Chronic Angst Allostasis and Pathology

McEwen and his colleagues (McEwen and Stellar, 1993; McEwen, 1998a, b, 1999; McEwen and Seeman, 1999) formulated and developed the terms allostasis and allostatic overload in an attempt to account for preserving physiological stability amid changing circumstances. For example, when uncertainty persists for long periods or is perceived as going beyond one's control, it results in negative consequences that my colleagues and I called anticipatory angst in an earlier paper (Schulkin et al., 1994). There is a plethora of animal and human data on the negative consequences to bodily and psychological health in such a circumstance. This occurs when normal physiological adaptation is run beyond what it was designed to tolerate.

The diverse physiological systems for maintaining bodily viability to acute challenges are reflected in mobilization of cardiovascular function, activation of metabolic fuels, activation of immune defense, and engagement of central nervous systems function (McEwen, 1998a, b; Sapolsky et al., 2000). But the chronic condition (allostatic state; Koob and Le Moal, 2001) can result in allostatic overload and cardiovascular, metabolic, im-munological, and neuronal pathology.

Adaptation to uncertainty is a fact of life because uncertainty pervades life. In the short run, allostatic mechanisms can provide physiological and behavioral resources that help maintain equilibrium. Unfortunately, these resources are finite. Chronic signals from physiological mediators (cytokines, cortisol, catecholamines, etc.) take their toll on bodily function, resulting in vulnerability to a variety of diseases such as those that concerned Sterling and Eyer (1988) and later McEwen and Seeman (1999; including hypertension, diabetes, atherosclerosis, bone loss, sleep disruption, disruption of immune and reproductive functions, inhibition of neurogenesis, aging process; Seeman et al., 2001). Vulnerability to these events can occur from prenatal events (Barker, 1997; Welberg and Seckl, 2001).

Within the literature, something beyond traditional conceptions of homeostasis was needed to account for regulatory events. To Selye and others (Goldstein, 1995a, b, 2000; Chrousos, 1998; Berntson and Cacioppo, 2000), the breakdown of systems was well-known and well-studied. Adaptation can only go so far in the attempt to maintain internal stability amid changing circumstances. The mechanisms for short-term regulation can lead to pathology when pushed beyond their adaptive time frames. To explain wide variation in physiological regulatory events, a biological basis of individual differences was noted.

Anticipatory regulation is a cognitive achievement and built into our brains (Gallistel, 1992; Schulkin, 2000). After all, evolution favored those who could not only react to events but also anticipate them. Thus, it is very reasonable to distinguish reactive from predictive homeostasis (Moore-Ede, 1986). Allostasis accounts for long-term responses—not simply short-term adaptations—and reflects feedforward and cephalic influences over behavioral and physiological events. The concept of allostasis forces one to broaden one's view of maintaining internal viability in changing and uncertain circumstances (but see Goldstein, 2000 for a very detailed depiction of homeostatic systems). But the concept also highlights the regulatory costs, in terms of the initial protective mechanisms and the longer-term damaging consequences of allostatic overload (e.g., the long-term changes in excitatory amino acid by chronic high levels of glucocorticoids; McEwen, 1999, 2001). The time scale in which to envision regulatory events by the use of the concept of allostasis is expanded quite considerably. What occurs quite naturally is the link between normal variation in use and descent into overload. The mediators of allostasis are different from the standard mediators of homeostasis such as pH, osmolarity, oxygen, and body temperature. Standard homeostatic mediators are less variable in the context of adaptation and bodily viability.

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