Biological Predictors of Change in Functioning in the Whitehall II Study MEENA KUMARI, PHD, TERESA SEEMAN, PHD, AND MICHAEL MARMOT, FRCP PURPOSE: To examine whether risk factors for CHD are related to change in functioning independent of the presence or development of disease. METHODS: Longitudinal follow up of 4768 men and 2034 women civil servants from 20 London-based departments with complete data for the SF-36, biological variables, and BMI and health related behaviors. Data are used from two phases of the Whitehall II study, phase 3 (1991–1993) and phase 4 (1995) with an interval of 36 months. Weight, height, fasting insulin, 2-hour post load glucose, total and HDL- cholesterol, fibrinogen, von Willebrand factor, diastolic and systolic blood pressure, and waist hip ratio were measured at phase 3. Demographic and socio-economic information, health related behaviors, and the SF-36 were obtained at both phases by questionnaire. RESULTS: Waist hip ratio, fasting insulin, triglycerides, and HDL-cholesterol were associated with a decline in physical functioning in the total cohort and when those with poor health at baseline were removed from the analyses. Principal component analysis revealed that these variables clustered with total cholesterol and may represent insulin resistance. The biological variables had a cumulative effect on decline in physical functioning such that those with poor waist hip ratio, fasting insulin, triglycerides, and HDL-cholesterol was two times greater than those without. This relationship was independent of exercise, smoking, and alcohol intake which explained only 17% and 5.4% of the association in men and women, respectively. CONCLUSIONS: A number of biological variables, which may represent insulin resistance, are associ- ated with decline in physical functioning in men and women independent of prevalent ill health or health related behaviors. Ann Epidemiol 2004;14:250–257.  2004 Elsevier Inc. All rights reserved. KEY WORDS: Health Status, Cardiovascular Risk Factors, Insulin Resistance. INTRODUCTION In an ageing population, maintenance of good physical and mental functioning is an important goal. Functioning pre- dicts use of health services and a number of disease outcomes including coronary heart disease (CHD) (1–4). It has become increasingly important to identify predictors of changes in functioning to determine areas for intervention and also as determinants of successful ageing because From the International Centre for Health and Society, Department of Epidemiology and Public Health, University College London, London, UK (M.K., M.M.); and Department of Medicine, Division of Geriatrics, UCLA, Los Angeles, USA (T.S.). Address correspondence to: Dr. Meena Kumari, International Centre for Health and Society, Department of Epidemiology and Public Health, University College London, 1-19 Torrington Place, London, WC1E 6BT, UK. Tel.: +44-207-679-5637; Fax: +44-207-813-0280. E-mail: M.Kumari@ public-health.ucl.ac.uk The Whitehall II study has been supported by grants from the Medical Research Council; British Heart Foundation; Health and Safety Executive; Department of Health; National Heart Lung and Blood Institute (RO1- HL36310), US, NIH; National Institute on Aging (RO1-AG13196), US, NIH; Agency for Health Care Policy Research (RO1-HS06516); and the John D. and Catherine T. MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health. M.M. is supported by the Medical Research Council. Received April 29, 2002; accepted September 16, 2003.  2004 Elsevier Inc. All rights reserved. 1047-2797/04/$–see front matter 360 Park Avenue South, New York, NY 10010 doi:10.1016/j.annepidem.2003.09.011 continuous decline in mental and physical functioning is not an inevitable consequence of ageing (5, 6). Healthy individuals over 60 years of age had greater decline in physi- cal functioning with increased baseline burdens of physio- logical dysregulation (i.e., “allostatic load”) in a study of successful ageing (7). As proposed by McEwen and Stellar (8) and amplified by McEwen (9), the allostatic load hy- pothesis posits that there is a physiological “toll” paid by homeostatic mechanisms (10) resulting in dysregulated patterns of activity over time. The hypothesis further pre- dicts that this cumulative dysregulation in biological param- eters should be associated with decline in functioning independent of manifest disease. In this report we will describe the relationship between risk factors for CHD and change in functioning in male and female office workers, to whom the SF-36, a widely used measure of health functioning (11–15) was administered in the same way twice. Because there is an association between physical and mental morbidity (16, 17) both of these components of the SF-36 are investigated. A large array of biological information was also collected at the time the first questionnaire was administered. The aims of this study are to examine the hypothesis that: 1) risk factors for CHD are also risk factors for decline in functioning; and 2) these associations are direct effects that are independent