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bioRxiv · 10.1101/240606

Boosting ATM Activity Promotes Longevity in Nematodes and Mice

Qian, M.·Liu, Z.·Peng, L.·Meng, F.·Tang, X.·Ao, Y.·Shi, L.·Zhou, M.·Wang, M.·Qin, B.·Cao, X.·Wang, Z.·Zhou, Z.·Liu, B.
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Abstract

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.

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Qian, M., Liu, Z., Peng, L., Meng, F., Tang, X., Ao, Y., Shi, L., Zhou, M., Wang, M., Qin, B., Cao, X., Wang, Z., Zhou, Z., Liu, B.. 2017-12-28. Boosting ATM Activity Promotes Longevity in Nematodes and Mice. https://doi.org/10.1101/240606

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