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

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2021-06-06

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Ramos-Marquès, Estel
García-Mendívil, Laura
Pérez-Zabalza, María
Santander-Badules, Hazel
Srinivasan, Sabarathinam
Oliveros, Juan Carlos
Torres-Pérez, Rafael
Cebollada, Alberto
Vallejo-Gil, José María
Fresneda-Roldán, Pedro Carlos

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Wiley-Blackwell Publishing Ltd.
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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.

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Medical Subject Headings::Phenomena and Processes::Physiological Phenomena::Physiological Processes::Growth and Development::Aging
Medical Subject Headings::Check Tags::Male
Medical Subject Headings::Anatomy::Cardiovascular System::Heart::Heart Ventricles
Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans
Medical Subject Headings::Check Tags::Female
Medical Subject Headings::Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Antisense Elements (Genetics)::RNA, Antisense::MicroRNAs
Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Structures::Base Sequence::Regulatory Sequences, Nucleic Acid::Gene Regulatory Networks
Medical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Transcription, Genetic::Transcriptome
Medical Subject Headings::Persons::Persons::Tissue Donors::Living Donors
Medical Subject Headings::Anatomy::Cardiovascular System::Heart::Myocardium
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Probability::Risk::Risk Factors
Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Phenotype
Medical Subject Headings::Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Computational Biology

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Keywords

Biological aging, Biomarkers, Gene regulation network, Heart aging, microRNA, Transcriptomic age marker, Transcriptome, Living donors, Myocardium, Heart ventricles, Envejecimiento, Biomarcadores, Redes reguladoras de genes, MicroARNs, Transcriptoma, Donadores vivos, Miocardio, Ventrículos cardíacos

Citation

Ramos-Marquès E, García-Mendívil L, Pérez-Zabalza M, Santander-Badules H, Srinivasan S, Oliveros JC, et al. Chronological and biological aging of the human left ventricular myocardium: Analysis of microRNAs contribution. Aging Cell. 2021 Jul;20(7):e13383