RT Journal Article
SR Electronic
T1 Boosting ATM Activity Promotes Longevity in Nematodes and Mice
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 240606
DO 10.1101/240606
A1 Minxian Qian
A1 Zuojun Liu
A1 Linyuan Peng
A1 Fanbiao Meng
A1 Xiaolong Tang
A1 Ying Ao
A1 Lei Shi
A1 Mingyan Zhou
A1 Ming Wang
A1 Baoming Qin
A1 Xinyue Cao
A1 Zimei Wang
A1 Zhongjun Zhou
A1 Baohua Liu
YR 2017
UL http://biorxiv.org/content/early/2017/12/28/240606.abstract
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.