Xiaoqian Liu,1,5,6,7,21 Zunpeng Liu,1,5,7,21 Zeming Wu,2,5,7,21 Jie Ren,3,5,7,21 Yanling Fan,3,7 Liang Sun,9 Gang Cao,8 Yuyu Niu,11,12,13 Baohu Zhang,1,7 Qianzhao Ji,2,7 Xiaoyu Jiang,2,7 Cui Wang,3,7 Qiaoran Wang,3,7 Zhejun Ji,1,5,7 Lanzhu Li,2,7 Concepcion Rodriguez Esteban,18 Kaowen Yan,2,5,7 Wei Li,4 Yusheng Cai,2,5,7 Si Wang,4,5,7,15,16 Aihua Zheng,7,19 Yong E. Zhang,7,14 Shengjun Tan,14 Yingao Cai,7,14 Moshi Song,2,5,6,7 Falong Lu,7,10 Fuchou Tang,17 Weizhi Ji,11,12,20 Qi Zhou,1,5,6,7,20 Juan Carlos Izpisua Belmonte,18,20 Weiqi Zhang,3,5,7,* Jing Qu,1,5,6,7,* and Guang-Hui Liu2,4,5,6,7,22,*

1State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China

 2 State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China

3 CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China

4 Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China

5 Institute for Stem cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China

6 Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China

7 University of Chinese Academy of Sciences, Beijing 100049, China

8 State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China

9 NHC Beijing Institute of Geriatrics, NHC Key Laboratory of Geriatrics, Institute of Geriatric Medicine of Chinese Academy of Medical Sciences, National Center of Gerontology/Beijing Hospital, Beijing 100730, China

10 State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, The Innovative Academy of Seed Design, Chinese Academy of Sciences, Beijing 100101, China

11 State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, Yunnan 650500, China

12 Yunnan Key Laboratory of Primate Biomedical Research, Kunming, Yunnan 650500, China

13 Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan 650500, China

14 Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China

15 Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital, Capital Medical University, Beijing Municipal Geriatric Medical Research Center, Beijing 100053, China

16 The Fifth People’s Hospital of Chongqing, Chongqing 400062, China

17 Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China

18 Altos Labs, Inc., San Diego, CA 94022, USA

19 State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China

20 Senior author

21 These authors contributed equally

22 Lead contact

*Correspondence: 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。 (W.Z.), 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。 (J.Q.), 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。 (G.-H.L.)

https://doi.org/10.1016/j.cell.2022.12.017

SUMMARY

Whether and how certain transposable elements with viral origins, such as endogenous retroviruses (ERVs) dormant in our genomes, can become awakened and contribute to the aging process is largely unknown. In human senescent cells, we found that HERVK (HML-2), the most recently integrated human ERVs, are unlocked to transcribe viral genes and produce retrovirus-like particles (RVLPs). These HERVK RVLPs constitute a transmissible message to elicit senescence phenotypes in young cells, which can be blocked by neutralizing antibodies. The activation of ERVs was also observed in organs of aged primates and mice as well as in human tissues and serum from the elderly. Their repression alleviates cellular senescence and tissue degeneration and, to some extent, organismal aging. These findings indicate that the resurrection of ERVs is a hallmark and driving force of cellular senescence and tissue aging.