Acyl-CoA-binding protein as a driver of pathological aging

• 成果类型: Article
• 署名作者: Montegut, Lea; Lambertucci, Flavia; Moledo-Nodar, Lucas; Fiuza-Luces, Carmen; Rodriguez-Lopez, Carlos; Serra-Rexach, Jose Antonio; Lachkar, Sylvie; Motino, Omar; Abdellatif, Mahmoud; Durand, Sylvere; Aprahamian, Fanny; Carbonnier, Vincent; Le Corre, Delphine; Richard, Sophie Mouillet-; Chen, Hui; Sauvat, Allan; Dong, Yanbing; Li, Sijing; Rong, Yan; Pietrocola, Federico; Puig, Pierre Laurent-; Lopez-Otin, Carlos; Martins, Isabelle; Barcena, Clea; Lucia, Alejandro; Kroemer, Guido
• 署名单位: Universite Paris Cite; Institut Universitaire de France; Institut National de la Sante et de la Recherche Medicale (Inserm); Sorbonne Universite; UNICANCER; Gustave Roussy; University of Oviedo; Instituto de Salud Carlos III; General University Gregorio Maranon Hospital; Complutense University of Madrid; Universidad de Valladolid; Medical University of Graz; Institut Universitaire de France; Universite Paris Cite; Institut National de la Sante et de la Recherche Medicale (Inserm); Sorbonne Universite; Karolinska Institutet; Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Europeen Georges-Pompidou - APHP; Universidad Antonio de Nebrija; European University of Madrid; Icahn School of Medicine at Mount Sinai
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12664
• DOI: 10.1073/pnas.2501584122
• 发表日期: 2025-07-15
• 关键词: autophagy; coenzyme; cells; senescence; expression; acbp

摘要

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 mAb 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 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 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.