Atypical pathways of NF-kappaB activation and aging

The eukaryotic transcription factor Nuclear Factor-kappaB (NF-kappaB) is a master regulator for inflammatory responses, mediating cellular defense against infectious agents and environmental and cellular stress. However, recent evidence-based studies have demonstrated that constitutive activation of NF-kappaB is a ubiquitous phenomenon among various cell types in the aging phenotype, contributing deleterious effects that oppose the acutely beneficial effects of NF-kappaB seen in the inflammatory response. Expression of NF-kappaB with age is consistent with elevated levels of inflammatory markers and a pro-inflammatory phenotype, manifested in many age-associated diseases. While inducible activating mechanisms for NF-kappaB in the innate immune response are well characterized, constitutive activation in aging cells warrants further investigation of mechanisms collectively called atypical pathways. In this review, we provide a comprehensive examination of such NF-kappaB activating mechanisms, including mitochondrial dysfunction, endoplasmic stress response, organelle cross-talk, secondary messengers and DNA damage. Investigation of mechanisms of NF-kappaB in aging as an important marker of cellular stress provides guidance for the development of a systems view of cellular aging.