PT - JOURNAL ARTICLE AU - Minxian Qian AU - Zuojun Liu AU - Linyuan Peng AU - Fanbiao Meng AU - Xiaolong Tang AU - Ying Ao AU - Lei Shi AU - Mingyan Zhou AU - Ming Wang AU - Baoming Qin AU - Xinyue Cao AU - Zimei Wang AU - Zhongjun Zhou AU - Baohua Liu TI - Boosting ATM Activity Promotes Longevity in Nematodes and Mice AID - 10.1101/240606 DP - 2017 Jan 01 TA - bioRxiv PG - 240606 4099 - http://biorxiv.org/content/early/2017/12/28/240606.short 4100 - http://biorxiv.org/content/early/2017/12/28/240606.full AB - DNA damage accumulates with age1. However, whether and how robust DNA repair machinery promotes longevity is elusive. Here, we demonstrate that activation of ataxia-telangiectasia mutated (ATM) via low dose of chloroquine (CQ) promotes DNA damage clearance, rescues age-related metabolic shift, and extends lifespan in nematodes and mice. Molecularly, ATM phosphorylates SIRT6 deacetylase and thus prevents MDM2-mediated ubiquitination and proteasomal degradation. Extra copies of Sirt6 in Atm-/- mice extend lifespan, accompanied with restored metabolic homeostasis. In a progeria mouse model with low ATM protein level and DNA repair capacity, the treatment with 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.