Boosting ATM activity alleviates ageing and extends lifespan in a mouse model of progeria
- Shenzhen University Health Science Center, China
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, China
- The University of Hong Kong, Hong Kong
- 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
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Boosting ATM Activity Promotes Longevity in Nematodes and MicePublicly available at the NCBI Gene Expression Omnibus (accession no: GSE109280).
Article and author information
Author details
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).
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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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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Liquid-liquid phase separation (LLPS) involving intrinsically disordered protein regions (IDRs) is a major physical mechanism for biological membraneless compartmentalization. The multifaceted electrostatic effects in these biomolecular condensates are exemplified here by experimental and theoretical investigations of the different salt- and ATP-dependent LLPSs of an IDR of messenger RNA-regulating protein Caprin1 and its phosphorylated variant pY-Caprin1, exhibiting, for example, reentrant behaviors in some instances but not others. Experimental data are rationalized by physical modeling using analytical theory, molecular dynamics, and polymer field-theoretic simulations, indicating that interchain ion bridges enhance LLPS of polyelectrolytes such as Caprin1 and the high valency of ATP-magnesium is a significant factor for its colocalization with the condensed phases, as similar trends are observed for other IDRs. The electrostatic nature of these features complements ATP’s involvement in π-related interactions and as an amphiphilic hydrotrope, underscoring a general role of biomolecular condensates in modulating ion concentrations and its functional ramifications.
