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Riddle DR, editor. Brain Aging: Models, Methods, and Mechanisms. Boca Raton (FL): CRC Press/Taylor & Francis; 2007.

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Brain Aging: Models, Methods, and Mechanisms.

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Chapter 13Stress and Glucocorticoid Contributions to Normal and Pathological Aging

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There is great interest in uncovering the mechanisms that underlie age-related changes in cognitive function. This task is complicated by the observation that there is considerable variation in the effects of aging across individuals. Although animals exhibit an age-related decline in performance of cognitive tasks on average, it is clear that some aged animals display cognitive performance comparable to that of younger animals while other animals are severely impaired. This phenomenon has been described across a wide variety of organisms, including humans [1, 2], primates [3], and rodents [4, 5]. One factor that may contribute to variable age-related changes in brain function is individual differences in the stress system. These differences in the stress system could arise through natural genetic variation or through dissimilar environmental exposure to stressors over the lifespan of the individual.

During a stressor, a wide variety of hormones are released through and regulated by a system termed the hypothalamus-pituitary-adrenal (HPA) axis. These hormones exert their effects in numerous central and peripheral sites to produce adaptive effects (see [6] for a review), including the mobilization of energy from storage sites, maintenance of the immune system, and inhibition of nonessential processes such as reproductive function. Collectively, these functions enable “fight or flight” behaviors to remove the organism from immediate danger, while later restoring bodily homeostasis.

Although many hormones are released in response to stress, much research has focused on the role of glucocorticoids (GCs). It is important to note, however, that stress and elevated GC levels are not equivalent, though their effects on behavior, plasticity, and other measures may be similar. GCs are synthesized in the adrenal glands, released directly into the peripheral circulatory system, and readily cross the blood-brain barrier. Two forms of GC receptors, the mineralocorticoid receptor (MR) and glucocorticoid receptor (GR), are each widely distributed throughout the brain [7–10], enabling GCs to have tremendous influence on brain function. The primary GC in humans and other primates is cortisol, whereas the main GC in rodents is corticosterone.

Links between GCs and peripheral signs of aging were first proposed after clinicians observed that patients with Cushing’s syndrome (also called hypercortisolemia; characterized by excessive secretion of GCs via the adrenal glands) exhibit pathologies often seen in aged individuals [11, 12]. These problems include heart disease, osteoporosis, hypertension, Type II diabetes, depression of the immune system, and loss of muscle. The idea that GCs might contribute to brain aging did not emerge until the early 1970s. At that time, studies had revealed that one particular region of the brain, the hippocampus, was especially enriched for GC receptors [13], and the contribution of the hippocampus to reducing activation of the HPA axis was beginning to be appreciated [14]. It was also known that the hippocampus was especially vulnerable to both normal and pathological changes observed with aging [15, 16]. These factors led scientists to propose a glucocorticoid hypothesis of aging [17–20]. This hypothesis predicted that life-long exposure to normal levels of GCs would cause deleterious effects of GCs to accumulate in GC-sensitive neurons, such as those of the hippocampus. Moreover, because hippocampal dysfunction could reduce hippocampus-mediated inhibition of the HPA axis [21], GC secretion was predicted to gradually increase over time, leading to an acceleration of both damage and dysfunction.

In accordance with the GC hypothesis of aging, basal plasma levels of GCs [22–24] and other hormones in the HPA axis [23, 25] increase in senescent rodents. Additionally, older rodents exhibit exaggerated endocrine stress responses; peak levels of stress hormones are unaffected with age, however GC levels take longer to return to basal levels [22, 26]. In contrast, the relationship between GC levels and aging is not as straightforward in primates. Generally, studies of nonhuman primates [27, 28] and humans [29, 30] reveal no increase in basal levels of GCs with aging until considering extremely aged cohorts. However, aged primates and humans do show some alterations in measures of HPA axis activity. For example, older primates exhibit higher cortisol levels and prolonged elevation of cortisol in response to some types of stimuli relative to younger primates [28, 32]. Some studies of aged humans have reported mild alterations in the diurnal cortisol rhythm [32–34]. Interestingly, several recent studies have suggested that age-related changes in HPA activity exhibit high levels of variability in primates, and identified sub-groups of rhesus monkeys [35] and humans [36–38] that have increasing and high basal cortisol levels with aging. These sub-groups were identified by tracking cortisol levels in individuals across a span of years, a time-consuming approach that is rarely used. Because cortisol levels vary widely within a day, due both to an innate diurnal rhythm and to the recent experiences of the individual, repeated measures over time likely produce a more reliable indicator of cumulative GC exposure.

