Cellular Senescence Disrupts Adrenal Gland Circadian Rhythm in Aging Mice
This research makes for interesting reading in the context of a recent paper discussing a mismatch between brain and body circadian clocks as a contributing factor to degenerative aging. Researchers here show that an accumulation of senescent cells in the adrenal gland disrupts its adherence to circadian rhythm, while targeted removal of those cells restores function. We might add this to the many good reasons to remove lingering senescent cells from the aging body. These cells secrete a potent mix of pro-inflammatory factors that are disruptive to surrounding cell and tissue function, and are an important contributing cause of degenerative aging throughout the body and brain.
Aging progresses through the interaction of metabolic processes, including changes in the immune system and endocrine system. 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 older than 18 months old, resulting in the disappearance of diurnal variation. Furthermore, senescent cells progressively accumulated in the zona fasciculata (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, SF1-HP).
Removal of senescent cells with the senolytic treatment of 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 senescence-associated secretory phenotype factors, 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.
SGLT2 inhibition eliminates senescent cells and alleviates pathological aging
It has been reported that accumulation of senescent cells in various tissues contributes to pathological aging and that elimination of senescent cells (senolysis) improves age-associated pathologies. Here, we demonstrate that inhibition of sodium-glucose co-transporter 2 (SGLT2) enhances clearance of senescent cells, thereby ameliorating age-associated phenotypic changes. In a mouse model of dietary obesity, short-term treatment with the SGLT2 inhibitor canagliflozin reduced the senescence load in visceral adipose tissue and improved adipose tissue inflammation and metabolic dysfunction, but normalization of plasma glucose by insulin treatment had no effect on senescent cells. Canagliflozin extended the lifespan of mice with premature aging even when treatment was started in middle age. Metabolomic analyses revealed that short-term treatment with canagliflozin upregulated 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, enhancing immune-mediated clearance of senescent cells by downregulating expression of programmed cell death-ligand 1. These findings suggest that inhibition of SGLT2 has an indirect senolytic effect by enhancing endogenous immunosurveillance of senescent cells.
https://www.nature.com/articles/s43587-024-00642-y