© 2019 Elsevier B.V. To evaluate the combined effect of age and glycemic state on circulating levels of the inflamma-miR‐146a levels, 188 healthy subjects (CTR) aged 20–104 years and 144 type-2 diabetic patients (T2DM), aged 40‐80 years, were analyzed. In CTR subjects, miR-146a levels showed a significant age-related decline. When a gender-stratified analysis was ran, the miR‐146a age-related trajectory was confirmed only in men and a negative correlation with PAI-1, uric acid, and creatinine was also observed. In women, miR-146a circulating levels showed negative correlations with azotemia, uric acid, waist/hip ratio and ferritin. A significant miR-146a decline with aging was also observed in T2DM patients. Significant positive correlations were found between miR-146a in diabetic patients and total cholesterol, LDL-C, ApoA1, ApoB, and platelets, and negative correlations with serum iron and ferritin. Notably, miR-146a was significantly overexpressed in T2DM patients treated with metformin. MiR-146a levels were significantly lower in diabetic patients than in age-matched CTR and negatively correlated to both fasting glucose and HbA1c in males. Finally, age-related trajectories for circulating miR-146a levels showed an inverted U-shaped relationship; however, in T2DM patients the trajectory was significantly shifted towards lower levels. Our findings support the hypothesis that miR-146a could be a functional biomarker of healthy/unhealthy aging.