflammation plays an important role in the cause of cardiovascular diseases and may contribute to the association linking an unhealthy diet to chronic age-related diseases. However, to date the long-term associations between diet and inflammation have been poorly described. Our aim was to assess the extent to which adherence to a healthy diet and dietary improvements over a 6-year exposure period prevented subsequent chronic inflammation over a 5-year follow-up in a large British population of men and women.
Data were drawn from 4600 adults (mean ± standard deviation, age 49.6 ± 6.1 years, 28% were women) from the prospective Whitehall cohort II study. Adherence to a healthy diet was measured using Alternative Healthy Eating Index (AHEI) scores in 1991-1993 (50.7 ± 11.9 points) and 1997-1999 (51.6 ± 12.4 points). Chronic inflammation, defined as average levels of serum interleukin-6 from 2 measures 5 years apart, was assessed in 1997-1999 and 2002-2004.
After adjustment for sociodemographic factors, health behaviors, and health status, participants who maintained a high AHEI score (ie, a healthy diet, n = 1736, 37.7%) and those who improved this score over time (n = 681, 14.8%) showed significantly lower mean levels of interleukin-6 (1.84 pg/mL, 95% confidence interval [CI], 1.71-1.98 and 1.84 pg/mL, 95% CI, 1.70-1.99, respectively) than those who had a low AHEI score (n = 1594, 34.6%) over the 6-year exposure period (2.01 pg/mL, 95% CI, 1.87-2.17).
These data suggest that maintaining and improving adherence to healthy dietary recommendations may reduce the risk of long-term inflammation.
PMCID: PMC4315808  PMID: 25305231
Alternative Healthy Eating Index; Diet quality indices; Inflammatory marker; Interleukin-6; Middle-aged population; Nutritional Epidemiology; Prospective cohort
2.  Bidirectional association between physical activity and symptoms of anxiety and depression: the Whitehall II study 
European journal of epidemiology  2012;27(7):537-546.
Although it has been hypothesized that the association of physical activity with depressive and anxiety symptoms is bidirectional, few studies have examined this issue in a prospective setting. We studied this bidirectional association using data on physical activity and symptoms of anxiety and depression at three points in time over 8 years. A total of 9,309 participants of the British Whitehall II prospective cohort study provided data on physical activity, anxiety and depression symptoms and 10 covariates at baseline in 1985. We analysed the associations of physical activity with anxiety and/or depression symptoms using multinomial logistic regression (with anxiety and depression symptoms as dependent variables) and binary logistic regression (with physical activity as the dependent variable). There was a cross-sectional inverse association between physical activity and anxiety and/or depressive symptoms at baseline (ORs between 0.63 and 0.72). In cumulative analyses, regular physical activity across all three data waves, but not irregular physical activity, was associated with reduced likelihood of depressive symptoms at follow-up (OR = 0.71, 95 % CI 0.54, 0.99). In a converse analysis, participants with anxiety and depression symptoms at baseline had higher odds of not meeting the recommended levels of physical activity at follow-up (OR = 1.79, 95 % CI 1.17, 2.74). This was also the case in individuals with anxiety and/or depression symptoms at both baseline and follow-up (OR = 1.70, 95 % CI 1.10, 2.63). The association between physical activity and symptoms of anxiety and/or depression appears to be bidirectional.
PMCID: PMC4180054  PMID: 22623145
Common mental disorders; Physical activity; Bidirectional association; Longitudinal studies
3.  Associations Between Change in Sleep Duration and Inflammation: Findings on C-reactive Protein and Interleukin 6 in the Whitehall II Study 
American Journal of Epidemiology  2013;178(6):956-961.
Cross-sectional evidence suggests associations between sleep duration and levels of the inflammatory markers, C-reactive protein and interleukin-6. This longitudinal study uses data from the London-based Whitehall II study to examine whether changes in sleep duration are associated with average levels of inflammation from 2 measures 5 years apart. Sleep duration (≤5, 6, 7, 8, ≥9 hours on an average week night) was assessed in 5,003 middle-aged women and men in 1991/1994 and 1997/1999. Fasting levels of C-reactive protein and interleukin-6 were measured in 1997/1999 and 2002/2004. Cross-sectional analyses indicated that shorter sleep is associated with higher levels of inflammatory markers. Longitudinal analyses showed that each hour per night decrease in sleep duration between 1991/1994 and 1997/1999 was associated with higher levels of C-reactive protein (8.1%) and interleukin-6 (4.5%) averaged across measures in 1997/1999 and 2002/2004. Adjustment for longstanding illness and major cardiometabolic risk factors indicated that disease processes may partially underlie these associations. An increase in sleep duration was not associated with average levels of inflammatory markers. These results suggest that both short sleep and reductions in sleep are associated with average levels of inflammation over a 5-year period.
PMCID: PMC3817449  PMID: 23801012
change in sleep duration; C-reactive protein; inflammatory markers; interleukin-6; sleep duration
4.  Increased risk of coronary heart disease among individuals reporting adverse impact of stress on their health: the Whitehall II prospective cohort study 
European Heart Journal  2013;34(34):2697-2705.
