A causal role of ATM- and NEMO-dependent NF-κB activation in DNA damage-induced senescence and aging

The accumulation of senescent cells induced by intracellular and extracellular stress contributes to multi-organ dysfunction and aging. Persistent DNA damage chronically accumulates with aging initiating a cellular stress response termed DNA damage response (DDR). Ataxia-telangiectasia mutated (ATM) kinase, a core component of DDR signaling, is involved in p53-p21 and p16-Rb senescent effector pathways, and is essential for senescence-associated secretory phenotype (SASP). In addition, ATM activates NEMO-dependent NF-κB pathway in response to genotoxic stress. However, the underlying molecular mechanisms through which DNA damage drives senescence and aging remain poorly characterized. Here we used the Ercc1-/Δ mouse model of a human progeria that spontaneously develops osteoporosis, disc degeneration, glomerulonephropathy and neurodegeneration, to address the causal link between DDR-dependent NF-κB activation, cellular senescence and aging. In the first part, we demonstrated that DDR signaling, concomitant with NF-κB, was highly activated in Ercc1-/Δ mice. A causal role of ATM in DNA damage-induced aging was demonstrated by genetic depletion of ATM in Ercc1-/Δ mice, which extended health span as well as alleviated aging-related pathology. Moreover, ATM haploinsufficiency showed significantly reduced NF-κB activation and SASP. In vitro assays support an activation of ATM- and NEMO-dependent canonical NF-κB activation in response to oxidative stress. In the second part, we developed novel small molecule inhibitors to disrupt the interaction between IKKβ and NEMO/IKKγ. We demonstrated that novel NBD mimetics, in particular SR12343 and SR12460, efficiently inhibited both TNF-α and LPS-induced NF-κB activation in vitro. Additionally, the chronic treatment with SR12343 and SR12460 reduced LPS-induced acute inflammation in lung and liver, and improved muscle pathology in mdx mice, a murine model of Duchenne muscular dystrophy. In the third part, we demonstrated that chronic treatment of Ercc1-/Δ mice with SR12343 significantly improved aging symptoms and prolonged healthspan, as well as reduced the level of cellular senescence. Furthermore, suppression of IKK/NF-κB attenuated lipodystrophy and associated impaired glucose tolerance by reducing cellular senescence in fat. Taken together, these results suggest that NF-κB activation promotes cellular senescence and aging through an ATM-dependent pathway in Ercc1-/Δ mice and the ATM-IKK-NF-κB pathway represents a key target for the development of novel approaches for healthy aging