Researchers here provide evidence for expression of the hormone ACBP to be detrimental, an accelerator of degenerative aging. Knocking down ACBP improves kidney and heart resilience in a number of circumstances, while circulating ACBP levels correlate with aspects of aging and age-related loss of function. At the present time therapies to reduce circulating levels of a given protein (such as monoclonal antibodies or forms of gene therapy targeted to the cells expressing the protein) are relatively expensive, though given a broadly beneficial use case one might imagine that costs will fall commensurate with the scale of use.
The tissue hormone acyl coenzyme A-binding protein (ACBP, encoded by the gene diazepam-binding inhibitor, DBI) has been implicated in various facets of pathological aging. Here, we show that ACBP plasma concentrations are elevated in (close-to-)centenarians (mean ± SD age 99.5 ± 4.5 y) commensurate with their health deterioration, correlating with a reduced glomerular filtration rate and a surge in senescence-associated cytokines. ACBP neutralization by means of a monoclonal antibody (mAb) improved health span in a strain of progeroid mice.
In a mouse model of chronic kidney injury induced by cisplatin, anti-ACBP mAb administration counteracted both 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 prevented by anti-ACBP monoclonal antibody treatment in additional mouse models of accelerated aging. This applied to liver damage induced by a combination of high-fat diet and carbon tetrachloride, where hepatic cells become senescent.
Moreover, administration of anti-ACBP monoclonal antibody 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 an anti-ACBP-reversible dysregulation 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 age-promoting effect of ACBP across different organ systems.
Link: https://doi.org/10.1073/pnas.2501584122
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