Allostatic Load

Measurement Issues &

Future Directions

Noreen Goldman
The University of Colorado Population Center &
Institute of Behavioral Science
Summer Course in Biodemography
June 11-13, 2007
Abbreviated 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)
ƒ Thus, stress can make people sick
Allostasis/ 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 underactivity
of allostatic systems
„ Ultimate effects are a broad range of chronic conditions
Allostatic Load and a Seesaw

Source: 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 Load

Source: McEwen, BS. 1998. Protective and damaging effects of stress mediators. NEJM, 171-179
Types of Allostatic Load

Source: McEwen, BS. 1998. Protective and damaging effects of stress mediators. NEJM, 171-179
These Patterns Really do Occur
Cortisol responses to public speaking & mental arithmetic task

Source: Kirschbaum et al. 1995. Persistent high cortisol responses to repeated psychological stress in a subpopulation of healthy men.
Psychosomatic Medicine, 468-74.
HPA-Axis & Other Components of Hormonal
Stress Response

Source: McEwen B with EN Lasley.2002. The End of Stress As We Know It. Joseph Henry Press: Washington, D.C.
Autonomic Nervous System, especially
Sympathetic Nervous System

Source: 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 the
opposite 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 list
Disorders Linked to Cortisol

Source: 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 Med
Calculation 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
Score

Source: Singer B et al. 2004. “Operationalizing Allostatic Load.” Pp.113-149 in Jay Schulkin
(eds.) Allostasis, Homeostasis, and the Costs of Physiological Adaptation. Cambridge, U.K.: Cambridge University Press
.
Number/Types of Biomarkers Vary by Study

Source: Szanton, SL et al. 2005. Allostatic Load: A Mechanism of Socioeconomic Health Disparities?
Biological Research for Nursing, 7-15.
 Brief Description of Biomarkers

Source: Turra CM et al. 2005 Determinants of Mortality at Older Ages: The Role of Biological Markers of Chronic Disease. Pop Dev Rev, 675-698.
Extensions of Method
‡ Seplaki et al. (2005) examined alternative
scores, most of which are counts
„ Use of 16 rather than 10 markers (including immune
system markers)
„ Use of deciles rather than quartiles to define risk zones
„ Use of two-tails of risk when appropriate
‡ Cortisol, BMI, diastolic blood pressure are clear candidates
‡ 10/90 and 25/75 were chosen although need not be
symmetric
„ Use of z-score in lieu of a dummy variable to identify
high risk (think about outliers)
„ Grade of Membership (GoM) score
‡ Measures similarity of each individual’s set of biomarkers to
four profiles that represent high risk (high or low on
primary mediators and secondary outcomes)
Which Type of Score is Best?
‡ How should we assess preferences for one
measure over another?
‡ Seplaki et al. conclude that:
„ additional markers and use of two-tails (with 10/90)
cutoffs improves performance
„ Z-score works as well as counts
„ G0M has nice features, but it is very complicated.
Prediction of Various Health Outcomes
Using Different Allostatic Load Scores

Source: Seplaki, CL et al. 2005. A comparative analysis of measurement approaches for physiological
dysregulation in an older population. Experimental Gerontology, 438-449
Other Modifications
‡ These days, investigators frequently add new
biomarkers but sometimes at the expense of the
notion of allostatic load
„ Seeman et al. (2004) consider low peak flow, low
creatinine clearance as well as other biomarkers
„ Markers of ‘performance’ may have stronger
associations with health and survival than the ‘typical
biomarker’
‡ Should we consider renaming measures of
allostatic load as cumulative physiological
dysregulation (or biological risk)?
Expanded Set of Biological Risk Factors

Source: Seeman, TE et al. 2004. Cumulative biological risk and socio-economic differences in mortality:
MacArthur Studies of Successful Aging. Soc Sci Med, 1985-1997
ORs Vary Substantially
ORs associated with individual biomarkers in predicting 7.5 year mortality

Source: Seeman, TE et al. 2004. Cumulative biological risk and socio-economic differences
in mortality: MacArthur Studies of Successful Aging. Soc Sci Med, 1985-1997
Drawbacks of Allostatic Load Scores
‡ Measures used now are largely atheoretical
‡ Which biomarkers should we include?
„ We are generally limited to non-invasive easy to measure
markers. How invasive can non-invasive be?
‡ Examples from Taiwan
„ How should we measure the biomarkers (mean vs. variability,
reactivity vs. basal levels, type of specimen, etc.)
‡ Heart rate variability is an important measure of PNS regulation
believed to be related to psychosocial stressors (Sloan et al.,
2005); 20-minute EKG or Holter monitor
‡ Overnight cortisol or morning rise? Blood, urine or saliva?

‡ What are most appropriate cutpoints?

