Accumulation of senescent cells in the adrenal gland induces hypersecretion of corticosterone via IL1β secretion

• Published in: Aging cell 2024-09, Vol.23 (9), p.e14206-n/a
• Main Authors: Okudaira, Noriyuki, Akimoto, Mi‐Ho, Susa, Takao, Akimoto, Miho, Hisaki, Harumi, Iizuka, Masayoshi, Okinaga, Hiroko, Almunia, Julio A., Ogiso, Noboru, Okazaki, Tomoki, Tamamori‐Adachi, Mimi
• Format: Article
• Language: English
• Subjects: Adrenal cortex; adrenal gland; Adrenal glands; Adrenal Glands - cytology; Adrenal Glands - metabolism; Age; Aging; Aging - metabolism; Animals; Cellular Senescence - physiology; Circadian Rhythm - physiology; Circadian rhythms; Corticosterone; Corticosterone - metabolism; Cytochrome; Diurnal variations; Endocrine system; glucocorticoids; Hypothalamic-pituitary-adrenal axis; Hypothalamus; IL1β; Immune response; Interleukin-1beta - metabolism; Male; Mice; Mice, Inbred C57BL; p16INK4A; Pituitary; Plasma; Proteins; Quercetin; Retinoblastoma; Senescence; SF1 (Ad4BP/SF1); Steroids; Stress; Therapeutic targets; Transcription factors
• ISSN: 1474-9718; 1474-9726; 1474-9726
• DOI: 10.1111/acel.14206

Aging progresses through the interaction of metabolic processes, including changes in the immune and endocrine systems. Glucocorticoids (GCs), which are regulated by the hypothalamic–pituitary–adrenal (HPA) axis, play an important role in regulating metabolism and immune responses. However, the age‐related changes in the secretion mechanisms of GCs remain elusive. Here, we found that corticosterone (CORT) secretion follows a circadian rhythm in young mice, whereas it oversecreted throughout the day in aged mice >18 months old, resulting in the disappearance of diurnal variation. Furthermore, senescent cells progressively accumulated in the zF of the adrenal gland as mice aged beyond 18 months. This accumulation was accompanied by an increase in the number of Ad4BP/SF1 (SF1), a key transcription factor, strongly expressing cells (SF1‐high positive: HP). Removal of senescent cells with senolytics, dasatinib, and quercetin resulted in the reduction of the number of SF1‐HP cells and recovery of CORT diurnal oscillation in 24‐month‐old mice. Similarly, administration of a neutralizing antibody against IL1β, which was found to be strongly expressed in the adrenocortical cells of the zF, resulted in a marked decrease in SF1‐HP cells and restoration of the CORT circadian rhythm. Our findings suggest that the disappearance of CORT diurnal oscillation is a characteristic of aging individuals and is caused by the secretion of IL1β, one of the SASPs, from senescent cells that accumulate in the zF of the adrenal cortex. These findings provide a novel insight into aging. Age‐related hypersecretory GCs could be a potential therapeutic target for aging‐related diseases. Corticosterone is highly secreted throughout the day in older male mice, resulting in the loss of diurnal variation. Senolytics improve CORT levels along with the removal of senescent cells accumulated in the adrenal gland. IL1β expression is increased in aged adrenals, and causes overproducing CORT as well as inducing adrenocortical cells to be a senescent state.