The nature of individual differences in HPA function in human populations is not well understood, but there are a variety of sources that may contribute to group differences in GC secretion, which could, in turn, drive differences in susceptibility to GC-accelerated aging. One factor that may contribute to sub-populations with increased GC release is the presence of neuropathological conditions in that sub-population. There are a number of conditions, including Alzheimer’s disease [39] and depression [40], that result in high levels of cortisol, which have been speculated to contribute to accelerated brain aging [41]. A second factor that may contribute to individual differences in GC secretion is cumulative exposure to stress. Some chronic stressors in rodents [42, 43] and primates [44, 45] produce elevated basal GC levels. Similarly, in human populations, stressors such as caregiving or chronic illness can result in increased basal GC secretion [46, 47]. Another factor that may shape HPA axis activity is early life experiences. In rodents, unpredictable prenatal stress (produced by stressing the pregnant dam) causes life-long increases in HPA activity [48, 49]. In contrast, mild postnatal stress (short-term separation of the pups from the mother) is sufficient to reverse the effects of prenatal stress, and causes decreased activity of the HPA axis [50, 51]. Handling rodents during infancy causes long-lasting increases in GC receptors in the hippocampus, which enhances negative feedback of the HPA axis [51]. In these rat models of early experience, prenatal stress accelerates brain aging while mild postnatal stress of a form most readily construed as “stimilation” slows brain aging [52, 53]. A fourth modulator of HPA axis activity is genetic influences. It has been shown that people with genetically small hippocampi are more vulnerable to the pathological effects of stress [54]. It has also been shown that the human gene for GR has three single nucleotide polymorphisms, two of which produce a mild augmentation to psychosocial stress (reviewed in [55]).

Collectively, this evidence suggests that GC-mediated HPA activity is altered by aging, at least in a subset of the aged population. Whatever the underlying cause of age-related changes in GCs, many studies have now contributed to our understanding of the effects of GCs on neuronal function. These studies have revealed that stress and GCs have profound consequences for learning and memory and synaptic plasticity. Additional data have revealed that stress and GCs also contribute to neuronal atrophy, changes in rates of neuronal turnover, and perhaps to neuronal death. Subsequent work has provided evidence that these GC-and stress-induced changes are present in senescent animals, and have also demonstrated that interventions designed to reduce HPA activity can reduce signs of brain aging. By understanding the ways in which stress and GCs exacerbate brain aging, we also gain insight into ways to promote healthy brain aging.


The ability of stress and GCs to affect learning and memory has been extensively documented, particularly in the hippocampus where GC receptors are highly expressed. It has been shown that the levels of GCs at the time of learning and testing, as well as the cumulative history of GC exposure prior to learning and testing, are each capable of influencing learning and memory. In rodents, transient alterations in GC levels produced by a single injection of exogenous corticosterone cause concentration-dependent, biphasic modulation of brain function. Both low and high physiological levels of circulating GCs impair multiple measures of brain function, including learning and memory, whereas middle levels facilitate these measures, giving a characteristic “inverted-U” shaped dose-response curve (see [56] for a review). Stressors given immediately prior to assessment of learning and memory may similarly impair [57, 58] or facilitate [59] memory. The effects of repeated stress or GC exposure appear more uniform. Chronic stress consistently impairs measures of brain function. For example, chronic stress has been shown to adversely affect hippocampus-dependent spatial learning [60–63]. Deficits in hippocampus-dependent learning after chronic stress have also been noted for other organisms, including the tree shrew [64] and humans [65]. The effects of chronic stress on hippocampal function appear to be mediated by GCs, despite other stress-induced neuroendocrine changes. Removal of the adrenal glands prior to chronic stress is sufficient to prevent stress-induced memory problems [60]. Also, repeated injections of high physiological levels of exogenous GCs are sufficient to impair hippocampus-dependent task performance in rodents [60, 66].