Response to stress can vary greatly between individuals. However, it remains unknown whether perceived impact of stress on health is associated with adverse health outcomes. We examined whether individuals who report that stress adversely affects their health are at increased risk of coronary heart disease (CHD) compared with those who report that stress has no adverse health impact.
Methods and results
Analyses are based on 7268 men and women (mean age: 49.5 years, interquartile range: 11 years) from the British Whitehall II cohort study. Over 18 years of follow-up, there were 352 coronary deaths or first non-fatal myocardial infarction (MI) events. After adjustment for sociodemographic characteristics, participants who reported at baseline that stress has affected their health ‘a lot or extremely’ had a 2.12 times higher (95% CI 1.52–2.98) risk of coronary death or incident non-fatal MI when compared with those who reported no effect of stress on their health. This association was attenuated but remained statistically significant after adjustment for biological, behavioural, and other psychological risk factors including perceived stress levels, and measures of social support; fully adjusted hazard ratio: 1.49 (95% CI 1.01–2.22).
In this prospective cohort study, the perception that stress affects health, different from perceived stress levels, was associated with an increased risk of coronary heart disease. Randomized controlled trials are needed to determine whether disease risk can be reduced by increasing clinical attention to those who complain that stress greatly affects their health.
PMCID: PMC3766148  PMID: 23804585
Epidemiology; Stress; Coronary heart disease; Prospective studies
5.  Study protocol: the Whitehall II imaging sub-study 
BMC Psychiatry  2014;14:159.
The Whitehall II (WHII) study of British civil servants provides a unique source of longitudinal data to investigate key factors hypothesized to affect brain health and cognitive ageing. This paper introduces the multi-modal magnetic resonance imaging (MRI) protocol and cognitive assessment designed to investigate brain health in a random sample of 800 members of the WHII study.
A total of 6035 civil servants participated in the WHII Phase 11 clinical examination in 2012–2013. A random sample of these participants was included in a sub-study comprising an MRI brain scan, a detailed clinical and cognitive assessment, and collection of blood and buccal mucosal samples for the characterisation of immune function and associated measures. Data collection for this sub-study started in 2012 and will be completed by 2016. The participants, for whom social and health records have been collected since 1985, were between 60–85 years of age at the time the MRI study started. Here, we describe the pre-specified clinical and cognitive assessment protocols, the state-of-the-art MRI sequences and latest pipelines for analyses of this sub-study.
The integration of cutting-edge MRI techniques, clinical and cognitive tests in combination with retrospective data on social, behavioural and biological variables during the preceding 25 years from a well-established longitudinal epidemiological study (WHII cohort) will provide a unique opportunity to examine brain structure and function in relation to age-related diseases and the modifiable and non-modifiable factors affecting resilience against and vulnerability to adverse brain changes.
PMCID: PMC4048583  PMID: 24885374
Epidemiology; Magnetic resonance imaging; Diffusion tensor imaging; White matter; Functional MRI; Connectome; Resting state brain networks; Neuropsychology; Dementia; Affective disorders
6.  Predicting cognitive decline 
Neurology  2013;80(14):1300-1306.
Our aim was to compare 2 Framingham vascular risk scores with a dementia risk score in relation to 10-year cognitive decline in late middle age.
Participants were men and women with mean age of 55.6 years at baseline, from the Whitehall II study, a longitudinal British cohort study. We compared the Framingham general cardiovascular disease risk score and the Framingham stroke risk score with the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) risk score that uses risk factors in midlife to estimate risk of late-life dementia. Cognitive tests included reasoning, memory, verbal fluency, vocabulary, and global cognition, assessed 3 times over 10 years.
Higher cardiovascular disease risk and higher stroke risk were associated with greater cognitive decline in all tests except memory; higher dementia risk was associated with greater decline in reasoning, vocabulary, and global cognitive scores. Compared with the dementia risk score, cardiovascular and stroke risk scores showed slightly stronger associations with 10-year cognitive decline; these differences were statistically significant for semantic fluency and global cognitive scores. For example, cardiovascular disease risk was associated with −0.06 SD (95% confidence interval [CI] = −0.08, −0.05) decline in the global cognitive scores over 10 years whereas dementia risk was associated with −0.03 SD (95% CI = −0.04, −0.01) decline (difference in β coefficients = 0.03; 95% CI = 0.01, 0.05).
The CAIDE dementia and Framingham risk scores predict cognitive decline in late middle age but the Framingham risk scores may have an advantage over the dementia risk score for use in primary prevention for assessing risk of cognitive decline and targeting of modifiable risk factors.
PMCID: PMC3656460  PMID: 23547265
7.  Glycemia, Insulin Resistance, Insulin Secretion, and Risk of Depressive Symptoms in Middle Age 
Diabetes Care  2013;36(4):928-934.
The extent to which abnormal glucose metabolism increases the risk of depression remains unclear. In this study, we investigated prospective associations of levels of fasting glucose and fasting insulin and indices of insulin resistance and secretion with subsequent new-onset depressive symptoms (DepS).
In this prospective cohort study of 3,145 adults from the Whitehall II Study (23.5% women, aged 60.6 ± 5.9 years), baseline examination included fasting glucose and insulin level, the homeostasis model assessment of insulin resistance (HOMA2-%IR), and the homeostasis model assessment of β-cell insulin secretion (HOMA2-%B). DepS (Center for Epidemiologic Studies Depression Scale ≥16 or use of antidepressive drugs) were assessed at baseline and at 5-year follow-up.
