Activation of NF-kappaB transcription factor signaling is one of the hallmarks of genotoxic stress. Recently, the NEMO shuttle was revealed to mediate this nucleo-cytoplasmic signaling linking DNA damage to the activation of NF-kappaB system. DNA damage is the causative factor of several segmental progeroid syndromes, such as Werner syndrome and Hutchinson-Gilford syndrome. Although the gene defects have been well characterized, the molecular mechanisms of premature aging process still need to be defined. Here we review the details of the NEMO shuttle, a dual-signal sensor linking DNA damage to NF-kappaB activation, and present evidence for the hypothesis that DNA damage in progeroid syndromes may activate the NEMO shuttle and subsequently increase the pressure on the activation of NF-kappaB system evoking a premature aging phenotype. The NEMO shuttle may link genotoxic stress to the activation of the innate immunity system and cause premature aging via inflamm-aging process.