Studies in humans also support a link between high circulating GC levels and poor learning and memory, although these impairments are not specific to hippocampal function. However, two studies in nonhuman primates have indicated that GC receptors are expressed in the frontal and prefrontal cortices at levels similar to or greater than the hippocampus [10, 68], predicting that GC effects on memory may not be greatest in hippocampus-dependent tasks in the primate. Injection of synthetic cortisol in young adults during the peak (highest level) or trough (lowest level) of the diurnal rhythm of endogenous secretion produced an impairment or facilitation of memory, depending on the time of injection [68]. That is, at the highest levels (the combination of both exogenous and endogenous GCs), acutely elevated GCs impaired performance, while at the lowest levels, performance improved. Repeated injections of synthetic cortisol over ten days in healthy, young adult humans have been shown to produce deficits in tasks depending on the frontal cortex [69]. In humans with clinical depression, cortisol levels are elevated during the cicadian trough overall and levels are predictive of memory performance: high levels of cortisol correlate with poor task performance [70]. Finally, hypercortisolemic patients with Cushing’s syndrome have been shown to have impaired performance on both cortical [71] and hippocampal [72] tasks. Thus, long-term exposure to high GC levels is capable of impairing learning and memory.

The effects of aging on learning and memory are similar to those produced by GCs and stress in younger animals. For example, rodents show age-related impairment of hippocampal function on a variety of hippocampus-dependent tasks such as spatial navigation [73, 74], the radial arm maze [75, 76], and contextual fear conditioning [77, 78]. Aged rats also show impairments on behavioral tasks that depend on frontal cortices, including medial frontal [79] and orbitofrontal [80, 81]. However, for all of these tasks, age-dependent impairment of learning and memory is quite variable, with subsets of animals exhibiting impairment and other cohorts showing little or no impairment [73–75, 81–86]; such variability can reflect important factors, such as strain or developmental history. Aged primates, including both monkeys [3, 87, 88] and humans [36, 38, 89, 90] show deficits in learning and memory, particularly in tasks that depend on the frontal cortices or hippocampus. In general, small sample sizes in these studies have precluded examining many of the factors that give rise to variability in these endpoints.

There is evidence to suggest that age-related impairments in learning and memory are related to GC levels. Increased HPA activity correlates with age-related cognitive impairment in rodents [4, 52, 91] and humans [5, 37], such that the greater the degree of cognitive impairment, the greater the measures of HPA activity. Adrenalectomy of rodents in mid-life, coupled with low-dose supplementation of exogenous GCs, retards age-related memory deficits [92]. In humans, elderly persons with subjective memory impairment have elevated basal cortisol levels [93]. Also, elderly humans with persistently high levels of basal cortisol measured across several years exhibited poorer performance on a hippocampus-dependent delayed memory task than elderly persons with lower cortisol levels [36, 38]. Finally, in humans with elevated basal cortisol levels, administration of metyrapone, a drug that maintains cortisol secretion at low basal rates, has been shown to reverse age-related memory impairments [94].


Studies examining synaptic plasticity in animal models have demonstrated that putative cellular substrates for learning and memory are also regulated by stress and GCs. Acute administration of corticosterone to young adult rodents produces parallel effects on behavioral indicators of memory and synaptic plasticity; low to medium doses of corticosterone produce dose-dependent increases of hippocampal long-term potentiation (LTP, an increase in synaptic strength [95]),; whereas high doses impair LTP [96, 97]. High levels of exogenous corticosterone administered to young adult rats also reduce hippocampal prime burst potentiation (PBP, a form of LTP [98] in which stimulation patterns are designed to mimic stimulation of the hippocampus under natural conditions) [96, 99]. Similar reductions in PBP are observed after acute, intense psychological stress [100] or exposure to predator odor [101]. Repeated stress in young rats causes multiple changes in hippocampal electrophysiological measures, including reduction of stimulation thresholds, reduction of field EPSP amplitude, and a decrease in frequency potentiation (FP; a form of short-term plasticity in hippocampus [102] of the field EPSP) [103]. Intense, acute stress [104] and repeated stress [105] also impair LTP in young rats. Both acute and repeated stressors facilitate long-term depression (LTD [106], a reduction in synaptic strength) [107, 108].

