Acyl CoA binding protein as a potential driver of pathological aging.
The tissue hormone acyl coenzyme A binding protein (ACBP, encoded by the gene diazepam binding inhibitor, DBI) has been involved in various facets of pathological aging. Here, we show that ACBP plasma concentrations are elevated in (close-to-)centenarians commensurate with their health deterioration, correlating with a reduced glomerular filtration rate and a surge in senescence-associated cytokines. In a mouse model of chronic kidney injury by cisplatin, we observed that ACBP neutralization by means of a monoclonal antibody (mAb) prevented histopathological and functional signs of organ failure. ACBP inhibition also prevented the senescence of tubular epithelial cells and glomerular podocytes induced by cisplatin or doxorubicin, respectively, as measurable by the immunohistochemical detection of cyclin dependent kinase inhibitor 1A (CDKN1A, best known as p21). Senescence was also blocked by anti-ACBP mAb in additional mouse models of accelerated aging. This applies to liver damage induced by a combination of high-fat diet and carbon tetrachloride, where hepatocytes become senescent. In addition, administration of anti-ACBP mAb prevented natural and doxorubicin-accelerated cardiomyocyte senescence. We performed single nucleus RNA sequencing to study the transcriptome of hearts that had been exposed to doxorubicin and/or anti-ACBP in vivo. In cardiomyocytes, doxorubicin caused the anti-ACBP-reversible dyregulation of mRNAs coding for cardioprotective proteins involved in autophagy, fatty acid oxidation, mitochondrial homeostasis and oxidative phosphorylation. Altogether, these findings plead in favor of a broad antiaging effect of ACBP neutralization across different organ systems. Overall design: Nuclei extracted from left ventricles from C57Bl/6J female mice aged 12 weeks, after four weekly cycles of: - Control (n = 2): PBS and mouse IgG2a isotype control - Anti-ACBP/DBI (n = 2): PBS and Anti-ACBP/DBI mAb - DOXO (n = 2): Doxorubicin and mouse IgG2a isotype control - Anti-ACBP/DBI + DOXO (n = 2): Doxorubicin and anti-ACBP/DBI mAb