Over the 5-year follow-up, DepS developed in 142 men and 84 women. Women in the lowest quintile of insulin secretion (HOMA2-%B ≤55.3%) had 2.18 (95% CI 1.25–3.78) times higher odds of developing DepS than those with higher insulin secretion. This association was not accounted for by inflammatory markers, cortisol secretion, or menopausal status and hormone replacement therapy. Fasting insulin measures were not associated with DepS in men, and fasting glucose measures were not associated with new-onset DepS in either sex.
Low insulin secretion appears to be a risk factor for DepS in middle-aged women, although further work is required to confirm this finding.
PMCID: PMC3609527  PMID: 23230097
8.  Education Modifies the Association of Wealth with Obesity in Women in Middle-Income but Not Low-Income Countries: An Interaction Study Using Seven National Datasets, 2005-2010 
PLoS ONE  2014;9(3):e90403.
Education and wealth may have different associations with female obesity but this has not been investigated in detail outside high-income countries. This study examines the separate and inter-related associations of education and household wealth in relation to obesity in women in a representative sample of low- and middle-income countries (LMICs).
The seven largest national surveys were selected from a list of Demographic and Health Surveys (DHS) ordered by decreasing sample size and resulted in a range of country income levels. These were nationally representative data of women aged 15–49 years collected in the period 2005–2010. The separate and joint effects, unadjusted and adjusted for age group, parity, and urban/rural residence using a multivariate logistic regression model are presented
In the four middle-income countries (Colombia, Peru, Jordan, and Egypt), an interaction was found between education and wealth on obesity (P-value for interaction <0.001). Among women with no/primary education the wealth effect was positive whereas in the group with higher education it was either absent or inverted (negative). In the poorer countries (India, Nigeria, Benin), there was no evidence of an interaction. Instead, the associations between each of education and wealth with obesity were independent and positive. There was a statistically significant difference between the average interaction estimates for the low-income and middle-income countries (P<0.001).
The findings suggest that education may protect against the obesogenic effects of increased household wealth as countries develop. Further research could examine the factors explaining the country differences in education effects.
PMCID: PMC3946446  PMID: 24608086
9.  Job insecurity and incident coronary heart disease: the Whitehall II prospective cohort study 
Atherosclerosis  2013;227(1):178-181.
This study uses a prospective design to examine the association between self-reported job insecurity and incident coronary heart disease; an association which has been little investigated previously.
Participants were 4174 British civil servants (1236 women and 2938 men), aged 42 to 56 with self-reported data on job insecurity and free from coronary heart disease at baseline (1995-6). These participants were followed until 2002-4, an average of 8.6 years, for incident fatal coronary heart disease, clinically verified incident non-fatal myocardial infarction, or definite angina (a total of 168 events).
Cox proportional hazard models adjusted for socio-demographic characteristics showed job insecurity to be associated with a 1.42-fold (95% CI, 1.05-1.93) risk of incident coronary heart disease compared with secure employment. Adjustment for physiological and behavioral cardiovascular risk factors had little effect on this estimate; 1.38 (1.01-1.88).
This study suggests that job insecurity may adversely affect coronary health.
PMCID: PMC3940189  PMID: 23332775
job insecurity; stress; incident coronary heart disease; angina; middle-aged; prospective
10.  Trajectories of the Framingham general cardiovascular risk profile in midlife and poor motor function later in life: The Whitehall II study☆☆☆ 
Vascular risk factors are associated with increased risk of cognitive impairment and dementia, but their association with motor function, another key feature of aging, has received little research attention. We examined the association between trajectories of the Framingham general cardiovascular disease risk score (FRS) over midlife and motor function later in life.
A total of 5376 participants of the Whitehall II cohort study (29% women) who had up to four repeat measures of FRS between 1991–1993 (mean age = 48.6 years) and 2007–2009 (mean age = 65.4 years) and without history of stroke or coronary heart disease in 2007–2009 were included. Motor function was assessed in 2007–2009 through objective tests (walking speed, chair rises, balance, finger tapping, grip strength). We used age- and sex-adjusted linear mixed models.
Participants with poorer performances for walking speed, chair rises, and balance in 2007–2009 had higher FRS concurrently and also in 1991–1993, on average 16 years earlier. These associations were robust to adjustment for cognition, socio-economic status, height, and BMI, and not explained by incident mobility limitation prior to motor assessment. No association was found with finger tapping and grip strength.
Cardiovascular risk early in midlife is associated with poor motor performances later in life. Vascular risk factors play an important and under-recognized role in motor function, independently of their impact on cognition, and suggest that better control of vascular risk factors in midlife may prevent physical impairment and disability in the elderly.
PMCID: PMC3991855  PMID: 24461963
CVD, cardiovascular disease; FRS, Framingham general cardiovascular disease risk score; SES, socioeconomic status; BMI, body mass index; SD, standard deviation; Cardiovascular risk score; Motor function; Aging; Stroke; Cohort study
11.  Job Strain and the Risk of Inflammatory Bowel Diseases: Individual-Participant Meta-Analysis of 95 000 Men and Women 
PLoS ONE  2014;9(2):e88711.
