Collaborative study headed by Kurian Lab discovers sphinganine as major driver of cardiac aging

03/21/2019

indicating that restoring histone acetylation levels in cardiomyocytes by histone acetylases inhibition prevents the sphinganine-induced DNA damage and functional decline both in vitro and in vivo.

- Rejuvenating the aging heart

Aging leads to progressive weakening of the heart, substantially affecting the life quality in older individuals and subsequently leading to death. This makes the need for understanding molecular mediators of cardiac ageing as well as development of anti-ageing therapies all the more urgent and a major bottleneck in our quest to extend the healthy lifespan.

In a multi-model collaborative study to address cardiac aging using vertebrate models including Killifish (the shortest living vertebrate in laboratory conditions with an average life span of ~9 weeks) and humans, the Kurian lab discovered a biomolecule, sphinganine (DHS), that deteriorates cardiac health by causing extensive DNA damage in cardiomyocytes, the functional building blocks of the heart. Mechanistically, sphinganine progressively accumulates in cardiomyocytes with age and its phosphorylated derivatives are potent inhibitors of histone deacetylases (HDACs).

This inhibition of HDACs in cardiomyoctyes leads to histone hyperacetylation and transcription-dependent DNA damage. Importantly, Kurian lab devised three independent small-molecule based interventions to prevent the cardiotoxicity caused by sphinganine.

Exogenous increase in cardiac sphinganine levels in healthy young adult mice leads to DNA damage in cardiomyocytes. Signifying its pivotal role in cardiac ageing, an increase in sphinganine levels in young mice leads to severe defects in cardiac function, mimicking the functional deterioration of the aged heart. Importantly, inhibition of histone acetylases (HATs) using an array of small molecules, including the natural compound curcumin, prevents the DHS-mediated cardiotoxicity in vivo suggesting a viable therapeutic strategy to rejuvenate the aged heart.

“Cardiac ageing is a complex process in which cardiomyotcyes start to lose their functionality, so it is critical for us to find the molecular drivers of ageing. In this study, we discovered a major driver of cardiac aging, sphinganine. Elevated sphinganine levels and loss of genomic integrity is an evolutionarily conserved hallmark of the aged vertebrate heart. Our data indicate that restoring histone acetylation levels in cardiomyocytes by HAT inhibition prevents the DHS-induced DNA damage and functional decline both in vitro and in vivo” says Gaurav Ahuja, the first author of the current study.

Collectively, these data illustrate the significance of lysosphingolipid-mediated loss of genomic integrity in the cardiac ageing process. Future efforts will focus on developing strategies to prevent sphinganine accumulation specifically in the heart to suppress ageing and enhance cardiac health to be used as a preventive clinical approach.  

This study is detailed in EMBO Reports on March 18th. [Epub ahead of print]
https://www.ncbi.nlm.nih.gov/pubmed/30886000
https://rdcu.be/brHPu

Loss of genomic integrity induced by lysosphingolipid imbalance drives ageing in the heart.
Ahuja G, Bartsch D, Yao W, Geissen S, Frank S, Aguirre A, Russ N, Messling J, Dodzian J, Lehmann K, Vargas N, Muck JS, Brodesser S, Baldus S, Sachinidis A, Hescheler J, Dieterich C, Trifunovic A, Papantonis A, Petrascheck M, Klinke A, Jain M, Valenzano D*, Kurian L*. (*co-corresponding Author)

Papantonis lab (CMMC, Cologne), Tirfunovic lab (CECAD, Cologne), Sachinidis lab (Institute for Neurophysiology, Cologne), Dieterich Lab (University of Heidelberg), Jain Lab (UCSD, San Diego USA) and Petrascheck lab (Scripps Research Institute, San Diego, USA) contributed to this study.

The Valenzano lab (funded by MPI-AGE) provided the Killifish samples and partially supported the study financially.

The Kurian lab is supported by the NRW Stem Cell Network Independent Group Leader Grant, CMMC, German Heart Association (DZHK), Else Kröner-Fresenius Stiftung (EKFS), Deutsche Forschungsgemeinschaft (DFG) and University of Cologne.

Contact:

Dr. Leo Kurian
Laboratory for developmental and regnerative RNA Biology
Institute for Neurophysiology and Center for Molecular Medicine Cologne
University Hospital Cologne and University of Cologne - Cologne, Germany

leo.kurian[at]uni-koeln.de
www.kurianlab.com

https://www.cmmc-uni-koeln.de/research/research-areas-projects/research-area-c-molecular-mechanisms-and-metabolic-control-of-tissue-degeneration-and-regeneration/leo-kurian-assoc-jrg-i/