Open AccessChronological and biological aging of the human left ventricular myocardium: Analysis of microRNAs contribution
Author(s) -
RamosMarquès Estel,
GarcíaMendívil Laura,
PérezZabalza María,
SantanderBadules Hazel,
Srinivasan Sabarathinam,
Oliveros Juan Carlos,
TorresPérez Rafael,
Cebollada Alberto,
VallejoGil José María,
FresnedaRoldán Pedro Carlos,
FañanásMastral Javier,
VázquezSancho Manuel,
MatamalaAdell Marta,
SorribasBerjón Juan Fernando,
Bellido‑Morales Javier André,
Mancebón‑Sierra Francisco Javier,
Vaca‑Núñez Alexánder Sebastián,
BallesterCuenca Carlos,
JiménezNavarro Manuel,
Villaescusa José Manuel,
GarridoHuéscar Elisa,
SegoviaRoldán Margarita,
OlivánViguera Aida,
GómezGonzález Carlos,
Muñiz Gorka,
Diez Emiliano,
Ordovás Laura,
Pueyo Esther
Publication year - 2021
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.13383
Subject(s) - transcriptome , biology , cdkn2a , senescence , microrna , biomarker , biological age , ventricle , gene expression , phenotype , ageing , bioinformatics , medicine , gene , genetics , evolutionary biology
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.