Abstract
Circulating microRNAs (miRNAs) are emerging as key regulators of aging and age-related diseases. Among them, the so-called inflammamiRs miR-21-5p, miR-23a-3p, and miR-26a-5p have been repeatedly linked to inflammation, tissue remodelling, and metabolic dysregulation. In this cross-sectional study, we investigated their expression in older adults (65-103 years) to explore associations with frailty, comorbidity, and major clinical and functional indicators of aging. Plasma miRNA levels were measured by quantitative PCR and correlated with comprehensive clinical, functional (frailty status, Activities of Daily Living [ADL], and Cumulative Illness Rating Scale [CIRS]), and biochemical parameters. Bioinformatic pathway analyses were also performed to identify shared molecular targets. All three miRNAs showed a progressive, age-dependent increase in expression. Their associations with clinical and functional parameters remained significant after adjustment for age and sex and were confirmed in stratified analyses by sex, age, and comorbidity burden. miR-21-5p and miR-23a-3p were elevated in frail individuals, and miR-23a-3p was inversely associated with hand grip strength. miR-21-5p correlated with renal dysfunction markers, while miR-26a-5p was related to reduced ADL scores and higher comorbidity burden. Together, the three miRNAs were associated with biochemical indicators of electrolyte imbalance and systemic dysregulation, including anemia and inflammation. In silico analyses revealed convergent enrichment in the TGF-β/SMAD and RUNX1 signaling pathways, suggesting a coordinated regulatory role in inflammation-mediated fibrogenic processes. These findings identify circulating miR-21-5p, miR-23a-3p, and miR-26a-5p as potential biomarkers reflecting molecular mechanisms underlying aging and age-related decline.