A new study published in Aging shows a clear link between the natural response to genomic damage and cellular senescence, illustrating a principal method by which the effects of a primary hallmark of aging flow downstream.
An ATM you don’t want to withdraw from
When our DNA is damaged, the cell responds with signals, summoning enzymes and protein tools to repair the break. One main signal is Ataxia-telangiectasia mutated (ATM) kinase, which has both positive and negative effects.
In this highly technical, in-depth study, the researchers outline a very clear biochemical link between ATM and the inflammatory NF-κB pathway, which the researchers note is linked to many other age-related diseases, including atherosclerosis, osteoporosis, Type 2 diabetes, and proteostasis-related brain disorders – and cellular senescence itself.
In order to test its effects, the researchers used ordinary wild-type aged mice along with progeric (age-accelerated) mice that did not fully express ATM. Compared to their progeric and naturally aged counterparts, ATM-deficient mice exhibited fewer of the telltale signs of cellular senescence, including factors associated with the senescence-associated secretory phenotype (SASP), which, itself, is linked to inflammaging, the chronically elevated inflammation associated with old age.
The researchers also used an ATM kinase inhibitor, KU-55933, to achieve similar effects; in particular, they rescued cells from a fate of cellular senescence. However, this treatment also reduced Poly [ADP-ribose] polymerase 1 (PARP1), which is used in DNA repair.
The study’s authors conclude that reducing ATM signaling in aged humans is worth exploring as a therapy. If effective, such a therapy would reduce cellular senescence and inflammatory NF-κB signaling, providing broad utility against multiple age-related diseases.
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.
While this study documents the benefits of reducing ATM in aged mice, this kinase is instrumental in DNA damage response signaling , so removing it in all cases has potential problems; it is yet another double-edged sword, like many things in biology. However, the research is clear, and in older individuals who have perpetually elevated levels of ATM, modulating its presence may form the basis of an effective therapy.
 Shiloh, Y., & Ziv, Y. (2013). The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nature reviews Molecular cell biology, 14(4), 197-210.