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Homeostasis & Stress Physiology - The Concept of Allostasis
Homeostasis & Stress Physiology - The Concept of Allostasis
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www.elsevier.com/locate/yhbeh
Laboratory of Neuroendocrinology, The Rockefeller University, Box 165, 1230 York Avenue, New York, NY 10021, USA
b
Department of Zoology, Box 351800, University of Washington, Seattle, WA 98195, USA
Received 28 February 2002; accepted 8 September 2002
Abstract
Living organisms have regular patterns and routines that involve obtaining food and carrying out life history stages such as breeding,
migrating, molting, and hibernating. The acquisition, utilization, and storage of energy reserves (and other resources) are critical to lifetime
reproductive success. There are also responses to predictable changes, e.g., seasonal, and unpredictable challenges, i.e., storms and natural
disasters. Social organization in many populations provides advantages through cooperation in providing basic necessities and beneficial
social support. But there are disadvantages owing to conflict in social hierarchies and competition for resources. Here we discuss the concept
of allostasis, maintaining stability through change, as a fundamental process through which organisms actively adjust to both predictable
and unpredictable events. Allostatic load refers to the cumulative cost to the body of allostasis, with allostatic overload being a state in which
serious pathophysiology can occur. Using the balance between energy input and expenditure as the basis for applying the concept of
allostasis, we propose two types of allostatic overload. Type 1 allostatic overload occurs when energy demand exceeds supply, resulting in
activation of the emergency life history stage. This serves to direct the animal away from normal life history stages into a survival mode
that decreases allostatic load and regains positive energy balance. The normal life cycle can be resumed when the perturbation passes. Type
2 allostatic overload begins when there is sufficient or even excess energy consumption accompanied by social conflict and other types of
social dysfunction. The latter is the case in human society and certain situations affecting animals in captivity. In all cases, secretion of
glucocorticosteroids and activity of other mediators of allostasis such as the autonomic nervous system, CNS neurotransmitters, and
inflammatory cytokines wax and wane with allostatic load. If allostatic load is chronically high, then pathologies develop. Type 2 allostatic
overload does not trigger an escape response, and can only be counteracted through learning and changes in the social structure.
2003 Elsevier Science (USA). All rights reserved.
Introduction
Modern biology provides a framework not only for understanding how the interplay of genes and environment
produces individual characteristics, and how these individuals interact in social groups and with other species, but also
for understanding how these interactions lead to pathophysiology and disease. For example, knowledge of how the life
cycles of organisms are integrated and controlled in the
natural world will allow us to assess the effects upon ecosystems of global climate change, disturbance by humans,
and endocrine disrupters. Of equal importance is a need to
use basic biological frameworks in human society to conceptualize and measure the cumulative impact of social
* Corresponding author. Fax: 1-212-327-8634.
E-mail address: mcewen@rockvax.rockefeller.edu (B.S. McEwen).
0018-506X/03/$ see front matter 2003 Elsevier Science (USA). All rights reserved.
doi:10.1016/S0018-506X(02)00024-7
Definition of terms
Homeostasis
Homeostasis is the stability of physiological systems that
maintain life, used here to apply strictly to a limited number
of systems such as pH, body temperature, glucose levels,
and oxygen tension that are truly essential for life and are
therefore maintained within a range optimal for the current
life history stage.
Allostasis
Allostasis is achieving stability through change. This is a
process that supports homeostasis, i.e., those physiological
parameters essential for life defined above, as environments
and/or life history stages change. This means that the setpoints and other boundaries of control must also change.
There are primary mediators of allostasis such as, but not
confined to, hormones of the hypothalamopituitaryadrenal (HPA) axis, catecholamines, and cytokines. Allostasis
also clarifies an inherent ambiguity in the term homeostasis and distinguishes between the systems that are essential
for life (homeostasis) and those that maintain these systems in balance (allostasis) as environment and life history stage change.
We note, however, that another view of homeostasis is
the operation of coordinated physiological processes that
maintain most of the steady states of the organism (Cannon,
1929). In this interpretation, homeostasis and allostasis
might seem to mean almost the same thing. The reason they
do not is that the notion of steady state is itself vague and
does not distinguish between those systems essential for life
and those that maintain them. It also does not differentiate
changes in state to enable reproduction (and other life cycle
processes) that are not required for immediate survival (e.g.,
Bauman, 2000; Kuenzel et al., 1999; Mrosovsky, 1990).
Allostatic state
The allostatic state refers to altered and sustained activity
levels of the primary mediators, e.g., glucocorticosteroids,
that integrate physiology and associated behaviors in response to changing environments and challenges such as
social interactions, weather, disease, predators, pollution,
etc. Originally proposed for understanding physiological
aspects of drug abuse (Koob and LeMoal, 2001), an allostatic state results in an imbalance of the primary mediators,
reflecting excessive production of some and inadequate production of others. Examples are hypertension, a perturbed
cortisol rhythm in major depression or after chronic sleep
deprivation, chronic elevation of inflammatory cytokines
and low cortisol in Chronic Fatigue Syndrome, and imbalance of cortisol, CRF, and cytokines in the Lewis rat that
increases risk for autoimmune and inflammatory disorders.
Allostatic states can be sustained for limited periods if food
the two distinctive directions described above. This is particularly severe if the overload is permanent such as with
injury, disease, and some lifestyles. These are all secondary
outcomes that can be measured and are associated with
increased risk for a disease.
