miR-21 and miR-146a: The microRNAs of inflammaging and age-related diseases.

The first paper on "inflammaging" published in 2001 paved the way for a unifying theory on how and why aging turns out to be the main risk factor for the development of the most common age-related diseases (ARDs). The most exciting challenge on this topic was explaining how systemic inflammation steeps up with age and why it shows different rates among individuals of the same chronological age. The "epigenetic revolution" in the past twenty years conveyed that the assessment of the individual genetic make-up is not enough to depict the trajectories of age-related inflammation. Accordingly, others and we have been focusing on the role of non-coding RNA, i.e. microRNAs (miRNAs), in inflammaging. The results obtained in the latest 10 years underpinned the key role of a miRNA subset that we have called inflammamiRs, owing to their ability to master (NF-κB)-driven inflammatory pathways. In this review, we will focus on two inflammamiRs, i.e. miR-21-5p and miR-146a-5p, which target a variety of molecules belonging to the NF-κB/NLRP3 pathways. The interplay between miR-146a-5p and IL-6 in the context of aging and ARDs will also be highlighted. We will also provide the most relevant evidence suggesting that circulating inflammamiRs, along with IL-6, can measure the degree of inflammaging.