The joint effects of energy restriction and age on adrenal glucocorticoid synthesis, liver signalling and liver thyroid hormone metabolism were examined. Adrenal type 1 11β-hydroxylase expression was chosen as a marker of adrenal steroidogenesis, liver 11β-hydroxysteroid dehydrogenase 1 and glucocorticoid receptor proteins as measures of glucocorticoid signalling, and liver type 1 and 3 deiodinase proteins as determinants of thyroid hormone metabolism. A nine-week study covered two groups (n = 21 each) of 17- and 45-week-old Sprague-Dawley male rats fed ad libitum and on diets with 20% or 40% energy deficit. Adrenal type 1 11β-hydroxylase mRNA and protein, hepatic type 1 11β-hydroxysteroid dehydrogenase level, glucocorticoid receptor and type 1 and 3 deiodinase protein levels, as well as plasma adrenocorticotropic hormone (ACTH) and corticosterone concentrations. Calorie restriction increased ACTH plasma concentrations and type 1 11β-hydroxylase protein levels were determined. Plasma ACTH and type 1 11β-hydroxylase protein were higher in older rats, while in the younger group, type 1 deiodinase protein exceeded the enzyme level in older rats. Calorie restriction decreased plasma corticosterone and type 1 11β-hydroxysteroid dehydrogenase only in older rats. Direct relationships between glucocorticoid receptors and type 1 and 3 deiodinases, as well as between type 3 deiodinase and type 1 11β-hydroxysteroid dehydrogenase, were observed. Taken together, the results indicate that responses of the rat pituitary-adrenal axis to calorie deficit are age-dependent. Moreover, the observed correlations suggest a mechanism linking an increase in glucocorticoid receptors with a reduction in peripheral thyroid hormone action resulting from a rise in the level of type 3 deiodinase.