The Ercc1−/− and Ercc1-/Δ7 mouse models of the human progeroid syndrome XFE (Niedernhofer et al., 2006; Gregg et al., 2012; Schermer et al., 2013; Pieren et al., 2021) provide compelling evidence that the persistent activation of DNA damage-driven innate immune responses lead to tissue-degenerative alterations. The gene discussed is ERCC1; the disease is XFE progeroid syndrome.