The glucocorticoid-induced leucine zipper (GILZ) is an immunomodulatory, ubiquitously expressed protein, with multiple roles in different pathophysiological processes. Aim of the present study was to evaluate the role of GILZ and glucocorticoid (GC) metabolism in two different settings: Statins, the most prescribed class of drugs for prevention of cardiovascular disease, exert beneficial lipid-lowering independent effects, as well as muscle-related adverse effects, by mechanisms not fully understood. The role of GILZ in these mechanisms was investigated. Statins were able to induce GILZ expression in skeletal muscle, endothelial cells, and macrophages. Moreover, using in vitro, ex vivo and in vivo approaches, we demonstrated that GILZ is an important mediator of statin-induced muscle damage. The second part of this study focused on aging, which is characterised by a chronic, low-grade inflammatory state —termed “inflammaging”— that contributes to age-related pathogenesis. The elucidation of the mechanisms that modulate this state is of interest to geroscience. Evaluation of the age-associated changes in the myeloid compartment of mice, focusing on glucocorticoid metabolism, showed reduced levels of circulating GCs that, together with perturbations in GC pre-receptor metabolism in aged macrophages, result in dysregulation of the anti-inflammatory networks in these innate immune cells and, thus, might promote the inflammaging phenotype.