Acyl-CoA-binding protein as a driver of pathological aging
Abstract
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (26)
Léa Montégut
Team Metabolism, Cancer & Immunity, Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France
Flavia Lambertucci
Team Metabolism, Cancer & Immunity, Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France
Lucas Moledo-Nodar
Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología, Universidad de Oviedo
Carmen Fiuza-Luces
Physical Exercise and Pediatric Cancer Research Group, Research Institute of the Hospital
Carlos Rodríguez-López
Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable, Instituto de Salud Carlos III
Jose Antonio Serra-Rexach
Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable, Instituto de Salud Carlos III
Sylvie Lachkar
Team Metabolism, Cancer & Immunity, Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France
Omar Motiño
Team Metabolism, Cancer & Immunity, Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France
Mahmoud Abdellatif
Team Metabolism, Cancer & Immunity, Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France
Sylvère Durand
Team Metabolism, Cancer & Immunity, Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France
Fanny Aprahamian
Team Metabolism, Cancer & Immunity, Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France
Vincent Carbonnier
Team Metabolism, Cancer & Immunity, Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France
Delphine Le Corre
Team Personalized Medicine, Phamacogenomics and Therapeutic Optimization, Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France
Sophie Mouillet-Richard
Team Personalized Medicine, Phamacogenomics and Therapeutic Optimization, Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France
Hui Chen
Allan Sauvat
Team Metabolism, Cancer & Immunity, Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France
Yanbing Dong
Team Metabolism, Cancer & Immunity, Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France
Sijing Li
Team Metabolism, Cancer & Immunity, Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France
Yan Rong
Team Metabolism, Cancer & Immunity, Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France
Federico Pietrocola
Department of Cell and Molecular Biology, Karolinska Institute, Solna
Pierre Laurent-Puig
Team Personalized Medicine, Phamacogenomics and Therapeutic Optimization, Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France
Carlos López-Otín
Isabelle Martins
Team Metabolism, Cancer & Immunity, Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France
Clea Barcena
Alejandro Lucia
Physical Exercise and Pediatric Cancer Research Group, Research Institute of the Hospital
Guido Kroemer