Abstract
Introduction
Hutchinson-Gilford Progeria Syndrome (HGPS) is an extremely rare genetic disorder. HGPS children present a high incidence of cardiovascular complications along with altered metabolic processes and an accelerated aging process. No metabolic biomarker is known and the mechanisms underlying premature aging are not fully understood.
Objectives
The present work aims to evaluate the metabolic alterations in HGPS using high resolution mass spectrometry.
Methods
The present study analyzed plasma from six HGPS patients of both sexes (7.7 ± 1.4 years old; mean ± SD) and eight controls (8.6 ± 2.3 years old) by LC–MS/MS in high-resolution non-targeted metabolomics (Q-Exactive Plus). Targeted metabolomics was used to validate some of the metabolites identified by the non-targeted method in a triple quadrupole (TSQ-Quantiva).
Results
We found several endogenous metabolites with statistical differences between control and HGPS children. Multivariate statistical analysis showed a clear separation between groups. Potential novel metabolic biomarkers were identified using the multivariate area under ROC curve (AUROC) based analysis, showing an AUC value higher than 0.80 using only two metabolites, and tending to 1.00 when increasing the number of metabolites in the AUROC model. Taken together, changed metabolic pathways involve sphingolipids, amino acids, and oxidation of fatty acids, among others.
Conclusion
Our data show significant alterations in cellular energy use and availability, in signal transduction, and lipid metabolites, adding new insights on metabolic alterations associated with premature aging and suggesting novel putative biomarkers.
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Acknowledgements
We are grateful to The Progeria Research Foundation for the availability of plasma samples, to Edna Aleixo from the Federal University of Rio de Janeiro for assistance with the importation process and to the Laboratório de Apoio ao Desenvolvimento Tecnológico (LADETEC) of the Chemistry Institute of the Federal University of Rio de Janeiro for providing high quality infrastructure for the LC–MS analysis.
Funding
This work was funded by the Ministry of Health (DECIT), the Brazilian National Research Council (CNPq), the Carlos Chagas Filho Rio de Janeiro State Research Foundation (FAPERJ) and National Institute of Science and Technology for Regenerative Medicine.
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GM and ACCC conceptualized the study and wrote the manuscript; GM, CGMS, JAME, GPCE, FCSN, GC, GBD, LM, ACCC acquired and analyzed the data; VOC, GBD, FCSN, ACCC critically revised the study and the manuscript.
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Monnerat, G., Evaristo, G.P.C., Evaristo, J.A.M. et al. Metabolomic profiling suggests systemic signatures of premature aging induced by Hutchinson–Gilford progeria syndrome. Metabolomics 15, 100 (2019). https://doi.org/10.1007/s11306-019-1558-6
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DOI: https://doi.org/10.1007/s11306-019-1558-6