The pathophysiological effects of glucocorticoid (GC) excess (Cushings syndrome) are similar to the aging phenotype. As such, we hypothesise that age-related changed in body composition (central obesity, reduced bone density, reduced muscle mass and skin thinning), and resultant chronic disease (type 2 diabetes, osteoporosis, sarcopenia and heart disease) may be caused by increased GC exposure with age. However, circulating GCs show little change with advancing age. Within key metabolic tissues, murine 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts 11-dehydrocorticosterone to the active GC, corticosterone and thus amplifies local GC action. We have previously shown 11β-HSD1 expression and activity to increase with age in primary osteoblasts and skin, which may underpin age-related osteoporosis and skin thinning respectively. In C57b/6 mice (8 weeks vs. 112 weeks) we found 11β-HSD1 activity to increase with age in several key metabolic tissues including: liver (2-fold, P<0.05), epididymal adipose (2.7-fold, P<0.05), quadriceps muscles (2.1-fold, P<0.01) and soleus muscles (1.7-fold, P<0.05). This was paralleled by increased mRNA expression of 11β-HSD1 in epididymal adipose tissue (2.3-fold, P<0.05), quadriceps muscles (6.3-fold, P<0.05), tibialis anterior muscles (8-fold, P<0.001) and soleus muscles (16-fold, P<0.001). Using C2C12 myotubes, corticosterone (100 μM, 24 h) increased the mRNA expression of key atrophy markers: MAFbx-1 (5.6-fold, P<0.001) and MuRF-1 (2-fold, P<0.001). Critically, these genes were also upregulated in quadriceps muscles (MAFbx: 3.5-fold, P<0.001; MuRF-1: 2.3-fold, P<0.001) and tibialis anterior muscles (MAFbx: 4-fold, P<0.001; MuRF-1: 1.9-fold, P<0.05) of the above mice with age. This was paralleled by an age-dependent decreased in fore (0.38-fold, P<0.001) and hind (0.51-fold, P<0.01) grip strength. In summary, the expression/activity of 11β-HSD1 increases with age in several key metabolic tissues, and this may accelerate sarcopenia and contribute to reduced healthy lifespan.
Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding: No specific grant from any funding agency in the public, commercial or not-for-profit sector.