Background and Aims
Many clinicians, patients and patient advocacy groups believe stress to have a causal role in inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis. However, this is not corroborated by clear epidemiological research evidence. We investigated the association between work-related stress and incident Crohn's disease and ulcerative colitis using individual-level data from 95 000 European adults.
We conducted individual-participant data meta-analyses in a set of pooled data from 11 prospective European studies. All studies are a part of the IPD-Work Consortium. Work-related psychosocial stress was operationalised as job strain (a combination of high demands and low control at work) and was self-reported at baseline. Crohn's disease and ulcerative colitis were ascertained from national hospitalisation and drug reimbursement registers. The associations between job strain and inflammatory bowel disease outcomes were modelled using Cox proportional hazards regression. The study-specific results were combined in random effects meta-analyses.
Of the 95 379 participants who were free of inflammatory bowel disease at baseline, 111 men and women developed Crohn's disease and 414 developed ulcerative colitis during follow-up. Job strain at baseline was not associated with incident Crohn's disease (multivariable-adjusted random effects hazard ratio: 0.83, 95% confidence interval: 0.48, 1.43) or ulcerative colitis (hazard ratio: 1.06, 95% CI: 0.76, 1.48). There was negligible heterogeneity among the study-specific associations.
Our findings suggest that job strain, an indicator of work-related stress, is not a major risk factor for Crohn's disease or ulcerative colitis.
PMCID: PMC3928274  PMID: 24558416
12.  Association Between Questionnaire- and Accelerometer-Assessed Physical Activity: The Role of Sociodemographic Factors 
American Journal of Epidemiology  2014;179(6):781-790.
The correlation between objective and self-reported measures of physical activity varies between studies. We examined this association and whether it differed by demographic factors or socioeconomic status (SES). Data were from 3,975 Whitehall II (United Kingdom, 2012–2013) participants aged 60–83 years, who completed a physical activity questionnaire and wore an accelerometer on their wrist for 9 days. There was a moderate correlation between questionnaire- and accelerometer-assessed physical activity (Spearman's r = 0.33, 95% confidence interval: 0.30, 0.36). The correlations were higher in high-SES groups than in low-SES groups (P 's = 0.02), as defined by education (r = 0.38 vs. r = 0.30) or occupational position (r = 0.37 vs. r = 0.29), but did not differ by age, sex, or marital status. Of the self-reported physical activity, 68.3% came from mild activities, 25% from moderate activities, and only 6.7% from vigorous activities, but their correlations with accelerometer-assessed total physical activity were comparable (range of r 's, 0.21–0.25). Self-reported physical activity from more energetic activities was more strongly associated with accelerometer data (for sports, r = 0.22; for gardening, r = 0.16; for housework, r = 0.09). High-SES persons reported more energetic activities, producing stronger accelerometer associations in these groups. Future studies should identify the aspects of physical activity that are most critical for health; this involves better understanding of the instruments being used.
PMCID: PMC3939851  PMID: 24500862
accelerometry; cohort studies; elderly; epidemiologic methods; physical activity; questionnaires
13.  Physical activity and inflammatory markers over 10 years follow up in men and women from the Whitehall II cohort study 
Circulation  2012;126(8):928-933.
Inflammatory processes are putative mechanisms underlying the cardio-protective effects of physical activity. An inverse association between physical activity and inflammation has been demonstrated but no long-term prospective data are available. We therefore examined the association between physical activity and inflammatory markers over a 10-year follow-up period.
Methods and Results
Participants were 4289 men and women (mean age 49.2 years) from the Whitehall II cohort study. Self-reported physical activity and inflammatory markers (serum high-sensitivity C-reactive protein [CRP] and interleukin-6 [IL-6]) were measured at baseline (1991) and follow-up (2002). Forty-nine percent of the participants adhered to standard physical activity recommendations for cardiovascular health (2.5 hours per week moderate to vigorous physical activity) across all assessments. Physically active participants at baseline had lower CRP and IL6 levels and this difference remained stable over time. In comparison to participants that rarely adhered to physical activity guidelines over the 10 years follow-up, the high adherence group displayed lower logeCRP (β=−0.07, 95% CI, −0.12, −0.02) and logeIL-6 (β=−0.07, 95% CI, −0.10, −0.03) at follow up after adjustment for a range of covariates. Compared to participants that remained stable, those that reported an increase in physical activity of at least 2.5 hours/wk displayed lower loge CRP (B coefficient =−0.05, 95% CI, −0.10, −0.001) and loge IL-6 (B coefficient =−0.06, 95% CI, −0.09, −0.03) at follow up.
Regular physical activity is associated with lower markers of inflammation over 10 years of follow-up and thus may be important in preventing the pro-inflammatory state seen with ageing.
PMCID: PMC3890998  PMID: 22891048
Ageing; C-reactive protein; exercise; physical activity; inflammation
14.  Adiponectin Trajectories Before Type 2 Diabetes Diagnosis 
Diabetes Care  2012;35(12):2540-2547.
The role of adiponectin in the natural history of diabetes is not well characterized. We set out to characterize prediagnosis trajectories of adiponectin in individuals who develop type 2 diabetes.
