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Loss of genomic integrity induced by lysosphingolipid imbalance drives ageing in the heart
Author(s) -
Ahuja Gaurav,
Bartsch Deniz,
Yao Wenjie,
Geissen Simon,
Frank Stefan,
Aguirre Aitor,
Russ Nicole,
Messling JanErik,
Dodzian Joanna,
Lagerborg Kim A,
Vargas Natalia Emilse,
Muck Joscha Sergej,
Brodesser Susanne,
Baldus Stephan,
Sachinidis Agapios,
Hescheler Juergen,
Dieterich Christoph,
Trifunovic Aleksandra,
Papantonis Argyris,
Petrascheck Michael,
Klinke Anna,
Jain Mohit,
Valenzano Dario Riccardo,
Kurian Leo
Publication year - 2019
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201847407
Subject(s) - ageing , personal integrity , biology , structural integrity , genetics , psychology , social psychology , structural engineering , engineering
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 ( DHS 1P) directly inhibits HDAC 1, causing an aberrant elevation in histone acetylation and transcription levels, leading to DNA damage. Accordingly, the pharmacological interventions, preventing (i) the accumulation of DHS 1P using SPHK 2 inhibitors, (ii) the aberrant increase in histone acetylation using histone acetyltransferase ( HAT ) inhibitors, (iii) the DHS 1P‐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.