Reactivation of senescence-associated endogenous retroviruses by ATF3 drives interferon signaling in aging

Reactivation of endogenous retroviruses (ERVs) has been proposed to be involved in aging. However, the mechanism of reactivation and contribution to aging and age-associated diseases is largely unexplored. In this study, we identified a subclass of ERVs reactivated in senescent cells (termed senescence-associated ERVs (SA-ERVs)). These SA-ERVs can be bidirectional transcriptionally activated by activating transcription factor 3 (ATF3) to generate double-stranded RNAs (dsRNAs), which activate the RIG-I/MDA5–MAVS signaling pathway and trigger a type I interferon (IFN-I) response in senescent fibroblasts. Consistently, we found a concerted increased expression of ATF3 and SA-ERVs and enhanced IFN-I response in several tissues of healthy aged individuals and patients with Hutchinson–Gilford progeria syndrome. Moreover, we observed an accumulation of dsRNAs derived from SA-ERVs and higher levels of IFNβ in blood of aged individuals. Together, these results reveal a previously unknown mechanism for reactivation of SA-ERVs by ATF3 and illustrate SA-ERVs as an important component and hallmark of aging.