Sex, stress and the hippocampus: allostasis, allostatic load and the aging process
Introduction
Individual differences in the aging process can be conceptualized as an accumulation of wear and tear of daily experiences and major life stressors which interact with the genetic constitution and predisposing early life experiences [52], [164], [175]. The neuroendocrine system, autonomic nervous system (ANS) and immune system are mediators of adaptation to challenges of daily life, referred to as “allostasis”, meaning “maintaining stability through change” [178]. Physiological mediators such as adrenalin from the adrenal medulla, glucocorticoids from the adrenal cortex and cytokines from cells of the immune system act upon receptors in various tissues and organs to produce effects that are adaptive in the short run but can be damaging if the mediators are not shut off when no longer needed. When release of the mediators is not efficiently terminated, their effects on target cells are prolonged, leading to other consequences that may include receptor desensitization and tissue damage. This process has been named “allostatic load” [121], [127], and it refers to the price the tissue or organ pays for an overactive or inefficiently managed allostatic response. Therefore, allostatic load refers to the “cost” of adaptation.
The brain is the master controller of the three systems noted above and is also a target of these systems, subject to both protection and damage. Allostasis also applies not only to circulating hormones but also to organs and tissues of the body. In the nervous system, neurotransmitters are released by neuronal activity, and they produce effects locally to either propagate or inhibit further neural activity. Neurotransmitters and hormones are usually released during a discrete period of activation and then are shut off, and the mediators themselves are removed from the intracellular space by reuptake or metabolism in order not to prolong their effects. When that does not happen, however, there is allostatic load and the brain is at increased risk for damage [103].
The processes of allostasis and allostatic load have been described and measured for metabolic and cardiovascular changes that are associated with obesity, Type 2 diabetes and cardiovascular disease [171]. However, the same type of elevated and prolonged secretion of glucocorticoids during aging has also been associated with impairment of cognitive function in rodents [92], [93], [165] and in humans [104], [105], [170]. Moreover, the endogenous excitatory amino acid neurotransmitters appear to play a major role in these changes [165] even though they are also an essential part of normal synaptic neurotransmission and plasticity. Their actions lead to the formation of excess free radicals that can damage nerve cells, leading to the search for agents that can interfere with free radical production or enhance free radical quenching. The “glucocorticoid cascade hypothesis” of aging [94], [120], [165], [166] is an example of a theory of aging that emphasizes the pivotal nature of aging of key brain structures such as the hippocampus, a brain region involved in key aspects of episodic, declarative, spatial and contextual memory and also in regulation of autonomic, neuroendocrine and immune responses. Agents that are protective against accelerated aging should be judged for their ability to protect key brain structures such as the hippocampus from the effects of a variety of insults, many of which involve excitotoxicity and damage from reactive oxygen species and free radicals. The “glucocorticoid cascade hypothesis” of aging is a prime example of allostatic load since it recognizes feed forward mechanism that gradually wears down a key brain structure, the hippocampus, while the gradually disregulated HPA axis promotes pathophysiology on tissues and organs throughout the body.
In spite of its vulnerability to allostatic load, the brain retains considerable resilience in the face of challenges to adapt through allostasis. Studies on the hippocampus reveal a number of types of structural plasticity, ranging from neurogenesis in the dentate gyrus to remodelling of dendrites to the formation and replacement of synapses. These changes, along with compensatory neurochemical and neuroendocrine responses, provide the brain with a considerable amount of resilience. This has led to a search for agents that help the brain maintain its resilience as it ages.
This article discusses allostasis and allostatic load in the brain in relation to the aging process and a number of brain disorders in which there is overactivity of stress mediators that causes brain dysfunction. Specifically, this article summarizes research on the protective and damaging effects of adrenal steroids and estrogens on the brain, particularly on the hippocampus. It also discusses the topic of neuroprotection and the potential value of estrogens and flavonoids as anti-oxidants in promoting allostasis and enhancing resilience and countering the allostatic load promoted by excitatory amino acids and other agents that promote the generation of free radicals such as the β-amyloid protein. “Resilience is an example of successful allostasis in which wear and tear is minimized, and estrogens exemplify the type of agent that works against the allostatic load associated with aging.” Before entering full-force into this discussion, it is important to review briefly the role of the biological mediators of stress in the protective and damaging aspects of stress on the brain and body and to discuss the terms “allostasis” and “allostatic load”.
