Resurrection of endogenous retroviruses during aging reinforces senescence

Xiaoqian Liu; Zunpeng Liu; Zeming Wu; Jie Ren; Yanling Fan; Liang Sun; Gang Cao; Yuyu Niu; Baohu Zhang; Qianzhao Ji; Xiaoyu Jiang; Cui Wang; Qiaoran Wang; Zhejun Ji; Lanzhu Li; Concepcion Rodriguez Esteban; Kaowen Yan; Wei Li; Yusheng Cai; Si Wang; Aihua Zheng; Yong E Zhang; Shengjun Tan; Yingao Cai; Moshi Song; Falong Lu; Fuchou Tang; Weizhi Ji; Qi Zhou; Juan Carlos Izpisua Belmonte; Weiqi Zhang; Jing Qu; Guang-Hui Liu

doi:10.1016/j.cell.2022.12.017

Resurrection of endogenous retroviruses during aging reinforces senescence

Cell. 2023 Jan 19;186(2):287-304.e26. doi: 10.1016/j.cell.2022.12.017. Epub 2023 Jan 6.

Authors

Xiaoqian Liu¹, Zunpeng Liu², Zeming Wu³, Jie Ren⁴, Yanling Fan⁵, Liang Sun⁶, Gang Cao⁷, Yuyu Niu⁸, Baohu Zhang⁹, Qianzhao Ji¹⁰, Xiaoyu Jiang¹⁰, Cui Wang⁵, Qiaoran Wang⁵, Zhejun Ji², Lanzhu Li¹⁰, Concepcion Rodriguez Esteban¹¹, Kaowen Yan³, Wei Li¹², Yusheng Cai³, Si Wang¹³, Aihua Zheng¹⁴, Yong E Zhang¹⁵, Shengjun Tan¹⁶, Yingao Cai¹⁵, Moshi Song¹⁷, Falong Lu¹⁸, Fuchou Tang¹⁹, Weizhi Ji²⁰, Qi Zhou¹, Juan Carlos Izpisua Belmonte¹¹, Weiqi Zhang²¹, Jing Qu²², Guang-Hui Liu²³

Affiliations

¹ State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
² State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
³ State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
⁴ 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; Institute for Stem cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
⁵ 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; University of Chinese Academy of Sciences, Beijing 100049, China.
⁶ 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.
⁷ State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China.
⁸ State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, Yunnan 650500, China; Yunnan Key Laboratory of Primate Biomedical Research, Kunming, Yunnan 650500, China; Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan 650500, China.
⁹ State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
¹⁰ State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
¹¹ Altos Labs, Inc., San Diego, CA 94022, USA.
¹² Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China.
¹³ Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China; Institute for Stem cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital, Capital Medical University, Beijing Municipal Geriatric Medical Research Center, Beijing 100053, China; The Fifth People's Hospital of Chongqing, Chongqing 400062, China.
¹⁴ University of Chinese Academy of Sciences, Beijing 100049, China; State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
¹⁵ University of Chinese Academy of Sciences, Beijing 100049, China; Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
¹⁶ Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
¹⁷ State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
¹⁸ University of Chinese Academy of Sciences, Beijing 100049, China; 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.
¹⁹ Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
²⁰ State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, Yunnan 650500, China; Yunnan Key Laboratory of Primate Biomedical Research, Kunming, Yunnan 650500, China.
²¹ 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; Institute for Stem cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: [email protected].
²² State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: [email protected].
²³ State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China; Institute for Stem cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: [email protected].

PMID: 36610399
DOI: 10.1016/j.cell.2022.12.017

Abstract

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.

Keywords: HERVK; aging; biomarker; driver; intervention.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aging* / genetics
Aging* / pathology
Animals
Cellular Senescence
Endogenous Retroviruses* / genetics
Humans
Mice
Primates