National Centre for Research Methods Working Paper 04/12 Allostatic load - a challenge to measure multisystem physiological dysregulation Sanna Read, London School of Hygiene and Tropical Medicine Emily Grundy, University of Cambridge NCRM Working paper 04/12 Allostatic load – a challenge to measure multisystem physiological dysregulation Sanna Read and Emily Grundy London School of Hygiene and Tropical Medicine and University of Cambridge September 2012 Abstract Allostatic load is a sub-clinical dysregulation state, resulting from the body’s response to stress. Allostatic load accumulates gradually over the life course and affects a number of physiological systems. Measuring multisystem dysregulation and changes in it over time is very challenging. In this paper, we discuss composite measures used to capture allostatic load and the challenges involved in deriving and using these measures. Our focus is on measuring allostatic load in later life. Contents 1 Introduction ........................................................................................................................ 2 2 Allostatic load – a multisystem response to stress ............................................................. 2 3 Measures of allostatic load ................................................................................................. 4 4 Measuring processes over time in allostatic load ............................................................... 6 5 Future directions in measuring allostatic load ..................................................................... 7 References ........................................................................................................................... 8 1 NCRM Working paper 04/12 1. Introduction In this paper, we discuss the use of composite measures of allostatic load and the problems involved in creating these measures and analysing changes in them over time. First, we introduce the concept of allostatic load as a measure of multisystem dysregulation. Secondly, we review the methods previously used for measuring allostatic load. Third, we discuss the need for longitudinal studies to measure change in allostatic load and its association with predictors and health outcomes. We conclude the paper with a summary of current promising approaches to the measurement of allostatic load. We also discuss future directions in developing measures of allostatic load and changes in allostatic load over time. 2. Allostatic load – a multisystem response to stress Daily stress and repeated stressful events over the life course can take a significant physiological toll on the body (McEwen & Stellar, 1993). The stress response in itself does not lead to adverse health outcomes, it actually protects the organism from harmful effects. However, each time the stress response is activated, physiological adjustments must be made and over time these adjustments lead to accummulated wear and tear (McEwen, 1998).The theory of allostatic load decribes this accumulated physiological wear and tear and how it may lead to a multisystem dysregulation state and further to poor health . According to this theory, the organism is in a recurrent process of maintaining physiological stability by adapting itself to environmental demands. This process is called allostasis. Allostatic load is the cost of adaptation to cumulative stress. From a biological perspective, stress is chronic activation of responsive physiological systems. However, the extent of activation depends on environmental (number and magnitude of live events) and psychological (evaluation of the stressful events) factors (Clark, Bond, & Hecker, 2007). Due to these different dimensions of stress, there are great individual differences in outcomes. Allostatic load can originate from repeated stress (more stressful events), but may also be a result of lack of adaptation or prolonged or inadequate stress response. Allostatic load is likely to develop when acute stress response becomes chronic. Consequently, health outcomes depend on successful adjustment to the changing demands of the environment: a rapid and promptly terminated stress response facilitates better health. How does the body react to stress? Allostasis-adaptation involves nervous, endocrine and immune systems. The immediate response to different stressors is the brain’s evaluation of the threat carried out by the amygdala, hippocampus and pre- frontal cortex (McEwen & Gianaros, 2011). This activates the sympathetic-adrenal- medullary (SAM) axis which releases catecholamines such as epinephrine. This is the acute response to the stress. The brain’s evaluation activates a sympathetic nervous system response for behavioural fight or flight that prepares the body to react to a stressful situation. It also triggers inflammation, an immune response to prevent tissue damage from pathogen infection. A more long-term response to stress is mediated by the hypothalamic- pituitary-adrenal (HPA) axis which releases glucocorticoids. The activation of the HPA axis supports the increase of metabolic activity to provide enough energy and also manages the parasympathetic nervous system to define the level of physiological arousal. Stress responses can alter health-related behaviours, such as smoking, alcohol use, sleep, diet and exercise, which in turn increase the risk of high allostatic load. How well the physiological system can adapt to the environmental challenges defines the extent of accumulation of physiological dysfunction, allostatic load. If it remains high for a long time, the sub-clinical dysfunction can develop into disease. The pathways to disease may derive from malfunction of several systems. For instance, cardiovascular diseases may result from stress related amygdale hyperactivity, elevation in inflammation and abnormal metabolic functioning. Stress related elevation in inflammation levels and cortisol secretion may on the other hand decrease cell sensitivity to insulin promoting the development of metabolic disorders, such as diabetes. Elevated inflammation levels and cortisol secretion may also promote neurodegeneration, which may lead to cognitive decline and dementia. Inflammation and metabolic abnormalities may contribute to shortening of a region of repetitive DNA at the end of chromosomes (telomere attrition) causing cellular aging (Danese & McEwen, 2012). 2 NCRM Working paper 04/12 A younger organism is often better equipped to react to stress and quicker to recover from it than an older one. However, a number of individual factors such as genetic makeup, developmental stage and previous personal experiences play important roles both in how stress is perceived and how the body reacts to and recovers from stressful situations. The allostasis-adaptation process often follows three stages of stress mediation (see Figure 1). In the first stage, the acute stress response activates the primary mediators including stress hormones (e.g. epinephrine, norepinephrine and cortisol) and anti-inflammatory cytokines (e.g. Interleukin-6). In the second stage, a more long-term stress response results in the secondary outcomes which include changes in metabolic (e.g. insulin, glucose, total cholesterol, triglycerides, visceral fat depositing), cardiovascular (e.g. systolic and diastolic blood pressure) and immune systems (e.g. C-reactive protein, fibrinogen). Finally, the allostasis-adaptation process results in the tertiary outcomes that can be poor health, cognitive decline, cellular aging, diseases, such as cardiovascular diseases and diabetes, and eventually death (Leahy & Crews, 2012; Seeman, McEwen, Rowe, & Singer, 2001). It is not clear how long it takes to develop secondary and tertiary outcomes after primary stress reactions. Characteristic of the allostasis-adaptation process is that the physiological mediators are interconnected, reciprocal and have non-linear effects (Juster, McEwen, & Lupien, 2010; McEwen & Gianaros, 2011). Allostatic load affects many organ systems highlighting the importance of measuring allostatic load as a multisystem concept. For this reason measurement is based on deriving a composite score based on indicators from a number of different systems. However, developing these composite measures is challenging. Allostatic load accumulates throughout life and therefore the study of processes in longitudinal settings is also needed. Because these processes are often non-linear and reciprocal, the estimation of change may become complex. Stress mediation System Biomarker Primary mediators Neuroendocrine Epinepherine, norepinephrerine, dopamine, cortisol, dehydroepiandrosterone (DHEAS), aldosterone Secondary outcomes Immune Interleukin-6, tumor necrosis factor- alpha, c-reactive protein (CRP), insulin-like growth factor-1 (IGF-1) Metabolic HDL and LDL cholesterole, triglycerides, glucosylated hemoglobin, glucose insulin, albumin, creatinine, homocysteine Cardiovascular and Systolic blood pressure, diastolic respiratory blood pressure, peak expiratory flow, heart rate/pulse Anthropometric Waist-to-hip ratio, body mass index (BMI) Tertiary outcomes Poor subjective health, disability, cognitive decline, cellular aging, diseases, death Figure 1. Stress mediation, systems and biomarkers used to measure allostatic load. 3 NCRM Working paper 04/12 3. Measures of allostatic load The usual approach to measuring allostatic load is through composite measures of a range of biomarkers, various measures that are sensitive to subtle changes in the biological state resulting from environmental