Circulating microRNAs and cross sectional and longitudinal measurements of physical functioning and frailty: An
Rossella La Grotta1, Cecilie Agergaard Sørensen2, Asmus Cosmos Skovgaard2
1Department of Biology, Ecology and Earth Sciences, University of Calabria, Via Pietro Bucci, Rende CS, Calabria 87036, Italy; Danish Twin Registry, and Research Unit for Epidemiology, Biodemography and Biostatistics, Department of Public Health, University of Southern Denmark, Campus Vej 55, Odense M 5320, Denmark.
Abstract:
During aging, physical functioning declines, and disability and frailty increase; phenotypes which are bidirectionally linked. MicroRNAs (miRNAs) are epigenetic regulators of various physiological processes and suggested aging biomarkers. Here we investigate the association between circulating plasma miRNAs and hand grip strength, chair stand, (Rockwood) frailty, and activity of daily living (ADL) in 86 monozygotic twins (73-88 years). In cross-sectional analysis, both individual and twin-pair level analyses were performed, the latter controlling genetic confounding. The majority (74-100 %) of miRNAs identified in the individual-level analysis were validated by twin-pair-level analysis, with 14 miRNAs showing significance (p < 0.05) in both. Longitudinal analysis (up to eight years of follow-up) yielded more significant results (75-93 miRNAs), indicating that miRNAs might be more accurate in predicting functional decline over time. Of these miRNAs, seven showed consistent directions of effects across phenotypes. For all analyses, most (65-79 %) of the observed effect sizes were negative, reflecting reduced functionality with increased miRNA levels. Enrichment analyses revealed pathways of gene expression (incl. p53- and FOXO-mediated transcription), signal transduction, the immune system, metabolism of RNA, among others. Of specific miRNAs, miR-1274a demonstrated negative association in both cross-sectional and longitudinal investigations of ADL. These findings support miRNAs as biomarkers of age-related functional decline.
Insights
Circulating microRNAs (miRNAs) show promise as biomarkers for age-related functional decline. Higher miRNA levels correlate with reduced physical function, with longitudinal data offering stronger predictive power.
Area of Science:
- Gerontology and Molecular Biology
- Epigenetics and Biomarker Discovery
Background:
- Aging is characterized by declining physical function, increasing disability, and frailty.
- MicroRNAs (miRNAs) are epigenetic regulators implicated in physiological processes and aging.
Purpose of the Study:
- To investigate the association between circulating plasma miRNAs and measures of physical function and frailty.
- To explore miRNAs as potential biomarkers for age-related functional decline.
Main Methods:
- Cross-sectional and longitudinal analyses of plasma miRNAs in 86 monozygotic twins (aged 73-88).
- Assessment of hand grip strength, chair stand, frailty, and activities of daily living (ADL).
- Twin-pair analyses controlled for genetic confounding.
Main Results:
- 14 miRNAs were significant in both individual and twin-pair analyses.
- Longitudinal analysis identified 75-93 miRNAs associated with functional decline.
- Seven miRNAs showed consistent effects across phenotypes, with most indicating reduced function with increased miRNA levels.
- miR-1274a was negatively associated with ADL in both cross-sectional and longitudinal analyses.
Conclusions:
- Circulating miRNAs are associated with age-related functional decline.
- MiRNAs may serve as valuable biomarkers for predicting functional decline over time.
- Enrichment analyses suggest involvement of gene expression pathways (p53, FOXO), signal transduction, and RNA metabolism.
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