Endothelial miR-15a/16-1 Regulation of SYNE1 Mediates Structural and Functional Recovery after Traumatic Brain Injury.

Benzodiazepines are among the most frequently used psychoactive drugs worldwide and remain common in ICU sedation regimens, particularly where rapid anxiolysis, anticonvulsant activity or deep sedation is required , . However, benzodiazepines are increasingly viewed as biologically active modifiers of immune-inflammatory, metabolic and neurocognitive pathways -not merely symptomatic therapies –. This perspective is especially relevant in septic shock and critical illness, where survival depends on calibrated inflammation, effective antimicrobial defense, metabolic flexibility, and preservation of brain function. The concept of “iatrogenic aging” posits that certain medications can accelerate hallmarks of biological aging, thereby worsening age-associated pathologies and reducing resilience to stress . A mechanistic entry point is the tissue stress hormone acyl-CoA binding protein/diazepam binding inhibitor (ACBP/DBI). ACBP/DBI is also termed “endozepine” (a neologism referring to its role as the endogenous equivalent of benzodiazepines) because it competes with the prototypic benzodiazepine diazepam for binding to gamma-aminobutyric acid (GABA) type receptors (GABAR) –. As diazepam, ACBP/DBI acts as a positive allosteric modulator on GABAR, which is broadly expressed, not only in the central nervous system, but also in multiple different peripheral cell types including epithelial cells (e.g. hepatocytes) and myeloid cells – (). ACBP/DBI has emerged as a targetable autophagy checkpoint and a mediator of pathological aging trajectories. In humans, plasma ACBP/DBI concentrations correlate with chronological age and cardiometabolic risk and predict future cardiovascular events and cancer diagnoses independent of age and body mass index (BMI), supporting its role as a biomarker of “biological” aging –. In centenarians, elevated ACBP/DBI associates with deterioration, reduced glomerular filtration, and increased senescence-associated cytokines . Experimentally, antibody-mediated ACBP/DBI neutralization reduces aging-like phenotypes (including senescence-linked readouts) in diverse contexts, consistent with systemic geroprotective activity , .