Studies suggest that some of these effects on synaptic plasticity are mediated by GCs released during stress. For example, chronic injection of high physiological levels of GCs impairs hippocampal LTP in young rats [97]. Similar decrements in LTP have been observed after 3 months of elevated corticosterone in middle-aged rats [60]. These studies demonstrate that GCs alone are capable of reducing plasticity in hippocampus. Adrenalectomy of adult rats reduces the ability of stress to diminish LTP [109]. Adrenalectomy also reduces afterhyperpolarizations in neurons of hippocampal slice preparations, enabling those neurons to fire action potentials in quicker succession; in contrast, bath application of GC agonists to hippocampal slice preparations from adrenalectomized rats enhances afterhyperpolarizations, indicating that GCs reduce the excitability of hippocampal neurons [110]. High levels of GCs also increase voltage-gated calcium currents in neurons [111, 112].

There are numerous studies that suggest that GC-induced changes in electrophysiological measures exist in aged animals. Paralleling the effects of stress and GCs, aging reduces both LTP, especially with lower intensity of stimulation [113, 114], and FP [115]. Aging rats also show increases in LTD [116]. Reductions in stimulation threshold and field EPSP amplitude, observed after stress in young rats, also are observed with normal aging [103]. Also, GC-sensitive afterhyperpolarizations in hippocampal neurons are greater in aged rats relative to young rats [117]. Finally, aged rats show increased calcium-dependent neuronal activity in hippocampus [118], and have large L-type calcium channel currents [119, 120], which contribute directly to impairment of synaptic plasticity [121].


Some studies suggest that stress and GCs may lead to neuronal death, but this conclusion is not without controversy. In rodents, chronic injection of exogenous stress levels of corticosterone in young rats produced neuronal loss of CA3 comparable to that seen in aged rats [19], but it has also been shown that this effect is observed only if treatment begins when the rats are juveniles and does not happen if prolonged corticosterone exposure occurs only during adulthood [122]. Thus, high levels of corticosterone do not always cause neuron loss. Stress is even less likely to produce overt neuronal death than GC exposure [123]. Only truly exceptional levels of stress have ever been shown to cause neuron loss in the brain. Wild-born monkeys that died in captivity exhibiting multiple signs of severe social subordination stress (gastric ulcers, bite wounds, increased adrenal weight) have been shown to have stress-related changes in hippocampal neurons. These monkeys showed reduced numbers of hippocampal neurons and pronounced atrophy in those hippocampal neurons that remained [124].

Unlike stress or GCs, it is clear that senescence is accompanied by cell loss, and this cell loss is indirectly linked to GC exposure. In the rat, age-related neuronal loss in hippocampus is greatest in Ammon’s horn pyramidal neurons, and minimal in the dentate gyrus [92, 125]. Because receptors for GCs are highest in Ammon’s horn, and less dense in dentate gyrus [126, 127], this anatomical pattern of neuron loss implicates GC actions in age-related decline of hippocampal volume. Removal of endogenous corticosterone by adrenalectomy of rodents in middleage attenuates this age-related loss of hippocampal neurons [92]. Both cognitive impairments and elevated corticosterone levels are correlated with hippocampal neuron loss in rats [4]. Finally, rats with low HPA activity as a result of postnatal handling as pups did not show age-related loss of hippocampal neurons, in contrast to their nonhandled littermates [51, 53]. Thus, GC levels clearly accelerate neuron loss in aged rodents.

