Resurrection of endogenous retroviruses during aging reinforces senescence
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Abstract
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 are 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. 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. In brief Liu and colleagues uncover the ways in which de-repression of human endogenous retrovirus triggers cellular senescence and tissue aging; the findings provide fresh insights into therapeutic strategies for alleviating aging. Highlights Derepression of the endogenous retrovirus contributes to programmed aging Upregulation of HERVK triggers the innate immune response and cellular senescence Extracellular HERVK retrovirus-like particles induce senescence in young cells Endogenous retrovirus serves as a potential target to alleviate agings Graphical abstract
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Aging hallmarks such as SPiDER-βGal-positive cells, P21, 4-HNE, γH2AX-positive cells, and MMTV-positive cells are upregulated with advancing age across various tissues.
“As expected, aging hallmarks such as SPiDER-βGal-positive cells, P21, 4-HNE, γH2AX-positive cells, and MMTV (a mouse homolog of human HERVK)-positive cells were found to be upregulated with advancing age across various tissues43”
From Spatial transcriptomic landscape unveils immunoglobin-associated senescence as a hallmark of aging (2024) · cites this paper as [43]
The section ‘Human endogenous retrovirus can be used as a biomarker of aging’ reports increased HERVK expression in older human skin and cells, supporting an age-related rise in a retroviral marker. Figure 3 also examines senescence-associated β-galactosidase in cultured cells. The cited paper does not establish that MMTV-positive cells or the listed SPiDER-βGal, P21, 4-HNE, and γH2AX markers all increase with age across various tissues. (LLM, conf=0.83)
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Self-citation
- Authors
- Liu, X., Liu, Z., Wu, Z., Ren, J., Fan, Y., Sun, L., Cao, G., Niu, Y., Zhang, B., Ji, Q., Jiang, X., Wang, C., Wang, Q., Ji, Z., Li, L., Esteban, C. R., Yan, K., Li, W., Cai, Y., Wang, S., Zheng, A., Zhang, Y. E., Tan, S., Cai, Y., Song, M., Lu, F., Tang, F., Ji, W., Zhou, Q., Belmonte, J. C. I., Zhang, W., Qu, J., & Liu, G.-H.
- Affiliations
- Chinese Academy of Sciences (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Huazhong Agricultural University (CN)
- Kunming University of Science and Technology (CN)
- Capital Medical University (CN)
- Peking University (CN)
- Corresponding author
- Zhang, Weiqi
- Qu, Jing
- Liu, Guang-Hui
- ORCID
- Liu, Xiaoqian
- Liu, Zunpeng
- Wu, Zeming
- Ren, Jie
- Sun, Liang
- Cao, Gang
- Niu, Yuyu
- Zhang, Baohu
- Ji, Qianzhao
- Jiang, Xiaoyu
- Wang, Cui
- Wang, Qiaoran
- Yan, Kaowen
- Li, Wei
- Cai, Yusheng
- Wang, Si
- Zheng, Aihua
- Zhang, Yong E.
- Tan, Shengjun
- Cai, Yingao
- Song, Moshi
- Lu, Falong
- Tang, Fuchou
- Ji, Weizhi
- Zhou, Qi
- Zhang, Weiqi
- Qu, Jing
- Liu, Guang-Hui
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2023-01
- Volume
- 186
- Issue
- 2
- Pages
- 287-304.e26
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W4313638435
- Cited by
- 390
- References
- 111
- Citations by year
- 2026: 89 · 2025: 119 · 2024: 97 · 2023: 74 · 2022: 8 · 2021: 3
- FWCI
- 67.31
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell (publishedVersion, cc-by-nc)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Tsinghua University
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Keywords
- endogenous retroviruses, cellular senescence, aging, retrovirus-like particles, transposable elements, viral transcription, neutralizing antibodies, tissue degeneration, primates, mice
- MeSH terms
- Aged, Aging, Animals, Humans, Primates, Cellular Senescence, Endogenous Retroviruses, Mice
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