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

Area of Science:

• Molecular Biology
• Genetics
• Aging Research

Background:

• Nuclear factor kappa B (NF-κB) is a transcription factor crucial for cellular responses to stress, senescence, and aging.
• Ataxia-telangiectasia mutated (ATM) kinase is a key player in DNA damage response, known to activate NF-κB.
• Cellular senescence, a state of irreversible growth arrest, is implicated in aging and age-related diseases.

Purpose of the Study:

• To investigate the role of ATM kinase in DNA damage-induced cellular senescence and aging.
• To determine if ATM inhibition can ameliorate aging phenotypes and extend healthspan.
• To evaluate ATM as a potential therapeutic target for slowing the aging process.

Main Methods:

• Assessed ATM activation in senescent cells and aged mouse tissues (Ercc1-deficient and naturally aged).
• Utilized genetic (Atm heterozygosity) and pharmacologic (KU-55933) inhibition of ATM in Ercc1 mouse models.
• Measured NF-κB activity, senescence markers, senescence-associated secretory phenotype (SASP), stem cell function, and age-related pathologies.

Main Results:

• ATM kinase is activated in senescent cells and tissues from accelerated and natural aging models.
• Inhibition of ATM reduced NF-κB activation, senescence markers, and SASP in senescent cells.
• Ercc1 mice heterozygous for Atm exhibited reduced senescence, improved muscle stem cell function, extended healthspan, and ameliorated age-related pathologies, particularly bone and intervertebral disc issues.

Conclusions:

• ATM kinase is a critical mediator of DNA damage-induced NF-κB signaling, cellular senescence, and aging.
• Targeting ATM kinase can mitigate cellular senescence, stem cell dysfunction, and age-related pathologies.
• ATM represents a promising therapeutic target for interventions aimed at slowing aging and improving healthspan.