The metabolic syndrome (MetS) presents an increasing prevalence in elderly people. A significant role in MetS is played by the stress response and cortisol. The hypothalamic-pituitary-adrenal (HPA) axis activity is increased by central (loss of hippocampal glucocorticoid receptors) and peripheral (11β-hydroxysteroid dehydrogenase type 1, 11β-HSD1, hyperactivity) mechanisms. The HPA hyperactivity has been found in chronic diseases affecting the endocrine (abdominal obesity with MetS, type 2 diabetes), cardiovascular (atherosclerosis, essential hypertension), and nervous systems (dementia, depression), in aging. A novel therapeutic approach (11β-HSD1 inhibition) is promising in treating the HPA axis hyperactivity in chronic diseases with MetS. A large-scale national clinical trial (AGICO, AGIng, and COrtisol study) has been proposed by our group to evaluate the role of cortisol and MetS in the main pathologies of aging (vascular and degenerative dementia, cardiovascular diseases, type 2 diabetes, abdominal obesity).

Serum BDNF levels may be considered as a marker of response to antidepressant treatment for depression in the elderly.

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The stress response during chronic conditions increases vulnerability to diseases through the activation of adaptive systems, in particular, the hypothalamus-pituitary-adrenal (HPA) axis. Dysregulation in HPA activity (central and peripheral) has been reported in chronic diseases, like metabolic syndrome, type-2 diabetes mellitus, atherosclerosis-related disease, essential hypertension, dementia, depression, particularly during comorbid conditions. Different targets of anti-glucocorticoid treatment have been proposed, acting at supra-hypothalamic, HPA axis, glucocorticoid receptor and post-receptor levels. The recent promising patents on the therapy against glucocorticoid-mediated damage will be presented and discussed.