Nuclear lamina erosion-induced resurrection of endogenous retroviruses underlies neuronal aging

Hui Zhang; Jiaming Li; Yang Yu; Jie Ren; Qiang Liu; Zhaoshi Bao; Shuhui Sun; Xiaoqian Liu; Shuai Ma; Zunpeng Liu; Kaowen Yan; Zeming Wu; Yanling Fan; Xiaoyan Sun; Yixin Zhang; Qianzhao Ji; Fang Cheng; Peng-Hu Wei; Xibo Ma; Shiqiang Zhang; Zhengwei Xie; Yuyu Niu; Yan-Jiang Wang; Jing-Dong J Han; Tao Jiang; Guoguang Zhao; Weizhi Ji; Juan Carlos Izpisua Belmonte; Si Wang; Jing Qu; Weiqi Zhang; Guang-Hui Liu

doi:10.1016/j.celrep.2023.112593

Nuclear lamina erosion-induced resurrection of endogenous retroviruses underlies neuronal aging

Cell Rep. 2023 Jun 27;42(6):112593. doi: 10.1016/j.celrep.2023.112593. Epub 2023 May 31.

Authors

Hui Zhang¹, Jiaming Li², Yang Yu³, Jie Ren⁴, Qiang Liu⁵, Zhaoshi Bao⁶, Shuhui Sun⁷, Xiaoqian Liu⁸, Shuai Ma⁷, Zunpeng Liu⁹, Kaowen Yan⁷, Zeming Wu⁷, Yanling Fan², Xiaoyan Sun², Yixin Zhang⁹, Qianzhao Ji¹, Fang Cheng¹⁰, Peng-Hu Wei¹¹, Xibo Ma¹², Shiqiang Zhang¹³, Zhengwei Xie¹⁴, Yuyu Niu¹⁵, Yan-Jiang Wang¹⁶, Jing-Dong J Han¹³, Tao Jiang¹⁷, Guoguang Zhao¹⁸, Weizhi Ji¹⁵, Juan Carlos Izpisua Belmonte¹⁹, Si Wang²⁰, Jing Qu²¹, Weiqi Zhang²², Guang-Hui Liu²³

Affiliations

¹ 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.
² 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.
³ Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology and Key Laboratory of Assisted Reproduction, Ministry of Education, Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China; Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing, 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, CAS, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
⁵ Department of Neurology, Tianjin Medical University General Hospital, Tianjin 300052, China.
⁶ Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China; Chinese Glioma Genome Atlas Network & Asian Glioma Genome Atlas Network, Beijing 100070, China.
⁷ State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, CAS, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China.
⁸ 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, CAS, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, 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 University of Chinese Academy of Sciences, Beijing 100049, China; National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
¹¹ Beijing Municipal Geriatric Medical Research Center, Beijing 100053, China; MAIS, State Key Laboratory of Multimodal Artificial Intelligence Systems, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China; School of Artificial Intelligence, University of Chinese Academy of Sciences, Beijing 100049, China.
¹² MAIS, State Key Laboratory of Multimodal Artificial Intelligence Systems, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China; School of Artificial Intelligence, University of Chinese Academy of Sciences, Beijing 100049, China.
¹³ Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Center for Quantitative Biology (CQB), Peking University, Beijing 100871, China.
¹⁴ Peking University International Cancer Institute, Peking University Health Science Center, Peking University, Beijing 100191, China.
¹⁵ State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, Yunnan 650500, China.
¹⁶ Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing 400042, China; State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
¹⁷ Beijing Neurosurgical Institute, Beijing 100070, China; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China; Chinese Glioma Genome Atlas Network & Asian Glioma Genome Atlas Network, Beijing 100070, China.
¹⁸ Department of Neurosurgery, Xuanwu Hospital Capital Medical University, Beijing 100053, China; Clinical Research Center for Epilepsy Capital Medical University, Beijing 100053, China; Beijing Municipal Geriatric Medical Research Center, Beijing 100053, China.
¹⁹ Altos Labs, Inc., San Diego, CA, USA.
²⁰ Advanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China; Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China; The Fifth People's Hospital of Chongqing, Chongqing 400062, China. Electronic address: wangsi@xwh.ccmu.edu.cn.
²¹ 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, CAS, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China. Electronic address: qujing@ioz.ac.cn.
²² 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, CAS, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: zhangwq@big.ac.cn.
²³ State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, CAS, Beijing 100101, China; Advanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China; University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China. Electronic address: ghliu@ioz.ac.cn.

PMID: 37261950
DOI: 10.1016/j.celrep.2023.112593

Abstract

The primate frontal lobe (FL) is sensitive to aging-related neurocognitive decline. However, the aging-associated molecular mechanisms remain unclear. Here, using physiologically aged non-human primates (NHPs), we depicted a comprehensive landscape of FL aging with multidimensional profiling encompassing bulk and single-nucleus transcriptomes, quantitative proteome, and DNA methylome. Conjoint analysis across these molecular and neuropathological layers underscores nuclear lamina and heterochromatin erosion, resurrection of endogenous retroviruses (ERVs), activated pro-inflammatory cyclic GMP-AMP synthase (cGAS) signaling, and cellular senescence in post-mitotic neurons of aged NHP and human FL. Using human embryonic stem-cell-derived neurons recapitulating cellular aging in vitro, we verified the loss of B-type lamins inducing resurrection of ERVs as an initiating event of the aging-bound cascade in post-mitotic neurons. Of significance, these aging-related cellular and molecular changes can be alleviated by abacavir, a nucleoside reverse transcriptase inhibitor, either through direct treatment of senescent human neurons in vitro or oral administration to aged mice.

Keywords: CP: Cell biology; CP: Neuroscience; aging; brain; endogenous retroviruses; inflammation; nuclear lamina.

Publication types

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

MeSH terms

Aging / physiology
Animals
Cellular Senescence / genetics
Endogenous Retroviruses*
Mice
Neurons
Nuclear Lamina
Primates