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Chronological and biological aging of the human left ventricular myocardium: Analysis of microRNAs contribution
Estel Ramos-Marquès1,2, Laura García-Mendívil1,2, María Pérez-Zabalza1,2
1Biomedical Signal Interpretation and Computational Simulation group (BSICoS), Aragón Institute of Engineering Research, University of Zaragoza, Zaragoza, Spain.
Insights
Biological age (BA) better reflects cardiac aging than chronological age (CA). This study reveals novel molecular insights into heart aging, identifying key microRNAs for future therapeutic and biomarker research.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Gerontology
Background:
- Aging is a primary risk factor for cardiovascular diseases, yet human cardiac aging is poorly understood.
- Current research often relies on chronological age (CA), potentially overlooking crucial physiological variations.
- Biological age (BA) offers a more accurate measure of organ aging, impacting structure and function.
Purpose of the Study:
- To investigate the transcriptome dynamics of the aging human left ventricle (LV) using both CA and BA.
- To identify microRNAs involved in cardiac aging and their regulatory roles.
- To compare the efficacy of BA markers against CA in explaining transcriptomic changes.
Main Methods:
- Bioinformatics analysis of 132 human LV samples.
- Measurement of BA using CDKN2A expression (senescence marker) and apparent age (AppAge).
- Validation of BA markers against cardiac fibrosis and in vitro/in vivo microRNA studies.
Main Results:
- BA markers (CDKN2A, AppAge) better represent transcriptomic changes in the aging LV than CA.
- BA analysis revealed depleted cardiac-specific processes missed by CA.
- Twenty BA-related microRNAs were identified, including two heart-enriched, plasma-detectable microRNAs.
Conclusions:
- Biological age is a more sensitive indicator of transcriptomic changes in the aging myocardium than chronological age.
- Novel molecular insights into human LV biological aging were uncovered.
- Findings support future research in cardiac aging therapeutics and biomarkers.
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.