Using these definitions as a starting point, we now discuss the overused term stress and how, in its place, the
concept of allostasis may allow us to consider the life cycle
in general as a continuum from daily routines to allostatic
overload and the accompanying pathologies. Within the
framework of allostasis, a narrower and more precise definition of stress has an important place. This is particularly
heuristic because it allows us to include individual variation
due to experience, genetics, and social status. It incorporates
thresholds and transitions among physiological and behavioral states that also vary from individual to individual.
Despite this complexity, the framework illustrates that similar hormone systems may be involved. Furthermore, the
framework allows formulation of clear predictions that can
be tested experimentally.
anxiety are capable of exacerbating and potentiating physiological mediators of health outcomes.
Protection vs damage
From the standpoint of survival and health of the individual, the most important feature of mediators associated
with allostasis is that they have protective effects in the
short run. However, they can have damaging effects over
longer time intervals if there are many adverse life events or
if hormone secretion is dysregulated as in a sustained allostatic state that leads to allostatic overload (McEwen, 1998).
In contrast to Selye (1956), this view holds that mediators of
allostasis have a spectrum of actions that depend on the time
courses over which they are being produced, and other
events that are taking place at the same time that is, the
general adaptation syndrome is not really so general, after
all (Goldstein and Eisendorfer, 2000; Goldstein and Pacak,
2000). Below we illustrate how the immediate effects of the
secretion of mediators of allostasis such as glucocorticosteroids and catecholamines are largely protective and adap-
10
There are animal models of this. The thrifty genes hypothesis has been proposed for many decades and asserts
that humans and perhaps all animals have genes for efficient
and potentially excessive energy accumulation. In fluctuating environments when food shortages (EG) are common,
this would be highly adaptive. In modern times with no food
shortage, at least in developed countries, it leads to chronic
obesity, hypertension, and diabetes (Lev-Ran, 2001; Neel,
1962; Neel et al., 1998). Many animals from fish to toads
11
12
Table 1
Relative risk for three disorders involving the nervous system
Income
$019K
$2034K
$3569K
$ 70K
Education
Years 011
Years 12
Years 1315
Years 16
Affective
Disorders
Anxiety
Disorders
Substance
Abuse
1.73*
1.13
1.01
1.00
2.12*
1.56*
1.50
1.00
1.92*
1.12
1.11
1.00
1.79*
1.38*
1.37*
1.00
2.82*
2.10*
1.60*
1.00
2.10*
1.80*
1.70*
1.00
Note. Data are compiled for both income and education based upon
Kessler et al. (1994) and Regier et al. (1993). Table prepared by Dr. Nancy
Adler, University of California, San Francisco, as a personal communication to the author. Reprinted from McEwen (2000) by permission.
Conclusions
Most vertebrate organisms have regular patterns and
routines that involve obtaining food and carrying out life
history stages such as breeding, migrating, molting, hibernating, etc. These life history stages occur in set sequences
on a time scale of about 1 year. Each has energetic requirements that vary according to demand. Often, life history
stages such as reproduction and migration are energetically
demanding, whereas others rely on stored energy only (hibernation). The annual sequence of stages is geared to
maximize fitness by allowing individuals to breed at the
optimal time and in the best condition. Acquisition, utilization, and storage of energy reserves are critical to lifetime
reproductive success. Animals are also exposed to unpredictable perturbations of the environment that have the
potential to disrupt the life cycle and may even result in
development of pathologies if the perturbation becomes
chronic. Thus individuals must respond to challenges that
are both predictable, such as seasonal changes, and unpredictable, such as storms and natural disasters. Social organization also plays an important role in the integration of
life cycles.
Here we have discussed the concept of allostasis, maintaining stability through change, as a fundamental process
through which organisms actively adjust to these predictable and unpredictable events. It is a particularly heuristic
concept because it joins the energetic costs of life history
stages with those accompanying social challenges and perturbations of the environment into a continuum. Glucocorticosteroid secretion, catecholamines, and cytokines increase in parallel with this continuum allostatic load.
One very attractive aspect of this idea is that the term
stress can now be restricted to the environmental perturbations that lead to allostatic load. The term allostasis subsumes stress as the process by which physiological stability
is maintained in the face of change. In the past the term
stress could refer to the environmental challenges as well as
the process of attempted adaptation and the result development of pathologies. This often led to confusing phrases
such as the stress of reproduction or migration as opposed to
the stress of being chased by a predator, or the result of
social trauma. Clearly the former is part of the normal life
cycle whereas the latter are perturbations that go beyond the
norm. Allostasis forms a continuum between events of the
normal life cycle and unpredictable perturbations with clear
transition points and outcomes.
Allostatic load refers to the cumulative cost to the body
of allostasis as individuals adjust their morphology, physi-
Acknowledgments
J.C.W. is grateful for several grants from the Division of
Integrated Biology and Neuroscience, and the Office of
Polar Programs, National Science Foundation. He also acknowledges a John Simon Guggenheim Fellowship, a Benjamin Meaker Fellowship (University of Bristol, UK), and a
Russell F. Stark University Professorship (University of
Washington). B.Mc. acknowledges the intellectual support
from colleagues in the MacArthur Research Network for
Socioeconomic Status and Health, Nancy Adler, UCSF,
Chair. In particular, Teresa Seeman, UCLA, and Burton
Singer, Princeton, have played a major role in formulating
and validating the concepts of allostasis and allostatic load.
He acknowledges grant support from the NIH.
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