Biological aging is associated with physiological deteriorations and its’ remodeling, which are partly due to changes in the hormonal profile. MicroRNAs are known to post-transcriptionally regulate various cellular processes associated with cell senescence; differentiation, replication and apoptosis. Measured from the serum, microRNAs have the potential to serve as noninvasive markers for diagnostics/prognostics and therapeutic targets. We analysed the association of estrogen-based hormone replacement therapy (HRT) with selected microRNAs and inflammation markers from the serum, leukocytes and muscle tissue biopsy samples obtained from 54-62 year-old postmenopausal monozygotic twins (n=11 pairs) discordant for the use of HRT. Premenopausal 30-35 year-old women (n=8) were used as young controls. We focused on the hormonal aging and more specifically, on the interaction between HRT use and the modulation of inflammation associated microRNAs, miR-21 and miR-146a, and classical inflammation markers. Fas-ligand (FasL) was analysed since it functions in both apoptosis and inflammation. The inflammatory profile is healthier among the premenopausal women compared to the older, postmenopausal twins. The serum miR-21 and miR-146a expression levels and FasL concentrations were lower in the HRT users when compared to their non-using co-twins, demonstrating their responsiveness to HRT. Based on the pairwise FasL analysis, the FasL serum concentration is likely to be genetically controlled. Overall, we suggest that postmenopausal estrogen deficiency sustains the development of “inflamm-aging” in women. Estrogen sensitive, specific circulating microRNAs could be potential, early biomarkers for age-associated physiological deteriorations. Highlights:  Unique study design of postmenopausal MZ twins discordant for HRT  Serum miR-21 and miR-146a expressions are lower in HRT users compared to non-users  FasL serum concentrations are lower in HRT users and possibly genetically regulated  Postmenopausal systemic estrogen deficiency partly contributes to the “inflamm-aging”  Serum miR-21/-146a early indicators of age-associated physiological deteriorations