Boosting ATM activity alleviates ageing and extends lifespan in a mouse model of progeria

  1. Minxian Qian
  2. Zuojun Liu
  3. Linyuan Peng
  4. Xiaolong Tang
  5. Fanbiao Meng
  6. Ying Ao
  7. Mingyan Zhou
  8. Ming Wang
  9. Xinyue Cao
  10. Baoming Qin
  11. Zimei Wang
  12. Zhongjun Zhou
  13. Guangming Wang
  14. Zhengliang Gao
  15. Xu Jun
  16. Baohua Liu  Is a corresponding author
  1. Shenzhen University Health Science Center, China
  2. Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, China
  3. The University of Hong Kong, Hong Kong
  4. Tongji University School of Medicine, China

Abstract

DNA damage accumulates with age (Lombard et al., 2005). However, whether and how robust DNA repair machinery promotes longevity is elusive. Here, we demonstrate that ATM-centered DNA damage response (DDR) progressively declines with senescence and age, while low dose of chloroquine (CQ) activates ATM, promotes DNA damage clearance, rescues age-related metabolic shift, and prolongs replicative lifespan. Molecularly, ATM phosphorylates SIRT6 deacetylase and thus prevents MDM2-mediated ubiquitination and proteasomal degradation. Extra copies of Sirt6 extend lifespan in Atm-/- mice, with restored metabolic homeostasis. Moreover, the treatment with CQ remarkably extends lifespan of Caenorhabditis elegans, but not the ATM-1 mutants. In a progeria mouse model with low DNA repair capacity, long-term administration of CQ ameliorates premature ageing features and extends lifespan. Thus, our data highlights a pro-longevity role of ATM, for the first time establishing direct causal links between robust DNA repair machinery and longevity, and providing therapeutic strategy for progeria and age-related metabolic diseases.

Data availability

Sequencing data have been deposited in GEO under accession code GSE109280

The following data sets were generated
    1. Qian M
    2. Liu B
    (2018) Boosting ATM Activity Promotes Longevity in Nematodes and Mice
    Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE109280).

Article and author information

Author details

  1. Minxian Qian

    Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Shenzhen University Health Science Center, Shenzhen, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Zuojun Liu

    Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Shenzhen University Health Science Center, Shenzhen, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Linyuan Peng

    Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Shenzhen University Health Science Center, Shenzhen, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Xiaolong Tang

    Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Shenzhen University Health Science Center, Shenzhen, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4744-5846
  5. Fanbiao Meng

    Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Shenzhen University Health Science Center, Shenzhen, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Ying Ao

    Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Shenzhen University Health Science Center, Shenzhen, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Mingyan Zhou

    Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Shenzhen University Health Science Center, Shenzhen, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Ming Wang

    Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Shenzhen University Health Science Center, Shenzhen, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Xinyue Cao

    Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Shenzhen University Health Science Center, Shenzhen, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Baoming Qin

    South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Zimei Wang

    Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Shenzhen University Health Science Center, Shenzhen, China
    Competing interests
    The authors declare that no competing interests exist.
  12. Zhongjun Zhou

    School of Biomedical Sciences, The University of Hong Kong, Hong Kong, Hong Kong
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7092-8128
  13. Guangming Wang

    East Hospital, Tongji University School of Medicine, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  14. Zhengliang Gao

    Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  15. Xu Jun

    East Hospital, Tongji University School of Medicine, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8565-1723
  16. Baohua Liu

    Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Shenzhen University Health Science Center, Shenzhen, China
    For correspondence
    ppliew@szu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1599-8059

Funding

National Natural Science Foundation of China (81422016)

  • Baohua Liu

Ministry of Science and Technology of the People's Republic of China (2017YFA0503900)

  • Baohua Liu

National Natural Science Foundation of China (81501206)

  • Minxian Qian

Natural Science Foundation of Guangdong Province (2014A030308011)

  • Baohua Liu

Natural Science Foundation of Guangdong Province (2015A030308007)

  • Baoming Qin

Shenzhen Science and Technology Innovation Commission (CXZZ20140903103747568)

  • Baohua Liu

National Natural Science Foundation of China (91439133)

  • Baohua Liu

National Natural Science Foundation of China (81571374)

  • Baohua Liu

Ministry of Science and Technology of the People's Republic of China (2016YFC0904600)

  • Baohua Liu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Mice were housed and handled in the laboratory animal research center of Shenzhen University. All experiments were performed in accordance with the guidelines of the Institutional Animal Care and Use Committee (IACUC). The protocols were approved by the Animal Welfare and Research Ethics Committee of Shenzhen University (Approval ID: 201412023).

Reviewing Editor

  1. Matt Kaeberlein, University of Washington, United States

Publication history

  1. Received: January 5, 2018
  2. Accepted: April 16, 2018
  3. Accepted Manuscript published: May 2, 2018 (version 1)
  4. Version of Record published: May 17, 2018 (version 2)

Copyright

© 2018, Qian et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Minxian Qian
  2. Zuojun Liu
  3. Linyuan Peng
  4. Xiaolong Tang
  5. Fanbiao Meng
  6. Ying Ao
  7. Mingyan Zhou
  8. Ming Wang
  9. Xinyue Cao
  10. Baoming Qin
  11. Zimei Wang
  12. Zhongjun Zhou
  13. Guangming Wang
  14. Zhengliang Gao
  15. Xu Jun
  16. Baohua Liu
(2018)
Boosting ATM activity alleviates ageing and extends lifespan in a mouse model of progeria
eLife 7:e34836.
https://doi.org/10.7554/eLife.34836

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