Section snippets
Protective and damaging effects of stress mediators: homeostasis and allostasis
Before discussing the brain and individual differences in the cumulative wear and tear during the aging process, it is important to clarify ambiguities in some key terms. In common usage, stress usually refers to an event or succession of events that challenges homeostasis and causes a response, often in the form of “distress” but also, in some cases, referring to a challenge that leads to a feeling of exhilaration, as in “good” stress [54]. But, the term “stress” is often used to mean the
The measurement of allostasis, allostatic states and allostatic load
How can we measure allostasis and its consequences in terms of allostatic states and allostatic load, particularly when it comes to following the events that lead to disease over the life course in individual human subjects and groups of individuals? This is a major goal of the biologist in working with social scientists and epidemiologists in attempting to answer questions such as the relationship between working, living environments and socioeconomic conditions and health or disease [4]. And
Allostasis and allostatic load in the brain
As defined earlier in this article, allostasis is the process of adaptation to challenge that maintains stability, or homeostasis, through an active process [178], and allostatic load is the wear and tear produced by the repeated activation of allostatic, or adaptive, mechanisms, frequently involving allostatic states of chronically elevated or disregulated activity of key tissue and hormonal mediators [121], [127]. Four types of allostatic states leading to allostatic load have been identified
Age-related shifts of calcium homeostasis and its consequences
The hippocampus is a brain region that is very important for declarative and spatial learning and memory, and yet is a particularly vulnerable and sensitive region of the brain that expresses high levels of receptors for adrenal steroid “stress” hormones [30], [44]. Hippocampal neurons are vulnerable to seizures, strokes and head trauma, as well as responding to stressful experiences [30], [123], [166]. At the same time these neurons show remarkable and paradoxical plasticity, involving
Developmental determinants of individual differences in allostatic load
The vulnerability of many systems of the body to stress is influenced by experiences early in life. In animal models, unpredictable prenatal stress causes increased emotionality and increased reactivity of the HPA axis and ANS and these effects last throughout the lifespan [193]. Postnatal handling in rats, a mild stress involving brief daily separation from the mother, counteracts the effects of prenatal stress and results in reduced emotionality and reduced reactivity of the HPA axis and ANS
Adaptive plasticity—another role for excitatory amino acids and hormones
The hippocampus is not only a vulnerable brain structure to damage but is also a very plastic region of the brain and expresses high levels of adrenal steroid receptors. Adrenal steroids, which, as we have noted, have a bad reputation as far as their role in exacerbating these forms of damage [165], are also involved in three types of adaptive plasticity in the hippocampal formation. “Adaptive plasticity is a form of allostasis that enables the brain to respond to a changing environment and
Adaptive plasticity and the concept of resilience
We have noted that the young brain is resilient and able to withstand challenges and adapt, and the structural plasticity noted above is an example of this resilience and adaptability. The term allostasis means adaptation and coping and implies resilience. Allostasis operates most efficiently when the body is doing its best to maintain homeostasis without doing harm. As noted and illustrated above, allostatic load is the cost of adaptation, reflecting both the overuse of the system by repeated
Stress and estrogen interactions affecting brain function
There are a number of points of interaction with ovarian hormones that indicate that estrogens may have a neuroprotective role in relation to stress and glucocorticoid secretion and actions in the brain. For example, estrogens stimulate neurogenesis in the female dentate gyrus [182]. Moreover, female rats appear to be resistant to the stress-induced atrophy of hippocampal dendrites seen in male rats [47]. Because there are developmentally programmed structural and functional sex differences in
Resilience of the brain in the face of stress and allostatic load
We have seen that stress and glucocorticoids act in concert with excitatory amino acids to modulate the branching of dendrites in the hippocampus of experimental animals and the replacement of neurons in the dentate gyrus [122]. Atrophy of dendrites and inhibition of neurogenesis caused by stress compromises cognitive functions that depend on the hippocampus, such as spatial, declarative and contextual memory. However, these effects are reversible, along with the morphological changes, as long
Conclusions
In conclusion, allostatic states and the cumulative wear and tear (allostatic load) that the body experiences as a result of daily life experiences, differences in individual life style, major life events and socioeconomic status is a highly individual matter, dependent on genotype, early experience and the types of experiences throughout life. Initial attempts to measure allostatic states and allostatic load have been successful enough to encourage further development of methods for measuring
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