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

eLife | 2018

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 ofextend lifespan inmice, with restored metabolic homeostasis. Moreover, the treatment with CQ remarkably extends lifespan of, but not themutants. 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.

Pubmed ID: 29717979 RIS Download

Mesh terms: Animals | Ataxia Telangiectasia Mutated Proteins | Caenorhabditis elegans | Chloroquine | DNA Repair | Longevity | Mice | Mice, Knockout | Motor Activity | Phosphorylation | Progeria | Protein Processing, Post-Translational | Proteolysis | Proto-Oncogene Proteins c-mdm2 | Sirtuins

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