Pathological aging is alleviated by neutralization of the autophagy-repressive tissue hormone DBI/ACBP.

Abstract

DBI/ACBP (diazepam binding inhibitor, acyl CoA-binding protein) is a macroautophagy/autophagy-inhibitory tissue hormone produced by multiple cell types. The plasma levels of DBI/ACBP rise with age and disease. In centenarians living in nursing homes, DBI/ACBP concentrations are approximately threefold higher than in younger adults (30-48 years old), but these levels increase further in centenarians hospitalized due to disease exacerbation. Elevated DBI/ACBP correlates with unfavorable clinical parameters, including high Charlson Comorbidity Index, elevated neutrophil:lymphocyte ratio, and decreased renal function. In mouse models, neutralization of DBI/ACBP using monoclonal antibodies ameliorates several aging-related pathologies. In zmpste24^-/- progeroid mice, anti-DBI/ACBP therapy improves posture, mobility, cutaneous and dental abnormalities, splenic atrophy, kidney function, and blood parameters. In models of renal aging induced by cisplatin or doxorubicin, DBI/ACBP neutralization suppresses renal fibrosis and cellular senescence. Similarly, in cardiac and hepatic aging models, anti-DBI/ACBP reduces expression of the senescence marker CDKN1A/p21 (cyclin dependent kinase inhibitor 1A) in cardiomyocytes and hepatocytes. Single-nucleus RNA sequencing of heart tissue revealed that anti-DBI/ACBP restores key metabolic and cardioprotective gene expression patterns suppressed by doxorubicin. Together, these findings establish DBI/ACBP as a marker and driver of pathological aging and demonstrate that its neutralization confers multi-organ anti-senescence effects. Thus, DBI/ACBP-targeting strategies hold therapeutic potential for improving healthspan.