Glucocorticoid Cascade Hypothesis

A Theory of Aging

BY: T. Franklin Murphy | April 8, 2022

What is Glucocorticoid Cascade Hypothesis?

The glucocorticoid cascade hypothesis theorizes that stress wears on mechanisms essential to the functioning of hypothalamic–pituitary–adrenal axis—a major neuroendocrine system that controls reactions to stress and regulates essential body processes, such as digestion, the immune system, mood and emotions, sexuality, and energy storage and expenditure.

Robert Sapolsky, Lewis Krey and Bruce McEwen presented the glucocorticoid cascade hypothesis in a 1986 paper. They postulated that as we age our bodies become less adapt at processing neurochemicals associated with stress. These neurochemicals then accumulate and have deleterious impact on neurological processes. Aging, therefore, produced a cascading, negative feedback loop.

Excessive glucocorticoid in our system can create havoc on our health, causing immunosuppression, muscle atrophy, osteoporosis, insulin resistance, hypertension, depression and insomnia. Because of the potential damaging impact of glucocorticoid, their production is strictly controlled by the hypothalamic-pituitary-adrenal (HPA) axis.

The Stress Response and Glucocorticoid

Glucocorticoid plays a primary role in the stress response. Glucocorticoid is a steroidal hormone produced through a cascade of responses flowing through the HPA axis during stress.

The cascade of responses begins when stress activates the hypothalamus which initiates a release of a corticotrophin-releasing hormone (CRH). CRH then signals to the anterior pituitary to release adrenocorticotrophin (ACTH). ACTH then signals to the cortical layer of the adrenal gland to release glucocorticoids, which act on peripheral tissues preparing the body for a response.

Glucocorticoids part of the stress response includes the metabolism of glucose for increased energy during stressful events. Glucocorticoids, along with adrenaline, enhance the formation of flashbulb memories during heightened emotional events.

Glucocorticoid Receptor

Glucocorticoids interact with other cells by attaching to glucocorticoid (GR) and corticosterone (B) receptors. The glucocorticoid receptor is the receptor to which cortisol, also activated during stress, and glucocorticoids bind.

The activated GR complex up-regulates the expression of anti-inflammatory proteins in the nucleus or represses the expression of pro-inflammatory proteins in the cytosol.

Acute stress damages these receptors. When too many of these receptors are damaged, the glucocorticoid remains in the body causing harm to surrounding organs and processes. This is the biological cost of stress known as the allostatic load.

Once the body returns to a homeostatic balance, energy is given to repairing damaged glucocorticoid receptors. The body repairs and the organism is prepared to respond to the next wave of stress.

However, when stress is prolonged the damage extends beyond the receptor, leading to neuronal loss, which cannot be repaired. Chronic stress can lead to long-term illness.

It appears that with age, we also suffer loss of some of these receptors. Sapolsky et. al. found that “glucocorticoid binding receptors are lost with age in the hippocampus” (1986).

The HPA axis’s efficient control of glucocorticoid production is inhibited by these age related damages int he hippocampus. “The hippocampus with its loss of neurons and of their B and possibly GR receptors, is doubly impaired in its regulation of adrenocortical secretion.” Sapolsky and colleagues continue to explain that, “the receptor depletion desensitizes the structure to the presence of circulating B and, in effect, causes circulating concentrations

Slowing the Aging Process

We can’t stop aging. As sure as we are born, we will die. We can, however, slow some of the aging process associate with glucocorticoid cascade hypothesis by efficiently managing stress. We must limit the amount of stress in our lives, giving time for our bodies to heal the damage of stressful incidents and heal for the next wave of difficulties. By managing stress, we prolong some of the aging processes.

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Sapolsky, R.M., Krey, L.C., & McEwen, B.S. (1986). The Neuroendocrinology of Stress and Aging: The Glucocorticoid Cascade Hypothesis. Endocrine Reviews, 7(3), 284-301.