Priority Research Paper Volume 12, Issue 6 pp 4688—4710
ATM is a key driver of NF-κB-dependent DNA-damage-induced senescence, stem cell dysfunction and aging
- 1 Department of Molecular Medicine and the Center on Aging, Scripps Research, Jupiter, FL 33458, USA
- 2 Institute on the Biology of Aging and Metabolism and Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota Medical School, Minneapolis, MN 55415, USA
- 3 Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
- 4 Department of Orthopaedic Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
- 5 Steadman Philippon Research Institute, Vail, CO 81657, USA
- 6 Department of Orthopaedic Surgery, Catholic University of Rome School of Medicine, “A. Gemelli” University Hospital, Roma, Italy
- 7 Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
- 8 Department of Comparative Medicine, University of Washington, Seattle, WA 98195, USA
received: December 9, 2018 ; accepted: March 8, 2020 ; published: March 22, 2020 ;https://doi.org/10.18632/aging.102863
How to Cite
Copyright © 2020 Zhao et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
NF-κB is a transcription factor activated in response to inflammatory, genotoxic and oxidative stress and important for driving senescence and aging. Ataxia-telangiectasia mutated (ATM) kinase, a core component of DNA damage response signaling, activates NF-κB in response to genotoxic and oxidative stress via post-translational modifications. Here we demonstrate that ATM is activated in senescent cells in culture and murine tissues from Ercc1-deficient mouse models of accelerated aging, as well as naturally aged mice. Genetic and pharmacologic inhibition of ATM reduced activation of NF-κB and markers of senescence and the senescence-associated secretory phenotype (SASP) in senescent Ercc1-/- MEFs. Ercc1-/Δ mice heterozygous for Atm have reduced NF-κB activity and cellular senescence, improved function of muscle-derived stem/progenetor cells (MDSPCs) and extended healthspan with reduced age-related pathology especially age-related bone and intervertebral disc pathologies. In addition, treatment of Ercc1-/∆ mice with the ATM inhibitor KU-55933 suppressed markers of senescence and SASP. Taken together, these results demonstrate that the ATM kinase is a major mediator of DNA damage-induced, NF-κB-mediated cellular senescence, stem cell dysfunction and aging and thus represents a therapeutic target to slow the progression of aging.