In a case-cohort study (335 incident diabetes case and 2,474 noncase subjects) nested in the Whitehall II study, serum adiponectin was measured up to three times per participant (1991–1993, 1997–1999, and 2003–2004). Multilevel models adjusted for age and ethnicity were fitted to assess 13-year trajectories of log-transformed adiponectin preceding diabetes diagnosis or a randomly selected time point during follow-up (year0) based on 755/5,095 (case/noncase) person-examinations.
Adiponectin levels were lower in diabetes case than in noncase subjects (median 7,141 [interquartile range 5,187–10,304] vs. 8,818 [6,535–12,369] ng/mL at baseline, P < 0.0001). Control subjects showed a modest decline in adiponectin throughout follow-up (0.3% per year, P < 0.0001) at higher levels in women than in men (difference at year0: 5,358 ng/mL, P < 0.0001). Female case and early-onset case (age at diagnosis <52 years) subjects had a steeper decline than control subjects (slope difference −1.1% per year, P = 0.001 in females, −1.6% per year in early-onset case subjects, P = 0.034). In men, adiponectin slopes for case and noncase subjects were parallel. The slope differences by diabetes onset were largely attenuated after adjustment for changes in obesity, whereas the sex-specific slope differences were independent of obesity.
Lower adiponectin levels were observed already a decade before the diagnosis of diabetes. The marked sex difference in trajectories suggests that sex-specific mechanisms affect the association between adiponectin levels and diabetes development.
PMCID: PMC3507593  PMID: 22933430
15.  Work Characteristics and Personal Social Support as Determinants of Subjective Well-Being 
PLoS ONE  2013;8(11):e81115.
Well-being is an important health outcome and a potential national indicator of policy success. There is a need for longitudinal epidemiological surveys to understand determinants of well-being. This study examines the role of personal social support and psychosocial work environment as predictors of well-being in an occupational cohort study.
Social support and work characteristics were measured by questionnaire in 5182 United Kingdom civil servants from phase 1 of the Whitehall II study and were used to predict subjective well-being assessed using the Affect Balance Scale (range -15 to 15, SD = 4.2) at phase 2. External assessments of job control and demands were provided by personnel managers.
Higher levels of well-being were predicted by high levels of confiding/emotional support (difference in mean from the reference group with low levels of confiding/emotional support  =  0.63, 95%CI 0.38–0.89, ptrend<0.001), high control at work (0.57, 95%CI 0.31–0.83, ptrend<0.001; reference low control) and low levels of job strain (0.60, 95%CI 0.31–0.88; reference high job strain), after adjusting for a range of confounding factors and affect balance score at baseline. Higher externally assessed work pace was also associated with greater well-being.
Our results suggest that the psychosocial work environment and personal relationships have independent effects on subjective well-being. Policies designed to increase national well-being should take account of the quality of working conditions and factors that facilitate positive personal relationships. Policies designed to improve workplaces should focus not only on minimising negative aspects of work but also on increasing the positive aspects of work.
PMCID: PMC3834222  PMID: 24260545
16.  Chronic inflammation as a determinant of future aging phenotypes  
The importance of chronic inflammation as a determinant of aging phenotypes may have been underestimated in previous studies that used a single measurement of inflammatory markers. We assessed inflammatory markers twice over a 5-year exposure period to examine the association between chronic inflammation and future aging phenotypes in a large population of men and women.
We obtained data for 3044 middle-aged adults (28.2% women) who were participating in the Whitehall II study and had no history of stroke, myocardial infarction or cancer at our study’s baseline (1997–1999). Interleukin-6 was measured at baseline and 5 years earlier. Cause-specific mortality, chronic disease and functioning were ascertained from hospital data, register linkage and clinical examinations. We used these data to create 4 aging phenotypes at the 10-year follow-up (2007–2009): successful aging (free of major chronic disease and with optimal physical, mental and cognitive functioning), incident fatal or nonfatal cardiovascular disease, death from noncardiovascular causes and normal aging (all other participants).
Of the 3044 participants, 721 (23.7%) met the criteria for successful aging at the 10-year follow-up, 321 (10.6%) had cardiovascular disease events, 147 (4.8%) died from noncardiovascular causes, and the remaining 1855 (60.9%) were included in the normal aging phenotype. After adjustment for potential confounders, having a high interleukin-6 level (> 2.0 ng/L) twice over the 5-year exposure period nearly halved the odds of successful aging at the 10-year follow-up (odds ratio [OR] 0.53, 95% confidence interval [CI] 0.38–0.74) and increased the risk of future cardiovascular events (OR 1.64, 95% CI 1.15–2.33) and noncardiovascular death (OR 2.43, 95% CI 1.58–3.80).
Chronic inflammation, as ascertained by repeat measurements, was associated with a range of unhealthy aging phenotypes and a decreased likelihood of successful aging. Our results suggest that assessing long-term chronic inflammation by repeat measurement of interleukin-6 has the potential to guide clinical practice.
doi: 10.1503/cmaj.122072
PMCID: PMC3826354  PMID: 24043651
17.  Diabetes Risk Factors, Diabetes Risk Algorithms, and the Prediction of Future Frailty: The Whitehall II Prospective Cohort Study 
To examine whether established diabetes risk factors and diabetes risk algorithms are associated with future frailty.
