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Boosting ATM activity alleviates aging and extends lifespan in a mouse model of progeria.
- Source :
-
ELife [Elife] 2018 May 02; Vol. 7. Date of Electronic Publication: 2018 May 02. - Publication Year :
- 2018
-
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.<br />Competing Interests: MQ, ZL, LP, XT, FM, YA, MZ, MW, XC, BQ, ZW, ZZ, GW, ZG, JX, BL No competing interests declared<br /> (© 2018, Qian et al.)
- Subjects :
- Animals
Ataxia Telangiectasia Mutated Proteins deficiency
Ataxia Telangiectasia Mutated Proteins metabolism
Caenorhabditis elegans
DNA Repair
Longevity
Mice
Mice, Knockout
Motor Activity
Phosphorylation
Protein Processing, Post-Translational
Proteolysis
Proto-Oncogene Proteins c-mdm2 metabolism
Chloroquine administration & dosage
Progeria drug therapy
Sirtuins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2050-084X
- Volume :
- 7
- Database :
- MEDLINE
- Journal :
- ELife
- Publication Type :
- Academic Journal
- Accession number :
- 29717979
- Full Text :
- https://doi.org/10.7554/eLife.34836