Endocrine Abstracts

Although life expectancy is increasing, deterioration in many tissues with age can substantially impair quality of life. Muscle loss and weakness, decreased bone density leading to fractures, insulin resistance leading to diabetic complications and cognitive decline increase substantially with age. These features are also seen in patients treated with high doses of glucocorticoids raising the possibility that glucocorticoids could be involved in the ageing process. However, circulating glucocorticoids levels do not change dramatically with age. At a tissue level glucocorticoid action is controlled by the 11β-hydroxysteroid dehydrogenase (11β-HSD) enzymes. 11β-HSD1 is a bidirectional enzyme which in vivo primarily converts inactive cortisone to active cortisol. 11β-HSD1 is expressed in liver, adipose, bone, skin and muscle as well as brain. 11β-HSD1 is regulated in a tissue specific manner but regulatory factors include many that change with age e.g. IGF1, adrenal androgens and pro-inflammatory cytokines. This suggests that age related features might be due to increased 11β-HSD1 activity. A role in age related bone loss is suggested by a dramatic increase in 11β-HSD1 activity in primary human osteoblasts with bone donor age. These findings have been confirmed within bone in ageing mice. Similar changes have been reported in skin biopsies taken from younger and older individuals with higher expression seen in aged skin. 11β-HSD1 expression is also higher in fat tissue obtained from post- compared to pre-menopausal women. 11β-HSD1 expression within brain is implicated in age-related changes in cognitive function. Hippocampal 11β-HSD1 expression increases with age and enzyme inhibition improves various aspects of memory. The mechanisms underpinning the age dependent regulation of 11β-HSD1 are currently being defined. Additionally, the impact of 11β-HSD1 inhibitors on features of ageing remains to be explored. Furthermore it is unclear whether there are advantages of an increase in 11β-HSD1 with age that could become apparent through 11β-HSD1 inhibition.

Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding: Declaration of Funding: This work was supported by the Medical Research Council, Arthritis Research UK and the European Research Council.