HPA Axis (hypothalamic-pituitary-adrenal)

The HPA axis works like a three-tier hormonal thermostat. The hypothalamus (paraventricular nucleus) releases corticotropin-releasing hormone (CRH); this travels to the anterior pituitary and triggers secretion of adrenocorticotropic hormone (ACTH); ACTH acts on the adrenal cortex to release cortisol, the principal human glucocorticoid. Cortisol follows a circadian rhythm—morning peak, nighttime trough—and exerts negative feedback on the hypothalamus, pituitary, and hippocampus to self-limit.

With aging, this negative feedback loses sensitivity: human studies show basal hypersecretion of ACTH and cortisol, flattening of the diurnal rhythm, and a blunted response to receptor blockade. The hippocampus, rich in glucocorticoid receptors, is especially vulnerable: chronically high cortisol shrinks its volume, which in turn weakens the axis brake further—a vicious cycle linked to cognitive decline and progression toward Alzheimer's disease.

In longevity, restoring HPA regulation is a key goal. Adaptogens such as ashwagandha lower morning cortisol in controlled trials; sleep hygiene, moderate exercise, and hormonal optimization help recover circadian rhythm and feedback sensitivity.