1. PATHWAYS Allostatic load measures in the English Longitudinal Study of Ageing (ELSA) Sanna Read & Emily Grundy Website http://pathways.lshtm.ac.uk Emailpathways@lshtm.ac.uk Twitter@pathwaysNCRM

2. Allostatic load a multisystem dysregulation state resulting from accumulated physiological ‘wear and tear’ Allostasis = a process whereby organism maintains physiological stability by adapting itself to environmental demands - > health is a state of responsiveness and optimal predictive fluctuation to adapt to the demands of the environment -> dynamic biological process interacting with context

3. Allostatic load Environmental stressors Major life events Trauma, (work, home, neighbourhood) abuse Perceived stress Behavioural responses (fight or flight, health- related behaviour – smoking, alcohol use, diet, exercise) Individual differences (genes, development, experience) Brain’s evaluation of threat Physiological responses Allostatic load Disease AllostasisAdaptation Adapted from McEwen, 1998

4. Multiple mediators of adaptation: 1)Primary effects: stress hormones (e.g. epinephrine, norepinephrine and cortisol), anti-inflammatory cytokines (e.g. Interleukin-6) 2)Secondary outcomes: metabolic (e.g. insulin, glucose, total cholesterol, triglycerides, visceral fat depositing), cardiovascular (e.g. systolic and diastolic blood pressure) and immune system (e.g. C-reactive protein, fibrinogen). 3)Tertiary outcomes: poor health, disease, death Mediators interconnected and reciprocal, non-linear effects on many organ systems in body - > should be measured as multisystem concept, challenging to develop measures Allostatic load accumulates throughout the life -> study processes in longitudinal settings AllostasisAdaptation

5. Measures of allostatic load MeasureDescription Group allostatic load indexthe number of biomarkers falling within a high risk percentile (e.g. upper or lower 25 th percentile) based on the sample distribution of biomarkers values Z-score allostatic load indexSummary measure of individual’s obtained z- scores for each biomarker based on the sample distribution of biomarker values. Change scoreMeasure change between two or more measurement occasions. This can be a simple difference score or dynamic measure of variability over time. A number of other methods also used for calculating composite measures: bootstrapping, canonical correlations, recursive partitioning, grade of membership, k-means cluster analysis, genetic programming.

6. Examples of biomarkers used in measuring allostatic load TypeBiomarker NeuroendocrineEpinepherine, norepinephrerine, dopamine, cortisol, dehydroepiandrosterone (DHEAS), aldosterone ImmuneInterleukin-6, tumor necrosis factor-alpha, c- reactive protein (CRP), insulin-like growth factor-1 (IGF-1) MetabolicHDL and LDL cholesterole, triglycerides, glucosylated hemoglobin, glucose insulin, albumin, creatinine, homocysteine Cardiovascular and respiratory Systolic blood pressure, diastolic blood pressure, peak expiratory flow, heart rate/pulse AnthropometricWaist-to-hip ratio, body mass index (BMI)

7. Factors associated with allostatic load in previous studies Socioeconomics: education, income, occupational status, downward mobility, homelessness Family: attachment, violence, single parent, separation, care-giving, demands/criticism, spouse Individual: type A/hostility, locus of control, a polymorphism of ACE gene Neigbourhoods: crowding, noise, lack of housing, rural/urban Allostatic load Ethnicity: Non- whites (U.S.) Spirituality: religious attendance, sense of meaning/purpose Social networks: emotional support, social position Work: control, demands, decisions, career instability, effort- reward imbalance

8. Sample English Longitudinal Study of Ageing (ELSA) waves 1 - 4 (2002-2008) Men and women (n = 5279) aged 50+ in 2002 Measures: – Biomarkers available in waves 2 and 4 – Health: self reported health, limitation in health, ADL and IADL limitation – Fertility history: number of children, birth before age 20 (women) or age 23 (men), birth after age 34 (women) and 39 (men), coresidence with child – Background factors: age, marital status, qualification, tenure status, net wealth quintile (non-pension wealth indicating financial, physical and housing wealth net of debts)

9. Selected biomarkers to measure allostatic load in ELSA Neuro- endocrine ImmuneCardiovascularRespiratoryMetabolicBody fat DHEAS* (dehydroepia ndrostorone sulphate) C-reactive protein Systolic blood pressure Peak expiratory flow Total blood cholesterol/ HDL cholesterol ratio Waist-hip ratio FibrinogenDiastolic blood pressure Triglycerides IGF-1* (insulin-like growth hormone) Glycated HgB * only in wave 4

10. Availability of valid measures in ELSA Measure% valid measure cross- sectionally % valid measure longitudinally among those who participated in wave 1 Wave 2Wave 4Wave 2Wave 4 Blood pressure70725846 Waist-hip ratio78766548 Lung function75706244 Blood measures*63585237 * CRP, Fibrinogen, cholesterole, triglycerides, glycated HgB, IGF-1, DHEAS

11. Allostatic load scores in ELSA Group allostatic load index: number of biomarkers indicating high risk (25th percentile) calculated separately for men and women, range 0 - 9 Upper 25 th percentileLower 25 th percentile Systolic blood pressureDiastolic blood pressure FibrinogenPeak expiratory flow Triglycerides C-reactive protein Glycated HgB Waist-hip ratio Total/HDL cholesterol ratio

12. Allostatic load scores in ELSA Challenges in creating composite scores: Extreme values Medication Non-linearity Missing values

13. Allostatic load measures in 2004 predicting ADL problems in 2006 in men in ELSA ADL problem % Lowest 25% Highest 25%

14. Allostatic load change in ELSA Comparison between wave 2 (2004) and wave 4 (2008): Low allostatic score (score 0-1) and high allostatic score (2+) High Low 20042008

15. Allostatic load change between 2004 and 2008 in ELSA

16. Allostatic load change in ELSA Is change associated with any of the following factors? Age Qualification, tenure status, net wealth quintile Being married Perceived support and critique received from family and friends Number of children Co-residence with child, early child birth, late child birth (among parents only)

17. Allostatic load change in ELSA Is change associated with poorer health? Poorer self-rated health, health limitation, and ADL/IADL limitation was most frequent among those who stayed in high allostatic load group in both waves. Those men who moved from low to high group rated their health poorer and those men who moved from high to low group rated better health. In women the differences in health were less clear. Those staying in low allostatic group rated their health best of all four groups.

18. Fertility history Allostatic load Health Education Is the association between fertility history and health mediated by allostatic load? Does SEP influence this association? The model to be tested Wealth

19. Is the association between fertility history and health mediated by allostatic load? - Yes, it is in men and to some extent also in women. In women there are also direct paths to health suggesting that there are other potential mediators. Does SEP influence this association? - In men, and to some extent in women, SEP mediates the association between fertility history and later allostatic load and health. Fertility history, allostatic load and health in ELSA

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