Allostatic LoadMeasurement Issues & Future DirectionsNoreen GoldmanThe University of Colorado Population Center & Institute of Behavioral ScienceSummer Course in BiodemographyJune 11-13, 2007Abbreviated History of Allostatic Load Hans Selye (1907-1982) General Adaptation Syndrome (GAS): the manner in which the body copes with “noxious agents” (“stress”) Stress is the nonspecific response of the body to a demand: hormonal and neurotransmitter mediators that set in motion responses of cells and tissues throughout the body. Importance of the HPA-axis Demands could be positive or negative (pathogen, lack of sleep, exercise) *Effects of stress on the body could be beneficial or damaging  Stages include “fight or flight,” subsequent adaptation, eventual exhaustion/disease if stress is sufficiently long (although Selye thought it was due to hormone depletion) Thus, stress can make people sickAllostasis/ Allostatic load Allostasis: term coined by Sterling & Eyer (1988) A dynamic regulatory process How body maintains stability through change in various physiological systems (autonomic nervous system, HPA, cardiovascular, metabolic, immune) in response to internal and external demands (e.g., noise, hunger, extreme temperatures). These systems are designed to operate within broad ranges, by constantly modify “set points.” Vs. homeostasis: maintaining constant internal state Allostatic load: McEwen and Stellar (1993) The cost or price of allostasis (being forced to adapt to adverse situations) Wear and tear on the body from chronic over- or underactivityof allostatic systems Ultimate effects are a broad range of chronic conditionsAllostatic Load and a SeesawSource: McEwen B with EN Lasley.2002. The End of Stress As We Know It. Joseph Henry Press: Washington, D.C.The Stress Response and Allostatic LoadSource: McEwen, BS. 1998. Protective and damaging effects of stress mediators. NEJM, 171-179Types of Allostatic LoadSource: McEwen, BS. 1998. Protective and damaging effects of stress mediators. NEJM, 171-179These Patterns Really do OccurSource: Kirschbaum et al. 1995. Persistent high cortisol responses to repeated psychological stress in a subpopulation of healthy men. Psychosomatic Medicine, 468-74. Cortisol responses to public speaking & mental arithmetic taskHPA-Axis & Other Components of Hormonal Stress ResponseSource: McEwen B with EN Lasley.2002. The End of Stress As We Know It. Joseph Henry Press: Washington, D.C.Autonomic Nervous System, especiallySympathetic Nervous SystemSource: McEwen B with EN Lasley.2002. The End of Stress As We Know It. Joseph Henry Press: Washington, D.C.Protective & Damaging Effects Recall the ‘protection-versus-damage paradox’ stressed by McEwen and others. For example,  Cortisol and epinephrine help mobilize energy in acute stress, help immune cells move to sites in the body to combat infection. But, if their secretion is not turned off, they can promote fat deposition,insulin resistance, hypertension, and immunosuppression (just theopposite of effect above), damage to nerve cells.Chronic Conditions Arising from Allostatic Load Research has shown that long-term out of normal range values of certain biological markers (e.g., blood pressure, cortisol) lead to many possible chronic illnesses & conditions –not just physical morbidity, but cognitive & mental health:  Atherosclerosis, hypertension, diabetes, myocardial infarction, obesity  Autoimmune disorders Memory loss (hippocampal atrophy), depression This is a very abbreviated listDisorders Linked to CortisolSource: McEwen B with EN Lasley.2002. The End of Stress As We Know It. Joseph Henry Press: Washington, D.C.Primary Mediators, Secondary & Tertiary Outcomes Primary mediators Hormonal factors, including markers of SNS activity, HPA axis activity, inflammation. These mediators regulate events at the cellular level (primary effects) such as the action of enzymes and receptors. These effects ultimately lead to secondary outcome.Secondary outcomes These are manifested at the level of tissues and organs. These outcomes include abnormal metabolism and cardiovascular disease, such as obesity, hypertension, high cholesterolTertiary outcomes Disease endpoints resulting from secondary outcomesThis entire process is likely to be a very long one.Some Biomarkers Thought to be Involved in Allostatic Load Cardiovascular & Metabolic Systems Diastolic & systolic blood pressure Obesity: waist to hip ratio, BMI Glycosylated hemoglobin, fasting glucose Cholesterol measurements C-reactive proteinNeuroendocrine Cortisol Catecholamines (epinephrine, norepinephrine) DHEASImmune/ Inflammatory Lymphocytes, natural killer cells, macrophages Tumor necrosis factor alpha Interleukins (IL-6) Insulin-like growth factor Immoglobulin levels Coagulation (fibrinogen) C-Reactive Protein Albumin FibrinogenOther HomocysteineBrain (not easily measurable)Operationalizing Allostatic Load:The Original Formulation For now, we focus on how researchers calculate AL scores rather than how they use them analytically Based on MacArthur Successful Aging Study, high functioning men & women 70-79* Idea is to summarize levels of physiological activity across range of regulatory systems related to stress response This formulation focused on 10 markers: CV risk factors/metabolic syndrome (syndrome X) HPA-axis activity SNS activityBiomarkers obtained from fasting blood, 12-hour urine and anthropometric measurements* Seeman et al. 1997. Arch Intern MedCalculation of Risk Score Define “risk zones” (distinct from clinical cut-offs) Highest risk quartile for each of 10 biomarkers based on high-functioning MacArthur cohort Highest quartile for all but DHEA-S and HDL (good) cholesterol, where lowest quartile used Some debate about whether cut-off should be sex (or age) specific Score calculated by summing number (out of 10) markers with high-risk values Authors note that equal weighting of different biomarkers was consistent with factor analysis Final score is a count of number of biomarkers ‘outside of normal operating ranges’Defining Risk Zones for Allostatic Load ScoreSource: Singer B et al. 2004. “Operationalizing Allostatic Load.” Pp.113-149 in Jay Schulkin(eds.) Allostasis, Homeostasis, and the Costs of Physiological