High plasma concentrations of acyl-coenzyme A binding protein (ACBP) predispose to cardiovascular disease: Evidence for a phylogenetically conserved proaging function of ACBP

Léa Montégut; Adrien Joseph; Hui Chen; Mahmoud Abdellatif; Christoph Ruckenstuhl; Omar Motiño; Flavia Lambertucci; Gerasimos Anagnostopoulos; Sylvie Lachkar; Silvia Dichtinger; Maria Chiara Maiuri; François Goldwasser; Benoit Blanchet; Frédéric Fumeron; Isabelle Martins; Frank Madeo; Guido Kroemer

doi:10.1111/acel.13751

High plasma concentrations of acyl-coenzyme A binding protein (ACBP) predispose to cardiovascular disease: Evidence for a phylogenetically conserved proaging function of ACBP

Aging Cell. 2023 Jan;22(1):e13751. doi: 10.1111/acel.13751. Epub 2022 Dec 12.

Authors

Léa Montégut^{1

2

3}, Adrien Joseph^{1

2

3

4}, Hui Chen^{1

2

3}, Mahmoud Abdellatif^{1

2

5

6}, Christoph Ruckenstuhl⁷, Omar Motiño^{1

2}, Flavia Lambertucci^{1

2}, Gerasimos Anagnostopoulos^{1

2

3}, Sylvie Lachkar^{1

2}, Silvia Dichtinger⁷, Maria Chiara Maiuri^{1

2}, François Goldwasser^{8

9}, Benoit Blanchet^{10

11}, Frédéric Fumeron¹², Isabelle Martins^{1

2}, Frank Madeo^{6

7

13}, Guido Kroemer^{1

2

14}

Affiliations

¹ Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Inserm U1138, Université Paris Cité, Sorbonne Université, Paris, France.
² Metabolomics and Cell Biology Platforms, Gustave Roussy Institut, Villejuif, France.
³ Faculté de Médecine, Université de Paris Saclay, Paris, France.
⁴ Service de médecine intensive réanimation, Hôpital Saint-Louis, Paris, France.
⁵ Department of Cardiology, Medical University of Graz, Graz, Austria.
⁶ BioTechMed-Graz, Graz, Austria.
⁷ Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.
⁸ Department of Medical Oncology, Cochin Hospital, AP-HP, Paris, France.
⁹ URP4466, Université Paris Cité, Paris, France.
¹⁰ Pharmacokinetics and Pharmacochemistry Unit, Cochin Hospital, Paris Descartes University, CARPEM, AP-HP, Paris, France.
¹¹ UMR8038 CNRS, U1268 INSERM, Faculty of Pharmacy, University of Paris, PRES Sorbonne Paris Cité, CARPEM, Paris, France.
¹² Institut Necker-Enfants Malades, Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Paris, France.
¹³ Field of Excellence BioHealth, University of Graz, Graz, Austria.
¹⁴ Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.

Abstract

Autophagy defects accelerate aging, while stimulation of autophagy decelerates aging. Acyl-coenzyme A binding protein (ACBP), which is encoded by a diazepam-binding inhibitor (DBI), acts as an extracellular feedback regulator of autophagy. As shown here, knockout of the gene coding for the yeast orthologue of ACBP/DBI (ACB1) improves chronological aging, and this effect is reversed by knockout of essential autophagy genes (ATG5, ATG7) but less so by knockout of an essential mitophagy gene (ATG32). In humans, ACBP/DBI levels independently correlate with body mass index (BMI) as well as with chronological age. In still-healthy individuals, we find that high ACBP/DBI levels correlate with future cardiovascular events (such as heart surgery, myocardial infarction, and stroke), an association that is independent of BMI and chronological age, suggesting that ACBP/DBI is indeed a biomarker of "biological" aging. Concurringly, ACBP/DBI plasma concentrations correlate with established cardiovascular risk factors (fasting glucose levels, systolic blood pressure, total free cholesterol, triglycerides), but are inversely correlated with atheroprotective high-density lipoprotein (HDL). In mice, neutralization of ACBP/DBI through a monoclonal antibody attenuates anthracycline-induced cardiotoxicity, which is a model of accelerated heart aging. In conclusion, plasma elevation of ACBP/DBI constitutes a novel biomarker of chronological aging and facets of biological aging with a prognostic value in cardiovascular disease.

Trial registration: ClinicalTrials.gov NCT04879316.

Keywords: aging; autophagy; cancer; cardiovascular diseases; diazepam-binding protein; metabolism.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cardiovascular Diseases* / genetics
Carrier Proteins*
Coenzyme A / metabolism
Diazepam Binding Inhibitor / genetics
Diazepam Binding Inhibitor / metabolism
Humans
Mice
Nuclear Proteins / metabolism

Substances

Carrier Proteins
Coenzyme A
Diazepam Binding Inhibitor
Nuclear Proteins

Associated data

ClinicalTrials.gov/NCT04879316