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.

Zhao, J., Zhang, L., Lu, A., Han, Y., Colangelo, D., Bukata, C., Scibetta, A., Yousefzadeh, M., Li, 1., Gurkar, A., Mcgowan, S., Angelini, L., O'Kelly, R., Li, H., Corbo, E., Sano, T., Nick, H., Pola, E., Pilla, S., Ladiges, W., Vo, N., Huard, J., Niedernhofer, L., Robbins, P., ATM is a key driver of NF-κB-dependent DNA-damage-induced senescence, stem cell dysfunction and aging., <<AGING>>, 2020; 2020 (12): 4688-4710. [doi:10.18632/aging.102863] [http://hdl.handle.net/10807/154814]

ATM is a key driver of NF-κB-dependent DNA-damage-induced senescence, stem cell dysfunction and aging.

Colangelo, Debora;Corbo, Emilio;Pola, Enrico;
2020

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 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.
2020
Inglese
Zhao, J., Zhang, L., Lu, A., Han, Y., Colangelo, D., Bukata, C., Scibetta, A., Yousefzadeh, M., Li, 1., Gurkar, A., Mcgowan, S., Angelini, L., O'Kelly, R., Li, H., Corbo, E., Sano, T., Nick, H., Pola, E., Pilla, S., Ladiges, W., Vo, N., Huard, J., Niedernhofer, L., Robbins, P., ATM is a key driver of NF-κB-dependent DNA-damage-induced senescence, stem cell dysfunction and aging., <<AGING>>, 2020; 2020 (12): 4688-4710. [doi:10.18632/aging.102863] [http://hdl.handle.net/10807/154814]
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