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.
Highlights
Age is the main risk factor for heart failure and other cardiovascular diseases
We aim to describe the transcriptome dynamics of the aging left ventricle (LV) in humans according to both chronological age (CA) and biological age (BA) and characterize the contribution of microRNAs, key transcriptional regulators
This study aims at describing gene and miRNA expression changes in the human LV induced by CA and transcriptomic BA through transcriptomic analysis of LV samples of the extensive Genotype-Tissue Expression (GTEx) RNA-seq dataset
Summary
Age is the main risk factor for heart failure and other cardiovascular diseases. Aged hearts undergo structural and functional changes at multiple levels that contribute to the pathogenesis of the disease. Studies carried out mainly in animal models (of considerably reduced lifespan, homogeneous genetic backgrounds and housing in controlled environments) limit translation to humans. The difficulties in discerning between the effects of aging and disease in humans, in conducting longitudinal studies and in obtaining cardiac samples, all contribute to this lack of knowledge. Studies investigating human aging are mainly conducted transversally in relation to chronological age (CA). The biological age (BA) of an organ, perceived as its actual structural and functional state, is a composite of both genetic and environmental factors acting together over time. The transcriptional dynamics of the aging heart, and the left ventricle (LV), have not been investigated yet from a biological point of view
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