Prospective cohort study. Risk algorithms at baseline (1997–1999) were the Framingham Offspring, Cambridge, and Finnish diabetes risk scores.
Civil service departments in London, United Kingdom.
There were 2707 participants (72% men) aged 45 to 69 years at baseline assessment and free of diabetes.
Risk factors (age, sex, family history of diabetes, body mass index, waist circumference, systolic and diastolic blood pressure, antihypertensive and corticosteroid treatments, history of high blood glucose, smoking status, physical activity, consumption of fruits and vegetables, fasting glucose, HDL-cholesterol, and triglycerides) were used to construct the risk algorithms. Frailty, assessed during a resurvey in 2007–2009, was denoted by the presence of 3 or more of the following indicators: self-reported exhaustion, low physical activity, slow walking speed, low grip strength, and weight loss; “prefrailty” was defined as having 2 or fewer of these indicators.
After a mean follow-up of 10.5 years, 2.8% of the sample was classified as frail and 37.5% as prefrail. Increased age, being female, stopping smoking, low physical activity, and not having a daily consumption of fruits and vegetables were each associated with frailty or prefrailty. The Cambridge and Finnish diabetes risk scores were associated with frailty/prefrailty with odds ratios per 1 SD increase (disadvantage) in score of 1.18 (95% confidence interval: 1.09–1.27) and 1.27 (1.17–1.37), respectively.
Selected diabetes risk factors and risk scores are associated with subsequent frailty. Risk scores may have utility for frailty prediction in clinical practice.
PMCID: PMC3820037  PMID: 24103860
Aging; frailty; diabetes risk scores; diabetes risk factors
18.  Education is associated with lower levels of abdominal obesity in women with a non-agricultural occupation: an interaction study using China’s four provinces survey 
BMC Public Health  2013;13:769.
The prevalence of obesity is increasing rapidly in low- and middle-income countries (LMICs) as their populations become exposed to obesogenic environments. The transition from an agrarian to an industrial and service-based economy results in important lifestyle changes. Yet different socioeconomic groups may experience and respond to these changes differently. Investigating the socioeconomic distribution of obesity in LMICs is key to understanding the causes of obesity but the field is limited by the scarcity of data and a uni-dimensional approach to socioeconomic status (SES). This study splits socioeconomic status into two dimensions to investigate how educated women may have lower levels of obesity in a context where labour market opportunities have shifted away from agriculture to other forms of employment.
The Four Provinces Study in China 2008/09 is a household-based community survey of 4,314 people aged ≥60  years (2,465 women). It was used to investigate an interaction between education (none/any) and occupation (agricultural/non-agricultural) on high-risk central obesity defined as a waist circumference ≥80 cm. An interaction term between education and occupation was incorporated in a multivariate logistic regression model, and the estimates adjusted for age, parity, urban/rural residence and health behaviours (smoking, alcohol, meat and fruit & vegetable consumption). Complete case analyses were undertaken and results confirmed using multiple imputation to impute missing data.
An interaction between occupation and education was present (P = 0.02). In the group with no education, the odds of central obesity in the sedentary occupation group were more than double those of the agricultural occupation group even after taking age group and parity into account (OR; 95%CI: 2.21; 1.52, 3.21), while in the group with any education there was no evidence of such a relationship (OR; 95%CI: 1.25; 0.92, 1.70). Health behaviours appeared to account for some of the association.
These findings suggest that education may have a protective role in women against the higher odds of obesity associated with occupational shifts in middle-income countries, and that investment in women’s education may present an important long term investment in obesity prevention. Further research could elucidate the mechanisms behind this association.
PMCID: PMC3844357  PMID: 23962144
Socioeconomic status; Obesity; Low- and middle-income countries; Epidemiology; Women; China; Education; Occupation; Waist circumference; Transition
19.  Vascular Risk Status as a Predictor of Later-life Depressive Symptoms: A Cohort Study 
Biological psychiatry  2012;72(4):324-330.
Common etiology of vascular diseases and later-life depression may provide important synergies for prevention. We examined whether standard clinical risk profiles developed for vascular diseases also predict depressive symptoms in older adults.
Data were drawn from the Whitehall II cohort study with baseline examination in 1991/93, follow-up screenings in 1997/99, 2003/04 and 2008/09, and additional disease ascertainment from hospital data and registry linkage, on 5318 participants (mean age 54.8 years, 31% women) without depressive symptoms at baseline. Vascular risk was assessed with the Framingham Cardiovascular, Coronary Heart Disease and Stroke Risk Scores. New depressive symptoms at each follow-up screening were identified by General Health Questionnaire caseness, a Center for Epidemiologic Studies Depression Scale (CES-D) score ≥ 16, and use of antidepressant medication.
Diagnosed vascular disease (that is, coronary heart disease or stroke) was associated with an increased risk for depressive symptoms, age- and sex-adjusted odds ratios from 1.5 (95% confidence interval 1.0–2.2) to 2.0 (1.4–3.0) depending on the indicator of depressive symptoms. Among participants without manifest vascular disease at baseline, the Stroke Risk Score was associated with CES-D depressive symptoms before age 65 [age- and sex-adjusted odds ratio per 10% absolute change in the score =3.1 (1.5–6.5)], but none of the risk scores predicted new-onset depressive symptoms in those aged ≥ 65 (odds ratios from 0.8 to 1.2).
