Dr. Ron’s Research Review – October 14, 2015

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This week’s research review focuses on the Glucocorticoid Hypothesis.

In the early 1970s, studies found that the hippocampus was especially enriched with glucocorticoid (GC) receptors. The glucocorticoid hypothesis of aging predicted that life-long exposure to normal levels of GCs would cause deleterious effects of GCs to accumulate in GC-sensitive neurons. Moreover, because hippocampal dysfunction could reduce hippocampus- mediated inhibition of the HPA axis, GC secretion was predicted to gradually increase over time, leading to an acceleration of both damage and dysfunction. (Goosens and Sapolsky, 2007)

Several results emerged that were inconsistent with the glucocorticoid brain aging hypothesis. A new version is proposed; its main premise is that aging selectively increases GC efficacy in some cell types (e.g., neurons), enhancing catabolic processes, whereas aging selectively decreases GC efficacy in other cell types (e.g., astrocytes), weakening GC anti-inflammatory activity. In addition, changes in GC efficacy might be mediated in part by cell type specific shifts in the antagonistic balance between GC and insulin actions, which may be of relevance for Alzheimer's disease pathogenesis. (Landfield et al., 2007)

The GC hypothesis may also be applied to prenatal care. Activation of the maternal HPA axis during pregnancy increases circulating levels of cortisol, which passes through the placenta where it is broken down by HSD2 into inactive cortisone. Overexposure of the developing fetus to excess cortisol leads to fetal HPA axis activation which is associated with low birthweight and long term adverse programmed outcomes including metabolic and brain sequelae. (Reynolds, 2013)

Dr. Ron


 

Articles

Stress and Glucocorticoid Contributions to Normal and Pathological Aging
            (Goosens and Sapolsky, 2007) Download
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.

A new glucocorticoid hypothesis of brain aging: implications for Alzheimer's disease.
            (Landfield et al., 2007) Download
The original glucocorticoid (GC) hypothesis of brain aging and Alzheimer's disease proposed that chronic exposure to GCs promotes hippocampal aging and AD. This proposition arose from a study correlating increasing plasma corticosterone with hippocampal astrocyte reactivity in aging rats. Numerous subsequent studies have found evidence consistent with this hypothesis, in animal models and in humans. However, several results emerged that were inconsistent with the hypothesis, highlighting the need for a more definitive test with a broader panel of biomarkers. We used microarray analyses to identify a panel of hippocampal gene expression changes that were aging-dependent, and also corticosterone-dependent. These data enabled us to test a key prediction of the GC hypothesis, namely, that the expression of most target biomarkers of brain aging should be regulated in the same direction (increased or decreased) by both GCs and aging. This prediction was decisively contradicted, as a majority of biomarker genes were regulated in opposite directions by aging and GCs, particularly inflammatory and astrocyte-specific genes. Thus, the initial hypothesis of simple positive cooperativity between GCs and aging must be rejected. Instead, our microarray data suggest that in the brain GCs and aging interact in more complex ways that depend on the cell type. Therefore, we propose a new version of the GC-brain aging hypothesis; its main premise is that aging selectively increases GC efficacy in some cell types (e.g., neurons), enhancing catabolic processes, whereas aging selectively decreases GC efficacy in other cell types (e.g., astrocytes), weakening GC anti-inflammatory activity. We also propose that changes in GC efficacy might be mediated in part by cell type specific shifts in the antagonistic balance between GC and insulin actions, which may be of relevance for Alzheimer's disease pathogenesis.

Glucocorticoid excess and the developmental origins of disease: two decades of testing the hypothesis--2012 Curt Richter Award Winner.
            (Reynolds, 2013) Download
Low birthweight, a marker of an adverse in utero environment, is associated with cardiometabolic disease and brain disorders in adulthood. The adaptive changes made by the fetus in response to the intra-uterine environment result in permanent changes in physiology, structure and metabolism, a phenomenon termed early life programming. One of the key hypotheses to explain programming, namely over exposure of the developing fetus to glucocorticoids, was proposed nearly two decades ago, following the observation that the fetus was protected from high glucocorticoid levels in the mother by the actions of the placental barrier enzyme, 11β-hydroxysteroid dehydrogenase, which converts active glucocorticoids into inactive products. Numerous mechanistic studies in animal models have been carried out to test this hypothesis using manipulations to increase maternal glucocorticoids. Overall, these have resulted in offspring of lower birthweight, with an activated hypothalamic-pituitary-adrenal (HPA) axis and an adverse metabolic profile and behavioural phenotype in adulthood. Altered glucocorticoid activity or action is a good candidate mechanism in humans to link low birthweight with cardiometabolic and brain disorders. We have carried out detailed studies in men and women showing that high levels of endogenous glucocorticoids, or treatment with exogenous glucocorticoids, is associated with an adverse metabolic profile, increased cardiovascular disease and altered mood and cognitive decline. Our laboratory carried out the first translational studies in humans to test the glucocorticoid hypothesis, firstly demonstrating in studies of adult men and women, that low birthweight was associated with high fasting cortisol levels. We went on to dissect the mechanisms underlying the high fasting cortisol, demonstrating activation of the HPA axis, with increased cortisol responses to stimulation with exogenous adrenocorticotrophin hormone, lack of habituation to the stress of venepuncture, and increased cortisol responses to psychosocial stress. We have developed new dynamic tests to dissect the mechanisms regulating HPA axis central negative feedback sensitivity in humans, and demonstrated that this may be altered in obesity, one component of the metabolic syndrome. There are now studies in humans demonstrating that high circulating levels of maternal cortisol during pregnancy correlate negatively with birthweight, suggesting that excess glucocorticoids can by-pass the placental barrier. Deficiencies in the barrier enzyme, potentially increasing fetal glucocorticoid exposure, can also arise in association with maternal stress, malnutrition and disease, and can be inhibited by consumption of liquorice, which contains glycyrrhizin, an HSD inhibitor. Importantly, studies in humans have now demonstrated that high maternal cortisol in pregnancy and/or inhibition of HSD2 are associated with programmed outcomes in childhood including higher blood pressure, behavioural disorders as well as altered brain structure. We are investigating this further, using novel magnetic resonance imaging techniques to study the developing fetal brain in utero. The translational studies in support of the glucocorticoid hypothesis, and demonstrating that glucocorticoids are both mediators and targets of programming, are exciting and raise the question of whether this information can be used to identify those individuals most at risk of later life disease. In a recent study we showed that alterations in DNA methylation at genes important in regulating cortisol levels, tissue glucocorticoid action, blood pressure and fetal growth, are present in adulthood in association with both early life parameters and cardiometabolic risk factors. These preliminary data add to the limited literature in humans indicating a persisting epigenetic link between early life events and subsequent disease risk. Such findings open novel avenues for further exploration of the contribution of glucocorticoids to later life disease.

 

References

Goosens, KA and RM Sapolsky (2007), ‘Stress and Glucocorticoid Contributions to Normal and Pathological Aging’, in Riddle, DR (ed.), Brain Aging: Models, Methods, and Mechanisms (Boca Raton (FL): CRC Press),
Landfield, PW, et al. (2007), ‘A new glucocorticoid hypothesis of brain aging: implications for Alzheimer’s disease.’, Curr Alzheimer Res, 4 (2), 205-12. PubMedID: 17430248
Reynolds, RM (2013), ‘Glucocorticoid excess and the developmental origins of disease: two decades of testing the hypothesis--2012 Curt Richter Award Winner.’, Psychoneuroendocrinology, 38 (1), 1-11. PubMedID: 22998948