Abstract
Cellular senescence is considered a physiological process along with aging and has recently been reported to be involved in the pathogenesis of many age-related disorders. Cellular senescence was first found in human fibroblasts and gradually explored in many other organs, including endocrine organs. The adrenal cortex is essential for the maintenance of blood volume, carbohydrate metabolism, reaction to stress and the development of sexual characteristics. Recently, the adrenal cortex was reported to harbor some obvious age-dependent features. For instance, the circulating levels of aldosterone and adrenal androgen gradually descend, whereas those of cortisol increase with aging. The detailed mechanisms have remained unknown, but cellular senescence was considered to play an essential role in age-related changes of the adrenal cortex. Recent studies have demonstrated that the senescent phenotype of zona glomerulosa (ZG) acts in association with reduced aldosterone production in both physiological and pathological aldosterone-producing cells, whereas senescent cortical-producing cells seemed not to have a suppressed cortisol-producing ability. In addition, accumulated lipofuscin formation, telomere shortening and cellular atrophy in zona reticularis cells during aging may account for the age-dependent decline in adrenal androgen levels. In adrenocortical disorders, including both aldosterone-producing adenoma (APA) and cortisol-producing adenoma (CPA), different cellular subtypes of tumor cells presented divergent senescent phenotypes, whereby compact cells in both APA and CPA harbored more senescent phenotypes than clear cells. Autonomous cortisol production from CPA reinforced a local cellular senescence that was more severe than that in APA. Adrenocortical carcinoma (ACC) was also reported to harbor oncogene-induced senescence, which compensatorily follows carcinogenesis and tumor progress. Adrenocortical steroids can induce not only a local senescence but also a periphery senescence in many other tissues. Therefore, herein, we systemically review the recent advances related to cellular senescence in adrenocortical biology and its associated disorders.
Highlights
Aging is a natural process accompanied by physiological degeneration of cellular function
Under genomic, aging or other uncertain factors, most aldosterone-producing micronodules (APMs) were recently reported to secrete aldosterone in an autonomous and renin-independent manner, considered a potential pathological process. This manner can contribute to a subclinical primary aldosteronism with normotension and normal electrolyte values accompanied by suppressed plasma renin activity with normal plasma aldosterone levels, which is frequently detected in older individuals as an age-related disease [88]
There was a positive correlation between dehydroepiandrosterone sulfotransferase (DHEA-ST) and p21 reported in cortisol-producing adenoma (CPA), indicating that DHEA-ST could induce in situ cellular senescence
Summary
Aging is a natural process accompanied by physiological degeneration of cellular function. Cortisol-producing adenomas (CPAs) were reported to produce excessive adrenal steroids, which resulted in in situ or local cellular senescence and more senescent phenotype being harbored than aldosterone-producing adenomas (APAs) [11,12,13]. Both APAs and CPAs were demonstrated to consist of two cellular subtypes, namely compact and clear tumor cells, which may harbor different senescent phenotypes reflecting intratumoral heterogeneity [11,12,14]. We systemically reviewed the recent advances related to the crosstalk between cellular senescence and adrenal biology, which has never been summarized before, in order to better understand the role of cellular senescence in the pathogenesis of disorders of the adrenal cortex and other organs
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