Gustavo Monnerat1,2, Geisa Paulino Caprini Evaristo2, Joseph Albert Medeiros Evaristo2, Caleb Guedes Miranda Dos Santos3, Gabriel Carneiro2, Leonardo Maciel1, Vânia Oliveira Carvalho4, Fábio César Sousa Nogueira2,5, Gilberto Barbosa Domont6, Antonio Carlos Campos de Carvalho7,8. 1. Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Av. Carlos Chagas Filho 373 - CCS - Bloco G, Rio de Janeiro, 21941-902, Brazil. 2. Laboratory of Proteomics, LADETEC, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. 3. Instituto de Biologia Do Exército, Ministério da Defesa do Brasil, Rio de Janeiro, Brazil. 4. Department of Pediatrics, Federal University of Paraná, Curitiba, Brazil. 5. Proteomics Unit, Institute of Chemistry, Federal University of Rio de Janeiro, Av. Carlos Chagas Filho 373 - CCS - Bloco G, Rio de Janeiro, 21941-902, Brazil. 6. Proteomics Unit, Institute of Chemistry, Federal University of Rio de Janeiro, Av. Carlos Chagas Filho 373 - CCS - Bloco G, Rio de Janeiro, 21941-902, Brazil. gilberto@iq.ufrj.br. 7. Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Av. Carlos Chagas Filho 373 - CCS - Bloco G, Rio de Janeiro, 21941-902, Brazil. acarlos@biof.ufrj.br. 8. National Institute of Cardiology, Rio de Janeiro, Brazil. acarlos@biof.ufrj.br.
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.
INTRODUCTION:Hutchinson-Gilford Progeria Syndrome (HGPS) is an extremely rare genetic disorder. HGPSchildren 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 HGPSpatients 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 HGPSchildren. 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.
Authors: Ashwin Prakash; Leslie B Gordon; Monica E Kleinman; Ellen B Gurary; Joseph Massaro; Ralph D'Agostino; Mark W Kieran; Marie Gerhard-Herman; Leslie Smoot Journal: JAMA Cardiol Date: 2018-04-01 Impact factor: 14.676
Authors: Gustavo Monnerat; Fernando A C Seara; Joseph Albert Medeiros Evaristo; Gabriel Carneiro; Geisa Paulino Caprini Evaristo; Gilberto Domont; Jose Hamilton Matheus Nascimento; Jose Geraldo Mill; Fabio Cesar Souza Nogueira; Antonio Carlos Campos de Carvalho Journal: J Steroid Biochem Mol Biol Date: 2018-06-18 Impact factor: 4.292
Authors: Thomas J Wang; Martin G Larson; Ramachandran S Vasan; Susan Cheng; Eugene P Rhee; Elizabeth McCabe; Gregory D Lewis; Caroline S Fox; Paul F Jacques; Céline Fernandez; Christopher J O'Donnell; Stephen A Carr; Vamsi K Mootha; Jose C Florez; Amanda Souza; Olle Melander; Clary B Clish; Robert E Gerszten Journal: Nat Med Date: 2011-03-20 Impact factor: 53.440
Authors: Leslie B Gordon; Monica E Kleinman; David T Miller; Donna S Neuberg; Anita Giobbie-Hurder; Marie Gerhard-Herman; Leslie B Smoot; Catherine M Gordon; Robert Cleveland; Brian D Snyder; Brian Fligor; W Robert Bishop; Paul Statkevich; Amy Regen; Andrew Sonis; Susan Riley; Christine Ploski; Annette Correia; Nicolle Quinn; Nicole J Ullrich; Ara Nazarian; Marilyn G Liang; Susanna Y Huh; Armin Schwartzman; Mark W Kieran Journal: Proc Natl Acad Sci U S A Date: 2012-09-24 Impact factor: 11.205
Authors: Melissa A Merideth; Leslie B Gordon; Sarah Clauss; Vandana Sachdev; Ann C M Smith; Monique B Perry; Carmen C Brewer; Christopher Zalewski; H Jeffrey Kim; Beth Solomon; Brian P Brooks; Lynn H Gerber; Maria L Turner; Demetrio L Domingo; Thomas C Hart; Jennifer Graf; James C Reynolds; Andrea Gropman; Jack A Yanovski; Marie Gerhard-Herman; Francis S Collins; Elizabeth G Nabel; Richard O Cannon; William A Gahl; Wendy J Introne Journal: N Engl J Med Date: 2008-02-07 Impact factor: 91.245
Authors: Dayle McClintock; Desiree Ratner; Meepa Lokuge; David M Owens; Leslie B Gordon; Francis S Collins; Karima Djabali Journal: PLoS One Date: 2007-12-05 Impact factor: 3.240