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. E.; Dodzian, J.; Lagerborg, K. A.; Vargas, N. E.; Muck, J. S.; Brodesser, S.; Baldus, S.; Sachinidis, A.; Hescheler, J.; Dieterich, C.; Trifunovic, A.; Papantonis, A.; Petrascheck, M.; Klinke, A.; Jain, M.; Valenzano, D. R.; Kurian, L.

doi:10.15252/embr.201847407

Item

ITEM ACTIONSEXPORT

Add to Basket

Local TagsRelease HistoryDetailsSummary

Released

Journal Article

Loss of genomic integrity induced by lysosphingolipid imbalance drives ageing in the heart

MPS-Authors

/persons/resource/persons278157

Valenzano, D. R.
Valenzano – Evolutionary and Experimental Biology of Ageing, Max Planck Research Groups, Max Planck Institute for Biology of Ageing, Max Planck Society;

External Resource

https://www.ncbi.nlm.nih.gov/pubmed/30886000
(Any fulltext)

Fulltext (restricted access)

There are currently no full texts shared for your IP range.

Fulltext (public)

There are no public fulltexts stored in PuRe

Supplementary Material (public)

There is no public supplementary material available

Citation

Ahuja, G., Bartsch, D., Yao, W., Geissen, S., Frank, S., Aguirre, A., et al. (2019). Loss of genomic integrity induced by lysosphingolipid imbalance drives ageing in the heart. EMBO Rep, 20(4), e47407. doi:10.15252/embr.201847407.

Cite as: https://hdl.handle.net/21.11116/0000-000B-432C-9

Abstract

Cardiac dysfunctions dramatically increase with age. Revealing a currently unknown contributor to cardiac ageing, we report the age-dependent, cardiac-specific accumulation of the lysosphingolipid sphinganine (dihydrosphingosine, DHS) as an evolutionarily conserved hallmark of the aged vertebrate heart. Mechanistically, the DHS-derivative sphinganine-1-phosphate (DHS1P) directly inhibits HDAC1, causing an aberrant elevation in histone acetylation and transcription levels, leading to DNA damage. Accordingly, the pharmacological interventions, preventing (i) the accumulation of DHS1P using SPHK2 inhibitors, (ii) the aberrant increase in histone acetylation using histone acetyltransferase (HAT) inhibitors, (iii) the DHS1P-dependent increase in transcription using an RNA polymerase II inhibitor, block DHS-induced DNA damage in human cardiomyocytes. Importantly, an increase in DHS levels in the hearts of healthy young adult mice leads to an impairment in cardiac functionality indicated by a significant reduction in left ventricular fractional shortening and ejection fraction, mimicking the functional deterioration of aged hearts. These molecular and functional defects can be partially prevented in vivo using HAT inhibitors. Together, we report an evolutionarily conserved mechanism by which increased DHS levels drive the decline in cardiac health.