Inhibition of ATM Kinase Reduces Cellular Senescence and SASP in Progeroid Mice

Progeroid mice with DNA repair deficiencies exhibit an accelerated formation of senescent cells and manifestation of age-related conditions. This class of animal model has been used in research relating to cellular senescence in order to cost-effectively demonstrate that targeted removal of senescent cells is beneficial. However, one still needs to be careful when drawing conclusions based on their peculiar biochemistry. Progeria of this nature is quite unlike normal aging at the detail level.

Cells become senescent in response to reaching the Hayflick limit, tissue injury, molecular damage, or a toxic environment. A senescent cell ceases replication and generates senescence-associated secretory phenotype (SASP), a mix of signals that encourages both tissue remodeling and an immune response to destroy the senescent cell. In young people near all senescent cells are efficiently destroyed soon after their creation, but in older people senescent cells linger to cause chronic inflammation and tissue dysfunction.

A great deal of effort is going into deeper explorations of the biochemistry of cellular senescence these days. This is in no small part because any new discovery might have the potential to become a therapy that can treat numerous age-related conditions, and even aging itself, by alleviating the burden of senescent cells and their inflammatory, harmful signaling.

Researchers here identify an important regulator gene linking DNA damage with cellular senescence. Suppressing it in progeroid mice that exhibit high levels of DNA damage reduces markers of cellular senescence. However, it isn't clear that interfering in this process is a good idea. Removing or at least halting replication for cells with meaningful damage to their DNA is necessary to reduce the risk of cancer. Allowing damaged cells to continue replication is a poor strategy. It is far better to allow cells to become senescent in response to circumstances that carry an elevated risk of cancer, and then destroy them with periodic application of senolytic therapies.

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

DNA damage is known to increase with aging as demonstrated by an increase in DNA damage foci and oxidative DNA lesions. Intriguingly, persistent DNA damage response (DDR) signaling mediated by ATM activation has been reported to contribute to cellular senescence and the senescence-associated secretory phenotype (SASP). In vitro, SASP is dependent on ATM activation, suggesting a molecular link between ATM and NF-κB. However, it is still unclear if aberrant DNA damage-induced activation of ATM in vivo exacerbates the cellular stress response to increase NF-κB, senescence, SASP and subsequently aging.

To address the role of ATM in driving NF-κB mediated senescence and aging, we used Ercc1-/Δ mice that model a human progeroid syndrome caused by impaired repair of DNA damage. The mice express only 5% of the normal level of the DNA repair endonuclease ERCC1-XPF that is required for nucleotide excision, interstrand crosslink, and repair of some double-strand breaks. As a consequence, the Ercc1-/Δ mice spontaneously and rapidly develop progressive age-related diseases, including osteoporosis, sarcopenia, intervertebral disc degeneration, glomerulonephropathy, neurodegeneration, peripheral neuropathy, and loss of cognition.

Here, we demonstrate that ATM and downstream effectors are persistently elevated in Ercc1-/∆ and naturally aged mice, concomitant with hyperactive NF-κB signaling. Reducing ATM activity either genetically or pharmacologically reduced cellular senescence and downregulated NF-κB activation in cell culture. Importantly, Ercc1-/Δ mice heterozygous for Atm exhibited significantly reduced NF-κΒ activity, reduced cellular senescence, improved muscle-derived stem cell and progenitor cell function and attenuated age-related bone and intervertebral disc pathologies, leading to an extension of healthspan. Similarly, inhibiting ATM in Ercc1-/∆ mice by treatment with the ATM inhibitor KU-55933 reduced senescence and SASP marker expression. These results demonstrate a key role for ATM in aging and suggest that it is a therapeutic target for delaying or improving numerous age-related diseases.


Off topic: 3 most important areas in terms of what should be developed first/most critical, at least for myself is 1. Therapies to reduce plaque within blood vessels. 2. AGE-breakers. Sugar accumulates in our bodies. 3. Senolytics. Now a funded area. There should be more focus on 1. Everyone can die without warnings of a cloth or stroke. I fear it more then cancer.

Posted by: Norse at April 5th, 2020 7:40 AM

@Norse I would add getting rid of lipofuscin as a 2nd. Before senolytics and breaking AGE. In mouse model it extends lifespan and healthspan as much or more as best senolytics known to date.

Posted by: SilverSeeker at April 6th, 2020 5:29 AM

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