These data suggest that public health measures to improve vascular risk status will influence the incidence of later-life depressive symptoms via reduced rates of manifest vascular disease.
PMCID: PMC3539141  PMID: 22425413
Depressive symptoms; vascular depression; late-onset depression; cardiovascular risk factors; risk prediction; aging
20.  Association of Lifecourse Socioeconomic Status with Chronic Inflammation and Type 2 Diabetes Risk: The Whitehall II Prospective Cohort Study 
PLoS Medicine  2013;10(7):e1001479.
Silvia Stringhini and colleagues followed a group of British civil servants over 18 years to look for links between socioeconomic status and health.
Please see later in the article for the Editors' Summary
Socioeconomic adversity in early life has been hypothesized to “program” a vulnerable phenotype with exaggerated inflammatory responses, so increasing the risk of developing type 2 diabetes in adulthood. The aim of this study is to test this hypothesis by assessing the extent to which the association between lifecourse socioeconomic status and type 2 diabetes incidence is explained by chronic inflammation.
Methods and Findings
We use data from the British Whitehall II study, a prospective occupational cohort of adults established in 1985. The inflammatory markers C-reactive protein and interleukin-6 were measured repeatedly and type 2 diabetes incidence (new cases) was monitored over an 18-year follow-up (from 1991–1993 until 2007–2009). Our analytical sample consisted of 6,387 non-diabetic participants (1,818 women), of whom 731 (207 women) developed type 2 diabetes over the follow-up. Cumulative exposure to low socioeconomic status from childhood to middle age was associated with an increased risk of developing type 2 diabetes in adulthood (hazard ratio [HR] = 1.96, 95% confidence interval: 1.48–2.58 for low cumulative lifecourse socioeconomic score and HR = 1.55, 95% confidence interval: 1.26–1.91 for low-low socioeconomic trajectory). 25% of the excess risk associated with cumulative socioeconomic adversity across the lifecourse and 32% of the excess risk associated with low-low socioeconomic trajectory was attributable to chronically elevated inflammation (95% confidence intervals 16%–58%).
In the present study, chronic inflammation explained a substantial part of the association between lifecourse socioeconomic disadvantage and type 2 diabetes. Further studies should be performed to confirm these findings in population-based samples, as the Whitehall II cohort is not representative of the general population, and to examine the extent to which social inequalities attributable to chronic inflammation are reversible.
Please see later in the article for the Editors' Summary
Editors' Summary
Worldwide, more than 350 million people have diabetes, a metabolic disorder characterized by high amounts of glucose (sugar) in the blood. Blood sugar levels are normally controlled by insulin, a hormone released by the pancreas after meals (digestion of food produces glucose). In people with type 2 diabetes (the commonest form of diabetes) blood sugar control fails because the fat and muscle cells that normally respond to insulin by removing sugar from the blood become insulin resistant. Type 2 diabetes, which was previously called adult-onset diabetes, can be controlled with diet and exercise, and with drugs that help the pancreas make more insulin or that make cells more sensitive to insulin. However, as the disease progresses, the pancreatic beta cells, which make insulin, become impaired and patients may eventually need insulin injections. Long-term complications, which include an increased risk of heart disease and stroke, reduce the life expectancy of people with diabetes by about 10 years compared to people without diabetes.
Why Was This Study Done?
Socioeconomic adversity in childhood seems to increase the risk of developing type 2 diabetes but why? One possibility is that chronic inflammation mediates the association between socioeconomic adversity and type 2 diabetes. Inflammation, which is the body's normal response to injury and disease, affects insulin signaling and increases beta-cell death, and markers of inflammation such as raised blood levels of C-reactive protein and interleukin 6 are associated with future diabetes risk. Notably, socioeconomic adversity in early life leads to exaggerated inflammatory responses later in life and people exposed to social adversity in adulthood show greater levels of inflammation than people with a higher socioeconomic status. In this prospective cohort study (an investigation that records the baseline characteristics of a group of people and then follows them to see who develops specific conditions), the researchers test the hypothesis that chronically increased inflammatory activity in individuals exposed to socioeconomic adversity over their lifetime may partly mediate the association between socioeconomic status over the lifecourse and future type 2 diabetes risk.
What Did the Researchers Do and Find?
To assess the extent to which chronic inflammation explains the association between lifecourse socioeconomic status and type 2 diabetes incidence (new cases), the researchers used data from the Whitehall II study, a prospective occupational cohort study initiated in 1985 to investigate the mechanisms underlying previously observed socioeconomic inequalities in disease. Whitehall II enrolled more than 10,000 London-based government employees ranging from clerical/support staff to administrative officials and monitored inflammatory marker levels and type 2 diabetes incidence in the study participants from 1991–1993 until 2007–2009. Of 6,387 participants who were not diabetic in 1991–1993, 731 developed diabetes during the 18-year follow-up. Compared to participants with the highest cumulative lifecourse socioeconomic score (calculated using information on father's occupational position and the participant's educational attainment and occupational position), participants with the lowest score had almost double the risk of developing diabetes during follow-up. Low lifetime socioeconomic status trajectories (being socially downwardly mobile or starting and ending with a low socioeconomic status) were also associated with an increased risk of developing diabetes in adulthood. A quarter of the excess risk associated with cumulative socioeconomic adversity and nearly a third of the excess risk associated with low socioeconomic trajectory was attributable to chronically increased inflammation.