„ Should cutpoints vary (by age? sex?)
„ Do we redefine cutpoints from each data set?
‡ When should we have two tails of risk?
Drawbacks of Allostatic Load Scores, con’t
‡ How should we weight different biomarkers?
„ The weights are likely to vary as a function of the health
outcome
‡ Is a sum type of score a good idea?
„ Are we masking effects of individual markers?
„ One compromise is to consider sub-scores of allostatic
load (see Seeman et al., 2004 in earlier slide)
„ What about interactions among biomarkers?
‡ Many persons in the sample use medications
which may mask underlying value of biomarkers
‡ How do we know if we have a good measure?
„ We will return to this very difficult issue
More Complex Measures of Allostatic Load
‡ Canonical Correlation
„ Karlamangla et al. (2002). “Allostatic load as a predictor
of functional decline: MacArthur studies of successful
aging.” Journal of Clinical Epidemiology 55: 696-710.
‡ Recursive Partitioning
„ Singer, Ryff and Seeman (2004). Chapter 4
(“Operationalizing Allostatic Load” in Schulkin (ed.))
„ Gruenewald et al. (2006). “Combinations of biomarkers
predictive of later life mortality.” PNAS 103: 14158-
14163.
‡ Future Directions
Canonical Correlation (CC)
‡ Use a set of biomarkers to predict multiple outcomes
(components of cognitive and physical functioning).
‡ Find the best linear combination of the biomarkers (at
baseline) that is maximally correlated with the best linear
combination of functional outcomes over the follow-up
period
‡ That is, canonical correlation finds a linear combination
of the variables from each set (biomarkers & outcomes)
– a canonical variable – such that the correlation
(canonical correlation) between the two is maximized.
‡ The weights in the best linear combination are known as
the canonical weights and are used to score AL.
„ One typically calculates weights after predictor & outcome
variables have been standardized
‡ The contributions of individual predictors and outcomes
to the overall association can be determined.
Canonical Weights Based on 10 Biomarkers

Source: Singer B et al. 2004. “Operationalizing Allostatic Load.” Pp.113-149 in Jay Schulkin
(eds.) Allostasis, Homeostasis, and the Costs of Physiological Adaptation. Cambridge, U.K.: Cambridge University Press
.
What Did CC Contribute to the AL Debate?
‡ In contrast to the conventional measure,
contributions of markers can vary
„ Some markers are not predictive (cholesterol), others
(epinephrine) matter a lot (Karlamangla et al., 2002)
‡ The Syndrome X markers do not tell the entire
story; the hormonal markers are useful
predictors
‡ Of course, these findings are likely to vary by
type of outcome
Recursive Partitioning (RP)
‡ Identify subclinical levels of biomarkers
(“pathways”) that lead to high risk outcomes
‡ Begin with a set of biomarkers and a set of
outcomes as in CC
‡ Step 1: Partition the data into 2 groups
„ Use the algorithm to search among the biomarkers and
possible binary cut points to the identify the best single
biomarker (and cut point) that differentiates individuals
by outcome (e.g., survival over follow-up period).
„ In the example that follows (Singer et al., 2004), DBP
was the best predictor with high risk defined as DBP <
60 mm Hg (hypotension)
„ Note that this could not have been discovered with
original formulation which looked only at high BP
First Stage in Recursive Partitioning Tree

- 727 Persons -
Is DBP > 60?

No Yes

#Dead / N = 19/43 = .44 #Dead / N = 135/684 = .20

Based on mortality in 7-year follow-up period in MacArthur study

Source: Singer B et al. 2004. “Operationalizing Allostatic Load.” Pp.113-149 in Jay Schulkin
(eds.) Allostasis, Homeostasis, and the Costs of Physiological Adaptation. Cambridge, U.K.: Cambridge University Press
.
Recursive Partitioning (RP), con’t
‡ Step 2: Partition each of 2 subgroups separately,
by identifying which biomarker (and cut point)
would lead to best survival prediction for that
subgroup
„ One can identify terminal nodes (no further
subdivisions) – e.g., group with DBP <60mm Hg was
designated to have terminal node with high mortality
(44%)
Second Stage in Recursive Partitioning Tree

- 727 Persons -
Is DBP > 60?
Yes
No

N = 684
#Dead / N = 19/43 = .44
Is DBP > 80?
No Yes

N = 413
#Dead / N = 73/271 = .27
Is HDL > 36?
No Yes

#Dead / N = 26/93 = .28 #Dead / N = 36/320 = .11

Source: Singer B et al. 2004. “Operationalizing Allostatic Load.” Pp.113-149 in Jay Schulkin
(eds.) Allostasis, Homeostasis, and the Costs of Physiological Adaptation. Cambridge, U.K.: Cambridge University Press
.
Recursive Partitioning (RP), con’t
‡ Step 3: Identify Boolean statements defining
High, Intermediate, and Low Levels of AL

