Reviewing the Aging of the Adrenal Gland

The smaller organs of the body tend to receive less attention from scientists in the field of aging research. There is a lot of ground to cover and only so many research groups. Attention is first given to better studied tissues with proven, direct connections to better studied diseases and causes of mortality. This includes the larger organs such as heart, lungs, liver, and so forth. Chemical factories and cell factories such as the adrenal gland and thymus are clearly important in aging, but indirect effects spread across many different age-related conditions are, it seems, more difficult to study and more difficult to obtain funding to study. Still, while much remains to be filled in at the detail level, much is known of the aging of smaller organs like the adrenal gland. The open access paper here is an interesting read.

The adrenal gland is an essential endocrine organ that is situated above the kidneys and functions to produce essential steroid hormones including mineralocorticoids, glucocorticoids, and androgens. The adrenal is composed of two compartments of distinct embryological origin: the cortex and the medulla, which are surrounded by an outer mesenchymal capsule layer. In this review, we will focus on age-related changes specifically within the adrenal cortex, which is subdivided into three functionally and histologically distinct zones.

The outermost zone, the zona glomerulosa (zG), is responsible for the production of mineralocorticoids that regulate salt and water balance. The intermediate zone, the zona fasciculata (zF), produces glucocorticoids in response to adrenocorticotropin (ACTH) under the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Finally, the innermost zone, the zona reticularis (zR), produces adrenal androgens, including dehydroepiandrosterone (DHEA) and its sulfated form, DHEA-S. As we age, the adrenal gland undergoes changes that disrupt its ability to maintain homeostatic hormone levels, which can significantly affect overall health and well-being. Thus, researching adrenal aging and interventions to delay the onset of age-associated adrenal pathologies has the potential to help increase endocrine function and improve health span.

Studying the effects of aging on the normal adrenal gland is a challenging task. First, information on "healthy" aged human adrenal glands in the literature is scarce. While rodents are the most commonly used model organism to investigate these phenomena, standard laboratory strains lack a functional zR due to silencing of Cyp17a1 after birth, which limits our use of these models to study adrenal androgens. Moreover, the mouse adrenal cortex contains an additional X-zone. The functional significance of the X-zone is incompletely understood.

With increasing age, features such as reduced adrenal cortex size, altered zonation, and increased myeloid immune cell infiltration substantially alter the structure and function of the adrenal cortex. Many of these hallmark features of adrenal cortex aging occur both in males and females, yet are more enhanced in males. Hormonally, a substantial reduction in adrenal androgens is a key feature of aging, which is accompanied by modest changes in aldosterone and cortisol. These hormonal changes are associated with various pathological consequences including impaired immune responses, decreased bone health, and accelerated age-related diseases.

One of the most notable changes with adrenal aging is the increased incidence of adrenal tumors, which is sex dimorphic with a higher prevalence in females. Increased adrenal tumorigenesis with age is likely driven by both an increase in genetic mutations as well as remodeling of the tissue microenvironment. Novel antiaging strategies offer a promising avenue to mitigate adrenal aging and alleviate age-associated pathologies, including adrenal tumors.