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.
Pubmed ID: 29717979 RIS Download
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View all literature mentionsMus musculus with name C57BL/6J from IMSR.
View all literature mentionsCell line HEK293T is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentionsThis polyclonal targets Cleaved Caspase-3 (Asp175)
View all literature mentionsThis monoclonal targets detection of MDM2, MDM2 p60 cleavage product and p53-MDM2 complexes
View all literature mentionsThis monoclonal targets CDKN1A
View all literature mentionsThis monoclonal targets ATM, phospho (Ser1981)
View all literature mentionsThis monoclonal targets ATM
View all literature mentionsThis monoclonal targets Histone H2A.X, phospho (Ser139)
View all literature mentionsThis unknown targets LC3B
View all literature mentionsThis monoclonal targets FLAG
View all literature mentionsThis monoclonal targets HA
View all literature mentionsThis monoclonal targets Phospho-ATM/ATR Substrate (S*Q) (D23H2/D69H5) Rabbit mAb
View all literature mentionsCell line HEK293 is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line Hep-G2 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsThis polyclonal targets Cleaved Caspase-3 (Asp175)
View all literature mentionsThis monoclonal targets ATM, phospho (Ser1981)
View all literature mentionsThis monoclonal targets detection of MDM2, MDM2 p60 cleavage product and p53-MDM2 complexes
View all literature mentionsThis monoclonal targets CDKN1A
View all literature mentionsThis monoclonal targets Histone H2A.X, phospho (Ser139)
View all literature mentionsThis monoclonal targets ATM
View all literature mentionsCell line Hep-G2 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsThis unknown targets LC3B
View all literature mentionsThis monoclonal targets FLAG
View all literature mentionsThis monoclonal targets HA
View all literature mentionsThis polyclonal targets Cleaved Caspase-3 (Asp175)
View all literature mentionsThis monoclonal targets Phospho-ATM/ATR Substrate (S*Q) (D23H2/D69H5) Rabbit mAb
View all literature mentionsThis monoclonal targets ATM, phospho (Ser1981)
View all literature mentionsThis monoclonal targets detection of MDM2, MDM2 p60 cleavage product and p53-MDM2 complexes
View all literature mentionsThis monoclonal targets CDKN1A
View all literature mentionsThis monoclonal targets Histone H2A.X, phospho (Ser139)
View all literature mentionsThis monoclonal targets ATM
View all literature mentionsCell line U2OS is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line Hep-G2 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsThis monoclonal targets HA
View all literature mentionsThis monoclonal targets FLAG
View all literature mentionsThis unknown targets LC3B
View all literature mentions