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Article: Boosting ATM activity alleviates aging and extends lifespan in a mouse model of progeria

TitleBoosting ATM activity alleviates aging and extends lifespan in a mouse model of progeria
Authors
Keywordsaging
animal cell
animal experiment
animal model
animal tissue
Issue Date2018
PublishereLife Sciences Publications Ltd. The Journal's web site is located at http://elifesciences.org/
Citation
eLife, 2018, v. 7, p. article no. e34836 How to Cite?
AbstractDNA 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 aging 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.
Persistent Identifierhttp://hdl.handle.net/10722/277182
ISSN
2019 Impact Factor: 7.08
2015 SCImago Journal Rankings: 6.356
PubMed Central ID

 

DC FieldValueLanguage
dc.contributor.authorQian, M-
dc.contributor.authorLiu, Z-
dc.contributor.authorPeng, L-
dc.contributor.authorTang, X-
dc.contributor.authorMeng, F-
dc.contributor.authorAo, Y-
dc.contributor.authorZhou, M-
dc.contributor.authorWang, M-
dc.contributor.authorCao, X-
dc.contributor.authorQin, B-
dc.contributor.authorWang, Z-
dc.contributor.authorZhou, Z-
dc.contributor.authorWang, G-
dc.contributor.authorGuo, Z-
dc.contributor.authorXu, J-
dc.contributor.authorLiu, B-
dc.date.accessioned2019-09-20T08:46:10Z-
dc.date.available2019-09-20T08:46:10Z-
dc.date.issued2018-
dc.identifier.citationeLife, 2018, v. 7, p. article no. e34836-
dc.identifier.issn2050-084X-
dc.identifier.urihttp://hdl.handle.net/10722/277182-
dc.description.abstractDNA 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 aging 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.-
dc.languageeng-
dc.publishereLife Sciences Publications Ltd. The Journal's web site is located at http://elifesciences.org/-
dc.relation.ispartofeLife-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectaging-
dc.subjectanimal cell-
dc.subjectanimal experiment-
dc.subjectanimal model-
dc.subjectanimal tissue-
dc.titleBoosting ATM activity alleviates aging and extends lifespan in a mouse model of progeria-
dc.typeArticle-
dc.identifier.emailZhou, Z: zhongjun@hku.hk-
dc.identifier.authorityZhou, Z=rp00503-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.7554/eLife.34836-
dc.identifier.pmid29717979-
dc.identifier.pmcidPMC5957528-
dc.identifier.scopuseid_2-s2.0-85051923407-
dc.identifier.hkuros305501-
dc.identifier.volume7-
dc.identifier.spagearticle no. e34836-
dc.identifier.epagearticle no. e34836-
dc.publisher.placeCambridge, UK-

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