What Do These Findings Mean?
These findings show a robust association between adverse socioeconomic circumstances over the lifecourse of the Whitehall II study participants and the risk of type 2 diabetes and suggest that chronic inflammation explains up to a third of this association. The accuracy of these findings may be affected by the measures of socioeconomic status used in the study. Moreover, because the study participants were from an occupational cohort, these findings need to be confirmed in a general population. Studies are also needed to examine the extent to which social inequalities in diabetes risk that are attributable to chronic inflammation are reversible. Importantly, if future studies confirm and extend the findings reported here, it might be possible to reduce the social inequalities in type 2 diabetes by promoting interventions designed to reduce inflammation, including weight management, physical activity, and smoking cessation programs and the use of anti-inflammatory drugs, among socially disadvantaged groups.
Additional Information
Please access these Web sites via the online version of this summary at
The US National Diabetes Information Clearinghouse provides information about diabetes for patients, health-care professionals, and the general public, including information on diabetes prevention (in English and Spanish)
The UK National Health Service Choices website provides information for patients and carers about type 2 diabetes; it includes peoples stories about diabetes
The nonprofit Diabetes UK also provides detailed information about diabetes for patients and carers, including information on healthy lifestyles for people with diabetes, and has a further selection of stories from people with diabetes; the nonprofit Healthtalkonline has interviews with people about their experiences of diabetes
MedlinePlus provides links to further resources and advice about diabetes (in English and Spanish)
Information about the Whitehall II study is available
PMCID: PMC3699448  PMID: 23843750
22.  Does Overall Diet in Midlife Predict Future Aging Phenotypes? A Cohort Study 
The American Journal of Medicine  2013;126(5):411-419.e3.
The impact of diet on specific age-related diseases has been studied extensively, but few investigations have adopted a more holistic approach to determine the association of diet with overall health at older ages. We examined whether diet, assessed in midlife, using dietary patterns and adherence to the Alternative Healthy Eating Index (AHEI), is associated with aging phenotypes, identified after a mean 16-year follow-up.
Data were drawn from the Whitehall II cohort study of 5350 adults (age 51.3 ± 5.3 years, 29.4% women). Diet was assessed at baseline (1991-1993). Mortality, chronic diseases, and functioning were ascertained from hospital data, register linkage, and screenings every 5 years and were used to create 5 outcomes at follow-up: ideal aging (free of chronic conditions and high performance in physical, mental, and cognitive functioning tests; 4%), nonfatal cardiovascular event (7.3%), cardiovascular death (2.8%), noncardiovascular death (12.7%), and normal aging (73.2%).
Low adherence to the AHEI was associated with an increased risk of cardiovascular and noncardiovascular death. In addition, participants with a “Western-type” diet (characterized by high intakes of fried and sweet food, processed food and red meat, refined grains, and high-fat dairy products) had lower odds of ideal aging (odds ratio for top vs bottom tertile: 0.58; 95% confidence interval, 0.36-0.94; P = .02), independently of other health behaviors.
By considering healthy aging as a composite of cardiovascular, metabolic, musculoskeletal, respiratory, mental, and cognitive function, the present study offers a new perspective on the impact of diet on aging phenotypes.
PMCID: PMC3743043  PMID: 23582933
Aging; Cognitive functioning; Dietary patterns; Diet quality indices; Mortality; Nutritional epidemiology; Overall diet; Physical functioning
24.  Adherence to healthy dietary guidelines and future depressive symptoms: evidence for sex differentials in the Whitehall II study1234 
Background: It has been suggested that dietary patterns are associated with future risk of depressive symptoms. However, there is a paucity of prospective data that have examined the temporality of this relation.
Objective: We examined whether adherence to a healthy diet, as defined by using the Alternative Healthy Eating Index (AHEI), was prospectively associated with depressive symptoms assessed over a 5-y period.
Design: Analyses were based on 4215 participants in the Whitehall II Study. AHEI scores were computed in 1991–1993 and 2003–2004. Recurrent depressive symptoms were defined as having a Center for Epidemiologic Studies Depression Scale score ≥16 or self-reported use of antidepressants in 2003–2004 and 2008–2009.
Results: After adjustment for potential confounders, the AHEI score was inversely associated with recurrent depressive symptoms in a dose-response fashion in women (P-trend < 0.001; for 1 SD in AHEI score; OR: 0.59; 95% CI: 0.47, 0.75) but not in men. Women who maintained high AHEI scores or improved their scores during the 10-y measurement period had 65% (OR: 0.35%; 95% CI: 0.19%, 0.64%) and 68% (OR: 0.32%; 95% CI: 0.13%, 0.78%) lower odds of subsequent recurrent depressive symptoms than did women who maintained low AHEI scores. Among AHEI components, vegetable, fruit, trans fat, and the ratio of polyunsaturated fat to saturated fat components were associated with recurrent depressive symptoms in women.
Conclusion: In the current study, there was a suggestion that poor diet is a risk factor for future depression in women.
PMCID: PMC3545684  PMID: 23283506

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