Allostasis allostatic load and ageing

Another shift in the neuroregulatory perspective is the proposal that ageing is related to lifetime stress, under the concepts of allostasis and allostatic load. Sterling & Eyer (1988) introduced the term allostasis to explain morbidity and mortality associated with chronic stress, especially social stress in human populations. They defined allostasis as 'maintaining stability through change'. The boundaries between allostasis and related constructs such as homeostasis, adaptation and pathology are sometimes unclear. It is a heuristic construct that is still being refined (for example by Koob & Le Moal 2001). Speaking generally, allostasis is distinct from homeostasis in maintaining a compensated equilibrium rather than a physiological equilibrium: stability is maintained at a price. The allostatic set point is abnormal relative to the homeostatic set point, the system is inherently less stable, and it has a relatively narrow dynamic range. Finally, a system in allostasis leads to pathology whereas a system in homeostasis does not.

The term allostatic load was introduced by McEwen & Stellar (1993) to denote the cost of responding repeatedly or chronically to stress. McEwen (1998) emphasized four types of responses that produce this 'wear and tear': (i) repeated acute stress challenges; (ii) failure to adapt (i.e. to extinguish) the acute (or chronic) stress responses normally with repeated (or chronic) exposure; (iii) excessively prolonged acute stress responses; and (iv) inadequate acute stress responses leading to elevated activity of other, normally counter-regulated allostatic systems after stress (for which the Lewis rat is a proposed model). Both developmental and genetic dimensions have been proposed as modifiers of allostatic load that may determine vulnerability and risk of pathology (McEwen 2000).

When we view the brain's response to stress, all the features of allostasis are discernible (McEwen 2000). Chronic stress produces changes in brain function and structure consistent with a compensated equilibrium and altered set points. These include increased activity of the HPA axis; impaired fast and delayed glucocorticoid feedbacks; and elevated circulating glucocorticoids. There is a restricted dynamic range, with diminished circadian amplitude and elevated nadir values. The resultant pathology includes decreased neurogenesis in the dentate gyrus; loss of terminal arborization in the forebrain projections of the LC and the raphe nuclei (Kitayama et al 1994, Duman et al 1997); dendritic regression in hippocampus; and loss of synapses in hypothalamus and cortex. Antidepressant treatments that induce mRNA for BDNF and TrkB can reverse these changes (Kitayama et al 1997, Nibuya et al 1995). The functional result of these changes is a feed-forward cascade of disinhibited HPA activity, and other dysregulations such as loss of oestrous cycling, impaired hedonic function (decreased spontaneous motor activity, caloric intake and sweet food preference, and intracranial self-stimulation), and decreased adaptive behaviours (Hatotani et al 1977, 1979, Katz 1982). These effects of chronic stress resemble those seen in ageing. Consistent with this similarity is the decreased longevity of inbred rat strains that are hyperreactive to stress. Mean lifespan is 15 months in the spontaneously hypertensive rat (SHR), and 21.5 months in the Wistar—Kyoto (WKY) rat, compared with 31 months for the Brown Norway rat (Gilad & Gilad 1987, Brandle et al 1997).

In summary, the neuropathological and neuroregulatory changes of normal ageing resemble those associated with chronic stress. These findings are consistent with the proposal that longevity is affected by allostatic load, and give new meaning to Selye's famous phrase, 'the stress of life'. The glucocorticoid-mediated allostatic effect on lifespan must be mediated through relatively subtle and chronic processes. Comparisons often invoked, for example by Sapolsky (2000), between chronic stress and grossly pathological hypercortisolaemic states like Cushing's disease are not appropriate or informative. The exposure of tissues to glucocorticoids in human and animal chronic stress paradigms is well below the cushingoid range. Two more relevant candidate mediators of allostatic pathology in chronic stress are proposed below.

First, the critical allostatic link between chronic stress, brain dystrophic change and longevity is not likely to be the exposure of tissues to pathologically raised concentrations of glucocorticoids. A chronobiological explanation is more likely, namely, an altered HPA circadian rhythm that leads to the continuous occupancy of glucocorticoid receptors (GRs) in target tissues. An important consideration here is that normally GRs are essentially unoccupied during 25—30% of the day (Dallman & Akana 1991). With the allostatic resetting of the circadian HPA programme by stress, elevated nadir values of cortisol or corticosterone are observed, which are sufficient to produce continuous occupancy of GRs over 24 h (e.g. Lopez et al 1998). Continuous GR occupancy is abnormal, as evidenced by tissue change such as thymic atrophy, even though the mean 24 h cortisol value is held normal (Akana et al 1991). GR-containing target sites in the brain affected by this process will include the LC, raphe nuclei and hippocampus, where stress-related dystrophic change occurs. Other GR-responsive tissues such as skin, bone and liver will also be affected, with consequent changes such as hair loss, skin ulceration, osteoporosis, decreased muscle mass, increased susceptibility to infections and glucose intolerance that are characteristic of chronically stressed rats.

A second candidate allostatic mechanism leading to pathology is the stress-associated phenomenon of elevated body temperature, which is most marked during the quiet phase of the activity and HPA circadian rhythms (Meerlo et al

1997). The persistent, subtle hyperthermia results in a hypermetabolic state that will accelerate general cellular ageing mechanisms. These include mitochondrial failure and mitochondrial DNA damage, accumulation of oxygen free radicals and protein conformational changes (Drachman 1997). The combination of chronic hyperthermia with abnormal GR occupancy may be additive for pathology. The significance of the allostatic load of nocturnal hyperthermia as a link between stress and ageing is apparent from studies that find body temperature differences associated with differential longevity (Hunter et al 1999). The SHR rat strain provides an especially good example of stress-associated hyperthermia, end organ pathology and shortened lifespan (Berkey et al 1990, Morley et al 1990). Parenthetically, calorie restriction, which dramatically increases longevity, leads to a persistent reduction of body temperature (Lane et al 1996). Thus, these two factors, abnormal GR occupancy and hyperthermia, which occur together during the quiet phase of the HPA circadian cycle, are candidate mechanisms for the subtle and chronic effects of stress on the brain and on longevity. Both factors operate also in major depression, a clear instance of an allostatic disorder.

How To Add Ten Years To Your Life

How To Add Ten Years To Your Life

When over eighty years of age, the poet Bryant said that he had added more than ten years to his life by taking a simple exercise while dressing in the morning. Those who knew Bryant and the facts of his life never doubted the truth of this statement.

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