Mao Jian, Zhang Qian, Zhuang Yang, Zhang Yinyu, Li Linmeng, Pan Juan, Xu Lu, Ding Yuxuan, Wang Miao, Cong Yu-Sheng
Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Zhejiang Key Laboratory of Medical Epigenetics, Hangzhou Normal University School of Basic Medical Sciences, Hangzhou, China.
Department of Clinical Laboratory, Zhuji People's Hospital of Zhejiang Province, Shaoxing, China.
Nat Aging. 2024 Dec;4(12):1794-1812. doi: 10.1038/s43587-024-00745-6. Epub 2024 Nov 14.
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.
内源性逆转录病毒（ERVs）的重新激活被认为与衰老有关。然而，其重新激活的机制以及对衰老和与年龄相关疾病的影响在很大程度上尚未得到探索。在本研究中，我们鉴定出了一类在衰老细胞中重新激活的ERVs（称为衰老相关ERVs，SA-ERVs）。这些SA-ERVs可被激活转录因子3（ATF3）双向转录激活，从而产生双链RNA（dsRNAs），后者激活RIG-I/MDA5-MAVS信号通路并在衰老的成纤维细胞中触发I型干扰素（IFN-I）反应。一致地，我们发现在健康老年人和哈钦森-吉尔福德早衰综合征患者的多个组织中，ATF3和SA-ERVs的表达协同增加，且IFN-I反应增强。此外，我们观察到老年个体血液中源自SA-ERVs的dsRNAs积累以及IFNβ水平升高。这些结果共同揭示了ATF3重新激活SA-ERVs的一种前所未知的机制，并表明SA-ERVs是衰老的一个重要组成部分和标志。