One recent proposal [128] has suggested an interesting mechanism by which GCs, through GR-mediated signaling, may contribute to cell death. According to this hypothesis, high levels of GCs must first pass through the cell membrane and bind to the cytoplasmic GR. The activated GR acts through a combination of nongenomic (depolarization of the mitochondrial membrane [129]) and genomic mechanisms (increasing gene transcription of pro-apoptotic proteins such as Bax that further depolarize the mitochondria). Factors promoting apoptotic cell death, such as cytochrome c, are released from mitochondria upon sustained depolarization. Thus, GC-mediated apoptosis of neurons [130] is hypothesized to be mediated by direct and indirect actions of GR on mitochondria.

It is not clear whether healthy aging in humans is accompanied by neuron loss, nor is it clear whether high levels of cortisol in humans could lead to cell death. In the few studies to quantify hippocampal neuron numbers in postmortem human brains, the number of hippocampal neurons decreased with age in area CA1, the dentate gyrus, and the subiculum [131, 132]. Using MRI techniques to estimate volumetric changes in brain structures, volumetric loss in healthy subjects is particularly pronounced in various cortical regions, including frontal and parietal cortices, but there appears to be little volumetric loss in subcortical areas such as hippocampus, thalamus, and the amygdala [134]. Young and middle-aged humans with elevated cortisol due to Cushing’s syndrome exhibit loss of hippocampal volume [134]; however, this effect is reversed when treatment is given to normalize corticosterone levels [135]. Although volumetric loss in human cases could be accounted for by cell death, the simple reversibility of volume loss in Cushing’s patients with high cortisol suggests that at least some volumetric changes are more likely due to reversible dendritic atrophy.

An abundant literature illustrates strong links between stress, GCs, and neuronal atrophy. In rodents, chronic stress has been shown to cause neuronal atrophy in numerous brain regions, including the inferior colliculus [136], medial prefrontal cortex [137], and the hippocampus [138]. Administration of exogenous corticosterone [139–141] or a synthetic GC [141] to young rodents produces neuronal atrophy in the same regions showing atrophy after chronic stress. In primates, exposure to chronic and severe social stress caused atrophy in hippocampus, frontal and pre-frontal cortices, and the cingulate cortex [124]. Implantation of a cortisol pellet directly into the hippocampus of adult monkeys caused extensive atrophy of local neurons after 1 year of cortisol exposure [142]. Administration of high levels of a synthetic GC to pregnant rhesus monkeys caused both hypercortisolemia (chronically elevated levels of cortisol) and marked hippocampal atrophy in the offspring [143].

If one accepts the premise that volumetric loss in humans is likely to reflect atrophy, then links can be made between stress, GCs, and atrophy in humans. For example, high levels of exogenous steroids administered to treat autoimmune disease in young and middle-aged humans caused brain atrophy, and the atrophy was reversed in several patients when steroids were no longer used [144]. As mentioned, patients with high cortisol levels due to Cushing’s syndrome have small hippocampal volumes [134] but hippocampal volumes increase after treatment to reduce cortisol levels [135]. Smaller hippocampal volumes have been reported in patients with stress-related psychiatric disorders including PTSD [145], borderline personality disorder with abuse [146], and depression [147], and dissociative identity disorder [148].

Caution must be used, however, when correlating psychiatric disease with alterations in brain volumes, as it is possible that volumetric differences precede the disease. Such a finding was recently demonstrated for smaller hippocampal volumes in patients with PTSD [54]. Researchers identified monozygotic twin pairs, one of whom had combat exposure (“combat exposed”) during military experience and the other without combat experience (“unexposed”). Of those pairs, a subset of the combat-exposed twins had developed PTSD after their combat experience, and the remainder did not; none of the “unexposed” subjects developed PTSD. By conducting volumetric MRI analysis of the hippocampus, the researchers were able to show that the combat veterans with PTSD had smaller right hippocampal volumes relative to individuals without PTSD. However, the identical twins of the combat-exposed veterans with PTSD also had smaller hippocampi relative to individuals without PTSD. This strongly suggests that small hippocampi constitute a risk factor for developing PTSD, and suggests that the “hippocampal atrophy” observed in some PTSD patients can reflect a preexisting condition and is not the result of trauma. Smaller hippocampi may reduce the ability of the hippocampus to inhibit the HPA axis during a stressor [21], thereby increasing the individual’s exposure to cortisol and other stress hormones during a traumatic event.

