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Boosting ATM activity alleviates aging and extends lifespan in a mouse model of progeria.
Qian, Minxian; Liu, Zuojun; Peng, Linyuan; Tang, Xiaolong; Meng, Fanbiao; Ao, Ying; Zhou, Mingyan; Wang, Ming; Cao, Xinyue; Qin, Baoming; Wang, Zimei; Zhou, Zhongjun; Wang, Guangming; Gao, Zhengliang; Xu, Jun; Liu, Baohua.
Afiliação
  • Qian M; Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Shenzhen University Health Science Center, Shenzhen, China.
  • Liu Z; Medical Research Center, Shenzhen University Health Science Center, Shenzhen, China.
  • Peng L; Department of Biochemistry and Molecular Biology, Shenzhen University Health Science Center, Shenzhen, China.
  • Tang X; Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Shenzhen University Health Science Center, Shenzhen, China.
  • Meng F; Medical Research Center, Shenzhen University Health Science Center, Shenzhen, China.
  • Ao Y; Department of Biochemistry and Molecular Biology, Shenzhen University Health Science Center, Shenzhen, China.
  • Zhou M; Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Shenzhen University Health Science Center, Shenzhen, China.
  • Wang M; Medical Research Center, Shenzhen University Health Science Center, Shenzhen, China.
  • Cao X; Department of Biochemistry and Molecular Biology, Shenzhen University Health Science Center, Shenzhen, China.
  • Qin B; Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Shenzhen University Health Science Center, Shenzhen, China.
  • Wang Z; Medical Research Center, Shenzhen University Health Science Center, Shenzhen, China.
  • Zhou Z; Department of Biochemistry and Molecular Biology, Shenzhen University Health Science Center, Shenzhen, China.
  • Wang G; Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Shenzhen University Health Science Center, Shenzhen, China.
  • Gao Z; Medical Research Center, Shenzhen University Health Science Center, Shenzhen, China.
  • Xu J; Department of Biochemistry and Molecular Biology, Shenzhen University Health Science Center, Shenzhen, China.
  • Liu B; Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Shenzhen University Health Science Center, Shenzhen, China.
Elife ; 72018 05 02.
Article em En | MEDLINE | ID: mdl-29717979
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 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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Progéria / Cloroquina / Sirtuínas Limite: Animals Idioma: En Revista: Elife Ano de publicação: 2018 Tipo de documento: Article País de afiliação: China

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Progéria / Cloroquina / Sirtuínas Limite: Animals Idioma: En Revista: Elife Ano de publicação: 2018 Tipo de documento: Article País de afiliação: China