Adrenal Aging and Its Implications on Stress Responsiveness in Humans

Abstract

Normal aging results in subtle changes both in ACTH and cortisol secretion. Most notable is the general increase in mean daily serum cortisol levels in the elderly, without a noteworthy alteration in the normal circadian rhythm pattern. Glucocorticoid excess seen in the elderly population can have serious consequences in both the structural and functional integrity of various key areas in the brain, including the hippocampus, amygdala, prefrontal cortex, with consequent impairment in normal memory, cognitive function, and sleep cycles. The chronically elevated glucocorticoid levels also impinge on the normal stress response in the elderly, leading to an impaired ability to recover from stressful stimuli. In addition to the effects on the brain, glucocorticoid excess is associated with other age-related changes, including loss of muscle mass, hypertension, osteopenia, visceral obesity, and diabetes, among others. In contrast to the increase in glucocorticoid levels, other adrenocortical hormones, particularly serum aldosterone and DHEA (the precursor to androgens and estrogens) show significant decreases in the elderly. The underlying mechanisms for their decrease remain unclear. While the adrenomedullary hormone, norephinephrine, shows an increase in plasma levels, associated with a decrease in clearance, no notable changes observed in plasma epinephrine levels in the elderly. The multiplicity and complexity of the adrenal hormone changes observed throughout the normal aging process, suggests that age-related alterations in cellular growth, differentiation, and senescence specific to the adrenal gland must also be considered.

Keywords: HPA axis; adrenal cortex; glucocorticoids; senescence; stress.

Figure 1

Schematic of components of the primary adrenal axis and main hormones produced in adrenal cortex and adrenal medulla.

Figure 2

Schematic of hypothalamic-pituitary-adrenal axis showing increased cortisol production in the elderly, which may be associated with decreased negative feedback at the hippocampus related to decreased glucocorticoid receptor concentration.

Figure 3

The adrenal axis and the end effector, cortisol, demonstrates tight interactions with various other hormonal axes, and systems, including thyroid axes, gonadal axis, and immune system, among others.