There are several studies that indicate that neuronal atrophy accompanies aging but few studies quantify atrophy in animal models of aging. This is likely because the techniques (such as Golgi staining) are labor intensive and the analysis is time consuming. Studies in senescent rats show reduction in dendritic branching of the hippocampus [149] and the anterior cingulate cortex [150]. The largest age-related decline in human subjects is in the prefrontal lobes [151, 152] but volumetric reductions also are observed in other cortices and a small reduction has been reported for the hippocampus [152]. Interestingly, these areas that show atrophy in humans are also the areas that have been shown in nonhuman primates to contain high levels of GR. However, there is no direct evidence that altering GC levels in either human or nonhuman primates affects the aging process.


New neurons are generated in the adult brain via mitotic cell division, a phenomenon termed “neurogenesis.” These new neurons have been shown to migrate from the subventricular zone and subgranular zone to the olfactory bulb and hippocampus respectively, and also to the neocortex, where they integrate with the local circuitry. Neurogenesis has been shown in several species, including the rat [153, 154], nonhuman and human primates [154–156], and the tree shrew [157], but occurs in limited fashion. That is, even within the olfactory bulb and hippocampus, new neurons comprise only a very small portion of the total number of neurons in the structure. Although the functional purpose of neurogenesis is highly debated, the fact that these newborn neurons mature, form synapses, and integrate into neural networks suggests that they may play an important role in hippocampal function (see [158] for a review; see also Chapter 6).

Neurogenesis has been shown to be very sensitive to stress and GCs. A wide variety of acute stressors reduce proliferation of hippocampal cells [157–159]. Chronic stressors also produce similar effects on hippocampal proliferation [161–163]. Prolonged and high levels of corticosterone reduce neurogenesis in rats [164], as does transient elevation of circulating GCs via a single injection of a high dose of corticosterone [165]. Increased basal corticosterone levels in the offspring of a female rat stressed while pregnant is correlated with reduced hippocampal neurogenesis [166]. Adrenalectomy reverses the ability of acute stressors to impair neurogenesis in young rats [167]. Adrenalectomy of young rats also reverses corticosterone-induced impairment of neurogenesis [164].

Age-related changes in neurogenesis parallel those changes observed after stress and GC treatment in younger animals. In rodents, tremendous decreases in hippocampal cell proliferation accompany senescence [168–170]. Within a cohort of aged rats, significant correlations have been observed between basal corticosterone levels and levels of hippocampal neurogenesis; those aged rats with the highest levels of corticosterone also had the lowest levels of neurogenesis [171]. In mice, neuronal precursor cells in older animals express higher levels of both MR and GR than precursor cells of younger animals, suggesting that cell proliferation is likely more sensitive to corticosterone as aging progresses [172]. In agreement with this suggestion, increased sensitivity to GCs with age has been suggested in tree shrews; older animals exhibited greater inhibition of hippocampal cell proliferation in response to chronic stress than younger animals [173]. Rodents adrenalectomized in mid-life do not show age-related increases in corticosterone levels, nor do they show age-related decline of neurogenesis [171, but see 174]. Adrenalectomy of aged rats is also capable of increasing hippocampal cell proliferation to levels comparable to that of young rats, suggesting that high corticosterone levels in aged rats act to suppress neurogenesis [170]. No studies have examined the effects of stress on neurogenesis in aged animals; but because aged animals show such a large suppression of neurogenesis, it may be that neurogenesis is not capable of further suppression.


An extensive body of work has substantiated the idea that repeated or prolonged exposure to GCs has a deleterious impact on brain function, and has also provided evidence that GCs likely contribute to age-related decline in brain function. These stress- and GC-mediated effects on age are evident across behavior, electrophysiological, and anatomical levels. Despite the sophistication of our knowledge of the effects of stress and GCs across many dimensions of brain function, future research will undoubtedly continue to expand our understanding of the ways by which this occurs and suggest new therapeutic targets for intervention within a subset of people whose brain function is disproportionately affected during senescence.


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