Journal article
ATM is a key driver of NF-κB-dependent DNA-damage-induced senescence, stem cell dysfunction and aging
Aging (Albany, NY.), Vol.12(6), pp.4688-4710
03/22/2020
DOI: 10.18632/aging.102863
PMCID: PMC7138542
PMID: 32201398
Abstract
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
-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
MEFs.
mice heterozygous for
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
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.
Details
- Title: Subtitle
- ATM is a key driver of NF-κB-dependent DNA-damage-induced senescence, stem cell dysfunction and aging
- Creators
- Jing Zhao - University of PittsburghLei Zhang - Scripps Research InstituteAiping Lu - The University of Texas Health Science Center at HoustonYingchao Han - University of PittsburghDebora Colangelo - Scripps Research InstituteChristina Bukata - Department of Molecular Medicine and the Center on Aging, Scripps Research, Jupiter, FL 33458, USAAlex Scibetta - The University of Texas Health Science Center at HoustonMatthew J Yousefzadeh - University of MinnesotaXuesen Li - Department of Molecular Medicine and the Center on Aging, Scripps Research, Jupiter, FL 33458, USAAditi U Gurkar - Department of Molecular Medicine and the Center on Aging, Scripps Research, Jupiter, FL 33458, USASara J McGowan - Scripps Research InstituteLuise Angelini - Scripps Research InstituteRyan O'Kelly - Institute on the Biology of Aging and Metabolism and Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota Medical School, Minneapolis, MN 55415, USAHongshuai Li - University of PittsburghLana Corbo - Department of Molecular Medicine and the Center on Aging, Scripps Research, Jupiter, FL 33458, USATokio Sano - Department of Molecular Medicine and the Center on Aging, Scripps Research, Jupiter, FL 33458, USAHeather Nick - Department of Molecular Medicine and the Center on Aging, Scripps Research, Jupiter, FL 33458, USAEnrico Pola - Agostino Gemelli University PolyclinicSmitha P S Pilla - University of WashingtonWarren C Ladiges - University of WashingtonNam Vo - University of PittsburghJohnny Huard - The University of Texas Health Science Center at HoustonLaura J Niedernhofer - Scripps Research InstitutePaul D Robbins - Scripps Research Institute
- Resource Type
- Journal article
- Publication Details
- Aging (Albany, NY.), Vol.12(6), pp.4688-4710
- DOI
- 10.18632/aging.102863
- PMID
- 32201398
- PMCID
- PMC7138542
- ISSN
- 1945-4589
- eISSN
- 1945-4589
- Grant note
- P30 AG024827 / NIA NIH HHS R01 AG044376 / NIA NIH HHS P01 AG043376 / NIA NIH HHS R56 AG059676 / NIA NIH HHS R01 AG063543 / NIA NIH HHS U19 AG056278 / NIA NIH HHS P01 AG062413 / NIA NIH HHS R00 AG049126 / NIA NIH HHS
- Language
- English
- Date published
- 03/22/2020
- Academic Unit
- Orthopedics and Rehabilitation; Radiation Oncology
- Record Identifier
- 9984303974402771
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