Circulating microRNAs and cross sectional and longitudinal measurements of physical functioning and frailty: an explorative study in older twins

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.