Iatrogenic aging caused by long-term glucocorticoid medication: A perspective on the role of ACBP/DBI

Isabelle Martins

Zhe Shen

1,2,3

Flavia Lambertucci

Frédéric Castinetti

Guido Kroemer

1,2,3,5,*

*Correspondence to: Guido Kroemer, Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université Paris Cité, Sorbonne Université, Inserm U1138, Paris 75006, France. E-mail: kroemer@orange.fr

Geromedicine. 2027;3:202643. 10.70401/Geromedicine.2026.0047

Received: June 22, 2026Accepted: November 10, 2026Published: November 11, 2026

This manuscript is made available in its unedited form to allow early access to the reported findings. Further editing will be completed before final publication. As such, the content may include errors, and standard legal disclaimers are applicable.

Abstract

Long-term glucocorticoid medication is indispensable for controlling inflammatory, autoimmune, allergic, neurologic and oncologic diseases, yet its cumulative toxicity resembles accelerated biological aging. We develop the concept that systemic glucocorticoids can cause iatrogenic aging by activating the acyl-CoA binding protein/diazepam-binding inhibitor (ACBP/DBI)-gamma-aminobutyric acid type A (GABAA) receptor axis. ACBP/DBI has emerged as a circulating biomarker of biological aging and age-related diseases in human cohorts, and as a driver of pathological aging in rodent models. Extracellular ACBP/DBI acts on a subset of GABAA receptors containing the gamma-2 subunit, overlapping with the benzodiazepine-sensitive receptor system. Epidemiological associations between chronic benzodiazepine exposure and dementia, cancer, cardiovascular events, infections and immune dysfunction therefore provide a pharmacological parallel to persistent ACBP/DBI signaling. Among endocrine stimuli, glucocorticoids are the strongest inducers of ACBP/DBI expression and secretion. Glucocorticoid receptor activation stimulates hepatocyte-derived ACBP/DBI release, converting endocrine stress into ACBP/DBI-mediated systemic autophagy inhibition, metabolic dysfunction and immunosuppression. In mice, genetic deletion, antibody-mediated neutralization or receptor-level interruption of ACBP/DBI signaling attenuates multiple features of glucocorticoid excess, including obesity, diabetes, dyslipidemia, sarcopenia, osteoporosis and impaired anticancer immunity. In sharp contrast, ACBP/DBI neutralization does not interfere with the anti-inflammatory action of glucocorticoids. Clinically, chronic endogenous or exogenous glucocorticoid exposure is associated with metabolic syndrome, unfavorable body-composition changes, osteoporosis, sarcopenia, cardiovascular disease, neurocognitive decline and infection susceptibility. In this Perspective, we propose that protracted systemic glucocorticoid therapy represents a paradigmatic form of iatrogenic aging that activates a stress-endocrine ACBP/DBI-GABAA receptor program. In practice, we strongly recommend avoiding chronic, high-dose glucocorticoid medications, whenever possible.

Keywords

Corticosteroid, cushing syndrome, endozepine, immunosenescence, senescence

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Martins I, Shen Z, Lambertucci F, Castinetti F, Kroemer G. Iatrogenic aging caused by long-term glucocorticoid medication: A perspective on the role of ACBP/DBI. Geromedicine. 2027;3:202643. https://doi.org/10.70401/Geromedicine.2026.0047

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Geromedicine

Iatrogenic aging caused by long-term glucocorticoid medication: A perspective on the role of ACBP/DBI

Isabelle Martins

Zhe Shen

Flavia Lambertucci

Frédéric Castinetti

Guido Kroemer

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Iatrogenic aging caused by long-term glucocorticoid medication: A perspective on the role of ACBP/DBI

Isabelle Martins

Zhe Shen

Flavia Lambertucci

Frédéric Castinetti

Guido Kroemer

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