Source: Singer B et al. 2004. “Operationalizing Allostatic Load.” Pp.113-149 in Jay Schulkin
(eds.) Allostasis, Homeostasis, and the Costs of Physiological Adaptation. Cambridge, U.K.: Cambridge University Press
.
Recursive Partitioning (RP), con’t
‡ Step 4: Continue without overfitting the data
(simplifying rules)
‡ Gruenewald et al. (2006) use alternative RP
procedures that lead to multiple trees (use of
suboptimal splits at the top) and subsequent
selection of a “forest from the trees” to consider
multiple pathways across the trees
Final Recursive Partitioning Tree

N = 727 Yes
DBP > 60 ? N = 684
DBP > 80 ? Yes
No No
#D/N = 73/271 = .27
#D/N = 19/43 = .44
N = 413
Yes
No HDL > 36 ?

N = 320
#D/N = 26/93 = .28 HDL > 38 ?
Yes
No
N = 296
#D/N = 0/24 = 0 Cortisol > 9.4 ?
Yes
No
N = 257
#D/N = 1/39 = .03 HDL > 79 ?
No
Yes
N = 239
SBP > 141 ?
No Yes #D/N = 0/18 = 0
#D/N = 22/185 = .12 N = 54
Glyc. Hem. > 6.8? Yes
No

#D/N = 0/20 = 0 #D/N = 13/34 = .38

Source: Singer B et al. 2004. “Operationalizing Allostatic Load.” Pp.113-149 in Jay Schulkin
(eds.) Allostasis, Homeostasis, and the Costs of Physiological Adaptation. Cambridge, U.K.: Cambridge University Press
.
Final Boolean Statements for RP

Source: Singer B et al. 2004. “Operationalizing Allostatic Load.” Pp.113-149 in Jay Schulkin
(eds.) Allostasis, Homeostasis, and the Costs of Physiological Adaptation. Cambridge, U.K.: Cambridge University Press
.
What Does RP Contribute to the AL debate?
‡ Empirical identification of cut points is less
arbitrary than predetermined percentiles
‡ Implicitly permits interaction among biomarkers
(and statements)
‡ Recognition of multiple pathways to downstream
health outcomes
‡ Identification of “dominant” markers: e.g.,
predominance of inflammatory biomarkers in
high risk pathways
Canonical Correlation & Recursive
Partitioning
‡ These 2 procedures differ in a fundamental way
from other methods of measuring allostatic load
(apart from being more statistically
sophisticated)
‡ How so?
‡ Is this a problem?
Future Directions:
A New Approach for Measuring AL

‡ Metabonomics
„ Identify and quantify time-related metabolic changes in
an integrated biological system – i.e., identify low
molecular weight molecules produced by active living
cells
‡ Find metabolites (e.g., gene & protein expression)
in biofluids (urine, serum), based on 1H-NMR
spectroscopy (high resolution, complex spectra)
Metabonomics, con’t
‡ Identify distinct metabolic signatures (e.g., amino
acids, lipoproteins) between populations high on
stressors/adverse histories vs. low on
stressors/positive experiences
‡ Analysis requires computer-based data reduction and
pattern recognition methods.
‡ Most work has been done in animals looking at
response to drug toxicity or disease profiles.

Source: Singer B et al. 2004. “Operationalizing Allostatic

Load.” Pp.113-149 in Jay Schulkin (eds.) Allostasis,
Homeostasis, and the Costs of Physiological Adaptation.
Cambridge, U.K.: Cambridge University Press
.
The Million Dollar Question:
What is the Evidence to Support “Allostatic Load”?
‡ Some claim that finding that cumulative score has
stronger association with health than individual markers
provides evidence
„ “The summary measure of AL was a much better predictor of
health outcomes than any individual component, supporting
the argument that AL reflects the cumulative burden of a
number of modest deviations from a range of systems.” (Clark
et al. Psychology, Health & Medicine). Do you buy this?
‡ Is there evidence that chronic stressors/adverse histories
are associated with AL?
„ There are not many such studies
‡ Is there evidence that AL is associated with downstream
health and survival?
„ Many studies suggest that this is the case
‡ This brings us to the next topic: linkages among the
social environment, stress, & physiological dysregulation
Final Conundrums
‡ There are obvious weaknesses in AL measures
in current use
‡ There are concerns with regard to using any
type of cumulative measure given our state of
knowledge
‡ So, how should we improve our measures of
cumulative physiological dysregulation?
‡ Allostatic load should not be measured at one-
point in time. But, how do we begin to deal with
multi-system changes in biomarkers over time?