RNA interference (RNAi) is a natural process that helps control which genes are active and keeps cells functioning properly. When this process doesn't work properly, it can lead to diseases. RNAi works through proteins called Argonaute (AGO) and small RNA molecules called miRNAs, which attach to messenger RNAs (mRNAs) and cause them to be degraded. Although we know a lot about how RNAi works in the main part of the cell (the cytoplasm), recent research shows that RNAi also occurs in the nucleus. My lab studies how RNAi works in the nucleus and how it affects health and disease. We have learned that the protein AGO is important in the nucleus during early development, but is normally kept outside the nucleus in healthy adult cells. However, during viral infections, cancer and even ageing, AGO can end up in the nucleus, which can worsen the disease/condition. Blocking AGO in the nucleus could therefore be a new way to treat these conditions. RNAi is increasingly recognized for its role in regulating aging, a complex process shaped by genetic, environmental and cellular factors. In this project, we will investigate the relationship between RNAi and aging, with a particular focus on nuclear RNAi processes. To achieve these goals, we will use patient cells from Progeria patients, which are characterized by accelerated aging, and patient cells with systemic sclerosis, which show a more normal aging process, as well as from young healthy and young subjects.