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

Elife. 2018 May 2:7:e34836. doi: 10.7554/eLife.34836.


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.

Keywords: ATM; SIRT6; ageing; biochemistry; chemical biology; chromosomes; gene expression; genome stability; mouse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins / deficiency
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Caenorhabditis elegans
  • Chloroquine / administration & dosage*
  • DNA Repair
  • Longevity
  • Mice
  • Mice, Knockout
  • Motor Activity
  • Phosphorylation
  • Progeria / drug therapy*
  • Protein Processing, Post-Translational
  • Proteolysis
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Sirtuins / metabolism*


  • Chloroquine
  • Mdm2 protein, mouse
  • Proto-Oncogene Proteins c-mdm2
  • Sirt6 protein, mouse
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Sirtuins

Grants and funding

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