Role of Endogenous Glucocorticoids in Cancer in the Elderly

Abstract

Although not a disease itself, aging represents a risk factor for many aging-related illnesses, including cancer. Numerous causes underlie the increased incidence of malignancies in the elderly, for example, genomic instability and epigenetic alterations that occur at cellular level, which also involve the immune cells. The progressive decline of the immune system functions that occurs in aging defines immunosenescence, and includes both innate and adaptive immunity; the latter undergoes major alterations. Aging and chronic stress share the abnormal hypothalamic⁻pituitary⁻adrenal axis activation, where altered peripheral glucocorticoids (GC) levels and chronic stress have been associated with accelerated cellular aging, premature immunosenescence, and aging-related diseases. Consequently, changes in GC levels and sensitivity contribute to the signs of immunosenescence, namely fewer naïve T cells, poor immune response to new antigens, decreased cell-mediated immunity, and thymic involution. GC signaling alterations also involve epigenetic alterations in DNA methylation, with transcription modifications that may contribute to immunosenescence. Immune cell aging leads to decreased levels of immunosurveillance, thereby providing tumor cells one more route for immune system escape. Here, the contribution of GC secretion and signaling dysregulation to the increased incidence of tumorigenesis in the elderly is reviewed.

Keywords: cancer; elderly; genomic instability; glucocorticoids; immunosenescence.

Figure 1

Aging and chronic stress share common mechanisms. Aging, characterized by hippocampal neuronal loss, glucocorticoid receptor (GR) reduction in the hippocampus and hypothalamic paraventricular nucleus, and inflammaging, together with chronic stress, induces hypothalamic–pituitary–adrenal (HPA) axis imbalance, with increased cortisol (red arrow, head up) and decreased dehydroepiandrosterone (DHEA) production and decreased response of target tissues to glucocorticoids (GCs). HPA-axis dysregulation contributes to both immunosenescence and epigenetic changes; the latter in turn aggravate immunosenescence (red arrows, head down), with the final result of thymic involution, immune cell alterations, and decreased immunosurveillance against cancer.