Pro-aging effects of chronic glucocorticoid signaling

May 28, 2026Cell metabolism

Long-term stress hormone signaling may promote aging

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Longevity & Aging on OpenScience ↗PubMed ↗DOI ↗

Abstract

Sustained exposure to glucocorticoids (GCs) is associated with earlier and more severe manifestations of age-related diseases.

Prolonged GC signaling may alter nutrient sensing and suppress processes that help clear damaged cells.
Chronic elevation of GCs could impair mitochondrial quality control and promote cellular aging.
The GC-responsive polypeptide ACBP/DBI is linked to increased metabolic and immune consequences of GC excess.
Sustained GC exposure is potentially connected to multiple age-related conditions, including metabolic syndrome and neurodegeneration.
Mechanistic links between GC signaling and systemic aging may reveal strategies to reduce the effects of persistent GC exposure.

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Glucocorticoids (GCs) are essential endocrine regulators coordinating stress responsiveness, metabolic flexibility, inflammatory resolution, and circadian physiology. While acute GC fluctuations are adaptive, sustained exposure (arising from psychosocial stress, circadian disruption, obesity, chronic inflammation, neoplasms, or steroid therapy) elicits pleiotropic effects that overlap with biological aging. Prolonged GC signaling intersects with multiple hallmarks of aging by altering nutrient sensing, suppressing autophagy, impairing mitochondrial quality control, and promoting cellular senescence. In this context, the GC-responsive polypeptide ACBP/DBI (acyl-coenzyme A [CoA]-binding protein/diazepam-binding inhibitor) has emerged as a stress-induced inhibitor of macroautophagy that amplifies several metabolic and immune consequences of GC excess linked to aging phenotypes. Clinically, chronic GC elevation is associated with earlier and more severe manifestations of age-related diseases, including metabolic syndrome, osteoporosis, sarcopenia, neurodegeneration, cardiovascular disease, immunosenescence, and cancer. Here, we review mechanistic links between GC signaling and systemic aging and discuss strategies to mitigate the age-accelerating consequences of persistent GC exposure.