Resurrection of human endogenous retroviruses during aging reinforces senescence

Human endogenous retroviruses (HERVs) are under strict control by the host surveillance system but can become awakened under pathological conditions. Among them, the HERVK family, comprised of the evolutionarily youngest HERVs, is able to transcribe viral genes and producing retrovirus-like particles (RVLPs). However, whether HERVK is mobilized in the aging process and contributes to aging-related pathologies is largely unknown. Using diverse senescence models, we show that epigenetic alterations unlock HERVK expression, which leads to the formation of RVLPs. Derepression of HERVK promotes cellular senescence, while inhibiting HERVK prevents cellular senescence. HERVK RVLPs released from senescent cells or aged individuals are capable of conferring a senescence phenotype to young cells. Conversely, using antibodies to block the HERVK RVLPs abrogates their transmissible pro-senescence effect. Moreover, endogenous retrovirus expression is increased in aged human tissues and serum from the elderly. These findings indicate that the activation of endogenous viruses is part of the driving force of aging.