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Chronological and biological aging of the human left ventricular myocardium: Analysis of microRNAs contribution

2021; Wiley; Volume: 20; Issue: 7 Linguagem: Inglês

10.1111/acel.13383

1474-9726

Estel Ramos Marquès, Laura García‐Mendívil, María Pérez‐Zabalza, Hazel Santander‐Badules, Sabarathinam Srinivasan, Juan Carlos Oliveros, Rafael Torres‐Pérez, Alberto Cebollada, José María Vallejo‐Gil, Pedro Carlos Fresneda‐Roldán, Javier Fañanás‐Mastral, Manuel Vázquez‐Sancho, Marta Matamala‐Adell, Juan Fernando Sorribas‐Berjón, Javier André Bellido‐Morales, Francisco Javier Mancebón‐Sierra, Alexánder Sebastián Vaca‐Núñez, Carlos Ballester, Manuel F. Jiménez‐Navarro, José Manuel Villaescusa, E Garrido-Huescar, Margarita Segovia‐Roldán, Aida Oliván‐Viguera, Carlos Gómez‐González, Gorka Muñíz, Emiliano Diez, Laura Ordovás, Esther Pueyo,

RNA Research and Splicing

Abstract Aging is the main risk factor for cardiovascular diseases. In humans, cardiac aging remains poorly characterized. Most studies are based on chronological age (CA) and disregard biological age (BA), the actual physiological age (result of the aging rate on the organ structure and function), thus yielding potentially imperfect outcomes. Deciphering the molecular basis of ventricular aging, especially by BA, could lead to major progresses in cardiac research. We aim to describe the transcriptome dynamics of the aging left ventricle (LV) in humans according to both CA and BA and characterize the contribution of microRNAs, key transcriptional regulators. BA is measured using two CA‐associated transcriptional markers: CDKN2A expression, a cell senescence marker, and apparent age (AppAge), a highly complex transcriptional index. Bioinformatics analysis of 132 LV samples shows that CDKN2A expression and AppAge represent transcriptomic changes better than CA. Both BA markers are biologically validated in relation to an aging phenotype associated with heart dysfunction, the amount of cardiac fibrosis. BA‐based analyses uncover depleted cardiac‐specific processes, among other relevant functions, that are undetected by CA. Twenty BA‐related microRNAs are identified, and two of them highly heart‐enriched that are present in plasma. We describe a microRNA‐gene regulatory network related to cardiac processes that are partially validated in vitro and in LV samples from living donors. We prove the higher sensitivity of BA over CA to explain transcriptomic changes in the aging myocardium and report novel molecular insights into human LV biological aging. Our results can find application in future therapeutic and biomarker research.